Integrative Gastroenterology Weil Integrative Medicine Library

Published and Forthcoming Volumes

series editor

andrew weil, md

Donald I. Abrams and Andrew Weil: Integrative Oncology Timothy Culbert and Karen Olness: Integrative Pediatrics Gerard E. Mullin: Integrative Gastroenterology Victoria Maizes and Tieraona Low Dog: Integrative Women’s Health Randy Horwitz and Daniel Muller: Integrative Rheumatology Daniel A. Monti and Bernard Beitman: Integrative Psychiatry Stephen Devries and James Dalen: Integrative Cardiology Integrative Gastroenterology

edited by Gerard E. Mullin, MD Associate Professor, Medicine Johns Hopkins University School of Medicine The Johns Hopkins Hospital Baltimore, MD

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______Library of Congress Cataloging-in-Publication Data

Integrative gastroenterology/[edited by] Gerard E. Mullin. p.; cm.—(Weil integrative medicine library) Includes bibliographical references and index. ISBN-13: 978-0-19-537110-9 (alk. paper) ISBN-10: 0-19-537110-0 (alk. paper) 1. Gastrointestinal system—Diseases. 2. Integrative medicine. I. Mullin, Gerard E. II. Series: Weil integrative medicine library. [DNLM: 1. Gastrointestinal Diseases—therapy. 2. Complementary Th erapies—methods. WI 140 I605 2010] RC817.I47 2010 616.3’3—dc22 2009023877 978-0-19537110-9 ______

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Typeset in Minion Pro Regular Printed on acid-free paper Printed in the United States of America

Th is material is not intended to be, and should not be considered, a substitute for medical or other professional advice. Treatment for the conditions described in this material is highly dependent on the individual circumstances. And, while this material is designed to off er accurate information with respect to the subject matter covered and to be current as of the time it was written, research and knowledge about medical and health issues is constantly evolving and dose schedules for medications are being revised continually, with new side eff ects recognized and accounted for regularly. Readers must therefore always check the product information and clinical procedures with the most up-to-date published product information and data sheets provided by the manufacturers and the most recent codes of conduct and safety regulation. Th e publisher and the authors make no representations or warranties to readers, express or implied, as to the accuracy or completeness of this material. Without limiting the foregoing, the publisher and the authors make no representations or warranties as to the accuracy or effi cacy of the drug dosages mentioned in the material. Th e authors and the publisher do not accept, and expressly disclaim, any responsibility for any liability, loss or risk that may be claimed or incurred as a consequence of the use and/or application of any of the contents of this material. To the more than 70 million Americans who are known to suff er from digestive disorders. To my loved ones for their unwavering support over the years. To the many who mentored me throughout my career. To Andrew Weil MD for selecting me to edit this textbook. And the beloved memory of my parents. This page intentionally left blank FOREWORD

few years ago, a leading gastroenterologist in Tucson asked me to meet with him. Over dinner, he expressed the hope that integrative Amedicine (IM) might have something to off er him. He was frustrated, he said, because, “ninety percent of the patients I see have problems that my training does not enable me to solve.” At that time, the Arizona Center for Integrative Medicine was off ering a comprehensive IM fellowship in distributed learning format to physicians and nurse practitioners. We were training family medicine doctors, internists, and surgeons, but had not yet had a GI specialist apply. Th at disappointed me, because I knew that integrative medicine could greatly enrich the fi eld of gastroenterology, increasing its effi cacy and reducing the frustration expressed by my colleague in Tucson and shared by many others. One of the core curricular areas of IM is mind/body medicine. It covers the theory and evidence base for interactions between mental/emotional states and physiology, as well as therapies that take advantage of those interactions. Steven Gurgevich, PhD, a clinical psychologist on the faculty of the American Society of Clinical Hypnosis, helped design the mind/body medicine module. He has said, “Patients with gastrointestinal problems should be seen by hypno- therapists before they go to gastroenterologists,” and over the years, I have referred many patients with GI complaints to him and other mind/body practitioners, with good outcomes. His reasoning is that the organs of the GI system, along with the skin, have the greatest amount of innervation of any organs and, as a result, are the most frequent sites of expression of stress- related disorders. Michael Gershon, MD, chairman of the Department of

vii viii FOREWORD

Anatomy and Cell Biology at Columbia University Medical Center, in an excellent book on enteric neurology, refers to the gut as the “second brain.” Many common GI disorders arise from disturbed function of the gut—in particular, an imbalance between its intrinsic motility and extrinsic control by the autonomic nervous system (oft en caused by stress-related overactivity of the sympathetic nerves). Without harmonious coordination, gut motility is abnormal and digestion impaired. In late stages of these disorders, we can visualize or otherwise detect pathological changes, but early on they present as functional complaints. Patients seek relief of GI symptoms; there are few or no measurable correlates of the symptoms. “Functional disorder” is a loaded term in conventional medicine. Oft en it is used to dismiss complaints of patients without visible pathology; at worst, it is used as a synonym for “imagined disease.” Patients are easily angered by suggestions that their GI problems are all in the mind. Practitioners must be able to help them understand the underlying somatopsychic mechanism that accounts for their very real symptoms. Traditional Chinese medicine (TCM) classifi es diseases as “visible” or “invisible” and postulates that all visible disease is preceded by an invisible stage, in which “energy” (chi) circulation through the body is disturbed. TCM practitioners believe that if invisible disease goes untreated (by acupuncture, herbal therapy, dietary adjustment, etc.), it will eventually produce pathological changes in the physical structure of the body. Th erefore, TCM prioritizes the diagnosis and treatment of what conventional Western medicine oft en dis- misses as functional disorders. Doctors here tend to minimize the signifi cance of these problems, in part because they fi nd it frustrating to manage them. Th eir training does not enable them to do so. Because dietary habits and other lifestyle factors can both trigger and aggravate this class of GI disorders, it is not suffi cient to send patients to stress- management training or hypnotherapy. Physicians must also give them specifi c recommendations about foods, beverages, physical activity, rest and sleep, and more. And they should know when the pharmaceutical drugs now so widely prescribed for GI problems are really indicated, and for how long patients should be on them. Proton-pump inhibitors for GERD and steroids for infl ammatory bowel disease may be useful for short-term suppression of symptoms, but over time the benefi t-to-risk ratio changes signifi cantly and unfavorably, and data on the risks are accumulating. Practitioners of integrative medicine are fully trained to diagnose and treat invisible and functional disease before it damages tissues and organs and requires drastic, costly intervention. Th ey work from the premise that the body can heal itself if given a chance, that mind/body interactions are real and oft en very relevant to issues of health and illness, that all aspects of lifestyle must be FOREWORD ix considered in evaluating patients, and that the doctor/patient relationship is a key factor in the outcome of treatment. In addition, they are familiar with a wide range of therapeutic options other than drugs. In recommending therapies not commonly included in mainstream practice, they pay attention to the evidence that supports them, always working from the principle that the greater the potential of a treatment to cause harm, the stricter the standards of evidence for effi cacy it must be held to. A major initiative of the Arizona Center for Integrative Medicine is “Integrative Medicine in Residency” (IMR). We have developed a 200-hour, comprehensive curriculum in IM, much of it taught online, that is currently a required component of eight residency programs around the United States. Th is is a pilot phase of IMR; the center’s long-range goal is to have this comprehensive curriculum become a required, accredited part of all residency training, including that of specialists and subspecialists. Th en all physicians (and surgeons), including gastroenterologists, will know the basics of nutritional medicine, botanical medicine, mind/body medicine, lifestyle infl uences on health, the indications for and strengths and weaknesses of other systems (like Chinese and Ayurvedic medicine) and of complementary and alternative therapies. I am certain that the resulting transformation of medicine is a prerequisite for building a functional, cost-eff ective health care system, one that emphasizes disease prevention and health promotion and that uses costly, technology-based interventions (including pharmaceutical drugs) only when they are really indicated, managing common forms of illness with simpler, less expensive interventions. It is my hope that this series of volumes from Oxford University Press will help achieve these goals. I have looked forward to the publication of Integrative Gastroenterology with great anticipation. Not only does it give all clinicians an overview of the subject and specifi c guidance about the integrative management of common GI problems, it has the potential to hasten the day when integrative gastroenterology will be a vital fi eld of research and practice. Th e editor, Gerard Mullin, MD, has done a commendable job of assembling expert contributors and informative articles. I have learned much from working with him on the project, and I hope the information in these pages will lessen the frustration of practitioners faced with GI problems that conventional education and training does not enable them to solve. Andrew Weil, MD Series Editor Tucson, Arizona May, 2009 This page intentionally left blank CONTENTS

Contributors xv

1. Why Integrative Gastroenterology?  Gerard E. Mullin 2. Th e American Digestive Disease Epidemic  Gerard E. Mullin 3. An Overview of Digestive, Sensing, and Immune Functions of the Gut  Patrick J. Hanaway, Laura K. Turnbull, and Gerard E. Mullin 4. Th e Intestinal Microbiota in Health and Disease: Bystanders, Guardians, or Villains?  Fergus Shanahan 5. Alternative Laboratory Testing for Gastrointestinal Disease  David M. Brady, J. Alexander Bralley, Richard S. Lord, and Gerard E. Mullin 6. New Molecular Techniques Revolutionize Understanding of the Infl uence of Gut Microbiota on Health and Disease  J. Alexander Bralley 7. Principles of Integrative Gastroenterology: Systemic Signs of Underlying Digestive Dysfunction and Disease  Laura K. Turnbull, Gerard E. Mullin, and Leonard B. Weinstock 8. Th e Skin and the Gastrointestinal Tract  Andrew G. Franks, Jr. 9. Premenstrual and Menstrual Exacerbation of IBS: An Integrative Medicine Analysis of the Bi-Directional Connection between Female Hormones and Gut Health  Joel M. Evans

xi xii CONTENTS

10. Fibromyalgia and Gastrointestinal Disorders  David M. Brady and Michael J. Schneider 11. Acupuncture for Digestive System  Sanghoon Lee and Ta-Ya Lee 12. Ayurveda and Digestive Health  David Simon and Valencia Porter 13. Osteopathic Medicine  Diane Clawson 14. Gastroenterology and an Integrative Chiropractic Approach  Loren Marks and David M. Durkin 15. Energy Medicine and Gastrointestinal Disorders  Ann Marie Chiasson 16. Guided Imagery and Gastroenterology  Martin L. Rossman 17. Hypnosis and Gastrointestinal Disorders  Anastasia Rowland-Seymour 18. Homeopathy Origins and Th erapeutic Principles  Savely Yurkovsky 19. Massage for Digestive Health  Stephanie Porcaro and Gerard E. Mullin 20. Mindfulness Based Stress Reduction for Health and Diseases  Padmini D. Ranasinghe 21. Naturopathic Medicine and Digestion  Joseph Pizzorno 22. Taiji, Qigong, and Digestive Health  Yang Yang and Bob Schlagal 23. Digestive Health and Reiki Energy  Beth Nolan 24. Self-Care Journaling for Digestive Health  Danna M. Park 25. Spirituality  Frederic C. Craigie, Jr. 26. What Patients Want from Th eir Doctors  Donna Jackson Nakazawa CONTENTS xiii

27. Th e Value of Support Groups  Pearl L. Lewis and Gerard E. Mullin, with a foreword by Bernie Siegel 28. Overview of Visceral Manipulation for the Integrative Gastroenterologist  Jean-Pierre Barral and Gail Wetzler 29. Probiotics in the Prevention and Treatment of Gastrointestinal Disease  Gerald Friedman 30. Th e Role of Nutritional Genomics and Functional Medicine in the Management of Crohn’s Disease  Sheila G. Dean and Kathie M. Swift 31. Functional Foods for Digestive Health and Disease  Elizabeth Lipski 32. Th e Role of Herbal Medicine in Integrative Gastroenterology  Tieraona Low Dog 33. Brief Review of Mind–Body Medicine in Gastroenterology Practice  Miranda A.L. van Tilburg, Stephan R. Weinland, and Olafur S. Palsson 34. Mind–Body Medicine in Digestive Disease  Douglas A. Drossman and William E. Whitehead 35. Yoga and Digestive Health  Sajida Chaudry and Beth Nolan 36. Integrative Approaches to Abdominal Pain  Robert A. Bonakdar and Emily G. Singh 37. Over-the-Counter Remedies for Digestive Health: Potion or Poison?  Jerry Hickey and Gerard E. Mullin 38. Systemic Interactions Between Dental and Gastroenterological Diseases  Philip E. Memoli 39. Upper Gastrointestinal Disorders: Dyspepsia, Heartburn, Peptic Ulcer Disease, and Helicobacter pylori  Anil Minocha xiv CONTENTS

40. Celiac Disease  S. Devi Rampertab and Peter H.R. Green 41. Food Reactions and Th eir Implications in the Irritable Bowel Syndrome  Trent W. Nichols, Gerard E. Mullin, and Laura K. Turnbull 42. An Evidence-Based Review of Complementary and Integrative Approaches for Irritable Bowel Syndrome  Octavia Pickett-Blakely, Ashwini S. Davison, and Gerard E. Mullin 43. Nutrition Strategies for the Treatment of IBS and the Prevention of Digestive Complaints  Ashley Koff 44. Alternative Approaches to the Patient with Infl ammatory Bowel Disease  Leo Galland, Katarzyna Kines, and Gerard E. Mullin 45. Obesity  Lawrence J. Cheskin and Katrina Seidman 46. Nutrition and Colorectal Health  Mitra Rangarajan and Gerard E. Mullin 47. Liver Disease  Matthew Cave, Naeem Aslam, Christopher Kulisek, Luis S. Marsano, and Craig J. McClain 48. Integrative Approaches to Diseases of the Pancreas and Gallbladder  Vinay Chandrasekhara and Anthony N. Kalloo 49. An Integrative Approach to Gender-Specifi c Digestive Health Issues  Laura K. Turnbull, Gerard E. Mullin, and Sharon Dudley-Brown 50. Gastrointestinal Disorders and Eating Disorders  Carolyn Coker Ross 51. Ethical Issues in Integrative Gastroenterology  Julie Stone 52. Th ere Is No Alternative to Evidence  Ronald L. Koretz

I n d e x 653 CONTRIBUTORS

Naeem Aslam, MD J. Alexander Bralley, PhD Fellow, Department of Medicine Chief Executive Offi cer Division of Gastroenterology and Metametrix Clinical Laboratory Hepatology Duluth, GA University of Louisville School of Medicine Matthew Cave, MD Louisville, KY Assistant Professor of Medicine Division of Gastroenterology/ Jean-Pierre Barral, DO Hepatology Director of the Department of Department of Medicine Osteopathic Manipulation University of Louisville University of Paris, School of Medicine Louisville, KY Paris, France Vinay Chandrasekhara, MD Robert Alan Bonakdar, MD, FAAFP Clinical Fellow Director of Pain Management Division of Gastroenterology & Scripps Center for Integrative Hepatology Medicine Johns Hopkins University School of Assistant Clinical Professor Medicine Department of Family and Baltimore, MD Preventative Medicine (Voluntary) University of California, San Diego, Sajida Chaudry, MD, MPH School of Medicine Family Medicine and Preventive San Diego, CA Medicine David M. Brady, ND, DC, CCN, Johns Hopkins Community Physicians DACBN Odenton, MD Vice Provost, Health Sciences Division Director, Human Nutrition Institute Associate Professor of Clinical Sciences University of Bridgeport Bridgeport, CT

xv xvi CONTRIBUTORS

Ann Marie Chiasson, MD, Ashwini S. Davison, MD MPH, CCFP Senior Resident Clinical Assistant Professor of Department of Internal Medicine Medicine Johns Hopkins Hospital Arizona Center for Integrative Baltimore, MD Medicine University of Arizona Sheila G. Dean, DSc, RD, LD, Tucson, AZ CCN, CDE Integrative Nutrition Solutions Lawrence J. Cheskin, MD, FACP Adjunct Professor of Nutrition Associate Professor of Health, Science Behavior & Society University of Tampa Joint Appointment in Medicine Palm Harbor, FL (Gastroenterology) Director, Johns Hopkins Weight Douglas A. Drossman, MD Management Center Professor of Medicine and Johns Hopkins Bloomberg School of Psychiatry Public Health Co-Director, UNC Center for Johns Hopkins University School of Functional GI and Motility Medicine Disorders Baltimore, MD Division of Gastroenterology and Hepatology, Diane Clawson, DO Department of Medicine Attending Physician University of North Carolina at Chapel Department of Psychiatry Hill Department of Pediatrics Chapel Hill, NC University of New Mexico Albuquerque, NM Sharon Dudley-Brown, PhD, FNP–BC Frederic C. Craigie, Jr., PhD Co-Director, Gastroenterology & Psychologist/Faculty, Maine- Hepatology Nurse Practitioner Dartmouth Family Medicine Fellowship Program Residency Johns Hopkins Hospital Associate Professor of Community and Assistant Professor Family Medicine Johns Hopkins University Schools of Dartmouth Medical School Medicine & Nursing Visiting Associate Professor Baltimore, MD Arizona Center for Integrative Medicine David Durkin, DC University of Arizona School of Chiropractor Medicine Durkin Chiropractic Center Augusta, Maine Gastonia, NC CONTRIBUTORS xvii

Joel M. Evans, MD Jerry Hickey, RPh Assistant Clinical Professor Scientifi c Director Department of Obstetrics, Gynecology, InVite Health, Inc. and Women’s Health New York, NY Albert Einstein College of Medicine Bronx, NY Anthony N. Kalloo, MD Th e Moses and Helen Golden Paulson Andrew G. Franks, Jr., MD, FACP Professor of Gastroenterology Clinical Professor of Dermatology and Chief, Division of Gastroenterology Medicine (Rheumatology) and Hepatology Director, Skin Lupus, and Connective Johns Hopkins Hospital Tissue Disease Baltimore, MD New York University School of Medicine Katarzyna Kines, MS, MA, LDN, New York, NY CNS, CN Holistic Nutrition Naturally, LLC Gerald Friedman, MD, PhD, MS, Contractual Practitioner with FACP, MACG Johns Hopkins Integrative Medicine Clinical Professor of Medicine and Digestive Center Department of Medicine, Division of Green Spring Station, Gastroenterology Lutherville, MD Th e Mount Sinai School of Medicine New York, NY Ashley Koff, RD Founder, AshleyKoff Approved.com Leo Galland, MD D i r e c t o r Ronald L. Koretz, MD Foundation for Integrated Medicine Emeritus Professor of Clinical New York, NY Medicine David Geff en–UCLA School of Peter H.R. Green, MD Medicine Professor of Clinical Medicine Department of Medicine Celiac Disease Center Olive View–UCLA Medical Center Columbia University College of Sylmar, CA Physicians and Surgeons New York, NY Christopher Kulisek, MD Resident, Department Patrick Hanaway, MD of Medicine Chief Medical Offi cer University of Louisville School of Genova Diagnostics Medicine Asheville, NC Louisville, KY xviii CONTRIBUTORS

Sanghoon Lee, OMD, PhD, DiplAc, LAc Tieraona Low Dog, MD Associate Professor of Acupuncture & Director of the Fellowship Moxibustion Arizona Center for Integrative College of Oriental Medicine Medicine WHO Collaborating Centre for Clinical Associate Professor Traditional Medicine Department of Medicine East–West Medical Research Institute University of Arizona Kyung Hee University Tucson, AZ Seoul, South Korea Dan Lukaczer, ND Ta-Ya Lee, MSN, CRNP, MAc, LAc, Associate Director of Medical MBA, MPH Education Johns Hopkins Community Physicians Institute for Functional Medicine Wyman Park Internal Medicine Gig Harbor, WA Canton Crossing Integrative Medicine Baltimore, MD Loren Marks, DC, DACBN Diplomate American Clinical Board Pearl L. Lewis of Nutrition Founder, Maryland Chapter Crohn’s Integrative Assessment Technique, and Colitis Foundation Founder Founder, Maryland Patient Advocacy 200 W 57 St. Ste 1010 NY Group Maryland Renal Advocate Luis S. Marsano, MD National Kidney Foundation of Professor of Medicine Maryland Jewish Hospital Distinguished National Kidney Foundation Professor of Hepatology Malignancy Advisory Board Division of GI/Hepatology Author, Access to Care for Special University of Louisville School of Needs Populations (19 states) Medicine Ellicott City, MD Louisville, KY

Liz Lipski, PhD, CCN Craig J. McClain, MD Director of Doctoral Studies Professor, Departments of Hawthorn University Medicine and Pharmacology & Founder of Innovative Healing Toxicology Founder of Access to Health Experts Associate Vice President for Asheville, NC Translational Research Distinguished University Scholar Richard S. Lord, PhD University of Louisville School of Chief Science Offi cer Medicine Metametrix Institute Louisville, KY Duluth, GA CONTRIBUTORS xix

Philip E. Memoli, DMD, Danna Park, MD, FAAP FAGD, CNC Medical Director Founder, Institute of Systemic Integrative Healthcare Department Medicine and Dentistry Mission Hospital Attending, Overlook Hospital Asheville, NC Summit, NJ and Octavia Pickett-Blakely, MD Private Practice Post Doctoral Fellow Berkeley Heights, NJ Division of Gastroenterology Johns Hopkins School of Medicine Anil Minocha, MD Baltimore, MD Professor of Medicine Joseph Pizzorno, ND LSU Health Sciences Center Editor-in-Chief, Integrative Medicine, Chief of Gastroenterology A Clinician’s Journal VA Medical Center Co-Author, Textbook of Natural Medicine Shreveport, LA President Emeritus, Bastyr University S e a t t l e , WA Donna Jackson Nakazawa Author and Lecturer Stephanie Porcaro, LMT Th e Autoimmune Epidemic Massage By Stephanie www.autoimmuneepidemic.com Baltimore, MD

Trent W. Nichols, Jr., MD Valencia Porter, MD, MPH Center for Digestive Disorders and Director of Women’s Health Nutrition Th e Chopra Center for Wellbeing H a n o v e r , P A Carlsbad, CA

Beth Nolan, LMT S. Devi Rampertab, MD Massage Th erapist Assistant Professor of Medicine Life Support Wellness Center Division of Gastroenterology Butler, NJ Penn State College of Medicine Hershey Medical Center Olafur S. Palsson, PsyD Hershey, PA Associate Professor of Medicine Division of Gastroenterology and Padmini D. Ranasinghe, MD, MPH Hepatology Assistant Professor of Medicine Department of Medicine Division of General Internal Medicine University of North Carolina at Johns Hopkins University School of Chapel Hill Medicine Chapel Hill, NC Baltimore, MD xx CONTRIBUTORS

Mitra Rangarajan, MSN, ANP-BC, Michael J. Schneider, DC, PhD MPH, CDE, MS, RD Visiting Assistant Professor Nurse Practitioner, Advanced School of Health & Rehabilitation Th erapeutic Endoscopy & GI Sciences Motility University of Pittsburgh Division of Gastroenterology & Pittsburgh, PA Hepatology Johns Hopkins University School of Katrina B. Seidman, MS, RD, LDN Medicine Registered Dietician Baltimore, MD Johns Hopkins Weight Management Center Carolyn Coker Ross, MD, MPH Department of Health, Behavior and Clinical Assistant Professor of Society Medicine Johns Hopkins Bloomberg School of University of Arizona, Tucson, AZ Public Health Eating Disorder, Addiction Medicine Baltimore, MD and Integrative Medicine Consultant Fergus Shanahan, MD D e n v e r , C O Professor and Chair, Department of Medicine Martin L. Rossman, MD Director, Alimentary Pharmabiotic Clinical Instructor Centre Department of Family and Cork University Hospital and Community Medicine University College Cork University of California San Francisco National University of Ireland Medical School San Francisco, CA David Simon, MD Medical Director, Co-Founder Anastasia Rowland-Seymour, MD Th e Chopra Center for Assistant Professor of Medicine Wellbeing Division of General Medicine Carlsbad, CA Department of Internal Medicine Johns Hopkins University School of Emily G. Singh, MD Medicine Division of Gastroenterology Baltimore, MD Scripps Clinic Carmel Valley San Diego, CA Bob Schlagal, PhD Professor Julie Stone, MA, LLB Department of Language, Reading, & Visiting Professor, Peninsula Medical Exceptionalities School Appalachian State University Universities of Exeter and Plymouth B o o n e , N C United Kingdom CONTRIBUTORS xxi

Kathie Madonna Swift, MS, RD Gail Wetzler, PT, EDO, BI–D Director, Food As Medicine Director of Physical Th erapy Center for Mind Body Medicine Center for Alternative Medicine Washington DC University of California, Irvine and and Lead Nutritionist Director of Curriculum and Program Kripalu Center for Yoga and Health Development Stockbridge, MA Barral Institute and Laura K. Turnbull, BA, RNc Owner of Wetzler Integrative Physical Johns Hopkins University School of Th erapy Center Nursing Newport Beach, CA Baltimore, MD William E. Whitehead, PhD Miranda A.L. van Tilburg, PhD Professor of Medicine and Adjunct Assistant Professor of Medicine Professor of Obstetrics and University of North Carolina School of Gynecology Medicine Co-Director of the Center for Department of Gastroenterology and Functional GI and Motility Hepatology Disorders UNC Center for Functional GI and University of North Carolina at Chapel Motility Disorders Hill Chapel Hill, NC Chapel Hill, NC

Stephan R. Weinland, PhD Yang Yang, PhD Assistant Professor of Medicine Adjunct Faculty University of North Carolina at Department of Kinesiology and Chapel Hill Community Health Center for Functional GI and Motility University of Illinois at Urbana- Disorders Champaign Chapel Hill, NC and D i r e c t o r Leonard B. Weinstock, MD Center for Taiji and Qigong Studies Associate Professor of Clinical New York, NY Medicine and Surgery Washington University School of Savely Yurkovsky, MD Medicine Private Practice Director, Specialists in Chappaqua, NY Gastroenterology, LLC St. Louis, MO This page intentionally left blank Integrative Gastroenterology This page intentionally left blank 1 Why Integrative Gastroenterology?

GERARD E. MULLIN

key concepts

■ Digestive diseases encompass more than 40 acute and chronic conditions of the gastrointestinal tract, ranging from common digestive disorders to serious, life-threatening diseases. ■ More than 70 million Americans are affl icted with diseases of the digestive system. ■ Digestive diseases are the second leading cause of disability due to illness in the United States, with more than 2 million Americans impaired to some degree. ■ Th e annual economic impact on the U.S. economy is more than $141 billion. ■ Westernized diet and lifestyles are the major cases of the digestive disease epidemic. ■ Many of the most common digestive diseases in the United States are also common in Canada and Europe, but are uncommon in Asia and Africa, suggesting that these diseases are preventable through dietary and lifestyle modifi cations. ■ Th e escalating prevalence of obesity, anxiety, depression, stress, fast food consumption, and food-borne illnesses, is contributing to the digestive disease epidemic. ■ Adoption of an integrative model by physicians would achieve more eff ective prevention and treatment of digestive disease. ■

3 Introduction

s gastroenterologists, internists, primary-care practitioners, nurse practitioners, or alternative providers, we need to realize that over A 50% of patients with digestive disorders incorporate complementary and alternative medicine (CAM) into their treatment regimen. Studies have shown that approximately 72% of patients who utilize alternative strategies are reluctant to disclose this to their providers for fear of being stigmatized. Since our patients seek our guidance and expertise in overseeing their healthcare, it is time for us to realize that consumer demand has driven the present dynamic of patients paying out of pocket to achieve improved health and well-being by “integrating” alternative strategies into their lives. Th ere is a body of experiential and evidence-based literature to support the utilization of these “alternative” strategies in digestive healthcare. Th us, the ongoing utilization of alternative strategies by the public, the evidence supporting its use, and the expanding groups of practitioners achieving improved health outcomes, led Dr. Andrew Weil to commission me to synthesize a comprehensive how-to guide for advising digestive disease patients, aimed at the everyday practitioner. Integrative medicine is a rapidly growing and highly credible fi eld that seeks to integrate the best of Western scientifi c medicine with a broader understanding of the nature of illness, healing and wellness. Dr. Andrew Weil defi nes integrative medicine as a “healing-oriented medicine that takes account of the whole person (body, mind and spirit), including all aspects of lifestyle. It emphasizes the therapeutic relationship and makes use of all appropriate therapies, both conventional and alternative.”

The Principles of Integrative Medicine by Dr. Andrew Weil: • A partnership between patient and practitioner in the healing process • Appropriate use of conventional and alternative methods to facilitate the body’s innate healing response • Consideration of all factors that inﬂ uence health, wellness, and disease, including mind, spirit, and community, as well as body • A philosophy that neither rejects conventional medicine nor accepts alternative therapies uncritically • Recognition that good medicine should be based in good science, be inquiry driven, and be open to new paradigms • Use of natural, effective, less invasive interventions whenever possible Why Integrative Gastroenterology? 5

• Use of the broader concepts of promotion of health and the prevention of illness, as well as the treatment of disease • Training of practitioners to be models of health and healing, committed to the process of self-exploration and self-development.

Integrative medicine aims to transform healthcare by moving the boundaries of the existing ﬁ eld of medicine to include the wisdom inherent in healing the “whole person” — mind, body and spirit.

The Digestive Disease Epidemic

Digestive disease is known to aff ect more than 70 million Americans today. An estimated 70 % of Americans have either digestive disease or digestive symptoms over their lifetime. Countless others have migraines, arthritis, fi bromyalgia, chronic fatigue, depression, neurological disease, osteoporosis, skin disorders, menstrual irregularities, premenstrual syndrome (PMS), and other conditions that are related to undiagnosed core digestive discord. Th is emerging epidemic of digestive disease is a social disease that results from a breakdown in the infrastructure of society as we promote stress, meals on the run from fast-food vendors, unhealthy norms in food choices, and exposure to carcinogens and xenobiotics, while producing record rates of mental disorders, social isolation, obesity, and inactivity, which all adversely aff ect the gut. Th e end result is a nation in which one in three individuals have a digestive disorder, 63 million either have or show signs of autoimmune disease, and 125 million overall have a chronic disease. Th is is no accident!

Roots of Integrative Gastroenterology

“A person whose basic emotional and physical tendencies are in balance, Whose digestive power is balanced, Whose bodily tissues, elimination functions and activities are in balance, And whose mind, senses and souls are ﬁ lled with vitality, That person is said to be healthy.”

Sushruta Samhita, 2000 B.C. 6 INTEGRATIVE GASTROENTEROLOGY

AYURVEDIC MEDICINE

Th e human digestive system is our inside track to balanced health and vitality. Th is principle has been the fundamental basis of health and healing for centuries in Eastern civilization, which comprises most of the world’s population today. Sushruta Samhita is one of the founders of modern Ayurdevic medicine, which is used by healers worldwide to prevent disease and promote health. Th e driving principle of Ayurveda (translated as the wisdom and science of life) is that disease is the absence of vibrant health, which begins in a breakdown of the spirit, and evolves in defi nable stages beginning with improper digestion. According to Sushruta Samhita, the Ayurvedic secret to a long, happy, and vital life is predicated upon balanced energetic, metabolic, and protective forces; strong digestion; optimal cellular, tissue and organ function; effi cient elimination; and clear senses, joyful mind, and transpersonal connection. For more about Ayurveda and digestive health, see Chapter 12.

TRADITIONAL CHINESE MEDICINE

Traditional Chinese medicine (TCM) was the fi rst formalized system of health and healing in modern civilization. In Eastern philosophy, all life occurs within a circle of nature, with all things in this matrix interconnected and mutually dependent upon each other. Human beings represent a microcosm of nature and are the juncture between heaven and earth. In TCM, health and vitality are predicated upon spiritual connection, balanced living, a vegetable-based diet, proper digestion, and peace of mind. Th e fl ow of energy, or chi, is the essence of health and well-being. A blockage in the fl ow of chi through energy channels called meridians is the beginning of illness, and loss of adaptability is the beginning of disease. In TCM, the foods we eat are not merely nutrients but are vehicles of energy to be dispersed to our body in either a healthy or unhealthy manner, as determined by the outcome of digestion. When the digestive fi re is too weak or too strong, the resultant energy imbalances create disharmony and illness. In TCM, chi is centered around the digestive tract in a ball of energy called the don tien . Th is virtual force fi eld of energy circling our digestive tract is essential to health and well-being. Ayurveda and TCM principles guide the care of billions who are among the world’s healthiest people. Th ese well-proven models of healthy living share in common sound mind, peace, wholeness and harmony, a healthy Why Integrative Gastroenterology? 7 vegetarian-based diet, spiritual connection, and herbs for early symptoms of illness. In both systems, individuals are the sum of their diet and lifestyle choices. Proper digestion of a healthy diet is the key to a life fi lled with vibrant health and free of disease.

WESTERN MEDICINE

“Let food be thy medicine and let medicine be thy food.” “Leave your drugs in the chemist’s pot if you can heal the patient with food.” “Above all else, do no harm.” — Hippocrates, 450 B.C.

Th e Western model of healthcare has been traced to Hippocrates, who is considered to be the father of medicine. As physicians, we recite the Hippocratic Oath at our medical school graduation. What I remember most, while reciting a moving self-proclamation of service to mankind by facilitating healing, is Hippocrates, as well as Sushruta Samhita and the early emperors of China, who believed that physicians are healers of the body, mind, and spirit. Th e job of the physician was to provide proper instruction of diet in the prevention and treatment of illness. Hippocrates also strongly believed that the body, mind, and spirit were inseparable in health and disease.

“As man thinketh in his head, so shall his life be made.” — Hippocrates, 1450 B.C.

Western Philosophy: The Doctor as Mechanic

In the seventeenth century, Rene Descartes and Sir Isaac Newton introduced the principle of “reductionism,” whereby human beings were viewed as the sum of their parts, and the matters of the “spirit” were left to religious organizations. Th is unfortunate sustained separation of “church and state” excommunicated the very soul of Western medicine, the doctor–patient relationship. People were merely the sum of body parts and molecules. Th e Cartesian principle of medicine forever transformed the delivery of care to its present-day assembly line of 10-minute offi ce visits, whereby the doctor writes a prescription and barely has time to lay eyes upon his or her patients. Rene Descartes began what managed care has fi nished— the near extinction of the physician as a healer. 8 INTEGRATIVE GASTROENTEROLOGY

Western medicine is a very sophisticated and advanced form of healthcare for acute illness, emergencies, curable malignancies, sustaining chronic disease, and surgical miracles. When it comes to optimizing health and preventing disease, our results are inferior compared to every country in the industrialized world. For example, the United States is 41st in longevity among industrialized countries— dead last! Despite our poor results, Western-trained physicians still consider the long-standing and highly successful Eastern healing arts to be archaic and quackery, and proudly view our modern system of care to be far superior. As a profession, we perpetuate this reductionist approach more than ever before. Doctors in training are now taught that our health is merely the result of the genes that we inherited from our parents, and that health is all prepro- grammed and predetermined. Th is view excludes the possibility that health also refl ects the accumulation of the choices that we make and the circumstances around us. Th e reality is that our health and well-being are the result of how our environment interacts with our genes. How we were parented, whether we were breastfed, how we connect to spirit, ourselves, and others, what we eat, how we process our food and emotions, and whether our lives are balanced or toxic, all have profound infl uences on health. Our genes can either become our protec- tors and partners for wellness, or target practice for pollutants and toxins in producing illness and disease. We do make choices every day that infl uence the expression of our genes.

Table 1.1. Comparison of Conventional, Western-Based Medicine versus Integrative Medicine

Aspects of care Conventional Integrative

Focus Disease detection Disease prevention

Orientation Doctor-centered Patient-centered

Treatment Drugs only All inclusive

Healing Drugs only Self-healing

Empathy Variable Loving

Offi ce visits Rushed, inattentive, Open mind, open heart, prescription-oriented healing

Doctor–Patient Doctor-centered Partnership Relationship

Satisfaction Low High Why Integrative Gastroenterology? 9

Nutritional genomics is an evolving fi eld, started by Nobel Laureate Dr. Linus Pauling and championed by his protégée, Dr. Jeff rey Bland. Th ere has been an explosion of research showing how nutrients derived from food directly infl uence genetic expression and cellular function. Th ere is more to health and wellness than just the genes that we inherit from our parents.

The Doctor–Patient Relationship: Returning to the Roots of Medicine

Digestive disease specialists are fi ghting to stay afl oat fi nancially by severely limiting their allotment of time to perform procedures and see patients for offi ce visits. In the end, patients are being treated as though they are on an assembly line, rather than being present in the nurturing environment of a doctor’s offi ce. Likewise, physicians are speeding through patient care encounters like a “rat race,” constantly fi ghting an uphill battle. As a measure of the modern doctor–patient relationship that has evolved in the era of Westernized managed care, a study was conducted to determine doctors’ empathy for patients. Previous work suggests that exploration and validation of patients’ concerns is associated with greater patient trust, lower healthcare costs, improved counseling, and more guideline-concordant care. Th e study by Dr. Ronald Epstein and colleagues included 4,800 patient surveys concerning doctor visits, and 100 covertly recorded visits by actors posing as patients. Th e results showed that only 15 % of the doctors voiced empathy. In the study, published in the Journal of General Internal Medicine, the researchers analyzed the patient surveys and actor visits and characterized the responses by type, frequency, pattern, and communication style, and correlated them with patient satisfaction ratings. Empathy was associated with higher patient ratings of interpersonal care.

“Th e best physicians are empathic. Th ey show neither sympathy nor disdain. Empathy does not develop as naturally as sympathy or disdain. We must nurture this emotion, allowing it to blossom. True empathy greatly helps the doctor–patient relationship.” — Robert M. Centor, 2005

A key element to Dr. Weil’s vision of integrative medicine is for the practitioner to return to the roots of medicine by fostering partnerships with patients. We know that the stronger the doctor–patient relationship, the more powerful the healing response. Th is is called the placebo response by researchers, but is underutilized in today’s version of “hit and run” medicine. Th e restoration of 10 INTEGRATIVE GASTROENTEROLOGY faith and trust in the treating practitioner by the patient is an essential element to healing. At Johns Hopkins, the fi rst physician-in-charge was Sir William Osler (1849–1919), who was the father of modern medicine. In his writings and teachings, Sir William Osler emphasized humanity, compassion, observing and listening to patients with an open mind and heart, and to minimize the use of pharmaceutical medications. Following are some excerpts from many of his famous quotations.

“Observe, record, tabulate, and communicate. Use your fi ve senses. Learn to see, learn to hear, learn to feel, learn to smell, and know that by practice alone you can become expert.” “It is much more important to know what sort of a patient has a disease than what sort of a disease a patient has.” “Th e good physician treats the disease; the great physician treats the patient who has the disease.” “Teach young physicians to care more particularly for the individual patient than for the special features of the disease.” — Sir William Osler (1849–1919)

The integrative practitioner should strive to: • Humanize healthcare: Combine old-fashioned caring with superb medical care • Prevent disease and promote health • Listen to and communicate effectively with patients and their families in order to form partnerships • Appreciate and bridge cultural differences, so that care plans are understood by their patients • Share decision making with patients and their families as partners • Emphasize the necessity of a team approach in caring for each patient • Integrate the best medical knowledge into healthcare that is accessible, patient friendly, and high quality • Act as an advocate for patients and the health needs of society • Act as a steadfast guide and source of support to patients, no matter where they choose to seek specialty care • Raise awareness that book-smart doctors can lack emotional intelligence, and appreciate how a disease affects a patient’s daily life

Sir William Osler followed in the footsteps of the ancient Greek physician, Hippocrates (460–377 B.C.). Th ese quotations by Hippocrates refl ect his Why Integrative Gastroenterology? 11 philosophy of the body’s natural healing force and the importance of proper nutrition and exercise to good health. Th ere is also a message to young physicians to guide the patient’s healing, that it is better to do nothing than to harm the patient.

“Everyone has a doctor in him or her; we just have to help it in its work. Th e natural healing force within each one of us is the greatest force in getting well.” “To do nothing is sometimes a good remedy.” “Walking is man’s best medicine.” “If we could give every individual the right amount of nourishment and exercise, not too little and not too much, we would have found the safest way to health.” — Hippocrates

Conclusions

Digestive diseases are responsible for a major economic burden in the United States and worldwide. Preventive care, education about the infl uence of diet and lifestyle on digestive disease development and treatment, and research support, all lag behind in meeting the need to correct the economic burden and to provide future generations of scientists in the digestive sciences. Given the American digestive disease epidemic, there is a need for governments to readdress this shortcoming and to review its methods of support, as well as for physicians to adopt an integrative approach to the prevention and treatment of digestive disease.

“Th e doctor of the future will give no medicine, but will interest her or his patients in the care of the human frame, in a proper diet, and in the cause and prevention of disease.” — Th omas A. Edison, U.S. inventor (1847–1931)

NOTES

I. Th e term iatrogenic is defi ned as “induced in a patient by a physician’s activity, manner, or therapy. Used especially to pertain to a complication of treatment.” II. Sources: Vital Statistics of the United States — 1970, National Center for Health Statistics, Table 1-26, “Deaths from 281 Selected Causes, by Age, Race, and Sex: United States, 1970”; death certifi cates from 31 states, reported in “Mortality of Dentists, 1968 to 1972,” Bureau of Economic Research and Statistics, Journal of the 12 INTEGRATIVE GASTROENTEROLOGY

American Dental Association, January 1975, pp. 195ff ; death reports collected by the American Medical Association, reported in “Suicide by Psychiatrists: A Study of Medical Specialists Among 18,730 Physician Deaths During a Five-Year Period, 1967–72,” Rich et al., Journal of Clinical Psychiatry, August 1980, pp. 261ff .; Vital Statistics of the United States —1990, National Center for Health Statistics, Table 1-27, “Deaths from 282 Selected Causes, by 5-Year Age Groups, Race, and Sex: United States — 1990”; National Occupational Mortality Surveillance database, reported in “Mortality Rates and Causes Among U.S. Physicians,” Frank et al., American Journal of Preventive Medicine, Vol. 19, No. 3, 2000. 2 The American Digestive Disease Epidemic

GERARD E. MULLIN

key concepts

■ Digestive diseases are highly prevalent in the United States. ■ Th e age-adjusted increase in the prevalence of digestive diseases between 1998 and 2004 was 35% . ■ Th e International Foundation of Functional Gastrointestinal Disorders (IFFGD) has projected that the prevalence in America today for gastroesophageal refl ux disease (GERD) is 30 to 60 million, and for irritable bowel syndrome (IBS), 30 to 45 million. ■ Th e annual cost of digestive diseases was estimated to be $142 billion annually in 2004. ■ Proton pump inhibitors (PPIs) have dominated the pharmaceutical market since 2000. Prescriptions for PPIs collectively represent 50.7 percent of total number of prescriptions and 77.3 percent of total cost in 2004. ■

Digestive Disease: The Cold, Hard Facts

n 2002, the American Gastroenterology Association (AGA) became the fi rst physician-based organization to address the growing burden of diges- I tive disease on the nation’s healthcare resources. Led by Dr. Robert S. Sandler, the AGA published a special report that outlined the prevalence and economic burden of digestive disease in the United States as of 1998, with fi nancial projections to the year 2000 (Sandler, Everhart, Donowitz et al., 2002 ).

13 14 INTEGRATIVE GASTROENTEROLOGY

Due to the changes in perceived disease prevalence, and the rising cost of technology, the AGA and the National Institutes of Digestive Diseases, Diabetes and Kidney Diseases (NIDDK) partnered to update the burden of digestive disorders to the U.S. economy, so that eff ective resources can be allocated and directed to disease prevention (Everhart & Ruhl, 2009a , 2009b , 2009c ). In Sandler’s 2002 report, the estimated direct costs for 17 of the most common digestive diseases in 1998 dollars was $85.5 billion for all direct costs, with estimated indirect costs of $22.8 billion, for a total of $108.8 billion. Dr. Everhardt and colleagues reported that in 2004, the total direct cost of digestive disease in the U.S. was $97.8 billion, with estimated indirect costs of $44 billion, for a total of $141.8 billion. Th e distribution of costs according to disease classifi cation in 2004 is shown in Table 2.2 . From 1998, the prevalence of Irritable Bowel Syndrome (IBS) has risen to aff ect from 30 to 45 million individuals (10% –15% of the U.S. population), according to the International Foundation for Functional Gastrointestinal Disorders (IFFGD). 1

THE PREVALENCE OF DIGESTIVE DISEASE IN AMERICA

Th e NIDDK of the National Institutes of Health (NIH) is a government agency that has collected data from a variety of sources to estimate the burden of digestive disease.2 Th e overall prevalence of digestive diseases was reported by the NIH in 1996 to be 60 to 70 million.

U.S. Government statistics of digestive disease prevalence were updated in a special report on February 02, 2009.(Everhart & Ruhl, 2009a ,b,c)

Th ere are numerous studies that analyze the burden of digestive disease in the United States. Th e past decade has seen a rapid expansion of individuals who suff er from chronic digestive symptoms. Th e prevalence of digestive disease in America has reached epidemic proportions. Based on the latest available evidence, we collected and summarized data on the prevalence of digestive disease in Tables 2.1 and 2.2 . Th e resulting burden to the U.S economy is shown in Tables 2.3 and 2.4 . Since prescription medications represent a great part of this fi nancial burden, the costliest medications to consumers are listed in Table 2.4 .

1 ( www.aboutgerd.org ) 2 ( http://digestive.niddk.nih.gov/statistics/statistics.htm ) The American Digestive Disease Epidemic 15

Table 2.1. The Burden of Digestive Diseases in America in 2008

Digestive disease Prevalence Prevalence Year Reference ( % U.S. population) (U.S. population in millions)

Abdominal wall hernia 1.66 4,968,809 1990 NIDDK

Cancer of digestive 0.9 255,640 2004 American Cancer system Society

Colonic adenomas 30% above age 50 24,980,000 2006 Levine & Ahnen (2006 ); Terhaar et al. ( 2009 )

Celiac disease** 1.0 3,000,000 2007 Green ( 2006 )

Clostridium diffi cle 1.0 3,000,000 2007 Ricciardi, colitis Rothenberger, Madoff , & Baxter ( 2007 )

Chronic liver disease/ 0.15 451,710 2007 NIDDK, cirrhosis population- adjusted

Constipation 1.0 3,100,000 1996 Adams, Hendershot, & Marano ( 1999 )

Diverticulosis 20 60,200,000 1969 Hughes ( 1969 )

Diverticular disease 0.9–2.2 2,500,000– 1996 NIDDK, Duggan (complicated) 4.0 6,000,000 2006 ( 2006 ) 12,040,000

Gallstones 11–22 30,000,000– 1999 NIDDK 60,000,000

Gastritis; non-ulcer 1.4 37,000,000 1996 Adams, dyspepsia Hendershot, & Marano ( 1999 )

GERD 30–42 90,000,000– 2007 Singh et al. 127,000,000 ( 2007 ); http:// www.aboutgerd. org

Helicobacter pylori 20–52 60,000,000– 2002 NEJM. 2003; infection 157,000 347:1175–1186

(Continued) 16 INTEGRATIVE GASTROENTEROLOGY

Table 2.1. (Continued)

Digestive Disease Prevalence Prevalence Year Reference ( % U.S. Population) (U.S. Population in Millions)

Hemorrhoids 3.2–4.4 8,500,000 1996 Adams, Hendershot & Marano ( 1999 )

Infectious diarrhea 36.4–44.8 135,000,000 1980– NIDDK 1998

IBD 0.33–0.47 1,000,000– 2007 www.ccfa.org 1,400,000

IBS 10–15 30–45,000,000 2007 http://www. aboutibs.org/

Lactose intolerance 10–16.7% 30–50,000,000 1994 Rusynyk & Still ( 2001 )

Non-alcoholic fatty 22–33% 66,250,788– 2003 Angulo ( 2007 ); liver disease (NAFLD) 99,376,182 Suzuki & Diehl ( 2005 )

P a n c r e a t i t i s 0.05% 160,000 1995 Everhart (1995 )

Peptic ulcer disease 4.90% 14,500,000 2003 NIDDK

Viral hepatitis

Hepatitis A 31% 93,500,000 1998– NIDDK, 1994 NHANES (2005)

Hepatitis B 0.05–5% 1,500,000– 1998– NIDDK, 15,057,000 2004 McQuillan et al. ( 1999 )

Hepatitis C 1.36–1.8% 4,100,000– 2007 NIDDK, 5,420,000 Armstrong et al. ( 2006 )

Hepatitis D unknown unknown; 1990 NIDDK 75,000 new cases

* US Population was 301,139,947 as of July 2007. * * Only 3 % of people with disease are diagnosed, according to Peter HR Green Available at http:// www.ncbi.nlm.nih.gov/pubmed/17593160/pubmed?term=%22Green%20PH%22%5BAuthor% 5D”Green PH Comment on: HYPERLINK “/pubmed/17355413”Am J Gastroenterol. 2007 Jul; 102(7):1454–60 The American Digestive Disease Epidemic 17

Table 2.2. The Prevalence and Costs of Digestive Disease in the United States from 1985 to 2004

Diseases 1985 1998 2004 1985 2004 prevalence prevalence prevalence cost cost ($millions) ($millions)

Abdominal hernias 4,741,000 4,500,000 4,968,809 2,760 6,078

Constipation 4,458,000 3,100,000 3,100,000 360 1,712

Diverticula 1,900,000 2,500,000 60,200,000 1,550 4,041

Enteric 8,300,00 135,000,000 135,000,000 4,990 7,300 infections*

Enteritis 5,700,000 75,000,000 75,000,000 820 1,119 (noninfectious)*

Gastritis– 2,793,000 3,700,000 3,700,000 1,130 1,269 dyspepsia, * * * *

Gallstones 956,000 20,500,000 30,000,000– 4,710 6,169 60,000,000

GERD** 546,000 53,000,000 90,000,000– 1,100 12,639 127,000,000

GI malignancy 258,000 227,700 255,560 6,080 24,148

Hemorrhoids 10,360,000 8,500,000 8,500,000 830 873

IBD 2,308,000 1,081,200 1,000,000– 820 2,166 1,400,000

IBS 1,379,000 2,100,000 30,000,000– 400 1,007 45,000,000

Liver disease 552,000 21,950,000 108,825,788– 3,250 13,095 (chronic)** 119,928,182

Peptic ulcer* 4,491,000 14,500,000 14,500,000 2,520 3,118

All Digestive 62,000,000 60,000,000– ?????????? 56,140 141,826 Disease 70,000,000 (Chronic) * * * *

* 2008 data based upon NIH/NIDDK statistics from 1996. * * GERD was not included in the 1985 report as a distinct entity, but rather incorporated as “GERD and related esophageal diseases.” * * * Chronic Liver Disease includes NAFLD and chronic viral hepatitis (B,C,D). * * * * Helicobacter pylori infection was not listed for 1985, and was not included for enteric infections or gastritis. * * * * Prevalence according to NIH/NIDDK; summation by hand shows the true number of digestive disease diagnoses in 1998 to be 345,658,900. 18 INTEGRATIVE GASTROENTEROLOGY

Table 2.3. NIH Research Expenditures by Disease in FY 2000

Research $$$

Diseases (in millions)

Chronic Liver Disease and Cirrhosis 218.6

Liver Cancer 46.2

Ulcerative Colitis and Crohn’s Disease 27.0

Pancreatic Cancer 20

Gallbladder Disease 14.5

Chronic Hepatitis C 66.5

Irritable Bowel Syndrome 8.2

Peptic Ulcer Disease 12.1

Foodborne Illness 57.5

Colorectal Cancer 205.2

Reprinted with permission from Everhart JE, Ruhl CE. Gastroenterology 2009;136(2):376–386.

Table 2.4. All Digestive Diseases: Costliest Prescriptions

Drug Prescription Prescription % Retail Cost Cost number

Lansoprazole 20,898,993 15.5% $3,104,963,208 25.2%

Esomerprazole 19,458,470 14.3 2,845,565,944 23.1

Pantoprazole 11,716,033 8.6 1,408,222,944 11.4

Raberprazole 8,019,431 5.9 1,135,819,908 9.2

Omeprazole 8,582,644 6.3 1,038,622,087 8.4

Mesalamine 2,448,971 1.8 468,426,719 3.8

Ranitidine 13,171,338 9.7 319,418,374 2.6

Tegaserod 1,618,699 1.2 238,030,688 1.9

Ribavirin 221,035 0.2 229,351,616 1.9

Peginterferon alfa-2a 131,001 0.1 191,754,177 1.6

Other 49,378,593 36.4 1,351,443,116 11.0

TOTAL 135,735,478 100.0% $12,331,718,182 100.0%

Reprinted with permission from Everhart JE, Ruhl CE. Gastroenterology 2009;136(4): 1134–1144. The American Digestive Disease Epidemic 19

Th e U.S. Congress has been relying on NIH/NIDDK fi gures in allocating funding initiatives. Th us, the NIH/NIDDK database for the economic impact of digestive disease was updated in 2009in order to properly advocate for and allocate government funding. However, an up to date reviewof the prevalence of digestive disease was not reported. Since individuals can carry more than one digestive disease diagnosis, it may be diffi cult to know with certainty the actual prevalence.

DIGESTIVE DISEASE AFFLICTS EVERY AMERICAN HOUSEHOLD

Based upon the data in Table 2.1 , there were enough digestive disorders in 2007 for each of 301,139,947 Americans to carry at least 2–3 diagnoses each! For example, in one study, 48% of patients diagnosed with IBS had concomitant GERD.(Nastaskin, Mehdikhani, Conklin, Park, & Pimentel, 2006 ). Likewise, many infl ammatory bowel disease IBD patients have IBS diagnosed as well. In other words, many patients suff er from more than one digestive disorder at a time. Th is is not surprising, since our Westernized diet and sedentary lifestyles have led to many of these digestive illnesses.

DIGESTIVE DISEASE: A GROWING EPIDEMIC IN OUR WESTERN WORLD

An epidemic3 is a classifi cation of a disease that appears as new cases in a given human population, during a given period, at a rate that substantially exceeds what is “expected” based on recent experience. In 1996 the prevalence of digestive diseases was estimated to aff ect 60 to 70 million Americans. Digestive diseases are a silent epidemic, and the incredible number of Americans with functional digestive disorders may be an underestimate of the true U.S. prevalence.

In Olmsted County, Minnesota, the reported prevalence of functional gastrointestinal disease (e.g., IBS, abdominal pain) was shown to be 42.3% in a recent study by the Mayo Clinic. (Halder et al., 2007 )

A study by Halder and colleagues showed that two-thirds of studied patients with functional gastrointestinal disorders had chronic symptoms 10 years aft er

3 (from Greek epi- upon + demos people). 20 INTEGRATIVE GASTROENTEROLOGY the onset of disease. Th is study out of the Mayo Clinic was the longest and most comprehensive, population-based, follow-up study of functional gastrointestinal disorder (FGID) patients, and the only long-term U.S. study. Dyspepsia (abdominal discomfort as a separate and additional diagnostic entity) has been recently reported to be present in 11.5 % to 14.7 % of the population (El-Serag & Talley, 2004 ).

LOSING THE DIGESTIVE DISEASE BATTLE

Th ere is no doubt that enormous economic resources are being consumed by the burden of digestive disease. Despite the losing battle being fought by many physicians, government funding is funding is inadequately allocated to combat diseases that are aff ecting easily over 60 million Americans today. In 2000, NIH research expenditures for digestive disease research reached a record $676 million.

The NIH spent more than 72.5 % of its digestive disease budget for just two groups of conditions— liver disease ($285 million) and colorectal cancer ($205.2 million).

Certainly, colorectal cancer and liver diseases are worthy causes toward which to devote available resources. However, there are more than 40 other known digestive disease conditions that constitute the vast majority of digestive disease prevalence in America, and that deserve proportionate allocation of resources. Despite concerted eff orts by the NIH to control the spread of digestive disease, its prevalence is rapidly rising. For example, celiac disease is now reported to aff ect 3 million Americans and is silent in 97 % of those who have the disease, according to Dr. Peter Green in his book, Celiac Disease: A Hidden Epidemic (Green, 2006 ). Th e detection rate can be increased 43-fold just by instituting proper screening of all patients who have suggestive symptoms. Other emerging silent epidemics include non-alcoholic fatty liver disease and hepatitis C (Angulo, 2007 ). Non-alcoholic fatty liver disease (NAFLD) has been estimated to aff ect from 22% to 33% of Americans and is closely linked to obesity and insulin resistance as the major factors for its rapid emergence (Angulo, 2007 ; Suzuki & Diehl, 2005 ). Th e hepatitis C virus is known to infect 4.1 million Americans and 200 million people worldwide, resulting from person-to-person transmission (Armstrong et al., 2006 ). Due to the epidemic proportion of hepatitis C in the United States, a special website was established The American Digestive Disease Epidemic 21 to educate the public and warn about its dangers. 4 Both diseases are silent killers. To demonstrate the magnitude of the economic impact of constipation today, a report published in 2007 analyzed the healthcare resource utilization of Medicaid patients in California. Dr. Gurkirpral Singh and colleagues from Stanford University showed that 105,130 patients of the state’s 10 million benefi ciaries (1.05 %) consumed $18.9 million to treat constipation in a 15-month period of time. Th e total economic impact of constipation on the U.S. economy was estimated to be $54.4 billion in 2007 (Singh et al., 2007 ).

The total economic impact to the United States economy would be $9.9 billion just to treat constipation for 18.2% of the population on Medicaid assistance.

Th e Singh et al. study was funded by the Novartis Pharmaceuticals Corporation of East Hanover, New Jersey. Although the report appears credible and highlights the magnitude of the problem of constipation in the United States, there is a self-serving interest for Novartis to fund this study. By showing that constipation produces an untoward economic burden on the U.S. economy, Novartis can make a strong argument to the FDA to reverse its ban on Zelnorm (touted as a magic bullet for constipation). In order to calculate the true total costs of digestive disease in 2007, the actual prevalence of disease would need to be known, along with the actual costs of prescription medications, hospitalizations, procedures, offi ce visits, and mortality, as well as indirect costs of lost wages and productivity. In 2002, an intensive eff ort by the American Gastroenterology Association estimated the burden of digestive diseases on the U.S. economy (Sandler RS, 2002 ). Since 1998, the Consumer Price Index (CPI) has risen approximately 4 % per year and the economic impact of digestive diseases today must be in excess of 40 % higher when compared to 1998 statistics, totaling $141.7 billion ((Everhardt JE. 2008 ). In 2008, the economic burden of digestive disease appears to be much greater than reported in 1998. (Everhardt JE. 2008 )We know from the IFFGD that the prevalence of the irritable bowel syndrome has risen two to three times since 1998. 5 In 2003, the estimated annual direct costs for irritable bowel syndrome rose to $1.35 billion, having an estimated impact to the U.S. economy upward of $30 billion annually, excluding prescription and over-the-counter

4 ( http://www.epidemic.org/theFacts/theEpidemic/ 5 ( http://www.aboutgerd.org/site/learning-center/congressional-testimony/2007 ) 22 INTEGRATIVE GASTROENTEROLOGY medications (Leong et al., 2003 ; Inadomi, Fennerty & Bjorkman, 2003 ; Hulisz, 2 0 0 4 ) .

IBS is second only to hypertension in healthcare costs in the United States annually. (Cash, Sullivan, & Barghout, 2005 )

Pancreatitis, an uncommon disorder, causes more than 200,000 hospitalizations and costs between $3.6 to $6.0 billion annually (Draganov & Toskes, 2 0 0 2 ) . Th e American Digestive Disease Epidemic (ADDE) is wreaking havoc in the lives of many, and is costing government and industry billions of dollars annually. Th e most common and costly digestive conditions can be either prevented (e.g. colorectal cancer) or treated (e.g. NAFLD, GERD) with diet, lifestyle modifi cations, improved self-care, and a more integrative approach to healthcare.

CELIAC DISEASE

Celiac disease is the most common genetic disease in Europe. About 1 in 250 people in Italy and about 1 in 300 people in Ireland have celiac disease. It is rarely diagnosed in African, Chinese, and Japanese people. Th e prevalence of celiac disease in the United States is similar to that of Europe. Th is is one example of how our North American and European gene pool renders susceptibility to a diet-induced digestive disorder. : In other words, a combination of genetic susceptibility and environment (Western lifestyle) produce the disease. Celiac disease, by itself, is of epidemic proportions, but only 3% of aff ected individuals have been diagnosed due to the silent nature of this disease. For example, neuropathy, diabetes, bone disease, anemia and other systemic conditions are caused by celiac disease, but physicians who are unaware of their association fail to connect the dots. As a consequence, physicians are under- utilizing available blood tests to screen for celiac disease due to their lack of recognition of its systemic occult manifestations.

DIVERTICULAR DISEASE: A WORLDWIDE OR WESTERN DISEASE?

“Westernized” nations such as the United States have prevalence rates of diverticular disease from 5 % to 45 %, depending on the method of diagnosis and age of the population. Th e prevalence of diverticular disease has increased from The American Digestive Disease Epidemic 23

5 % –10% eighty years ago, to 35 % –50% in an autopsy series published in 1969 (Hughes, 1969 ); there are no recent population-based studies. Th e prevalence of diverticular disease is age-dependent, increasing from less than 5% at age 40, to 30% by age 60, to 65% by age 85. Th e overall prevalence of diverticular disease in America is estimated to be 20% of the population. Th e hospital admission rate and surgical rate for diverticular disease has been reported to have increased by 16 % for males and by 12% –14% for females in England from 1990–2000 (Kang et al., 2003 ). Diverticulosis is another example of a disease that has a prevalence in Europe slightly lower, but not signifi cantly diff erent, than in the United States. Th e relatively high prevalence in Europe is related to Westernization of the European diet. Diverticulosis is rare in Africa and Asia (except in Japan, which has been rapidly become Westernized) and in cultures that consume a high- fi ber diet (Delvaux, 2003 ).

Diverticular disease is a Western condition due to a poor, low-ﬁ ber diet in our fast-food culture.

In contrast to the high prevalence in Western societies, the frequency of diverticulosis in Iran was recently reported to be 1.6% in people above the age of 20, 2.4 % in people above the age of 50, and 1.2 % in people between the ages of 20 and 50 (Dabestani, Aliabadi, Shah-Rookh, & Borhanmanesh, 1981 ). Th e prevalence of diverticula in an aging Western population is relatively high, compared with the low prevalence in developing countries where a high- vegetable diet is consumed, because a diet low in plant products is a precipi- tous factor in the pressure changes needed to produce diverticula. Th is is the most generally discussed cause of diverticular disease, and provides the basis for much of the advice given to reduce the prevalence of diverticular disease, as well as to manage established disease. Clearly, our unhealthy “Westernized” diets and lifestyles produce these stark diff erences in digestive diseases in the United States versus other, non-Western civilizations.

COLORECTAL CANCER

Colorectal cancer is another condition in which Western diets high in saturated fat and red meat and low in fi ber, compounded by sedentary lifestyles and high obesity rates, portend toward a greater susceptibility. Colorectal cancer is the most common cancer of the digestive organs, accounting for more than 60 % of all digestive organ cancers and 25% of all 24 INTEGRATIVE GASTROENTEROLOGY cancer mortality in the United States (Boyle & Ferlay, 2005 ). In 2004, more than 660,000 Europeans were living with a diagnosis of colon cancer. Colorectal cancer is the second most common cancer in Europe and the United States. Like diverticular disease, colon cancer is rare in Africa and Asia (except Japan). In both conditions, a high-fi ber diet appears to be protective. A high-fat diet is a risk factor for the development and recurrence of colorectal cancer (Rennert, 2007 ). Th e seven Western behavioral risk factors that are associated with an increased risk for colorectal cancer are: smoking; low physical activity; low fruit and vegetable intake; high caloric intake from fat; obesity; high alcohol intake; and low intake of multivitamins (Coups, Manne, Meropol, & Weinberg, 2007 ).

INFLAMMATORY BOWEL DISEASE

Th e highest incidence rates and prevalence for ulcerative colitis and Crohn’s disease (infl ammatory bowel disease) are reported in North America and northern Europe. Th e lowest incidence rates are reported in South America, Southeast Asia, Africa (with the exception of South Africa) and Australia. Aside from diff erences in sanitation, the dietary association between excessive consumption of carbohydrates, and polyunsaturated fats such as corn oil and margarine, correlate with the development of infl ammatory bowel disease (Riordan, Ruxton, & Hunter, 1998 ; Geerling et al., 2000 ).

GALLSTONE DISEASE

Gallstones are found more commonly in Europe (15.7% prevalence overall) and the UnitedStates, (13.2% ), than in Africa (5 % –10% ) and Asia (3.1% –6.1% ). Th e prevalence of gallstones in Europe is higher for northern countries (e.g., Norway, 19.7% ; Germany, 21.7 %) when compared to Chianciano (5.9% ) and Bari (0.1% ), Italy. Th is is believed to be related to the higher intake of saturated fat in the diet versus the Mediterranean-based diet of the Italian people (Kratzer et al., 1998 ; Kratzer, Mason, & Kachele, 1999 ).

IRRITABLE BOWEL SYNDROME

As for IBS, in the United States, Europe, and Canada, the prevalence is 10% –15 % with a female to male ratio of 2:1. IBS is less common in Asia and underdeveloped countries, and males and females have equivalent disease prevalence. The American Digestive Disease Epidemic 25

In China, the history of functional GI disorders (FGID) may be traced back more than 2,500 years, but it was not until 1987 that more attention began to be paid to FGID, especially IBS (Si, Chen, Sun & Dai, 2004 ). A 1996 randomized sampling study (2,486 subjects randomly chosen from urban, suburban, and rural areas of the United States) showed a point prevalence of IBS of 7.01% (7 % of the population at any given time presented with IBS symptoms (Drossman DA et al., 1996 ) Th e point prevalence of IBS in the United States doubled to tripled in 2004 when compared to 1998. Figure 2.1 shows the worldwide prevalence of IBS (Gwee, 2005 ).

GASTROESOPHAGEAL REFLUX DISEASE (GERD)

GERD is common in the United States, Canada, and Europe, and is uncommon in Asia (except Japan) and underdeveloped regions of the world (Wang, Luo, Dong, Gong, & Tong, 2004 ).Like other diseases we have discussed, diet and lifestyle play a role in disease pathogenesis. Th e prevalence of GERD and obesity in Japan has approximated that in the United States in recent years, unlike the rest of Asia, possibly due to the Westernization of their society. For example, since the fi rst McDonald’s fast food restaurant opened in Japan on May 1, 1971, there have been 104 franchises opened, which correlate with the growth of obesity and GERD.

Western-Based Digestive Diseases

Celiac Disease Gallstone Disease Diverticular Disease Irritable Bowel Syndrome Colorectal Cancer Gastroesophageal Reﬂ ux Disease Inﬂ ammatory Bowel Disease

Conclusions

Despite our affl uence and economic world leadership, the United States continues to struggle with suboptimal pay for performance in healthcare outcomes, infant mortality, and life expectancy. America and Western societies continue to be sedentary, obese, consume a nutrition-poor Western-based diet, and rely solely upon pharmaceutical agents to prevent and treat disease— thus, digestive disease prevalence continues to soar. An emerging digestive 26 INTEGRATIVE GASTROENTEROLOGY disease epidemic is damaging the physical and economic health of the United States. Lessons should be learned from the low prevalence of digestive disease in countries that adopt more nutritious diets and active lifestyles, and are less avid consumers of pharmaceutical drugs. Th e remainder of this book is devoted to helping those who have a digestive condition to restore their health, and to those who want to prevent alimentary tract disease and enjoy optimum h e a l t h . 3 An Overview of Digestive, Sensing, and Immune Functions of the Gut

PATRICK J. HANAWAY , LAURA K. TURNBULL , AND GERARD E. MULLIN

key concepts

■ Th e gastrointestinal tract is a “tube within a tube” that performs a myriad of functions for each individual. ■ We ingest 30–40 tons of nutrients as food in our lifetime. Th e ability of the gut to properly digest, absorb, and extract the nutrients we need determines which of the essential macronutrients and micronutrients are available for our cells to function properly. ■ Th e gut is our principal interface with our environment, acting as the barrier and the sorter of information in the form of food and organisms. ■ Th e concept of “oral tolerance” is the education of our immune system by exposure to phytonutrients and organisms (primarily bacteria) within the gut that arise aft er we are born. ■ Th e bacteria, yeast, viruses, and parasites that coexist within our gastrointestinal tract are known as the commensal fl ora, or gut microfl ora . ■ We are born with the keys (known as toll-like receptors and pattern-recognition receptors ) to relate directly to, learn from, and integrate the messages from our environment (food and fl ora) directly into our beings via our immune systems. ■ Th e enteric nervous system, or “second brain,” has more neurotransmitters in the gastrointestinal tract than in the entire brain. ■

27 Introduction

his chapter moves beyond the descriptive view of gut function, and serves to illustrate the systems approach to understanding the interre- T lationship of major gut functions. Th e evaluation of fundamental processes helps us to understand when, how, and if there is an imbalance within the gut, as well as how to bring it back into balance (i.e., treat it!). Th us, we have organized the chapter according to the fi ve elements of traditional Chinese medicine, the very roots of integrative gastroenterology:

• the process of digestion and absorption (EARTH/nurturance) • the selective barrier function that defi nes our relationship to the “outside” world (WOOD/structure) • the commensal microfl ora of the gut with which we are interdependent (METAL/interrelationship to the web of life) • the physiologic infl ammation that is necessary to activate and maintain the immune surveillance system (FIRE/connection) • the enteric nervous system, which communicates with the rest of the body — based upon all of the above inputs. (WATER/balance).

THE GASTROINTESTINAL TRACT

Th e gastrointestinal tract, the tube within a tube, connects us to our environment through a dynamic interface that is larger than a doubles tennis court. Over the course of our lifetimes, we will ingest 30–40 tons of macronutrients, micronutrients, chemicals, and toxins, providing the building blocks for everything human. Disturbances in our functional ability to make the most of these nutrients have ramifi cations on every aspect of our being, and imbalance in the gastrointestinal system has implications that extend far beyond gastrointestinal symptoms. Th us, in nearly every clinical interaction, the clinician must be vigilant to gastrointestinal dysfunction. Classically, the role of digestion and absorption are considered the principal functions of the gastrointestinal epithelium. Th e quality of discernment that traditional Chinese medicine (TCM) attributes to the “small intestine offi cial” is manifested through its ability to “separate the wheat from the chaff ” (Jarrett, 1999 ), but is also seen in the intertwined relationship of the innate and adaptive immune system within the gastrointestinal system. Th e role of diet and nutrients in the balance of the commensal fl ora, the role of digestion and absorption in providing proper macronutrients and micronutrients, An Overview of Digestive, Sensing, and Immune Functions of the Gut 29 the appropriate physiologic infl ammation, the development of “oral tolerance,” the production of neurochemicals within the “second brain,” and the appropriate excretion of waste, are the functions that must remain within balance to foster health and well-being. Dysfunction within the gastrointestinal system manifests in typical digestive diseases such as: gastroesophageal refl ux “disease” (GERD), irritable bowel syndrome (IBS), infl ammatory bowel disease (IBD; Sansonetti, 2004 ), nonalcoholic steatohepatitis (NASH; Angulo, 2002 ), and even colorectal cancer (CRC; McGarr, Ridlon, & Hylemon, 2005 ). It is also necessary for us to recognize that gastrointestinal dysfunction can manifest as imbalanced immunologic function, thus creating both atopic illness (Brandtzaeg, 2002 ), including allergy and asthma, and autoimmune dysfunction (Rook et al., 2004 ), including rheumatoid arthritis, Type I Diabetes Mellitus, and Hashimoto’s thyroiditis.

Other diseases of immune dysregulation and gastrointestinal dysfunction now include the autism spectrum disorders.

Th e evolution of these diseases begins long before the presentation of symptoms; thus, the opportunity for prevention and early intervention can have tremendous impact on the burden of suff ering and disease. Dietary approaches provide the most eff ective means of returning balance to dysfunction within the gastrointestinal system, and there are many opportunities to bring these tools to patients. However, the profound dietary changes that man has adopted over the past 10,000 years, and that have accelerated over the past 100 years, have created a discord between the nutritional input that our genetic structure has evolved to maximize, and what we are choosing to ingest (Cordain et al., 2005 ). Th is discordance creates a much more complex array of clinical opportunities for supporting the whole being to regain balance and optimal function. Diagnostic considerations include, fi rst and foremost, an extensive health history with an exploration of the patient’s dietary inputs, as well as his or her utilization of antibiotics, laxatives, fi ber, herbs, etc. In addition, one must elicit the current pattern of bowel movements including frequency, history, abdominal pain, gas, bloating, duration, and relationship of bowel elimination to meals. It is amazing how many patients consider their altered bowel movements to be normal. Western medicine does not have a defi ned norm of bowel movement frequency, while other forms of healing such as Ayurveda and TCM (see fi gure 3.1 A) view the regular functioning of the gastrointestinal tract to be a critical barometer of health and well-being, with one well-formed bowel movement per day to be the norm (Svoboda & Lade, 1988 ). Other diagnostic 30 INTEGRATIVE GASTROENTEROLOGY considerations include the evaluation of stool to gather information on parameters of digestion, absorption, infl ammation, infection, intestinal permeability, and altered gut fl ora (known as dysbiosis ). Let us look more closely at the specifi c functional imbalances faced by clinicians, as we examine how they manifest in pathophysiology and how they can be rebalanced to optimize health.

Digestion and Absorption

DIGESTION

As simple as it seems, basic evaluation of digestion and absorption are oft en not part of the initial evaluation of gastrointestinal function in patients with IBS.

Factors that have a negative impact on digestion of food include: inadequate mastication, hypochlorhydria, pancreatic insufﬁ ciency, bile insufﬁ ciency, and villous atrophy. Mastication is a simple clinical point to make with patients and is often overlooked (see Chapter 38 by Dr. Memoli).

IATROGENIC HYPOCHLORHYDRIA AND GERD

Th e plethora of advertisements claiming we have too much stomach acid appears to limit the clinical relevance of hypochlorhydria when, in fact, there is no evidence to support this assertion. In actuality, the symptoms associated with gastroesphageal refl ux are more likely attributed to our current diets and lifestyle (i.e., obesity), leading to laxity of the gastroesophageal (GE) junction and causing excessive refl ux of gastric enzymes, acid, and bile. Measures to block the production of gastric acid do not address the root cause of the pathologies and core imbalances that produce the symptoms of heartburn — mainly, disordered gut motility and impaired lower esophageal sphincter pressure from structural derangements (i.e., hiatal hernia). By overlooking these structural anomalies and, instead, emphasizing pharmaceuticals to reduce stomach acid, we induce a state of hypochlorydria, making patients more susceptible to vitamin and mineral defi ciencies, as well as alterations in the normal microbial fl ora. A more integrative approach to heartburn that addresses these core imbalances is addressed by Dr. Minocha in Chapter 39. An Overview of Digestive, Sensing, and Immune Functions of the Gut 31

Consequences of suppressing gastric acid production include: vitamin deﬁ -

ciency (folate, B12 ), mineral deﬁ ciencies (calcium, magnesium, zinc, iron, chromium, manganese, and copper), altered bowel ﬂ ora, dysbiosis, and small bowel bacterial overgrowth.

IATROGENIC HYPOCHLORHYDRIA AND SMALL INTESTINAL BACTERIAL OVERGROWTH (SIBO)

In addition to the important nutrient absorption implications, the role of low stomach acid in IBS is particularly notable in small intestinal bacterial overgrowth (SIBO). Pimentel, Chow, and Lin ( 2000 ) demonstrated that 78% of IBS patients tested were positive for SIBO, a condition in which coliform and anaerobic bacteria from the large intestine produce deleterious eff ects within the delicate environment of the small intestine. Th e common assay to evaluate for SIBO utilizes the fermentation of sugars, such as lactulose, which stimulates gas production (hydrogen and methane) measurable with a simple breath test. Total gases refl ect the quantity of coliform and anaerobic bacteria present in the small intestine. Treatment commonly includes the use of broad-spectrum antibiotics for 7–10 days to eliminate the overgrowth. Pimentel, Chow, and Lin ( 2000 ) reported that 48% of patients no longer met the Rome II criteria for IBS when treated with rifaximin. Although antibiotics are the mainstay treatment of conventional medicine, other herbal preparations containing berberine, along with essential oils, will have a similar bacteriocidal eff ect (see Chapter 7). Lactobacillus acidophilus and Lactobacillus casei help minimize the side eff ects of antibiotics, and independently decrease the hydrogen gas production (Gaon et al., 2002). While antimicrobial agents are important to eliminate excessive and dis- placed colonic fl ora, it is also necessary to address the underlying root causes of SIBO, including antacids, proton pump inhibitors, antihistamines, slowed transit time, maldigestion, lactose intolerance, and excess simple carbohydrates (see Chapter 7).

PANCREATIC INSUFFICIENCY

Pancreatic insuffi ciency is a common dysfunction that can be evaluated noninvasively. Beyond symptoms of maldigestion (belching, bloating, fl atus), 32 INTEGRATIVE GASTROENTEROLOGY there are relationships between decreased pancreatic function, osteoporosis (Moran et al., 1997 ), and diabetes (Hardt et al., 2000 ). Evaluation of pancreatic function can utilize pancreatic enzymes, such as chymotrypsin and elastase, or indirect markers, such as fecal fat. Elastase is the most sensitive marker of pancreatic insuffi ciency because, unlike chymotrypsin, it is not subject to bacterial degradation as it fl ows through the gastrointestinal tract. Treatment is simple, with pancreatic enzyme supplementation being a safe and eff ective therapeutic intervention to improve digestive function.

ABSORPTION

A fundamental source of malabsorption is maldigestion, as evidenced by the example of SIBO. Maldigestion of fermentable starches (i.e., legumes) can cause an overgrowth of bacteria, which injures the gut integrity and results in a subsequent decrease in absorptive capacity. In addition to its critical role in oral tolerance and immune activation, the intestinal mucosa absorbs nutrients while acting as a barrier to toxins and macromolecules.

Barrier Function

Th e ability of the body to be able to discern between friend and foe highlights the critical importance of the single-cell-layer gastrointestinal mucosa. Th is physical barrier, as large as a high school basketball court, provides the principal interface through which the body communicates with its environment. In addition to this single-cell layer, the gut microfl ora provide an additional barrier by competing with pathogens and producing a mucopolysaccharide matrix, known as the biofi lm . Alterations in barrier function through intestinal permeability [a.k.a. “leaky gut”], changes in the microfl ora, and alterations in the biofi lm layer can lead to immune upregulation. Permeability changes in the gut mucosa can have profound eff ects on anatomic and immunologic barriers to disease (Figure 3.2) (Baumgart & Dignass, 2002 ). Intestinal permeability can lead to increased infl ammatory cytokine production, and a propagation of infl ammation within the intestine (Clayburgh, Shen, & Turner, 2004 ). In fact, there is a great deal of evidence linking increased intestinal permeability with multiorgan system failure, systemic disease and immune dysfunction (DeMeo et al., 2 0 0 2 ) . An Overview of Digestive, Sensing, and Immune Functions of the Gut 33

ALTERED BARRIER FUNCTION: INCREASED INTESTINAL PERMEABILITY

A central theme of this book is that a number of conditions (stress, toxins, infl ammation, infection, poor diet, etc.) can alter the barrier function and increase intestinal permeability, thus creating a “leaky gut” (see Chapter 7). Animal models demonstrate that stress signifi cantly increases intestinal permeability (Baumgart & Dignass, 2002 ), particularly in the cases of trauma and sepsis (Wells, Hess, & Erlandsen, 2004 ). Th is process of intestinal permeability is not a disease entity unto itself, but rather a dysfunction that can increase the overall toxic and antigenic burden. When the paracellular junctions are altered, there is an increased antigen presentation to the immune system (Figure 3.3, Table 3.1 ). Alessio Fasano, one of the world’s leading researchers on celiac disease, proposes that intestinal permeability is also a necessary precursor for many autoimmune diseases, and these processes can be prevented by reestablishing intestinal barrier function (Fasano & Shea-Donohue, 2005 ). With autoimmune disease, the presentation of an environmental antigen to the gastrointestinal mucosal immune system fi rst requires that the antigen pass from the intestinal lumen into the submucosal layer, then on to the mesenteric lymph nodes and the Peyer’s patches. Immune activation occurs if and when there is a genetic predisposition to respond aberrantly (overactively) to the environmental antigen (Clemente et al., 2003 ). For example, those patients who are DQ2 and DQ8 positive will have the genetic basis for gliadin’s activation of the infl ammatory cytokine pathways. Th is pathophysiologic process is predicated upon the incompletely digested molecule traversing the intestinal barrier to initiate this sequence of events.

Table 3.1. Diagnoses of Altered Intestinal Permeability

Intestinal permeability test interpretation

Mannitol Lactulose Suspect

Normal/High High Increased Permeability

Low Low Malabsorption

Low High Increased Permeability & Malabsorption 34 INTEGRATIVE GASTROENTEROLOGY

Increased permeation of intestinal luminal antigens into the portal circulation leads to an increase in the infl ammatory and metabolic stress on the liver. Removal of the initial conditions is necessary to reverse this increase in intestinal permeability. L-glutamine and zinc carnosine have been demonstrated to be important in supporting the healthy growth of enterocytes and microvilli (Zhou et al., 2003 ). Probiotics have also been shown to reverse increased intestinal permeability in infants, over and above their anti- infl ammatory eff ects (Isolauri, Kirjavainen, & Salminen, 2002 ).

MALABSORPTION: DECREASED INTESTINAL PERMEABILITY

Absorption of nutrients is impaired when there is chronic infl ammation of the small intestine, which injures the villi. Th e absorption of dipeptides, monosaccharides, and long-chain fatty acids is dependent upon the available surface area of small intestine. Since microvilli increase the absorptive area of the small intestine by a log-order of magnitude, minimal assaults have a tremendous impact upon vitamin and nutrient absorption. Conditions that may produce substantial infl ammation and injury to the small intestine include, but are not limited to, Crohn’s disease, celiac disease, and infections. However, iatrogenic injury from medications such as nonsteroidal anti-infl ammatories is an overlooked but common cause.

GUT FLORA

Th e makeup of the community of organisms that comprise the microfl ora of the gut is principally established during the fi rst one to two years of life, and is maintained throughout our lives. Th e composition of the gut fl ora is indicative of our environmental exposures prenatally, intrapartum, and throughout infancy. Factors that infl uence the succession of gut fl ora from that time forward include type of delivery (Penders et al., 2006 ), feeding habits (Harmsen et al., 2000 ), gestational age, hospitalization (Björkstén, 2004 ), and infant antibiotic use (Teitelbaum & Walker, 2002 ). At birth, the digestive tract is sterile but begins to be colonized within the fi rst few days of life. During the subsequent two years of life, the GI tract becomes home to 100 trillion commensal bacteria, fed by milk and other foods. Th ese simple foods that stimulate the growth and maintenance of bowel fl ora are known as prebiotics . Cordain describes the dietary patterns most common today, and compares them with the characteristics of ancestral diets Cordain et al., 2005 ).Th ere are signifi cant alterations in glycemic load, fi ber content, essential fatty acid An Overview of Digestive, Sensing, and Immune Functions of the Gut 35 composition, pH balance and macronutrient/micronutrient composition. All of these factors have tremendous eff ects on the balance of the commensal fl ora within the gastrointestinal tract.

Because nearly 70% of the immune system is localized to the digestive tract, a state of controlled physiologic inﬂ ammation, along with environmental contact with commensal bacteria, is essential for proper development of the immune system.

New evidence is evolving that the persistent interactions between host and bacteria taking place in the gut may constantly reshape the immune system (Guarner & Magdelena, 2005). Clinicians see the profound eff ects of altered commensal fl ora in the nearly 20% of the population who are aff ected by the functional GI disorder, irritable bowel syndrome (IBS) (Drossman, Camilleri, & Whitehead, 1997 ). It is also becoming clear that the immune dysregulation of Crohn’s disease and ulcerative colitis (IBD) is profoundly infl uenced by the role of gut fl ora (Shanahan, 2004 ). Immune balance is maintained as gastrointestinal microfl ora compete with pathogens to prevent infl ammation and intestinal permeability. In addition, metabolic processes facilitate the proper breakdown of foods, thus minimizing gastrointestinal infl ammation. Finally, these bacteria help to stimulate growth and epithelial cell diff erentiation. Th ese processes together provide the importance of gastrointestinal microfl ora in preventing and treating intestinal permeability.

BIOFILMS

In addition to the role of individual organisms within the gastrointestinal microfl ora in promoting homeostasis and decreasing intestinal permeability, there is an additional interest in the collective action of these bacteria working together to form unique ecological niches, the biofi lm layer . Th is 30-micron- thick layer of “pond scum” acts to protect the intestinal lining, metabolize food remnants (especially carbohydrates), and may communicate with the immune system. In fact, it is postulated that the short-chain fatty acid (SCFA) synthesis that provides energy to the gut epithelium may also be involved in the “crosstalk” that infl uences the development of humoral and cell-mediated portions of the mucosal immune system. When an infl ammatory process is present within the gut, the 30-micron-thick biofi lm layer decreases in thickness, and there is a concomitant increase in intestinal permeability (Swidsinski et al., 2 0 0 7 ) . 36 INTEGRATIVE GASTROENTEROLOGY

Th e bacteria growing in these biofi lm structures oft en behave diff erently from their nonadherent counterparts, with changes in the nature and effi ciency of their metabolism (Macfarlane & Macfarlane, 2006 ). Once the bacteria in the gut achieve a certain concentration, they begin to communicate across species, which changes the fundamental expression and action of the DNA from that of an individual cell to that of a multicelled organism. Th is phenomenon is known as quorum-sensing , a truly holistic phenomenon in which the “whole is greater than the sum of the parts” (Sifri, 2008 ).

GUT IMMUNOLOGY

Th e process of oral tolerance is analogous with the view of traditional Chinese medicine (TCM) regarding the “small intestine meridian.” Note that the channels of “chi” are not limited to physical properties; thus, the “sorter” (as this meridian is also known) is involved in “separating the wheat from the chaff ” through digestion and absorption, but it is also involved in the process of teaching the immune system to determine self from nonself via oral tolerance, as well as all other “sorting” functions throughout body, mind, and spirit. Th is phenomenon relates, deeper still, to the concept of sorting through information for decision making in which we have a “gut feeling,” and learning to trust that quality of “sorting”— even when it may not make sense. Th rough the process of evolution, the body has developed a number of methods to identify microbes and modulate the adaptive immune system, based upon the proper timing and presence of the bacterial stimuli. Th e body responds diff erentially to bacterial stimuli, and responds to a variety of structural components on each bacterium. Th e innate immune response stimulates the adaptive immune system and infl uences the nature of the adaptive response (Figure 3.4; see Abbas & Lichtman, 2003 ). Th e process of “oral tolerance” is an important example of this. (Brandtzaeg, 2002 ).

Oral tolerance is mediated by regulatory T cells (T reg), which have anti- infl ammatory capabilities. Precursor T cells are transformed into T reg cells when antigen-presenting dendritic cells (DCs) of the gut have not been exposed to infl ammation. Precursor T cells are transformed into Teff ector cells (TH 1 or

TH 2) when the DCs are mature (i.e., activated by infl ammatory signals) (McGuirk & Mills, 2002 ). However, gut fl ora (like Lactobacillus) can downregulate DC maturation, thus preventing the activation of T eff ector cells (Figure 3.5; see Christensen, Frø kiaer, & Pestka, 2002 ). Th e gut fl ora trains the innate immune system to begin to recognize “self.” Th ere are molecules of recognition — pattern recognition receptors (PRR), An Overview of Digestive, Sensing, and Immune Functions of the Gut 37 toll-like receptors (TLR), and pathogen-associated molecular patterns (PAMP) — that facilitate the mucosal immune system’s awareness of the bacterial environment, and determine its release of stimulating or suppressive cytokines (see fi gure 3.6). Th e epithelial mucosa is equipped with PRRs that recognize bacterial DNA from commensal bacteria and eff ectively modulate immune function (Jijon et al., 2004 ). Pathogenic bacteria will upregulate the adaptive immune system (via IL-12) within the Peyer’s patches and the mesenteric lymph nodes, inducing NF-kB activation of the infl ammatory cascade Figure 3.7). Conversely, the normal gut microfl ora promotes immune modulation (via IL-10) and has anti-infl ammatory properties (Figure 3.8 and 3.9). Disruption of gut fl ora disrupts oral tolerance by driving the T eff ector responses in the gut toward a TH 1 proinfl ammatory response. Correction of gut fl ora improves oral tolerance. Th us, the immune system is dynamically educated by the presence of bacteria at the interface of the intestinal epithelium. Th e gut fl ora interacts with our innate immunity, and infl uences the adaptive immune response, in an important dialogue between the immune system and the environment. Commensal bacteria are also able to modulate expression of host genes involved in important intestinal functions, including nutrient absorption, mucosal stimulation, xenobiotic metabolism, and intestinal maturation (Hooper et al., 2001 ). Diff erent bacteria induce diff erent immunologic responses. Nonpathogenic bacteria also elicit diff erent cytokine responses from epithelial cells, inducing diff erential eff ects on the gut-associated lymphoid tissue GALT and the adaptive immune system (Borruel et al., 2002 ).Because of this dynamic interplay between the gut fl ora and the GALT, the immunologic response system can be modifi ed, based upon dietary change (in the form of prebiotics) and benefi cial bacteria (in the form of probiotics). Hooper and Gordon (2001 ) have highlighted the eff ects of imbalance within this complex ecosystem. Th eir work has expanded our understanding of the metabolic eff ects of the microfl ora by highlighting the metabolic eff ects that altered gut fl ora can have on the development (and treatment!) of obesity. Th e increasing prevalence of allergy and atopy are associated with alterations of intestinal colonization, and decreased tolerance to common food proteins and inhaled allergens. Treatment with probiotics has helped to shift these symptoms back to normal (Kallomaki et al., 2003 ). Overall, we see that these critical environmental interactions highlight immunologic dysregulation arising from the combination of varied bacterial species (commensal and pathogenic), altered adaptive immune system activation, and multiple anti- g e n i c s t i m u l i . 38 INTEGRATIVE GASTROENTEROLOGY

Enteric Nervous System

FACTORS INVOLVED IN GUT HOMEOSTASIS

Gastrointestinal homeostasis requires a dynamic balance of the “fi ve elements” of gastrointestinal function (digestion/absorption, intestinal barrier, enteric commensal fl ora, enteric nervous system, mucosal immunity; see Figure 3.1). Under the guidance of the central nervous system (CNS), the enteric nervous system regulates digestive functions (i.e., digestion, motility) and is crucial to our overall health and well-being. In order to achieve homeostasis, the enteric and central nervous systems communicate via bidirectional signaling. Our ability to adapt to psychological and physical stressors depends upon an optimal functioning of this signaling pathway. In the face of emotional stress, a sympathetic dominant state of nervous system operation diminishes blood fl ow and motility to the gut, leading to severe impairments in digestive function (Schwetz, Bradesi, & Mayer, 2004 ). Th us, when there are interferences in Enteric nervous system – central nervous system ENS–CNS coordination in functional bowel disorders such as IBS, consequent disordered modulation of gastrointestinal motility, visceral pain thresholds, barrier defenses, mucosal immune responses, and nutrient processing occur (see Chapter 33).

ROLE OF GUT MICROBIOTA

It has been long thought that disordered regulation of serotonin production played a central role in the pathogenesis of IBS (Sikander, Ranam, & Prasad, 2009 ). However, emerging evidence suggests that the crosstalk between the enteric nervous system (ENS) and the central nervous system (CNS) is infl u- enced by the interplay between by-products of the gut microbiota and the enteric nerve terminals (ENTs), through the enterochromaffi n cells (ECs; see Rhee, Pothoulakis, & Mayer, 2009 ). Th us, the enteric microbiota can directly infl uence the relationship between the ENS and the CNS (Figure 3.10 .). Rhee and colleagues have recently reviewed 85 articles that, in totality, suggest that the enteric microbiota maintain gut homeostasis by regulating motility, immune responses, and processing of nutrients (2009). An Overview of Digestive, Sensing, and Immune Functions of the Gut 39

UNIDIRECTIONAL SIGNALING (BRAIN ENTERIC)

Altered brain states, such as psychological stress, can modulate the biomass and composition of the enteric microbiota (Bailey, Lubach, & Coe, 2004 ). Furthermore, the enteric bacterial environment may be directly linked to the increased motility caused by stress states (resulting in shedding of the organisms). Th e emotional motor system (EMS) of the brain causes changes in the fl ora in two ways (either alone or in combination) (Holstege, Bandler, & Saper, 1996 ):

• Directly via host enteric microbiota signaling • Indirectly via changes in the fl oral environment

As to which populations of the enteric fl ora are most infl uenced by the EMS, reports suggest that the bacteria in biofi lms that adhere to the epithelium are actually less vulnerable than luminal populations to the changes in motility and luminal contents. As a consequence, bacteria in biofi lms are more involved in bidirectional signaling than luminal populations (Macfarlane & D i l l o n , 2 0 0 7 ) .

CNS-Related Changes in the Gut Environment

PARASYMPATHETIC TONE

In the state of parasympathetic tone, the vagus nerve of the CNS establishes the rhythmic propagation of gastrointestinal (GI) motility to ensure its “house- keeper” function. Th us, GI motility aff ects the delivery of nutrients to enteric fl ora, alters the pH of the luminal environment in both healthy and diseased states, and protects the proximal gut against the buildup of the colonic type of enteric fl ora (i.e., SIBO; see Van Felius et al., 2007).

SYMPATHETIC NERVOUS SYSTEM, ENTERIC FLORA AND MUCOSAL IMMUNITY

Th e aforementioned biofi lm is the part of the enteric fl ora that is adherent to the gut epithelium. Or, Th ese bacteria infl uence mucosal immunity and enteric nerves diff erently than luminal microbes. Th e intestinal mucus layer is 40 INTEGRATIVE GASTROENTEROLOGY the habitat for the biofi lm. In a sympathetic dominant state, unregulated stimulation of the autonomic nervous system (ANS), or insuffi cient regulation by the parasympathetic nervous system, impairs proper mucus secretion, thus aff ecting the biofi lm (Cooke, 2000 ). As shown in Figure 3.11 XXX., the sympathetic nervous system can moderate the mucosal immune system’s response to luminal bacteria via degranulation of mast cells, whose by-products (i.e., corticotropin-releasing factor; CRF) increase intestinal permeability, thus allowing even more nonselective antigen presentation to gut macrophages driving the process in a feed-forward manner. Under stress conditions, intestinal barrier function is weakened by a number of diff erent mechanisms other than local release of CRF, and is reviewed elsewhere (Demaude et al., 2 0 0 6 ) .

BIDIRECTIONAL SIGNALING (BRAIN ENTERIC)

Enteric microbes can aff ect intestinal motility, which can either assist (especially Bifi dobacterium bifi dum & Lactobacillus acidophilus, to promote motility) or harm (Escherichia inhibits motility) the host (Mazmanian, Round, & Kasper, 2008 ). Since the by-products of bacteria within the intestines can infl uence gut motility by stimulating the enteric nervous system, dysbiosis can, therefore, alter gut motility in the host — which, in turn, aff ects the balance of enteric microbes. Another key concept that is central to this discussion is that there is an ongoing dialogue between the enteric fl ora and the intestinal epithelium, as well as crosstalk between diff erent luminal bacterial species themselves (a.k.a., interkingdom signaling; see Figure 3.12 (Hughes & Sperandio, 2008 ). For example, enteric bacteria can cause the release of norepinephrine into the intestinal lumen, along with an increased expression of adrenergic receptors on the gut epithelium, to infl uence fl uid and electrolyte secretion and local immune function (Valet et al., 1993 ). As mentioned previously, quorum sensing (Lowery, Dickerson, & Janda, 2008 ) is a type of decision-making process used by decentralized groups to coordinate behavior. Many species of bacteria use quorum sensing to coordinate their gene expression according to the local density of their population. It is used by bacteria to regulate gene expression by responding to signals from both other bacteria and the host. Th e signals received by the bacteria (from the host and other bacteria) regulate physiological processes within the bacteria, including pathogenicity, metabolite production, and bacterial motility. Th erefore, through interkingdom signaling and quorum sensing, the host’s nervous system can infl uence microbial behavior (Hughes & Sperandio, 2008 ). An Overview of Digestive, Sensing, and Immune Functions of the Gut 41

While this has been demonstrated in pathogenic bacteria, it is likely that it is also the case in commensal fl ora.

Microbial signals can interact with afferent nerve terminals when there is compromised intestinal integrity (as in leaky gut, stress, or inﬂ ammation). As intestinal permeability increases, bacterial by-products and inﬂ ammatory mediators are able to directly access nerve endings in the mucosa.

Neuroendocrine Immune Signaling

Th e signals released from bacteria interact with receptors on both other bacteria and on host cells, which infl uence the nervous system via endocrine, immune, and neural signaling mechanisms . Th e eff ects on gastrointestinal function of signals released by enteric microbes are widely studied, but the systemic consequences are less well known (Walsh & Mayer, 1993 ). Enterochromaffi n cells (EC cells) produce mediators (i.e., serotonin) that serve as signal transducers to translate bidirectional signals from the enteric microbes to the nerve terminals. EC cells have access to the microbes on the luminal side, and both aff erent and eff erent nerve terminals on the lamina propria, making them ideal for bidirectional signaling. Enterochromaffi n cells secrete signaling-gut-derived peptides such as serotonin, CRF, cholecystokinin and somatostatin, in response to factors elaborated by gut microbes (Figure 3.12; see Wheatcroft et al., 2005 ). EC cells can aff ect gut motility via elaboration of the main neurotransmitter of the gut, serotonin, whose production is impaired in IBS (Sikander, Ranam, & Prasad, 2009 ). Furthermore, the state of the luminal environment is transmitted to the CNS by the vagus nerve, the nerve terminals of which are near EC cells. Th us, signaling from EC cells to the aff erent terminals of the vagus nerve could directly connect chemical signaling within the lumen to supraspinal networks .

In unhealthy people where there is increased intestinal permeability, microbe signaling is able to directly access the nerve terminals, which may be a port of entry for the microbes to interact with the CNS (brain). However, in healthy individuals with an intact intestinal barrier, the mechanism by which this microbe–brain communication occurs is principally governed by EC cells. 42 INTEGRATIVE GASTROENTEROLOGY

Conclusions

Proper balance of form and function are required for the human system to be in homeostasis. Nowhere in the body is this more true than in the principal interface we have with our environment — taking in food, digesting and absorbing, defending ourselves from invaders, stimulating the development of our immune system, communicating the “status quo” throughout the body, and living in “right relationship” with the gastrointestinal microfl ora. Each of these functional components will produce pathophysiologic changes when they are not in balance. Th e diagnostic and therapeutic approach of integrative (or functional) gastroenterology is to observe the patient through these lenses, rather than the fi nal symptom complex referred to as ICD-9 diagnoses. Th e functional approach focuses on returning the system to balance, rather than elimination of symptoms, and off ers tools that help with gastrointestinal disease but also help with many diseases throughout the body that have their origins within the gastrointestinal tract. 4 The Intestinal Microbiota in Health and Disease: Bystanders, Guardians or Villains?

FERGUS SHANAHAN

key concepts

■ A resurgence of interest in the gut microbiota, enabled by advances in nonculture-based molecular techniques, has shown the importance of host–microbe interactions in gastrointestinal maturation and homeostasis. ■ Th e microbiota is a health asset, but occasionally a contributor to the pathogenesis of gastrointestinal disease and to certain extra-intestinal disorders. ■ Elements of a modern lifestyle, such as urbanization, domestic hygiene, antibiotic usage, and family size, represent proxy markers of environmental infl uence on the composition of colonizing microbiota in early life. ■ Comparative studies of germ-free and colonized animals predict the existence of microbial-derived signals which can be mined for bioactives or novel drug discovery. ■ Host–microbe interactions in the gut are bidirectional. ■

Introduction

here is an ongoing resurgence of interest in the alimentary microbiota (fl ora). For basic scientists, this is being driven, in part, by improve- T ments in technology, particularly molecular approaches for studying

43 44 INTEGRATIVE GASTROENTEROLOGY the microbiota. For clinicians, the discovery that Helicobacter pylori causes peptic ulcer disease is a continual reminder of the possibility that other chronic diseases may have a microbial basis. Indeed, the most important lesson of that discovery is that the solution to some diseases may never be found if research remains focused on the host, without due attention to the host–environment interface. Furthermore, the contribution of the microbiota to gastrointestinal maturation and maintenance of mucosal homeostasis has stimulated the exploration of host–microbe interactions.

Composition of the Microbiota

Th e complexity and quantity of microbes in the alimentary tract is greatest at the orifi ces. Th e oral cavity harbors a relatively large and diverse bacterial population, whereas gastric acid restricts bacterial numbers to fewer than 10 3 colony-forming units (CFU)/ml of gastric contents. Along the small intestine, bacterial density increases distally with a sharp gradient across the ileocecal valve, with approximately 108 bacteria per gram of ileal contents and up to 10 12 per gram of colonic contents, which comprises more than 1,000 diff erent bacterial species (O’Hara & Shanahan, 2006 ; Turnbaugh et al., 2007 ). Th ere is also a gradient in the composition of bacteria from mucosa to lumen. Almost all of the culturable bacteria in the ileum and the colon are obligate anaerobes, but the ratios of anaerobes to aerobes are lower at mucosal surfaces. In addition, culture-independent molecular techniques have shown that mucosa- associated bacteria diff er from those recovered from feces (Zoetendal et al., 2 0 0 2 ) . In the proximal small bowel, the resident bacteria are predominantly gram- positive facultative bacteria, although enterobacteria and Bacteroides also may be present. Peristalsis is the principal factor restricting bacterial numbers in t h e s m a l l b o w e l .

In the distal small bowel, the composition of the ﬂ ora resembles that of the colon, with a preponderance of Gram-negative anaerobes. The most promi- nently represented genera in the distal bowel include Bacteroides, Clostridium, Lactobacillus, Fusobacterium, Biﬁ dobacterium, Eubacterium, Peptococcus, and Escherichia. The Intestinal Microbiota in Health and Disease 45

Environmental and Lifestyle Modiﬁ ers of the Microbiota

Molecular profi ling has shown that the microbiota is distinct in diff erent people. Studies of twins suggest that the individuality of the human microbiota may be determined, in part, by host genetics (Zoetendal et al., 2001 ), but environmental variables including diet, sanitation and other lifestyle factors appear to have profound eff ects, particularly on early intestinal colonization (Sonnenburg, Angenent, & Gordon, 2004 ). Indeed, many of the elements of a modern lifestyle such as domestic hygiene, antibiotic usage, urbanization, and family size are proxy markers of microbial exposure during the early stages of life (Bernstein & Shanahan, 2008 ).

Although the numbers and composition of the microbiota are relatively stable after infant weaning, the metabolic activity of the microbiota is continually subject to dietary and other lifestyle variables.

Techniques for Studying the Microbiota

Most enteric bacteria cannot be cultured, because of a lack of selective growth media (Marchesi & Shanahan, 2007 ). Furthermore, because most of the indigenous bacteria are obligate anaerobes, there are logistical diffi culties sampling the gut ecosystem. Th erefore, molecular strategies have been devised to study bacterial nucleic acid extracted from feces or mucosal biopsy samples (Vaughan et al., 2000 ). Th e small ribosomal subunit RNA (16S rRNA in bacteria) contains highly conserved regions of base sequences that refl ect an absence of evolutionary change, and that are interspersed with hypervariable regions that contain mutational changes refl ecting the evolutionary divergence of diff erent species. Sequencing of 16S rRNA permits identifi cation and phylogenetic classifi cation of intestinal bacteria. For rapid profi ling, 16S rRNA can be amplifi ed by polymerase chain reaction (PCR) and a profi le of the mixture of hypervariable RNA fragments is achieved by variations in migration distance upon denaturing gradient gel electrophoresis. Th is refl ects the diversity of 16S “species” in the sample. Other molecular techniques for identifi cation of specifi c bacterial species are now possible because their genomic sequence has become available. Strategies include fl uorescence in situ hybridization (FISH), fl ow cytometry 46 INTEGRATIVE GASTROENTEROLOGY

(FISH-FLOW), and bacterial DNA microarrays. In addition, metagenomic techniques, which involve sequencing genes from mixed microbial populations, will address many of the unresolved questions about the microbiota in health and disease.

Genetic information within the microbiota (microbiome) exceeds that of the host genome by approximately a hundredfold, but the combination of metagenomics with bioinformatics, biochemistry, and traditional bioassays, is yielding important insights into the metabolic capacity of the human gut microbiota. (Turnbaugh et al., 2007 )

Life without Bacteria

From comparative studies of germ-free and colonized animals, one can deduce that the intestinal microbiota must be a source of positive and negative regulatory signals for the development and function of the intestine. Life without bacteria is associated with reduced digestive enzyme activity and epithelial turnover, rudimentary lymphoid tissue, reduced mucosal cellularity and vascularity, and impaired motility, whereas enterochromaffi n cell mass is increased (Midtvedt, 1999 ). Th e molecular signals that permit maturation of the gut upon colonization with the microbiota are currently being explored (Hooper et al., 2001 ). Remarkably, colonization with only a single bacterial strain, Bacteroides thetaiotaomicron , has illustrated the impact of bacteria-derived signaling on the expression of host genes controlling mucosal barrier function, nutrient absorption, angiogenesis, and development of the enteric nervous system.

A diversity of incoming bacterial signals includes: secreted chemoattrac- tants, such as the formylated peptide, fMet-Leu-Phe (fLMP); cell wall constituents, such as lipopolysaccharide (LPS); and peptidoglycans, ﬂ agellin, and bacterial nucleic acids (e.g., CpG DNA). Detection of bacterial stimuli by the host, and discrimination of pathogens from commensals, are mediated, in part, by pattern recognition receptors, such as toll-like receptors (TLRs), that are present on epithelial and immune (dendritic) cells. Continual signaling by microbial ligands engaging TLRs is required not only for optimal mucosal and immune development, but also for mucosal homeostasis and responses to injury (Rakoff-Nahoum et al., 2004 ; Madara, 2004 ). The Intestinal Microbiota in Health and Disease 47

Transduction of Bacterial Signals

Th e enteric mucosa is well adapted to sampling the intraluminal microbial community, with its large surface area (approximately 400 m2 ) and only a single-cell layer separating the internal milieu from the lumen. Th e surface enterocytes serve an immunosensory role by producing chemokines in response to microbial danger signals, thereby alerting the host immune response to breaches in the mucosal barrier (Artis, 2008 ). Direct sampling of the lumen across the epithelium is mediated by mucosal dendritic cell processes that extend into the lumen between the surface enterocytes, and by M cells, which transport particulate antigens and intact microbes to underlying lymphoid follicles (Rescigno et al., 2001 ). Aft er uptake, antigenic material, including intact microbes, is transported by dendritic cells to the mesenteric lymph node (Macpherson & Uhr, 2004 ). Th ere, local immune responses are generated, and the mesenteric lymph node acts as a gatekeeper by preventing systemic entry by commensal bacteria. Th e discriminatory function of dendritic cells, depending on whether they are exposed to commensals or pathogens, is facilitated by their plasticity and versatility of responses, and by their tissue-specifi c specialization within the intestine. Transduction of bacterial signals into host immune responses aft er engage- ment of TLRs proceeds along several molecular pathways. Th e transcription factor, nuclear factor-κ B (NF-κ B), is the molecular switch for immune responses and is a pivotal regulator of epithelial responses to invasive pathogens. Nonpathogenic bacteria attenuate infl ammatory responses by several mechanisms, including delaying the degradation of I κ B, which is counterreg- ulatory to NF- κ B (Neish et al., 2000 ), and enhancing the nuclear export of the transcriptionally active subunit (RelA) of NF- κ B in a peroxisome proliferator– activated receptor- γ (PPAR-γ )-dependent manner (Kelly et al., 2004 ).

Host–Microbe Communication is Reciprocal

As with many other examples of interkingdom signaling (Hughes & Sperandio, 2008 ), host–microbe interactions in the gut are bidirectional. Th e apparent infl uence of host genetics on the composition of the commensal microbiota is supported by evidence for modulation by the immune system on the microbiota. Mucosal immune defects in diff erent species have been associated with aberrant expansion of certain commensal organisms (Ryu et al., 2008 ; 48 INTEGRATIVE GASTROENTEROLOGY

Suzuki et al., 2004 ). In addition, the transcription factor T-bet, which regulates immune development and function, has been shown to have an unexpected infl uence on commensal populations within the murine intestine. Deletion of T-bet appeared to lead to the emergence of a “colitogenic” microbiota with the capacity to transfer colitis (Garrett et al., 2007 ).

The Microbiota is a Health Asset and Occasional Contributor to Disease

Th e distinction between a commensal and a pathogen is oft en one of context. For example, the indigenous microbiota is generally a health asset, but becomes a liability in the setting of bacterial overgrowth syndromes, including C. diffi cile overgrowth aft er antibiotics. In other contexts, depending on the genetic susceptibility of the host, some but not all components of the microbiota may become contributors to the pathogenesis of disease, such as infl ammatory bowel disease (Sartor, 2008 ). While a comprehensive review of the microbiota in diff erent diseases is beyond the scope of this chapter, microbial alterations linked with infl ammatory bowel disease have attracted particular interest. Th ese include a reduction in fecal lactobacilli and bifi dobacteria (Murch, 2001 ), increased adherent-invasive E. coli (AIEC; see Rhodes, 2007 ), increased detection of Mycobacterium avium subspec paratuberculosis (MAP; see Feller et al., 2007 ) and reduced bacterial diversity by metagenomic analysis (Peterson et al., 2008 ). Th e latter includes reductions in the anti-infl ammatory commensal, Faecalibacterium prausnitzii (Sokol et al., 2008 ). Whether specifi c microbiota can be correlated with individual variations in the immune response is unclear, but there is evidence that this may be so (Ivanov et al., 2008 ).

The Gut Microbiota and Extraintestinal Disorders

In addition to its role in gut health, the microbiota has become an important consideration in the context of a variety of other disorders beyond the gut. For example, the impact of the microbiota on immune maturation is not limited to gut-associated lymphoid tissue; peripheral lymphoid structures are also infl u- enced (Mazmanian et al., 2005 ). As discussed later, the microbiota has been shown to be an environmental regulator of fat storage, and appears to infl u- ence the risk of developing obesity and metabolic syndrome (DiBaise et al., 2008 ). More recent work suggests that microbiota not only infl uences fat quantity but also fat quality, in terms of bioactive fatty acid composition in adipose and hepatic tissue (Wall et al., 2009 ). The Intestinal Microbiota in Health and Disease 49

In addition, the composition of the gut microbiota has been shown to modify the pathogenesis of T-cell mediated destruction of pancreatic islets in murine diabetes. Th e interaction between the microbiota and the host innate immune system appears to be a critical epigenetic modifying factor, although the relationship between the microbiota and risk of developing diabetes is complex (Wen et al., 2008 ).

Metabolic Activity of the Microbiota

Th e collective metabolic activity of the enteric microbiota is tantamount to that of a hidden organ (O’Hara & Shanahan, 2006 ). Coevolution with this inner biomass has several benefi ts for the host. In addition to the production of regulatory signals for mucosal homeostasis, the microbiota contributes metabolic properties not possessed by the host. Th ese include biotransformation of bile acids, degradation of oxalate, breakdown of otherwise indigestible dietary components, such as plant polysaccharides, and production of short- chain fatty acids— a major energy source for colonic epithelium— from fermentable carbohydrates. Other activities include synthesis of biotin, folate, and vitamin K. Bacterial enzymes, such as azoreductase, have been exploited therapeutically to convert prodrugs, such as sulfasalazine, to active drug metabolites, such as aminosalicylate. Other examples of bacterial action on drug bioavailability include the metabolism of L -dopa to dopamine, and degradation of digoxin.

In some instances, the metabolic changes induced by the enteric microbiota may not beneﬁ cial to the host. For example, bacteria may promote the production of carcinogens from dietary procarcinogens, although they probably also degrade some carcinogens (Rafter, 2003 ).

As alluded to earlier, the regulatory eff ect of the enteric microbiota on fat storage represents a compelling example of the impact of bacterial metabolism on the host (Backhed et al., 2004 ). Germ-free animals require a higher caloric intake to sustain a body weight similar to that of colonized animals. Th us, the microbiota of the colonized host confers a nutritional benefi t. Furthermore, intestinal bacteria promote fat storage by enhancing the bioavailability of dietary monosaccharides for absorption, and also by suppressing epithelial- derived, fasting-induced adipocyte factor (FIAF), which in turn releases lipoprotein lipase activity and promotes uptake of fatty acids into adipose tissue. Th us, the composition and activity of the intestinal microbiota should 50 INTEGRATIVE GASTROENTEROLOGY be considered as a variable infl uenced by Western diets that may infl uence susceptibility to obesity. Gas production is another familiar outcome of bacterial metabolic activity. % Of the fi ve gases — N2 , O 2 , CO 2 , H 2 , CH 4— that comprise 99 of fl atus, the latter three are produced by the enteric bacteria, and bacteria are the sole source of hydrogen and methane in the intestine. Hydrogen production by bacterial action on carbohydrates and, to lesser extent, on protein, normally occurs in the colon. Th e small bowel also becomes a site of H2 production when bacterial overgrowth occurs. Bacterial methanogens occur in the colon and produce methane from H 2 and CO 2, with detectable excretion in approximately 30 % of humans (Levitt & Engel, 1975 ; Levitt, 1980 ).

While the principal gases produced are odorless, bacterial metabolism also generates various trace and odiferous gases in fl atus, such as hydrogen disulfi de (Moore, Jessup, & Osborne, 1987 ; Suarez, Springfi eld, & Levitt, 1998 ). Qualitative and quantitative variability in gas production with diet illustrates the fl uctuations in bacterial metabolic activity, despite the composi- tional stability of the microbiota in adulthood.

Mining the Microbiota for Novel Drug Discoveries

Several predictions can be made regarding the identity of microbial-derived chemical signals suitable for mining, based on what is already known of the infl uence of the microbiota on host physiology and pathophysiology (see Table 4.1 ). Translation of these signaling molecules into bioactives or novel drugs is an exciting prospect for the future (Shanahan & Kiely, 2007 ).

Table 4.1. Examples of Opportunities to Mine the Microbiota for Novel Therapeutics

Observation Opportunity Translation Reference

Microbe–microbe Isolation of novel Application of Rea et al. communication ensures antibiotics (bacteriocins) lacticin to treatment ( 2007 ) stability of bacterial of pathogens such as numbers in the gut C. diffi cile

Commensals and Bacterial components or Evidence base for Grangette probiotics have metabolites for use as this remains to be et al. ( 2005 ) anti-infl ammatory anti-infl ammatory drugs explored and Obermeie eff ects on the host (e.g., lipoteichoic acid, exploited et al. (2003) CpG DNA) The Intestinal Microbiota in Health and Disease 51

Table 4.1. (Continued)

Observation Opportunity Translation Reference

Gut microbiota is Isolation of bacterial- Use of cell wall Mazmanian required for immune derived molecules as polysaccharides as et al. ( 2005 , maturation immunomodulatory immunomodulatory 2008 ) drugs drugs in IBD

Metabolic signals from Manipulation of the Use of food-grade Backhed the microbiota microbiota may alter organisms to modify et al. ( 2004 ) infl uence fat storage bioavailability of dietary composition of the Wall et al. and composition calories microbiota ( 2009 )

Some but not all Some components of the An intriguing Rousseaux commensals or microbiota may be observation that et al. ( 2007 ) probiotics are suitable for mining for awaits confi rmation benefi cial in irritable analgesic activities and exploitation bowel syndrome

Conclusions

Th e contribution of the microbiota to mucosal homeostasis is such that it is has become essential to study intestinal pathophysiology in the context of the resident bacteria. Lifestyle and environmental infl uences on the microbiota, and on the developing immune system, may underpin the changing epidemiology of several chronic infl ammatory disorders. Th e molecular basis of microbial-induced gastrointestinal and immune development is beginning to unfold, and may be “mined” for novel therapeutics in the future.

5 Alternative Laboratory Testing for Gastrointestinal Disease1

DAVID M. BRADY , J. ALEXANDER BRALLEY , RICHARD S. LORD , AND GERARD E. MULLIN

key concepts1

■ Gastric acid analysis is an important test to consider in patients with recurrent gastrointestinal infections and small intestinal bacterial overgrowth (SIBO). ■ Fecal elastase is a reliable noninvasive stool test for pancreatic insuffi ciency. ■ Intestinal hyperpermeability indicates ongoing injury to the intestinal epithelium, and is diagnosed using the lactulose- mannitol test — a simple, noninvasive and inexpensive test. ■ Lactulose breath hydrogen and methane testing can be used to detect abnormal fermentation in the upper digestive tract, indicative of small intestinal bacterial overgrowth. ■ Microbial analysis of stools using PCR technology may provide valuable information about the colonic fl ora and guide treatment of digestive conditions. ■

Introduction

ealthcare practitioners who manage digestive disorders are oft entimes challenged by the limited testing that is available without refer- H ring to specialists who perform invasive procedures. Th e principal 1 Excerpted and adapted from Richard S. Lord and J. Alexander Bralley (Eds), Chapter 7, Gastrointestinal Function in Laboratory Evaluations for Integrative and Functional Medicine. Metametrix Institute (2008) .

52 Alternative Laboratory Testing for Gastrointestinal Disease 53 diffi culty is that direct sampling of intestinal contents is impractical for non- gastroenterologists. Analysis of specimens such as peripheral blood, urine, and feces may give results that indirectly refl ect diffi culties with digestion and absorption. Due to the critical role of the gastrointestinal tract in nutrient supply, even partial answers can be of great value. Invasive procedures for observation or luminal specimen retrieval can be highly informative when performed in conjunction with noninvasive testing. Th is chapter will deal mainly with noninvasive laboratory evaluations of gastrointestinal function, as summarized in Table 5.1 .

Table 5.1. Summary of Laboratory Evaluations for Gastrointestinal Function

GI Aspect Function Testing Abnormal Intervention

Heidelberg pH – Mucosal building capsule protocol Direct pH – Betaine HCI readings – Free-form amino acids Gastric acid, (see Chapter 4, “Amino Stomach Indirect Multiple Pepsin Acids”) indicators trace – B-vitamins elements or – Trace elements amino acids (see Chapter 3, “Nutrient and Toxic Elements”)

Protease Fecal Activity Pancreatic replacement chymotrypsin enzymes (proteolytic, lipolytic and amylytic) and PABA index Index Pancreas essential fatty acids Lipase Plasma fatty PUFA acids

Fecal fats Fat

Liver/ Bile acid Fecal fatty Fatty acids Ox bile, choleretic herbs Gallbladder secretion acids (milk thistle) and essential fatty acids ≥ Schilling test Urinary B12 by injection or 1,000

B 12 μg/d sublingual Small Absorption Lactulose- Urinary Mucosal restoration intestine Mannitol mannitol challenge

Fasting plasma Multiple low Essential amino acid amino acids values mixtures

(Continued) 54 INTEGRATIVE GASTROENTEROLOGY

Table 5.1. (Continued)

GI Aspect Function Testing Abnormal Intervention

Food-specifi c Multiple Food elimination/Rotation IgG elevations diets

Water Butyrate Increase dietary fi ber resorption, Fecal butyrate Colon Butyrate enemas Microbial or other SCFA Isobutyrate containment

Immune Glycocalyx Serum, urinary Food- Eliminate off ending barrier antigen or fecal IgA specifi c IgA antigens binding Immune-support nutrients Allergy- Total IgE such as Glycerrhiza antigen Serum IgE glabra (licorice) root or elimination l -glutamine 3,000–6,000 mg daily

Many + foods Eliminate + foods by group Regulate (Rotation Diet) Add nutrient Serum IgG free-form amino acids and admission glutamine Zinc 50–100 Physical and restrict mg/d, B 100–200 mg/d barrier s toxicant and Lactulose- Urinary Eliminate + foods microbial Mannitol Lactulose access challenge Mannitol Mucosal restoration

Normal: Urinary Bacterial Herbal or pharmaceutical nutrient metabolic markers antibioitics (e.g., berberine delivery markers alkaloids, etc.)

Protozoal Prebiotics and probiotics markers with antiprotozoals Hydrogen- Yeast Restrict simple sugars with Methane Microbial markers antifungals breath test populations Pathogen: Expired Herbal or pharmaceutical toxin gases bacteriostatic agents production Stool microbial Growth Specifi c antibiotics DNA quantititation or culture & sensitivity Alternative Laboratory Testing for Gastrointestinal Disease 55

The Stomach

Standard medical treatments focusing on the gastrointestinal tract most oft en involve treating digestive symptoms by using proton pump inhibitors, which are among the most frequently prescribed medications with a myriad of potential adverse eff ects (see Chapter 37 by Hickey and Mullin). Stomach acid secretion is a principal line of defense against infection of the gastrointestinal (GI) tract (Giannella, Broitman, & Zamcheck, 1972 ). Th e critical function of low pH in the stomach is required to set up mineral absorption. High levels of ammonia, produced by bacterial action on amino acids, are even more directly associated with inadequate hydrochloric acid. Th e loss of bactericidal action and the failure to digest protein due to low stomach acid simultaneously leads to higher bacterial populations and greater availability of unassimilated amino acids for bacterial conversion.

Simultaneous low levels of iron, zinc, copper, and manganese in serum, erythrocytes, or hair, is often due to gastric acid inadequacy, especially when intake of trace elements is normal.

Th e proteolytic enzyme activity and low pH in normal gastric secretions kill most of the bacteria and parasites that contaminate food. Chronic hypochlorhydria, whether induced by habitual use of antacids or due to gastric disorders, increases the risk of infection and intestinal microbial overgrowth (Neal et al., 1996 ).

HEIDELBERG CAPSULE TEST

Th e Heidelberg capsule test is considered to accurately assess stomach acid, though it is time-consuming for the patient, taking up to 90 minutes to complete (Wright, 1979 ). Th is type of test can give defi nitive answers about the adequacy of gastric acid secretion. Th e test uses a tiny plastic encapsulated pH probe that is swallowed by the patient. Th e capsule, small enough to safely pass the circuitous course of the GI tract, contains a miniature radio transmitter that continuously measures gastrointestinal pH and transmits the data to a waistband antenna connected to a bedside receiver. Th e pH readings are recorded for a permanent record. Th e capsule can either be tied to a thin string for retrieval, or swallowed untethered. Th e latter approach allows additional 56 INTEGRATIVE GASTROENTEROLOGY measurements of upper intestinal pH to be gathered. Aft er swallowing the capsule, pH readings typically start around 7.0, and then drop toward 1.0 as the capsule settles toward the stomach bottom. Th e patient then drinks a challenge solution consisting of concentrated sodium bicarbonate (baking soda), which has strong buff ering capacity. Within half a minute, the pH will normally rise to approximately 7. If acid secretion is normal, the pH will fall again, returning to between 1.0 and 2.0 within 20 minutes. Th e challenge solution is given again and repeated up to four times, as long as the pH response time is less than 20 minutes. Hypochlorhydria is indicated for a patient requiring more than 20 minutes to re-acidify. With achlorhydria, the patient’s stomach secretes little acid and the pH will not fall below 4.0, even on the fi rst challenge (Wright, 1979 ). Experienced technologists must administer this test, because of factors such as the timing of bicarbonate solutions that are critical for accurate, reproducible results.

ENDOSCOPIC SAMPLING

An alternative method to sample stomach acid is to measure gastric pH aspirates during endoscopic procedures, or noninvasively by using a Smartpill analysis. Th e SmartPill GI Monitoring System is a new, in-offi ce method for assessing gastric motility. Th e wireless SmartPill capsule collects pH, pressure, and temperature data from throughout the entire gastrointestinal tract ( http:// www.smartpill.com ).

The Pancreas and Gallbladder

Pancreaticobiliary fl uid composition can be highly variable. Th e pancreas contributes to digestion by secreting alkaline bicarbonate and a variety of digestive enzymes. Secretion of pancreatic fl uid is controlled in part by vagus nerve stimulation. A more important regulatory mechanism of pancreatic secretion is the control exerted by the hormones secretin and cholecystokinin (CCK). Both are synthesized in the duodenum (upper small intestine) and secreted in response to the presence of acidifi ed chyme in the small intestine. Additionally, CCK stimulates the contraction of the gallbladder, causing the release of bile into the duodenum. Secretin stimulates the fl ow of bicarbonate-rich pancreatic fl uid that serves to raise the pH of normal chyme from below 4 to above 7, allowing trypsin and other pancreatic digestive enzymes to reach their maximal activities. Alternative Laboratory Testing for Gastrointestinal Disease 57

FECAL CHYMOTRYPSIN TEST

Th e fecal chymotrypsin test is a useful noninvasive test to determine chronic pancreatic insuffi ciency (Henry & Steinberg, 1993 ). False positive results of up to 10% have been reported in normal individuals. Greater reliability for diagnosing chronic pancreatitis can be obtained by performing the fecal chymotrypsin test in combination with the bentiromide (N-benzoyl-L-tyrosyl-p-aminobenzoic acid) test (Kataoka et al., 1997 ). Th e bentiromide test measures the amount of p-aminobenzoic acid (PABA) appearing in urine following an oral bentiromide loading, indicating successful chymotrypsin cleavage at the tyrosyl peptide bond. PABA excretion rates are lower in patients with compromised pancreatic function than in healthy control subjects (Gagee et al., 1 9 9 2 ) .

FECAL PANCREATIC ELASTASE

A newer alternative or companion test to the fecal chymotrypsin assay is fecal pancreatic elastase. Human pancreatic elastase, a member of the acidic elastase family, was fi rst detected by Sziegoleit as a new endoprotease and sterol-binding protein present in both human pancreatic secretions and feces (Chey, 1999 ; David-Henriau et al., 2005 ; Domínguez-Muñoz et al., 1995 ; Stein et al., 1996 ; Sziegoleit, 1984 ; Sziegoleit et al., 1989 ; Sziegoleit & Linder, 1991 ). Elastase, unlike chymotrypsin, has been found to remain unaff ected during intestinal transit, and to be stable in stool samples for up to a week at room temperature (Chey, 1999 ; Sziegoleit et al., 1989 ; Sziegoleit & Linder, 1991 ). Elastase cannot be detected in bovine or porcine pancreatic enzyme preparations. Th erefore, unlike chymotrypsin, it is not aff ected by oral pancreatic enzyme replacement therapy (Chey, 1999 ; see Figure 5.1 ).

FECAL FAT

Steatorrhea, defi ned as the presence of excess fat in the stool, is established by fat-balance studies (Kalivianakis et al., 2000 ). Normal fecal excretion of fat is less than 6 g/d. However, this test does not distinguish between fat maldigestion and fat malabsorption. Instead, tests for fecal triglycerides and long-chain free fatty acids can help diff erentiate between the two disorders. 58 INTEGRATIVE GASTROENTEROLOGY

FECAL FIBERS

Microscopic inspection of stool can reveal the presence of meat and vegetable fi bers. Th e increase in the amount of these fi bers that occurs with impaired digestion is an indirect indicator of hypochlorhydria or insuffi cient output of pancreatic enzymes (Lankisch, 1982 ; Moore et al., 1971 ).

Small Intestine

INTESTINAL HYPERPERMEABILITY

Patients with intestinal hyperpermeability have more than the normal 2 % “leakiness” to large molecules. Degradation of the physical barrier oft en is due to exposure to toxic substances within the intestinal lumen that can damage the “tight junctions” between intestinal epithelial cells, leading to an increase in passive paracellular absorption (Fink, 1990 ; Galland, 1996 ).Common causes of intestinal hyperpermeability are ethanol consumption (Anonymous, 1985 ), nonsteroidal anti-infl ammatory drugs (NSAIDs), and viral, bacterial, yeast, and protozoan infection (Batt et al., 1992 ; Riordan et al., 1997 ; Pignata et al., 1990 ; Serrander, Magnusson, & Sundqvist, 1984 ). Also, elevated levels of reactive oxygen species coming from a variety of sources, such as bile, food, cytotoxic drugs (Lifschitz & Mahoney, 1989 ), or infl ammatory cells (Grisham et al., 1990 ; Sundstrom et al., 1998 ), can increase paracellular permeability. Intestinal hyperpermeability is found in all chronic infl ammatory bowel diseases, where it may play an etiologic role, or it may be a secondary consequence due to the vicious cycle involving immune activation, hepatic dysfunction, and pancreatic insuffi ciency (Galland, 1995 ). Th e role of intestinal hyperpermeability in many diseases is oft en missed. Th e availability of noninvasive and aff ordable methods for measuring intestinal hyperpermeability makes it possible for clinicians to diagnose this condition in their patients, and to objectively assess the effi cacy of treatment.

LACTULOSE-MANNITOL INTESTINAL PERMEABILITY CHALLENGE TEST

Th e lactulose-mannitol protocol was developed to measure intestinal hyperpermeability for a wide range of conditions (Andre, 1986 ), including food sensitivities (Ventura et al., 2006 ), pancreatitis (Nagpal et al., 2006 ), Crohn’s Alternative Laboratory Testing for Gastrointestinal Disease 59

Table 5.2. The Four “R” Program for Intestinal Health

“R” Object Ampliﬁ cation

R e m o v e M i c r o b i a l Use bacteriostatic or mycostatic agents of suffi cient overgrowth strength to reduce excessive growth rates

Replace Digestive Support insuffi cient digestive secretory factors with factors oral replacements

Reinoculate Favorable Employ oral dosing of viable organisms known to microbes help control toxin-producing specie

Repair Tissue and Support the growth of healthy intestinal mucosal immune cells, goblet cells and immune cell responses with integrity key nutrients disease (D’Inca et al., 2006 ), and cirrhosis (Table 5.2 ). Lactulose-mannitol is a challenge test in which patients with suspected hyperpermeability ingest the metabolically inert sugars lactulose and mannitol. Mannitol, a monosaccha- ride, is passively absorbed through the intestinal mucosa. In contrast, lactulose, a disaccharide, is normally not absorbed unless the mucosal barrier is compromised. Since these sugars are not metabolized, any absorbed sugar is fully excreted in the urine within 6 hours. Th e urine is collected, and concentrations of the two sugars are measured. Percent absorptions are calculated using the following formula: % compound absorption = compound concentration (mg/ml) × × urrine volume (mL) 100

Lactulose-Mannitol Testing Protocol • Swallow a solution of 5 g mannitol and 5 g lactulose • Collect urine for 6 hours • AAssay for total lactulose and mannitol Calculate recoveriess < 14% Mannitol = Carbohydrate malabsorption > 1% Lactulosee = Disaccharide hyperpermeability

In the healthy intestine, the mean absorption of mannitol is 14% of the administered dose, whereas the mean absorption of lactulose is less than 1 % . Th e normal ratio of lactulose-mannitol recovered in urine is < 0.03. An elevated ratio indicates intestinal hyperpermeability. It is best to have the patient perform the lactulose-mannitol test twice — fi rst in the fasting state, then again 60 INTEGRATIVE GASTROENTEROLOGY aft er ingestion of a test meal (Andre et al., 1987 ). Th e lactulose-mannitol ratio was found to be an accurate predictor of relapse when measured in patients with Crohn’s disease who were clinically in remission (Wyatt et al., 1993 ). Recent intake of high carbohydrate meals and prolonged administration of the challenge solutions diminish responses to this test.

Mucosal Inﬂ ammation

GLUTEN SENSITIVE ENTEROPATHIES

Inherited factors make some individuals sensitive to a protein called gliadin , present in some cereal grains. Gliadin is a part of the total protein, or gluten, in the grains. When undigested gluten reaches the small intestine, gliadin peptides activate autoimmune reactions in susceptible individuals. As many as one in 133 Americans with no previous symptoms or family history of celiac disease may be aff ected (Fasano et al., 2003 ). For more information on celiac disease, including testing, see Chapter 40.

POLYMORPHONUCLEAR NEUTROPHIL DISORDERS

Human lactoferrin (Lf), an iron-binding glycoprotein secreted by mucosal membranes, is a major granular component of polymorphonuclear neutrophils. When these cells respond to infl ammatory signals, lactoferrin is released as part of the defense mechanism. Fecal Lf is a marker of intestinal infl ammation in which leukocytes infi ltrate the mucosa, increasing the release of neutrophil lactoferrin. Fecal Lf has been extensively used to diff erentiate infl ammatory bowel disease from irritable bowel syndrome (IBS) and noninfl ammatory bacterial infections, and it is useful for monitoring IBD treatment effi cacy (D’Inca et al., 2006 ; Logsdon &, Mecsas, 2006 ; Larsen et al., 2004 ; Buderus et al., 2004 ; Kane et al., 2003 ; Bard et al., 2003 ; Greenberg et al., 2002 ; Vaishnavi, Bhasin, & Singh, 2000 ; Saitoh et al., 2000 ). Various other neutrophil-derived proteins, such as calprotectin (Cal), poly- α morphonuclear neutrophil-elastase (PMN-e), 1 -antitrypsin, and lysozyme (Lys) have been shown to be reliable indicators of intestinal infl ammation, and can aid in the diff erentiation of organic intestinal disorders (i.e., infl ammatory bowel diseases (IBD), ulcerative colitis (UC), Crohn’s disease, infectious gastroenteritis, etc.) from functional intestinal disorders (i.e., IBS; see Larsen et al., 2004 ; Buderus et al., 2004 ; Kane et al., 2003 ; Bard et al., 2003 ; Gaya et al., 2005 ; Gearry et al., 2005 ; Langhorst et al., 2005 ; Liu et al., 2005 ; Alternative Laboratory Testing for Gastrointestinal Disease 61

Lundberg et al., 2005 ; Silberer et al., 2005 ; Tibble & Bjarnason, 2001 ; van der Sluys Veer A et al., 1999 ).Fecal levels of these proteins rapidly increase with the infl ux of leukocytes into the intestinal lumen during infl ammation. Among the neutrophil-derived proteins in feces, PMN-e, Cal and Lf represent the most accurate markers of disease activity and severity in patients with ulcerative colitis, with lysozyme being somewhat less useful (Langhorst et al., 2005 ; Liu et al., 2005 ).

Secretory IgA Test

Secretory IgA status may be evaluated by measurement of salivary or fecal secretory immunoglobulin A (sIgA) levels (Nagao et al., 1995 ). Salivary sIgA is a predictor of the release of sIgA at intestinal surfaces (Externest et al., 2000 ). A compromised immune barrier can lead to elevated serum IgA. Fecal sIgA correlates with salivary sIgA, and both may be predictors of partial mucosal sIgA defi ciency as defi ned by serum IgA > 0.05 g/l (Nagao et al., 1994 ). Many studies on the eff ects of extreme physical and/or emotional stress in test populations, such as military personnel in basic training and competitive endurance athletes, have demonstrated that levels of sIgA become depressed following such levels of stress, whereas cortisol levels increase (Brenner et al., 2000 ; Filaire, Bonis, & Lac, 2004 ; Gomez-Merino et al., 2003 ; McDowell et al., 1992; Nieman et al., 2002 ). Stress plays an important role in the compromise of the gastrointestinal mucosal immune response and the development of pan- allergy to foods and, potentially, the development of autoimmune phenomena via antigen–antibody complex cross-reactivity and molecular mimicry. Combining salivary sIgA with evaluation of cortisol and 5-dehydroepiandrosterone (DHEA) may be benefi cial in the overall assessment of the stress response and the management of gut hyperpermeability, food allergy, infl ammatory arthritides, immunogenic thyroiditis, autoimmunity, and other chronic diseases (Ansaldi et al., 2003 ; Gladman, 1991 ; Marker-Hermann & Schwab, 2000 ; Martinez-Gonzalez et al., 1994 ; Mielants, 1990 ; Petru et al., 1987 ; Pishak, 1999 ; Stebbings et al., 2002 ; Takuno, Sakata, & Miura, 1990 ; Tiwana et al., 1998 ; Tomer & Davies, 1993 ).

Microbial Population Assessment

Th e intestinal fl ora is a complex ecosystem consisting of over 400 bacterial species that greatly outnumber the total number of cells making up the entire human body (Finegold, Attebery, & Sutter, 1974 ). Th ese metabolically active 62 INTEGRATIVE GASTROENTEROLOGY bacteria reside close to the absorptive mucosal surface, and are capable of a remarkable repertoire of transforming chemical reactions. Any orally taken compound, or a compound entering the intestine through the biliary tract or by secretion directly into the lumen, is a potential substrate for bacterial transformation.

Anaerobic bacteria are the predominant microorganisms in the human GI tract, outnumbering aerobes by a factor of 10,000 to 1.

In health, the upper GI tract is sparsely populated with microorganisms. Th e vast majority of bacteria washed along with saliva from the oral cavity are destroyed in the stomach by gastric juice. Th e small intestine constitutes a zone of transition between the sparsely populated stomach and the luxuriant bacterial fl ora of the colon. In the distal ileum, the concentrations of bacteria increase to 10 6 –107 colony-forming units per milliliter (Fuller & Perdigón, 2003 ). Here, Gram-negative bacteria outnumber the Gram-positive species. Beyond the ileocecal valve, the bacterial concentration increases steeply. Colonic bacteria number between 10 11 and 1012 colony-forming units per milliliter of fecal material. Multiple dramatic shift s in populations of species occur between the ileocecal valve and the rectum. By the time they are passed from the body in stools, the large majority of the bacteria are no longer viable.

OPPORTUNISTIC OVERGROWTH AND DISEASE

Overgrowth of any one of the more than 400 microbial species in the healthy human gut can produce adverse clinical eff ects. Excessive colonization of the gut by undesirable microorganisms alters the metabolic or immunologic status of the host (Van Eldere et al., 1988 ; Rogers et al., 2006 ).When this state leads to disease or dysfunction, it has been termed dysbiosis to distinguish it from the correct balance denoted as orthobiosis (Galland & Barrie, 1993 ). Th e line between benign opportunistic overgrowth and infectious diseases is diffi cult to defi ne because apparently benign, small numbers of colony-forming units may be detected for pathogens such as enterohemorrhagic Escherichia coli .

THE TRANSITIONAL GUT

Th e microbial mass increases from levels around 1 × 105 to counts as high as 1 × 1011 in the region roughly encompassing the mid-ileum to the transverse colon. Alternative Laboratory Testing for Gastrointestinal Disease 63

Th is 6-orders-of-magnitude increase represents a fantastically high rate of new cell formation, with associated intense metabolic activity where metabolic products are formed. Th us, it is from this mid- or transitional gut that most of the microbial products found in breath or urine are chiefl y derived.

Breath Hydrogen and Methane Test

Th is test off ers reasonable sensitivity, and it is very convenient to administer, although it will sometimes give false negative results. For greater predictive value, it is best to also obtain a baseline breath sample from the patient before consumption of the challenge solution. Th e fasting patient drinks a challenge dose of lactulose (10 g) or glucose (75 g) solution. Breath samples should be collected every 15 minutes for up to 3 hours. If bacteria exist in the small intestine, they will ferment the sugar and release hydrogen and methane, which can be detected in the breath. Th e typical fasting breath sample contains less than 10 ppm hydrogen or methane; levels higher than 20 ppm indicate a high probability of bacterial overgrowth. Following a lactulose or glucose challenge, a two-phase response may be seen. Th e fi rst rise in breath hydrogen generally occurs within 30 to 60 minutes, when lactulose contacts the small intestine — the rise may be delayed beyond 60 minutes in those having gastroparesis and small intestinal transit. A second, more pronounced rise occurs about 2–3 hours later, when the sugar enters the large intestine. A rapid and prolonged fi rst-phase response is frequently due to small intestine bacterial overgrowth (Rhodes, Middleton, & Jewell, 1979 ). Interpretation of results is complicated by the large number of false positive fi ndings, as compared with results obtained from bacterial cultures of intestinal lumen aspirates (Corazza et al., 1990 ; Riordan et al., 1996 ).Combining the fi ndings of elevated fasting breath hydrogen (> 20 ppm), and raising the limit for the post-lactulose challenge increase in breath hydrogen and methane to greater than 20 ppm, will reduce the chance of false positive responses (Hamilton, 1992 ).

URINARY MARKERS OF BACTERIAL OVERGROWTH

Urinary Indican

Bacteria in the upper bowel produce the enzymes that catalyze the conversion of tryptophan to indole (Figure 5.2 ). Absorbed indole is converted in the liver to indoxyl, which is then sulfated to allow urinary excretion as indoxyl sulfate (indican). 64 INTEGRATIVE GASTROENTEROLOGY

Oral, unabsorbed antibiotics reduce indican excretion. Indican excretion is also reduced when the gut is populated with strains of Lactobacillus at levels above 105 organisms/g (Tohyama et al., 1981 ). Probiotics have been shown to decrease indican levels (Yoshida & Hirayama, 1984). Th e urine indican test may be performed aft er oral loading of 5 g tryptophan (Smith, 1982 ). Reference limits may also be set from data taken under nonloading conditions. Tryptophan loading, which can be monitored by measuring periodic levels of urinary indican, results in neuropsychiatric manifestations due to products of intestinal bacterial conversion of the amino acid (Yoshida & Hirayama, 1984 ). When elevations of phenol and p-cresol are included with that of indican as criteria of abnormal bacterial colonization of the small intestine, the number of false positives is reduced (Aarbakke & S c h j o n s b y , 1 9 7 6 ) .

Urinary Phenolic Compounds

Dietary polyphenolics are the principal substrates from which products of transitional gut bacterial metabolism are formed. In addition to the use of polyphenol compounds, intestinal bacteria that contain l -amino acid decarboxylase enzymes degrade tyrosine to tyramine. Th e tyramine is then deaminated and oxidized to p-hydroxyphenylacetate. Th is product is excreted unchanged and unconjugated in urine. It was used to identify small bowel disease and bacterial overgrowth syndromes in 360 randomly selected, acutely ill infants and children. In this study, no false negative and only 2% false positive results were found (Chalmers, Valman, & Liberman, 1979 ). Treatment with metronidazole or mepacrine has been shown to eliminate the p-hydroxyphenylacetic aciduria. Although p-hydroxyphenylacetate can be produced in the liver, abnormally high levels in urine are of bacterial origin.

Urinary D-Lactate

Another product of bacterial fermentation of sugar is d -lactic acid. d -lactic acidosis is usually a complication of short-bowel syndrome, or of jejunoileal bypass surgery (colonic bacteria being the source of acidosis). Elevated d - lactic acid can be found in cases of overpopulation of the small intestine with L. acidophilus, as a result of low endogenous stomach acid production or the chronic use of acid-reducing medications accompanied by ingestion of large quantities of dietary carbohydrate (Uribarri, Oh, & Carroll, 1998 ). Alternative Laboratory Testing for Gastrointestinal Disease 65

URINARY MARKERS OF YEAST OVERGROWTH

D-Arabinitol

d -Arabinitol (DA) is a metabolite of most pathogenic Candida species, in vitro as well as in vivo. DA is a fi ve-carbon sugar alcohol that can be assayed by enzymatic analysis. Immunocompromised patients with invasive candidiasis have elevated d -arabinitol/creatinine ratios in urine. Positive DA results have been obtained several days to weeks before positive blood cultures, and the normalization of DA levels has been correlated with therapeutic response in both humans and animals (Roboz, 1994 ; Christensson, Sigmundsdottir, & Larsson, 1999 ). Measuring serum DA allows prompt diagnosis of invasive candidiasis (Christensson, Sigmundsdottir, & Larsson, 1999 ; Tokunaga et al., 1992 ).

The Colon: Assessing Microbes in Stool

Th e population of the microbiota of the human GI tract is widely diverse and complex, with a high population density. All major groups of microorganisms are represented. Although they are predominately bacteria, a variety of protozoa are also present. In the colon there are over 1011 bacterial cells per gram, and over 400 diff erent species. Th ese bacterial cells outnumber host cells by at least a factor of 10 (Rowland, 1995 ). Th is microbial population has important infl uences on host physiological, nutritional, and immunological processes. In fact, this biomass should more rightly be considered a rapidly adapting, renewable organ, with considerable metabolic activity and signifi cant infl uence on human health. Consequently, there is renewed and growing interest in identifying the types and activities of these gut microbes (Mackie, Sghir, & Gaskins, 1999 ). Th e normal, healthy balance in microbiota provides colonization resistance to pathogens. Since anaerobes comprise over 95 % of these organisms, their analysis is of prime importance. Gut microbes might also stimulate immune responses to prevent conditions such as intestinal dysbiosis. Intestinal dysbiosis may be defi ned as a state of disordered microbial ecology that causes disease (Tamboli et al., 2004 ). Specifi cally, the concept of dysbiosis rests on the assumption that patterns of intestinal fl ora— specifi cally, overgrowth of some microorganisms found commonly in intestinal fl ora— have an impact on human health. Symptoms and conditions thought to be caused or complicated 66 INTEGRATIVE GASTROENTEROLOGY by dysbiosis include infl ammatory bowel diseases, infl ammatory or autoimmune disorders, food allergy, atopic eczema, unexplained fatigue, arthritis, mental/emotional disorders in children and adults, malnutrition, and breast and colon cancer (Galland & Barrie, 1993 ; Hawrelak & Myers, 2004 ).

DIFFICULTIES IN ASSESSING INTESTINAL MICROBIOTA

Most studies of microbiota in the GI tract have used fecal samples. Th ese do not necessarily represent the populations along the entire GI tract from stomach to rectum. Conditions and species can alter greatly along this tract, and generally run from lower to higher population densities. Th e stomach and proximal small intestine, with highly acid conditions and rapid fl ow, contain 103 to 105 bacteria per gram or milliliter of content. Th ese are predominated by acid-tolerant lactobacilli and streptococci bacteria. Th e distal small intestine to the ileocecal valve usually reaches to 10 8 bacteria per gram or milliliter of content. Th e large intestine generates the highest growth, due to longer residence time, and ranges from 1010 to 1011 bacteria per gram or milliliter of content. Th is region generates a low redox potential, and high amount of short-chain fatty acids. Not only does the microbiota content change throughout the length of the GI tract, but there are also diff erent microenvironments where these organisms can grow. At least four microhabitats exist: the intestinal lumen, the unstirred mucus layer that covers the epithelium, the deeper mucus layer in the crypts between villi, and the glycocalyx of the epithelial cells (Savage, 1977 ). Given this diverse ecological community, the question arises as to how to sample the various environments to identify populations of microbes, and ultimately understand the host–microbe interactions. Th is problem is an extremely diffi cult one, since any intervention to obtain a sample potentially disrupts the population. Fecal sampling has been used for years in microbiota assessment. But it should be understood that this sample most appropriately represents organisms growing in the lumen of the colon. In addition, > 98% of fecal bacteria will not grow in oxygen (Savage, 1977 ). Th erefore, standard culture techniques miss the majority of organisms present.

CONVENTIONAL TECHNIQUES VERSUS NEW TECHNOLOGIES

Conventional Techniques

Conventional bacteriological methods such as microscopy, culture, and identifi cation are used for the analysis and/or quantifi cation of the intestinal Alternative Laboratory Testing for Gastrointestinal Disease 67 microbiota (O’Sullivan, 1999 ; Tannock, 1999 ; Finegold & Rolfe, 1983 ). Limitations of conventional methods are their low sensitivities (Dutta et al., 2001), their inability to detect noncultivatable bacteria and unknown species, their time-consuming aspects, and their low levels of reproducibility due to the multitude of species to be identifi ed and quantifi ed. In addition, the large diff erences in growth rates and growth requirements of the diff erent species present in the human gut indicate that quantifi cation by culture is bound to be inaccurate. To overcome the problems of culture, techniques based on 16S ribosomal DNA (rDNA) genes were developed (Amann, Ludwig, & Schleifer, 1995 ; Wilson & Blitchington, 1996 ).Th ese include fl uorescent in situ hybridization (Franks et al., 1998 ; Jansen et al., 2000 ; Langendijk et al., 1995 ; Muyzer & Smalla, 1998 ; Welling et al., 1997 ), denaturing gradient gel electrophoresis (Suau et al., 1999 ; Simpson et al., 1999 ), and temperature gradient gel electrophoresis (Zoetendal, Akkermans, & De Vos, 1998 ). Th ese techniques have high sensitivities, but they are laborious and technically demanding. Another problematic issue with present stool analysis procedures is that of transport. Since analysis is culture dependent, sample collection must be done using nutrient broth containers to maintain microbial viability. Th is allows continued growth of species during transport and until the sample is actually plated out for culture. Th is growth allows for a signifi cant change in the balance of microbes present, since some species will more actively grow at the expense of others, especially in the presence of oxygen.

New Technologies

DNA analysis eliminates this problem by placing the specimen in vials which contain a fi xative for transport. Th is technique will be discussed in more detail in the next Chapter.

Microbial Metabolic Markers from Stool Testing

FECAL β -GLUCURONIDASE

Bacterial β -glucuronidase is an enzyme that can eff ectively reverse detoxifi cation that has taken place in the liver during the Phase II conjugation reactions. Bacterial fl ora may express large amounts of glycosidase enzyme activity, the principal glycosidase being β -glucuronidase. A report showing high levels of β-glucuronidase calls attention to the need to restore benefi cial bacterial populations, and to the potential for greater enterohepatic circulation that can aff ect metabolites such as estrogen. 68 INTEGRATIVE GASTROENTEROLOGY

Glycosides are compounds containing a nonsugar molecule (aglycone) attached to a sugar derivative, such as glucuronic acid, by α - or β-glycoside linkage. Glycosides enter the GI tract through dietary intake, or from the liver through bile secretions. Most dietary glycosides, predominately fl avonoids, come from vegetables and fruits. Glycosides coming from the liver include toxic compounds that are inactivated by β -glucuronide formation and subsequently secreted into the bowel by way of the bile. Th e intestinal fl ora can hydrolyze the β -glucuronide bond, leading to release of the toxic compound, which may be carcinogenic.

FECAL pH

Th e colonic microbial mass converts food components into organic acids and amines according to the nature of the substrate passing into the colon, and the type of organisms that predominate. A high rate of organic acid production gives acidic stools, whereas low acid formation with increased amines results in higher pH of stool. One of the most important colonic health practices is regular intake of high-fi ber foods, so that benefi cial organisms in the colon receive substrate for the production of favorable products such as butyric acid. Direct measurement of fecal pH provides an overall indicator of acid and base balance. Abnormally acidic or alkaline pH of the stool may be an indicator of poor digestive health. Th ere is increasing evidence that fecal pH can serve as a marker for colon cancer (Malhotra, 1982 ; Kashtan et al., 1990 ; Walker, Walker, & Walker, 1986 ; Newmark & Lupton, 1990 ).High fecal pH, however, is only indirectly associated with the development of colon cancer and, therefore, is a secondary, rather than a primary, measure of cancer risk (Kashtan et al., 1990 ). High stool pH appears to correlate with low levels of short-chain fatty acids (especially butyric acid; see (Zoran et al., 1997 ; Segal et al., 1995 ; Phillips et al., 1995 ; Folino, McIntyre, & Young, 1995 ). Alkalinity and low butyric acid levels in the stool appear to signal inadequate intake or digestion of fi ber and, possibly, low levels of benefi cial colonic fl ora. Various patterns of simultaneous elevation of multiple bacterial and protozoal by-products in urine are found in putrefactive dysbiosis that is also characterized by lowered ratio of Bifi dobacteria to Bacteroides, the major genera of the anaerobic organisms. Fecal pH may be elevated, and β -glucuronidase increases. Th is scenario has been linked to increased occurrence of colon and breast cancer (possibly due to deconjugation of estrogen-glucuronide complexes) and hepatic encephalopathy (Rowland, 1995 ). Alternative Laboratory Testing for Gastrointestinal Disease 69

FECAL SHORT-CHAIN FATTY ACIDS (SCFAs)

Frequently, disorders of the GI tract are associated with intestinal malabsorption. Many tests are useful in the diagnosis of GI disorders but do not eff ectively diff erentiate abnormalities of absorption (mucosal function) from digestion (pancreatic function). Th e fecal short-chain fatty acid test can be helpful in making a diff erential diagnosis. Short-chain fatty acids (SCFAs) are formed from bacterial fermentation of dietary carbohydrates and amino acids that escape absorption in the small bowel. An alteration in the proportion of various SCFAs, which stay constant in healthy colons, signifi es an impaired state of colonic health (Hoverstad, 1988 ). Short-chain fatty acids are well absorbed by the colon, and are a signifi cant source of energy for colonic cells. High acetic acid and low butyric acid in relation to total SCFAs in the feces are found in patients with large bowel adenomas and cancer (Latella & Caprilli, 1991 ). Th e fecal content of n -butyrate — formed by the bacterial fermentation of fi ber — is particularly critical for colonic health, since it is such an important source of energy for the epithelial cells of the colon (McCullough et al., 1998 ). Research suggests that inadequate amounts of colonic n -butyrate could be a primary factor in the etiology of infl ammatory bowel disease, ulcerative colitis, and colon cancer (Royall, Wolever, & Jeejeebhoy, 1990 ). Th e SCFA products of bacterial fermentation (or putrefaction), isobutyric, valeric and isovaleric acids, come principally from undigested protein (Rasmussen, Holtug, & Mortensen, 1988 ; Zarling & Ruchim, 1987 ).Th ese SCFAs are normally present at low concentrations in the healthy colon. However, maldigestion of protein due to pancreatic enzyme insuffi ciency can result in excess protein entering the colon. In these cases, fecal isobutyric acid, valeric acid, and isovaleric acid will be elevated. Th eir presence is more likely due to a pancreatic dysfunction, rather than an inadequacy of mucosal absorption.

FECAPENTAENES

Fecapentaenes are polyunsaturated ether lipids that are derived from human intestinal bacterial plasmalogens that have similar ether linkages (Van Tassell et al., 1989 ). Fecapentaenes cause DNA damage and mutations in human cells (Plummer et al., 1986 ; Gupta et al., 1984 ), and they are found in human feces, 70 INTEGRATIVE GASTROENTEROLOGY where they are thought to play a role in the initiation of colorectal cancer (Schiff man et al., 1989 ; Kingston, Van Tassell, & Wilkins, 1990 ).Th e structures of highly mutagenic fecapentaenes have been elucidated (Hirai et al., 1985 ), and methods for quantifi cation of eight specifi c fecapentaenes in human feces have been published (de Kok, ten Hoor, & Kleinjans, 1991 ; Kivits et al., 1990 ; Kleinjans et al., 1989 ). Some researchers have proposed that the widely varying ratios of two principal fecapentaenes can be traced to individual diff erences in intestinal fl ora (Baptista et al., 1984 ). Bacteroides have been identifi ed as the source of fecapentaenes in a human autopsy study (Schiff man et al., 1988 ). With the advent of more broad species identifi cation using 16S DNA identifi cation techniques, there is potential for identifying more closely the organisms in the general population with a capacity for fecapentaene p r o d u c t i o n .

Conclusions

Evaluation of gastrointestinal function includes detection of inadequate physical and immune barrier functions, and measures of the digestion and absorption of food. Pathogenic overgrowth of intestinal microbes in the upper gastrointestinal tract can be detected by measuring their unique products in urine. Th e patterns refl ect the type of organisms that are present within broad categories of bacteria, protozoa, or yeast. Th e information allows discrimination between putrefactive dysbiosis in the colon versus fermentative dysbiosis in the small intestine, or combinations of both. Th e number of compounds involved, and the degree of elevations found, change in direct proportion to the severity of pathogenic overgrowth and loss of mucosal integrity. Stool profi ling yields markers of digestive function and results in direct observation of microbial populations and can suggest specifi c antimicrobial therapies when necessary.

6 New Molecular Techniques Revolutionize Understanding of the Inﬂ uence of Gut Microbiota on Health and Disease

J. ALEXANDER BRALLEY

key concepts

■ Th e human GI tract contains a diverse and complex ecosystem of microbiota that can exert signifi cant infl uence on health. ■ New molecular techniques now allow exploration of this ecosystem. ■ Molecular techniques solve many of the problems of traditional culture-based microbiology. ■ Molecular techniques signifi cantly improve sensitivity and specifi city in parasitology and bacteriology of fecal samples. ■ Molecular techniques allow for better understanding of microbiota balance, which enhances treatment options and improves o u t c o m e s . ■

Introduction

acteria in the human gastrointestinal tract increase in concentration from stomach to rectum. Th ere are up to 1012 organisms per gram of B fecal material, of which approximately 95 % are anaerobic. Th e gut microbiota cell population outnumbers the host cells by a factor of 10. In fact, the gut microbiota may be looked upon as a metabolically and physiologically adaptable, rapidly renewable organ of the body, whose function is as critical to human health as any other vital organ.

71 72 INTEGRATIVE GASTROENTEROLOGY

While bacteria predominate, protozoa are commonly found. It has been estimated that more than 400 diff erent bacterial species are present (Macfarlane & . Macfarlane, 2 0 0 4 ) . Th is diverse population of bacteria can have a signifi - cant impact upon the host environment and health of the individual. Intestinal microbiota have been associated with the pathogenesis and pathophysiology of many diseases, including atopic dermatitis and allergies (Bjorksten et al., 2001 ; Penders, Stobberingh,van den Brandt, & Th ijs, 2007 ; Penders et al., 2007 ), chronic infl ammatory bowel diseases (Kleessen et al., 2002 ; Farrell &. LaMont, 2002 ; Linskens et al., 2001 ; Roediger & Macfarlane, 2002 ), ankylosing spondylitis (Blankenberg-Sprenkels et al., 1998 ; Tiwana et al., 1998 ; Stebbings et al., 2002 ), and rheumatoid arthritis (Wilson et al., 1998 ; Eerola et al., 1994 ; Peltonen et al., 1994 ). Th e positive clinical results of using probiotics (Isolauri, 2001 ) and prebiotics (Macfarlane, Steed, & Macfarlane, 2008 ) to control symptoms and improve health underline the critical role intestinal bacteria play in immune defense and general health. While the general makeup of the colonic bacteria population is similar in humans, there can be vast diff erences in the inter-individual balance on the genus and species levels. Ecological factors such as age, disease, diet, and antibiotic use can adversely aff ect this balance. Th ose factors that encourage ecological species diversity support structural stability and metabolic homeostasis in the population. Increased diversity has been associated with improved health, while decreased diversity has been linked to reduced ability to resist pathogens and infl ammatory bowel diseases. (Bartosch et al., 2004 ; Ott, Musfeldt, Wenderoth et al., 2004 ) Th e introduction of molecular techniques to assess this microbial population has revealed much about its structure and function. Th is vastly improves our ability to design therapies that manipulate gut ecology to optimize health. Molecular techniques provide various clinical benefi ts: an accurate measure of microbiota diversity; insight into genes for drug resistance; more sensitive parasite detection; identifi cation of species subtypes relating to potential pathogenicity; and information regarding microbial balance that infl uences energy metabolism, insulin resistance, and obesity. Th is chapter will briefl y review the molecular techniques used to identify and measure gut microbial population, and the clinical benefi ts that result from this quantum leap over culture techniques.

Techniques

Th e major advantage of molecular techniques is that they can quantitatively measure the entire range of microbiota present in the human gastrointestinal tract. New Molecular Techniques Revolutionize Understanding of the Inﬂ uence 73

Traditional culture methods cannot grow the vast majority of species present (Eckburg et al., 2005 ), as only 10% to 20 % of bacteria in a habitat are able to be cultured (Wilson & Blitchington, 1996 ; Nadkarni et al., 2002 ; Suau et al., 1999 ). Th ose that are cultured are usually quantifi ed using relative abundance scores such as + 1 to + 4 (Dutta et al., 2001 ; Tannock, 1999 ). In addition, the large differences in growth rates, growth requirements, and the interdependence of the diff erent species present in the human gut make quantifi cation by culture an inaccurate refl ection of the population. To overcome the problems of culture, genomic techniques for bacterial identifi cation have been developed (Wilson & Blitchington, 1996 ; Welling et al., 1997 ; Furrie, 2006 ). Th e circular bacterial genome possesses multiple copies of a gene that codes for the RNA contained in a ribosome. Th is ribosomal RNA gene or rDNA gene is made up of several regions referred to by their relative molecular weights. Th ese 16s, 5s and 23s segments are separated by internal transcribed spacer (ITS) regions (Figure 6.1 ). Th e rDNA genes have regions that are highly conserved, and are exactly the same in all bacterial species. Other regions are variable, and unique codon sequences for any bacteria can be identifi ed. Since these regions have now been fully sequenced for hundreds of bacteria, unique probes can be designed that select for and identify bacteria by genus or species, and even to the subtype level. By using unique primer sets binding to the variable regions of the 16s or 23s rDNA gene regions, single bacteria or groups of bacteria can be quantifi ed. With the use of general primers and universal probes, polymerase chain reaction (PCR), and hybridization array technology, large populations of bacteria can be defi ned and quantifi ed in a complex sample such as fecal material (Figure 6.2 ; see Lyons, Griff en, & Leys , 2000 ; Ott, Musfeldt, Ullmann, Hampe, & Schreiber, 2004 ).

Specimen Integrity and Transport Issues

Th e extremely complex fecal microbiota ecosystem relies on anaerobic conditions, pH, adequate nutrients, and temperature, for stability. Consequently, it has been long recognized that a sample in transit can undergo signifi cant changes in microbial balance (Ott, Musfeldt, Timmis et al., 2004 ). Since traditional analysis is culture dependent, sample collection requires nutrient broth containers to maintain microbial viability. Th is allows continued growth of species during transport, and until the sample is plated out for culture. Th is growth results in a signifi cant change in the balance of microbes present, because some species grow more actively at the expense of others. DNA analysis eliminates this problem by placing the specimen in formalin or alcohol vials for transport. 74 INTEGRATIVE GASTROENTEROLOGY

Recent studies in our laboratory illustrate this situation. One specimen was placed in two vials: one containing formalin, and another containing a nutrient broth commonly used for transport. Both vials were incubated for three days at room temperature, then DNA was extracted. Th e extract was incubated with three diff erent restriction enzymes, which cleave the DNA at specifi c base pair sequences (Figure 6.3 ). Th e digestate was amplifi ed by PCR, then placed on an agarose gel plate and the DNA fragments were electrophoretically separated. Since restriction enzymes cleave the DNA only at specifi c base pair sequences, broths with identical populations of microbes would produce the same patterns of banding in the electrophoretic runs. If, however, there were diff erent amounts and types of microbiota in the two tubes, diff erences would appear in the banding patterns. Th is was clearly demonstrated in the experiment (Figure 6.4 ). Another observation from the data is the loss of banding in the nutrient broth vial over time, indicating overgrowth of aerobes at the expense of the anaerobic populations, and consequent loss of diversity. Opportunistic, potentially pathogenic organisms also can overgrow under these conditions. Th is has been seen in our laboratory. For these reasons, nutrient broth transport vials cannot provide the specimen integrity required for accurate measurement of gut microbes.

Clinical laboratory data relying on transport of the specimen to the laboratory for culture are likely erroneous and can lead to inappropriate patient treatment.

Figures 6.5 through 6.7 illustrate the growth response of Bifi dobacteria, Candida species and Staphylococcus aureaus in one subject over three days. Th ese results indicate that clinical laboratory data relying on transport of the specimen to the laboratory for culture are likely erroneous, and can lead to inappropriate patient treatment. Candida species overgrowth is particularly notable. As these data indicate, Candida proliferates in nutrient broth transport media. Th is overgrowth in transport has likely fueled the common belief held by many practitioners, of the deleterious health eff ects of Candida albicans overgrowth in the gut. Th is may have resulted in inappropriate prescription of antifungal agents.

Drug Resistance Genes

All antibiotic resistance strategies that bacteria develop are encoded in one or more genes. Drug resistance genes are readily shared among and across New Molecular Techniques Revolutionize Understanding of the Inﬂ uence 75

species and genera, and even among distantly related bacteria. Th ese genes confer resistance to diff erent classes of drugs, and their sequences are known. Using PCR techniques, they can be readily detected in large populations like those found in fecal material. When considering treatment of a patient for a pathogen, it is important for the clinician to know if a drug resistance gene is present. If a pathogen is detected in stool, an analysis of the presence of antibiotic resistance genes and drug sensitivities can be performed. If the pathogen is found to be sensitive to two antibiotics, for example, but a gene that is resistant to one of the drugs is present in the sample (a very possible scenario), it is imperative that this drug not be used to treat the patient. Otherwise, even though the pathogen is killed, the other organisms that have the gene confer- ring resistance to the drug would thrive relative to other microbes present. Th is sets up a potentially dangerous situation where antibiotic resistance is maintained in the population, because that gene can be readily spread to other organisms in the individual and the environment (Bergeron & Ouellette , 1998 ; Martineau, Picard, Grenier et al., 2000 ; Martineau, Picard, Lansac et al., 2000 ). Knowledge of the presence of antibiotic resistance genes in fecal specimens represents a signifi cant advance in patient treatment and maintenance of health.

Parasitology

Parasitology is another fi eld of microbiology to benefi t greatly from molecular technologies. Parasite infections are a major cause of nonviral diarrhea, even in developed countries. Classically, parasites have been identifi ed by microscopy and enzyme immunoassays (Verweij et al., 2004 ). In recent studies, molecular techniques have proven to be more sensitive and specifi c than classic laboratory methods (Verweij et al; Ghosh et al., 2000 ; Morgan et al., 1998 ). Because Giardia cysts are shed sporadically, and the number may vary from day to day, laboratories have adopted multiple stool collections to help increase identifi cation rates for all parasite examinations (Ghosh et al.). Even with the advent of antigen detection systems, there has long been uncertainty in diagnosis when no ova or parasites are found. Due to the nearly 100 % sensitivity and specifi city of DNA analysis, combined with the need for very low amounts of genomic DNA (as low as 2.5 cells per gram (Ghosh et al.), the previously long specimen collection process, laborious and technically challenging microscopy, and resulting delays in reporting have been alleviated. With PCR technology, only one fecal sample is needed for near 100 % sensitivity and specifi city in parasitology examinations. 76 INTEGRATIVE GASTROENTEROLOGY

Blastocystis hominis subtypes have been associated with relative pathogenicity in humans (Hussein et al., 2008 ). Diff erentiation among pathogenic subtype populations in humans cannot be done using culture based techniques, and is a unique contribution only possible through PCR technology.

Gut Microbiota Inﬂ uences on Insulin Resistance and Obesity

Two predominant bacterial groups in the human GI tract are Bacteroidetes and Firmicutes. Th ese gut microbiota signifi cantly aff ect energy harvest from the diet, and energy storage in the host. Firmicutes bacteria, which include Bacillus , Clostridia , and Lactobacillus species, are very effi cient at metabolizing plant polysaccharides into monosaccharides and short-chain fatty acids. Th ese can then be absorbed by the gut and converted to more complex lipids in the liver. In addition, this group secretes a compound that results in increased activity of lipoprotein lipase in adipocytes, resulting in enhanced storage of these lipids. Th e Bacteroidetes group, which includes Bacteroides and Provetella species, are not as effi cient in this function. While excess caloric intake is a signifi cant factor in obesity, gut populations of microbiota that force an effi - cient extraction and storage of energy may play a signifi cant role in this growing health problem.

The ability to assess the balance of “fat bugs” in humans may prove to be an important advance in understanding and treating diabetes and obesity.

Recent studies have demonstrated another aspect of this intriguing story. Manipulation of the gut microbiota in mice signifi cantly alters their glucose/ insulin response (Membrez et al., 2008 ). Th e balance of bacterial populations can actually increase levels of a bacterial lipopolysaccharide endotoxin that dysregulates the infl ammatory tone, and triggers body weight gain and diabetes in mice (Cani et al., 2007 ). Th ese studies demonstrate the possibility in humans that modulation of gut microbiota can ameliorate glucose tolerance by altering the expression of hepatic and intestinal genes involved in infl ammation and metabolism, and change the hormonal, infl ammatory, and metabolic status of the host. Th e ability to recognize this aspect of microbiota eff ects in human health has only become available through the use of molecular techniques. New Molecular Techniques Revolutionize Understanding of the Inﬂ uence 77

Ongoing studies are exploring the relationship between gut microbiota and metabolic diseases. Th e use of specifi c diets and prebiotic and probiotic therapies may signifi cantly alter microbial balances that aff ect fat storage. Th e ability to assess the balance of these “fat bugs” in humans may prove to be an important advance in understanding and treating diabetes and obesity.

Ecosystem Diversity and Dysbiosis

Biodiversity in the gut microbiota ecosystem can now be elucidated by molecular techniques. Since traditional clinical microbiological aerobic culture procedures were only able to evaluate less than 5% of organisms present, clinicians were unable to truly assess diversity, or a “dysbiosis” condition commonly associated with ill health (Hawrelak & Myers , 2 0 0 4 ) . Th e term dysbiosis was coined to describe an imbalance in the gut microbiota caused by parasitic infection, antibiotic use, or other factors. Th is dysbiotic condition can contribute to the development of many chronic degenerative diseases. By using molecular techniques, one can examine the major fecal anaerobic genera in comparison to aerobic and fungal organisms, providing a much clearer picture of the diversity and potential dysbiotic structure of the ecosystem. By quantifying all of the major groups of microbiota and potential parasites present in the gut, the concept of dysbiosis can now be much better defi ned in terms of ecosystem diversity. Th is concept will be useful for clinicians as they assess how the gut microbiota infl uence disease processes, and how they might intervene. For example, lack of diversity has been associated with infl ammatory bowel diseases (Ott, Musfeldt, Wenderoth et al., 2004 ). Probiotics and prebiotics infl uence diversity and, therefore, may signifi cantly impact these diseases (Steed, Macfarlane, & Macfarlane, 2008 ). Recent research is showing that specifi c groups of bacteria can be preferentially stimulated to grow relative to other populations. Individually tailored prebiotic compounds may potentially be designed to selectively enhance bowel function through improved microbiota diversity (Macfarlane &. Macfarlane, 2004 ; Macfarlane, Steed, & Macfarlane, 2008 ; Macfarlane, & Cummings, 1999 ; Macfarlane, Furrie, & Macfarlane, 2004 ; Macfarlane et al., 2005 ). Evaluating the microbiota diversity balance using molecular techniques, and designing customized prebiotic and probiotic regimens, will be a powerful new tool for the clinician in battling infl ammatory bowel diseases and other gut-related disorders. 78 INTEGRATIVE GASTROENTEROLOGY

Table 6.1. Advantages of PCR vs. Culture

• Single specimen collection vs. several • Copies a single DNA sequence of a cell over a billion times within 1 to 2 hours, allowing sensitive quantitation • Detects parasites with as few as 5 cells per/g vs. 25,000 cells per/g for microscopic techniques • 5,000 times more sensitive • Ability to ID anaerobes (majority of bacteria — 95 % ) • No growth in transport vs. signifi cant growth in transport • Requires only 5 to 10 bacterial cells for ID vs. 1,000 to 5,000 for culture

Conclusions

Molecular techniques using DNA to identify bacterial genus and species are revolutionizing the understanding of how gut microbiota infl uence human health. Clinical laboratory tests that use these techniques can provide the clinician with practical new interventions targeted to the individual gut ecosystem.

7 Principles of Integrative Gastroenterology: Systemic Signs of Underlying Digestive Dysfunction and Disease

LAURA K. TURNBULL , GERARD E. MULLIN , AND LEONARD B. WEINSTOCK

key concepts

■ Many idiopathic syndromes overlap, and are caused by underlying gut dysfunction. ■ Acute and chronic GI infections trigger chronic systemic diseases by several mechanisms, including small intestinal bacterial overgrowth (SIBO), infl ammation, and autoimmune phenomena. ■ SIBO underlies many poorly understood syndromes, including irritable bowel syndrome (IBS), restless legs syndrome (RLS), fi bromyalgia syndrome (FMS), rosacea, and interstitial cystitis (IC). ■ Increased intestinal permeability and infl ammation are complications of SIBO. ■ Increased intestinal permeability may explain food allergies, and the increased involvement of diseases with eosinophils and mast cells (e.g., asthma). ■ S I B O t r e a t m e n t i s e ff ective treatment for IBS and SIBO-related s y n d r o m e s . ■

79 Introduction

astrointestinal (GI) dysfunction is defi ned as abnormal metabolic function, motility, structure, infection, or infl ammation, and there G are many systemic symptoms and signs (extraintestinal manifestations) that may be an expression of such dysfunction. Classic examples of extraintestinal manifestations include the fever and joint pain that occur during a fl are of Crohn’s disease, as well as various skin, eye, and hepatobiliary diseases associated with infl ammatory bowel disease (IBD). While these examples are correlated with overt GI illness, the underlying cause of many extraintestinal manifestations can also be attributed to underlying systemic infl ammation resulting from asymptomatic gut dysfunction— primarily, intestinal permeability. Two predominant causes of this breach in the integrity of the intestines are small intestinal bacterial overgrowth, and postinfectious enteric illness. Th roughout this chapter, we will primarily explore the consequences of SIBO and its relationship to systemic conditions. Th e prevalence of these disorders, and a review of integrative modalities to their treatment, will be discussed.

Common Extraintestinal Manifestations of GI Dysfunction

Increased Intestinal Permeability

Th ere are many barriers and defensive mechanisms by which the intestinal tract mucosa can be exposed to antigens, bacteria, and chemicals, yet still be selective about what is absorbed and secreted. Th is protection requires an intact immunological and microanatomical defense system— a process in which healthy commensal bacteria play a role. Th erefore, bacterial overgrowth and enteric infections are two major insults to the gut that result in increased permeability, as is shown in Figure 7.1 .

Genetics, Inﬂ ammation and Intestinal Permeability

Altered genetic background or phenotype may result in GI dysfunction in several ways. First, specifi c HLA genome subtypes are found in celiac disease, and Principles of Integrative Gastroenterology 81 result in predisposition for the disease. Furthermore, a variety of genetic markers have been found in Crohn’s disease patients, as discussed in Chapters 30 and 44 Lastly, in both celiac disease and Crohn’s disease, a genetically determined increased intestinal permeability may be a harbinger of clinical disease. Based on the phenotypic genetic makeup, the impact of various stimuli, including infl ammation and dysbiosis, can lead to a variety of diseases or syndromes. Infl ammation and infection of the intestinal lining can lead to increased intestinal permeability, by damaging the tight junctions of mucosal cells. Th e net eff ects are the stimulation of the infl ammatory network, and activation of lymphocytes and mast cells locally and systemically. Th is stimulation results in the release of various cytokines, which can lead to an increase of corticotropin-releasing hormone, which can in turn aff ect the central nervous system (CNS), the hypothalamic-pituitary-adrenal (HPA) axis, and the peripheral nervous system. Additionally, translocation of bacteria or the lipopolysaccharides (outer covering of Gram-negative bacteria) into a damaged mucosal lining can alter the HPA axis. Th e complex dynamics of the emotional motor system (EMS), and the interplay of stress, cytokines, cortisol, neurological, and neuroendocrine responses, are shown in Figure 7.2 .

Infections Triggering Digestive Disease and Systemic Illness

GI and respiratory viral infections (enterovirus and adenovirus) can trigger a number of gastrointestinal disorders (e.g. celiac disease, Crohn’s disease, IBS) and systemic diseases. Th ere are several good studies that have determined the risk of developing postinfectious irritable bowel syndrome (Pi-IBS). Th is risk ranges between 7 % –34% aft er a bacterial infection (see Table 7.1 ). Likewise, an existing GI condition can be worsened by a subsequent viral infection. For example, altered immune mechanisms triggered by an abnormal gene in Crohn’s disease can be a setup for an infection such as intramucosal E. coli, which may exacerbate the disease process (Darfeuille-Michaud, 2002 ). Histological studies have shown diff erences in adherence and invasion of bacteria into intestinal mucosa of patients with Crohn’s disease, and this may also be based on altered immunity (Swindsinski et al., 2002 ). Th e phenomenon of postenteric infections causing systemic diseases and syndromes is a critical concept because, of the approximately 76 million episodes of food poisoning per year in the United States, many of the diseases and syndromes that are linked to food poisoning are poorly documented 82 INTEGRATIVE GASTROENTEROLOGY

Table 7.1. Incidence of Postinfectious IBS

Author Follow-Up Number with acute % of patients with acute period(s) diarrhea diarrhea who developed IBS

Marshall 2005 2-3 yr 1137 34

Mearin 2005 1 yr 271 10

Okhuysen 2004 6 mo 60 10

Neal 1997 & 2003 6 mo 357 7 6yr 192 7

Th ornley 2000 6 mo 93 9

Gwee 1999 3 mo 100 22

McKendrick 1994 1 yr 38 31

(Sobel et al., 2002 ). Th e well-publicized tainted food products in the past few years have included beef, cheese, lettuce, peanut butter, spinach, sprouts, tomatoes, and a variety of canned food (Currie et al., 2007 ; Dechet et al., 2006 ). Hundreds of thousands of pounds of beef have been recalled because of concerns about E. coli and salmonella. Data from the Centers for Disease Control (CDC) show that foodborne illnesses cause 325,000 hospitalizations and 5,000 deaths per year. However, the subsequent manifestations are not as well publicized. Th e eff ects of acute food poisoning can be severe and long-lasting. Of those infected with E. coli O517:H7, 10 % develop hemolytic uremic syndrome, which can cause kidney failure and pancreatitis (Garg et al., 2003 ). Aft er recovery, 25 % of these patients will develop chronic renal disease and diabetes (Oakes, Kirkhamm, Nelson, & Siegler, 2008 ). Th e incidence of diabetes was determined from a review of 1,139 children from 13 studies (1966–1998, aged 0.2–16 years), and ranged from 0 % –15% , with a pooled incidence of 3.2% (Suri et al., 2005 ). Other systemic illnesses that can result from acute food poisoning include reactive arthritis, which can start 6 months or longer aft er a bout of Salmonella, Shigella and Yersinia. Eye infl ammation and urethritis are part of the classic triad of Reiter’s syndrome. One of the most severe postenteric complications, usually acquired from infected poultry, is camphylobacter-associated Guillain- Barré syndrome (Zilbauer, Dorrell, Wren, & Bajaj-Elliott, 2008 ). Antibodies against camphylobacter create an autoimmune syndrome with ascending paralysis. Subsequent gastrointestinal dysmotilities have been reported, as well (Nakazawa, 2008 ). Principles of Integrative Gastroenterology 83

SMALL INTESTINAL BACTERIAL OVERGROWTH (SIBO)

Th e colon is accustomed to having trillions of coliform bacteria, but complications arise when the coliform count grows in the small intestine.

There are several natural protective mechanisms that keep the small bowel bacteria at low colony counts, including the presence of stomach acid, gastrointestinal motility, digestive enzymes, mucosal immunity, and the integrity of the ileocecal valve.

To minimize bacterial counts in the small intestine (SI), one has to:

• maintain physiologic gastric acid production to reduce swallowed bacteria; • control the ingestion and have proper digestion of starches (i.e., legumes) to limit the nutrition necessary for bacterial growth; • retain normal small bowel motility (as driven by the migrating motor complex in the fasting state) to sweep the bacteria toward the colon; and • preserve an intact ileocecal valve to act as a physical barrier (between the SI and colon) to prevent the refl ux of stool/bacterial contents from the large intestine.

Th ese natural defenses are shown in Figure 7.3 . SIBO is defi ned as a disruption or increase of the normal small bowel bacterial population that can result in gas, bloating, fl atulence, altered bowel function, and/or malabsorption of nutrients. Bloating, diarrhea, and nutrient defi ciencies are induced by excess intraluminal small intestinal bacteria, which results from: (1) fermentation of nutrients producing gas, and (2) bile salt deconjugation by bacteria, leading to fat malabsorption and subsequent steatorrhea and secretory eff ects, causing diarrhea. Deconjugation of the hydrophilic components decreases absorption from the loss of the water-soluble state, which is involved in fat absorption. Th e change in bacteria and the eff ect of undigested starches are shown in Figure 7.4 . With chronicity, weakness and weight loss from villous atrophy, and/or malabsorption secondary to the eff ects of bile salt deconjugation, will become evident. Advanced cases may have peripheral edema from hypoalbuminemia 84 INTEGRATIVE GASTROENTEROLOGY and pallor from anemia (B12 defi ciency, chronic disease, and in some cases iron defi ciency, for which achlorhydria is the most common explanation). In advanced stages, cachexia and other changes of vitamin and nutrient defi - ciency may become evident. Chronic asymptomatic SIBO can result in systemic infl ammation (Lin, 2004 ). Circulating levels of cytokines, such as TNF-α and proinfl ammatory interleukins, are elevated in SIBO (Dinan et al., 2006 ). Recent evidence indicates that low-grade SIBO may present with virtually no GI symptoms, but may aff ect the body in profound ways because of the systemic infl ammation it causes. Th is may explain many syndromes and symptoms associated with chronic fatigue syndrome, rheumatoid arthritis, fi bromyalgia, interstitial cystitis, restless legs syndrome, and rosacea (Table 7.3 ). SIBO may also explain other syndromes due to the presence of systemic low-grade infl ammation and increased intestinal permeability.

CAUSES OF SIBO

SIBO occurs when the normal protective mechanisms that maintain bacterial balance are interrupted. Th e most common causes of SIBO are poor motility of the small intestine, allowing for overgrowth of coliform-type bacteria; pancreatitis, which allows for undigested nutrients to enhance bacterial growth; and gastroparesis.

GASTROINTESTINAL MOTILITY AND SIBO

Neuromuscular disorders of the esophageal body, lower esophageal sphincter, stomach, and small intestine, are important in the pathophysiology of many GI and systemic disorders. Functional disorders such as IBS, GERD, and non- ulcer dyspepsia are in part caused by disordered gastrointestinal motility. When small intestinal motility is disturbed, and the ability to “sweep” pathogenic organisms away from the upper gastrointestinal tract is impaired, the risk of SIBO is increased. Th ere is a growing prevalence of SIBO in IBS patients and, as the SIBO resolves the IBS, symptoms improve. Other gastrointestinal motility disorders that can contribute to SIBO are small intestinal pseudo obstruction, scleroderma, and postsurgical states. Th e latter is among the most well known causes of SIBO, and is due to the decreased motility and achlorhydria aft er certain gastrointestinal surgical procedures Principles of Integrative Gastroenterology 85 including, but not limited to, gastric bypass surgery and Whipple’s type surgical procedures. Additionally, gastrointestinal motility disorders, or lack of adequate production of gastric acid with subsequent ingestion of live bacteria, has been commonly recognized as contributing to SIBO (Lewis et al., 2001 ; Parlesak et al., 2003 ; Lipski, Kelly, Malhotra, & Mountford, 1992 ). Other classic examples of SIBO include pancreatic insuffi ciency, and abnormal small intestinal mucosal disorders, including celiac disease and Crohn’s disease, as shown in Table 7.2 . Finally, many systemic diseases and conditions can also cause SIBO — see Tables 7.2 and 7.3 and 7.4.

Table 7.2. Common Causes of SIBO

Scleroderma Achlorhydria

Small intestinal pseudo-obstruction Diabetes

Pancreatic insuffi ciency Radiation enteritis

Jejunal diverticulosis Immunodefi ciency: CLL, IgA defi ciency, T-cell defi ciency

Post-surgical anatomy: Billroth, Blind-loop, Celiac and Crohn’s diseases ICV resection, J–pouch

Table 7.3. Lesser Known Causes of SIBO

Chronic renal failure Rheumatoid arthritis

Cirrhosis Irritable bowel syndrome

Chemotherapy Fibromyalgia

Acromegaly Interstitial cystitis

Hypothyroidism Restless legs syndrome

Chronic fatigue syndrome Rosacea

SIBO has been reported in as many as 84 % of patients meeting diagnostic criteria for IBS. Other studies conﬁ rm a relationship of SIBO to IBS, as shown in Table 7.4 . 86 INTEGRATIVE GASTROENTEROLOGY

Table 7.4. Prevalence of Small Intestinal Bacterial Overgrowth in IBS Patients as Determined by a Positive Breath Test for Bacterial Overgrowth

Author Substrate # Prevalence Subjects (% )

McCallum, 2005 Glucose 143 38.5

Lupascu, 2005 Glucose 65 30.7

Nucera, 2005 Lactulose 98 65

Walters, 2005 Lactulose 39 10

Noddin, 2005 Lactulose 20 10

Nucera, 2004 Lactulose 200 75

Pimentel, 2000 –3 Lactulose 313 57, 76, 84

Weinstock, 2006 Lactulose 254 63

INTESTINAL GAS AND THE DIAGNOSIS OF SIBO

Th e obvious consequence of bacterial fermentation is the production of gas. Th e variety of gases that develop in the gut expand its diameter, causing abdominal bloating, distention, and discomfort from the triggering of stretch receptors (see Figure 7.5 ). Th is bloating is most oft en caused by excess hydrogen production from bacterial fermentation (King, Elia, & Hunter, 1998 ). Simple lactose maldigestion is well known to cause hydrogen and lactic acid production, with subsequent bloating and diarrhea. Diagnostic tests for SIBO are either direct invasive studies with bacterial cultures via nasal jejunal tubes, or indirect techniques using breath testing with either glucose or lactulose (Koshini, Dai, Lescano, & Pimentel, 2008 ). Hydrogen breath testing in particular is useful in identifying patients with IBS who are aff ected by SIBO, but other exhaled gases may have diagnostic benefi t, as well (Koshini, Sun-Chuan, Lezcano, & Pimentel, 2007 ). Specifi c characteristics of each gas pose their own hazard. Th e production of hydrogen sulfi de can cause increased nociception, as found in IBS and idiopathic constipation (IC). Excess hydrogen and methane result predominantly in bloating (as seen in IBS), while excess methane also results in altered motility, manifested primarily as constipation. Early studies of the association of methane production and altered motility looked at orocecal and whole gut transit, and found that each was signifi cantly delayed if methane excretion occurred early on in the lactulose Principles of Integrative Gastroenterology 87 breath test (LBT). As a result, abnormal methane production was shown to be strongly associated with constipation-predominant IBS (Pimentel et al., 2003 ). Methane was detected in 50 (17 %) of 296 patients with IBS, compared with 2 (3 %) of 78 patients with IBD ( P < .01). Subsequently, a study of 87 patients showed that, of the 20 that had methane production, severity of constipation was double that of non-methane-producing IBS subjects (Chatterjee et al., 2007 ). A correlation was found between the degree of methane production on the breath test and the severity of constipation. Infusion of methane into the small intestine has shown that gut transit can be reduced by up to 70% (Pimentel et al., 2006 ). Th us, methane as a by-product of fermentation can itself slow intestinal transit.

THERAPY FOR SMALL INTESTINAL BACTERIAL OVERGROWTH

Th e basis for SIBO treatment is the understanding that most cases of SIBO are caused by poor motility of the small intestine, which then allows for bacterial overgrowth and subsequent damage to the intestinal lining. Antibiotic treatment is the mainstay of treatment, and requires a broad-spectrum antibiotic to be eff ective. Treatment with quinolones, amoxicillin, tetracycline, and metronidazole, is somewhat eff ective, but can cause bacterial resistance and antibiotic-associated diarrhea.

RIFAXIMIN THERAPY FOR SIBO

Rifaximin off ers a unique profi le for SIBO, with its broad-spectrum activity, non-absorbable moiety, bile solvency (thus increasing activity in the small intestine), and low likelihood of long-term resistance (Su, Aberra, & Lichtenstein, 2006 ). It has been shown to be eff ective in patients with SIBO, IBS with SIBO, and scleroderma (Lauritano et al., 2005 ; Pimentel, Park, Mirocha, Kane, & Kong, 2006 ; Parodi et al., 2008 ). Th e effi cacy of Rifaximin in the treatment of SIBO, IBS, and functional bowel syndrome has been evaluated in several studies, as summarized in Table 7.5 (Di Stefano, Malservisi, Veneto, Ferrieri, & Corazza, 2000 ). Nucera et al. ( 2005 ) looked at a large group of patients who were treated with weekly courses of combination antibiotics every month for 4 months. Th ere was a signifi cant improvement in the breath tests using lactulose, lactose and fructose. Laurentino et al. ( 2005 ) showed that increasing the dose of rifaximin from 800 mg/day/week to 1,200 mg/day/week resulted in double the improvement in reversing the breath test. Th e UCLA group has subsequently 88 INTEGRATIVE GASTROENTEROLOGY

Table 7.5. Rifaximin Therapy for IBS-SIBO

Author Yr Patients Type Efﬁ cacy

Nucera ‘04 IBS-SIBO (n=200) Open label; Rfx 87-100% eff ective in + paramomycin treating SI BO by reversing 3 sugar BT’s

Lauritano ‘05 IBS-SIBO (n=90) Dose-ranging Dose response with Rfx

Lupascu ‘05 IBS-SIBO (n=80) Abx 1 wk of Rfx vs. metro/ comparison; levoquin 12/20 vs. 14/20 H2 open label BT normalized

Pimentel ‘05 IBS-SIBO (n=87) R/DB/PC Statistical sig. vs. placebo; duration of response over 2 months for 10-day Rx

Sharara ‘06 IBS (n=70) R/DB/PC Statistically sig. vs. placebo

Sharara ‘06 Fx-SIBO (n=54) R/DB/PC Numerically diff . vs. placebo

Weinstock ‘06 IBS-SIBO (n=254) Observational 60% mod-greatly improved

Weinstock ‘06 Fx-SIBO (n=85) Observational 63% mod-greatly improved

reported that reversing the breath test is critical in symptom resolution (Pimentel, Chow, & Lin, 2003 ). Pimentel, Park, Murocha et al.’s 2006 study showed that a 10-day course of 1,200 mg/day of rifaximin resulted in 10 weeks of improvement of IBS symptoms. Patients experienced a 36% mean improvement from baseline in the severity of IBS symptoms at 10 weeks post-treatment, compared with a mean improvement of 21% among 44 patients who received placebo (P = .02). Th e dose of rifaximin in Sharara et al.’s study (2006 ) was 800 mg/day for 10 days; global symptomatic response was achieved in 41 % of 37 patients, compared with 6 (18% ) of 33 patients who received placebo (P = .04). Aft er 10 days post- treatment, 10 (27% ) of 37 patients in the rifaximin group maintained their symptomatic response, compared with 3 (9 %) of 33 patients in the placebo group (p=0.05). In an open-label, observational study, a 10-day course of rifaximin 1,200 mg/day, as part of a comprehensive treatment regimen including tegaserod and probiotic therapy, improved IBS symptoms in 60 % of 81 patients (Weinstock et al., 2006 ;110:A1123). Our own experience shows that eff ective Principles of Integrative Gastroenterology 89 antibiotic therapy, (LBW) along with high doses of Coenzyme Q10, reduces the severity of fatigue in IBS patients with SIBO. Studies have also been done comparing the eff ectiveness of other antibiotics used in the treatment of SIBO compared to Rifaximin. A retrospective chart review of 98 patients with IBS who received antibiotic therapy (Yang J, Lee HR, Low K et al., 2008 ) showed that 58 (69% ) of 84 patients who received at least one course of rifaximin experienced clinical response, compared with 9 (38% ) of 24 patients who received neomycin (p<0.01) and 27 (44% ) of 61 patients who received other antibiotics (e.g. amoxicillin clavulanate and doxycycline; P < .01).

COMBINATION PROMOTILITY ANTIBIOTIC THERAPY FOR SIBO

Given that disturbances in gastrointestinal motility are key to the development of SIBO (via impaired “sweeping” of bacteria in the upper digestive tract), treatment with promotility agents are paramount to the therapy of this condition. In the past, long-term tegaserod (a serotonin agonist) was given in an attempt to improve the Phase III abnormality of the migrating motor complex found in patients with IBS who have SIBO (Spiller et al., 2000 ). A review of IBS-SIBO patients who were treated with antibiotics and then were given tegaserod (no longer available in the United States) versus low-dose erythromycin (50mg dose acts as a stimulant to the migrating motor complex) showed that tegaserod decreased recurrence of IBS-SIBO symptoms at a rate twice that of erythromycin, and four times that of no medication aft er rifaximin alone (Yang J, Lee HR, Low K et al., 2008 ). Th e problems with erythromycin include the potential for abdominal cramps, interference with birth control pills, and other drug interactions including an increased risk of muscle damage when used concurrently with statin medications. Low-dose naltrexone may be used as an alternative to erythromycin. Th is anti-opioid can stimulate the intestine, and some emerging data suggests that it has anti-infl ammatory properties, which might help repair the intestinal lining. Th e problems with naltrexone include general CNS stimulation (potential for jittery feelings, insomnia, and unusual dreams). It is contraindicated for people who take chronic opioids. Th e following are possible alternative treatments for SIBO:

• Probiotics can reduce infl ammation and improve permeability problems (Spiller, 2005 ; Resta-Lenert & Barrett, 2006 ; Ait-Belgnaoui et al., 2006 ). Specifi cally, bifi dobacteria-based probiotics may repair small 90 INTEGRATIVE GASTROENTEROLOGY

intestinal permeability and immune defects characteristic of SIBO, IBS, and postinfectious IBS (Spiller et al., 2000 ; Dunlap, Hebden, & Campbell, 2006 ; Plaza, 2001 ). • Zinc can theoretically help reverse defects in small intestinal permeability (Spiller, Jenkins, Th ornley et al., 2000 ). Experimental evidence shows that zinc supplementation improves intestinal permeability in toxin-induced colitis (Sturniolo, Fries, Mazzon et al., YEAR). Zinc carnosine (ZnC) stimulated migration and proliferation of cells in vitro, in a dose-dependent manner, and decreased gastric and small- intestinal injury (50 % reduction in villous shortening at 40 mg/ml; both p<0.01; see Mahmood et al., 2007 ). In volunteers, indomethacin caused a threefold increase in gut permeability in the control arm, while no signifi cant increase in permeability was seen when ZnC was co-administered. • Medical foods containing glutamine or aloe (either individually or in combination) are used by many practitioners to facilitate intestinal permeability resolution aft er therapy of SIBO. • Antimicrobial herbal preparations have been used by the author (G. Mullin) to resolve SIBO that is refractory to rifaximin and triple antibiotics (clindamycin, neomycin, metronidazole. Examples of products used by the author with success include: ° Dysbiocide (Biotics Research Laboratories) ° FC Cidal (Biotics Research Laboratories) ° ADP (Biotics Research Laboratories) • Th e role of diet therapy during the treatment of SIBO cannot be emphasized enough. Individuals need to be counseled to avoid fructose, fructans, and poorly digestible starches, such as beans (see Appendix A). • Since immune GI dysfunction plays a role in IBS, there are additional alternative approaches to SIBO treatment, including: ° Probiotics administered post-treatment, once SIBO is resolved ° Elimination diet to avoid allergens that can trigger immune and infl ammatory responses ° Avoiding food products (i.e., indigestible starches) that can ferment in the small intestine and facilitate the growth of the gut microbiota ° Hypnotherapy to downregulate the stress response on the immune system and the gut lining Principles of Integrative Gastroenterology 91

° Acupuncture to facilitate GI motility via resetting the migrating motor complex to sweep intestinal bacteria in an antegrade manner ° Immune enhancers such as: Arabinogalactans (raises mucosal sIgA levels) Saccharomyces boulardii (raises mucosal sIgA levels) IgG2000 (raises mucosal sIgA levels) Colostrum (rich in preformed antibodies) ° Behavioral therapy to attenuate the stress response, reset pain thresholds, and lower neuroendocrine and infl ammatory m a r k e r s .

Systemic Consequences of SIBO-Induced Gut Injury

CHRONIC FATIGUE SYNDROME

Chronic fatigue syndrome (CFS) is an idiopathic complex illness characterized by heightened reactive oxygen metabolites, along with mitochondrial defects that lead to aberrant fatty acid and energy metabolism. Research also indicates that CFS patients are under increased oxidative stress, have a Type 2 helper-cell-dominant cytokine profi le, frequently report allergies, have altered essential fatty acid (EFA) status, and may have malabsorption of certain micronutrients (Logan, Venket Rao, & Irani, 2003 ). Gastrointestinal links to chronic fatigue syndrome include marked alterations in microbial fl ora, including lowered levels of bifi dobacteria, and SIBO Lactic acid bacteria (LAB) found in probiotics have the potential to infl uence the immune system in CFS patients by supporting T-helper-cell-1-driven cellular immunity, and may decrease allergies. Systemic infl ammation induced by SIBO could be responsible for alterations in the hypothalamic pituitary adrenal axis, causing the fatigue found in the irritable bowel syndrome. Interestingly, IBS has also been associated with CFS and SIBO independently (Figure 7.2 ; see Cleare, Miell, Heap et al., 2001 ; Gaab, Rohleder, Heitz et al., 2005 ; Hamilton, Gallagher, Th omas, & White, 2009 ). Preliminary data by Pimentel et al. (2000 ) showed that SIBO was common in CFS (77% of 31 patients), and there was improvement in tender points and depression (but not in fatigue scores) when antibiotics improved S I B O . 92 INTEGRATIVE GASTROENTEROLOGY

RESTLESS LEGS SYNDROME (RLS)

Th e prevalence of RLS is estimated at 10 % of the general population, and it results in sleep disorders and a poor quality of life (Allen, Walters, Montplaisir et al., 2005 ) from the compelling urge to move the legs at night, oft en with discomfort. RLS is a central nervous system disorder that is either idiopathic (primary) or secondary to a number of conditions, including GI dysfunction. Possible mechanisms of action in RLS include iron defi ciency, infl ammation, and/or SIBO. In virtually all forms of RLS (primary, familial, and secondary), there is central nervous system iron defi ciency (Berger, Von Eckardstein, Trenkwalder et al., 2002 ; Allen, 2004 ). Additionally, RLS patients oft en have varying degrees of asymptomatic peripheral iron defi ciency (Aul, Davis, & Rodnitzky, 1998 ; Rama, Aul, Davis, & Rodnitzky, 1998 ). A chronic infl ammatory state caused by SIBO (Lin, 2004 ) could be related to RLS by aff ecting hepcidin production directly (Kemna, Pickkers, Nemeth et al., 2005 ) and indirectly (Liu Z, Li, & Neu, 2005 ), decreasing peripheral and central nervous system iron uptake and transportation (Earley, Connor, Beard et al., 2000 ; Clardy, Earley, Allen et al., 2006 ). Th ere is limited recognition that iron defi ciency is an integral part of the pathophysiology of RLS. Th e growing understanding of iron metabolism and the role of SIBO and systemic infl ammation in RLS is exciting. Th e role for modulation of dysbiosis will be determined with double-blind, placebo- controlled studies, which are in progress.

THEORY FOR SIBO CAUSING RLS AND CENTRAL IRON DEFICIENCY

Factors that are associated with secondary RLS include elderly status, diabetes, end-stage renal disease, fi bromyalgia, rheumatoid arthritis, and Parkinson’s syndrome. Furthermore, all of these conditions have also been associated with SIBO. Secondary RLS has also been associated with gastrointestinal conditions, such as gastric resection, chronic liver disease, IBS associated with SIBO, celiac disease, and Crohn’s disease (Banerji & Hurwitz, 1970 ; Franco, Ashwathnarayan, Deshpandee et al., 2008 ; Weinstock, Fern, & Duntley, 2008 ; Weinstock, Bosworth, Scherl et al., 2008 ). Patients with scleroderma also have a reported increased incidence of RLS, although in this single study the patients did not have symptoms of end-stage SIBO (Prado, Allen, Trevisani et al., 2002 ). Principles of Integrative Gastroenterology 93

TREATMENT OF SECONDARY RLS

Medical trials for RLS have been recently reviewed extensively, and are summarized in Table 7.6 (Trenkwalker, Hening, Montagna et al., 2008 ). Magnesium, folic acid, and exercise are frequently used in practice, but are considered to be investigational. Th e effi cacy of oral iron is also considered investigational; however, its effi cacy appears to depend on the iron status of subjects. Intravenous iron is likely effi cacious for the treatment of RLS secondary to end-stage renal disease, but investigational in RLS subjects with normal renal function (Earley, Heckler, & Allen, 2005 ). Most physicians who treat RLS feel that the fi rst approach aft er iron treatment is to initiate dopamine agonists (Comella, 2002 ). Ropinirole is marginally better than placebo augmentation, and a wide array of side eff ects of dopamine agonists have led to interest in fi nding therapeutic alternatives (García-Borreguero, Allen, Kohnen et al., 2007 ).

ANTIBIOTICS FOR RLS

Two pilot studies have evaluated the eff ect of rifaximin for the treatment of RLS. Th e fi rst prospective clinical trial of 13 IBS patients with both SIBO and RLS reported that 77% of patients (10/13) had ≥ 80% long-lasting improvement of RLS symptoms following open-label treatment with rifaximin 1,200 mg/day

Table 7.6. Medical Therapy for Restless Legs Syndrome

Dopaminergic agents Neuroleptics Anti-seizure medications Narcotics Benzodiazepines Iron Investigational Rifaximin antibiotic therapy Magnesium Acupuncture Botox injections 94 INTEGRATIVE GASTROENTEROLOGY for 10 days, followed by motility and probiotic therapy (Weinstock, Fern, & Duntley, 2008 ). Th e next study included patients with primary RLS who had a positive lactulose breath test for SIBO. Th e mean baseline IRLS score was 23.1 (Weinstock, Fern, & Duntley, 2008 ). Open-label treatment with rifaximin 1,200 mg/day/10 days, followed by 400 mg/every other day/20 days, resulted in a decrease in the IRLS score by 10.7 in 9 of 14 patients. Two of the fi ve RLS nonresponders had improvement with a second course of rifaximin when combined with metronidazole, and a third patient improved when she was later diagnosed with celiac disease and placed on a gluten-free diet and iron supplementation.

ALTERNATIVE THERAPIES FOR RLS

Th e common approaches used for many conditions include herbs, vitamins and/or minerals, acupuncture, botulinum toxin, hyperbaric therapy ∗ and chela- tion therapy∗ . Small studies have suggested improvement from magnesium, although scientifi c studies of magnesium in RLS have been nonsupportive (Hornyak, Voderholzer, Hohagen et al., 1998 ; Bartell & Zallek, 2006 ; Walters, Elin, Cohen et al., 2007 ). Acupuncture has been studied in 14 studies, but only 2 were judged worthy of comment based on the design, and there is insuffi cient evidence to support the use of acupuncture in RLS (Cui, Wang, & Liu, 2008 ). Intramuscular botulinum injections have shown success in 3 patients (Rotenberg, Canard, & Difazio, 2006 ). Finally, pneumatic sequential compres- sion devices on RLS symptoms showed success in 6 of 10 patients (Eliasson & Lettieri, 2007 ). Small, open-label studies with RLS are problematic, since the placebo response is so high.

RESTLESS LEGS SYNDROME (RLS), CELIAC, AND CROHN’S DISEASE

• Th e relationship between restless legs syndrome (RLS) and celiac disease has recently been reported (Weinstock, Bosworth, Scherl et al., 2008 ). • RLS was found to be a frequently associated condition in 85 celiac patients: the incidence was 35.5% and the prevalence was 24.7% , compared with spouse control group of 9.5 % . • Neurologic complications have only recently been reported in Crohn’s disease.

∗ Have not been reported in the literature. Principles of Integrative Gastroenterology 95

• Th e incidence of RLS was 42.7% in a large number of Crohn’s disease patients from three academic centers and one large community practice (Weinstock, Bosworth, Scherl et al., 2008). • Th e prevalence of RLS in Crohn’s disease was 30.2 %, compared to a prevalence of 8.4% in the sex-matched spouse control group.

Interstitial Cystitis (IC)

Interstitial cystitis (also known as painful bladder syndrome) is an idiopathic syndrome characterized by symptoms of urinary frequency, urinary urgency, pain with bladder fi lling, pelvic pain, and dyspareunia. Th ere is a signifi cant overlap of interstitial cystitis (IC) with food allergies, autoimmune disease, and IBS. GI dysfunction may play a role in IC, since food triggers, mast cells, neural crosstalk, and SIBO have been implicated in the pathophysiology. A connection to SIBO has been proposed, and a positive therapeutic study using SIBO open-label antibiotic therapy was reported (Lin, 2004 ; Weinstock, Klutke, & Lin, 2007 ). Th e potential interactions of mast cells, infl ammatory mediators, and the peripheral nervous system are shown in Figure 7.7 .

Possible Role of SIBO and IC Pathophysiology

ROLE OF FOOD ALLERGIES

Shorter et al. (2007 ) determined the prevalence of the eff ect of food substances on painful bladder syndrome/interstitial cystitis symptoms. Of the surveyed patients with IC, 90.2% indicated that the consumption of certain foods or beverages caused symptom exacerbation. Patients who reported that specifi c foods worsened symptoms tended to have more severe IC symptom scores. Th e most frequently reported foods causing symptom exacerbations were coff ee, tea, soda, alcoholic beverages, citrus fruits and juices, artifi cial sweeteners, and hot pepper.

Gut Permeability, Inﬂ ammation, and Pelvic Pain

Th e link between chronic pelvic pain, dyspareunia, and functional digestive diseases (i.e., IBS) has been long established (Vercellini, Somigliana, Viganò et al., 2009 ). Since SIBO, chronic infl ammation, altered HPA axis, and systemic 96 INTEGRATIVE GASTROENTEROLOGY proinfl ammatory cytokines are implicated in the pathogenesis of IBS, an experimental study was undertaken to investigate the mechanism of development of pelvic pain (Rudick, Chen, Mongiu, & Klumpp, 2007 ). One study explored, in an animal model of IBS, whether pelvic pain could develop remotely from the original site of infl ammation. Th ese investigators confi rmed that there is organ crosstalk (between the intestine and vagina), as well as modulation of pain responses by visceral inputs distinct from the infl amed site. Th us, SIBO/IBS can manifest in other organ systems distant from the site of pathology, via the common mucosal immune system (see Chapter 3).

Rosacea

Systemic infl ammation caused by GI dysfunction may be an explanation for rosacea, which is a common idiopathic disease that presents with transient or persistent facial erythema, telangiectasia, edema, papules, and pustules, usually confi ned to the central portion of the face (Buechner, 2005 ). In the past, genetic, environmental, vascular and infl ammatory factors, and microorganisms such as skin bacteria, including Demodex folliculorum , and gastric infections with Helicobacter pylori have been considered as etiologic factors.

ROSACEA AND DIGESTIVE DISORDERS

Rosacea has been associated with gastritis and hypochlorhydria; many people have nonspeciﬁ c gastrointestinal symptoms.

Helicobacter pylori

Th e role of Helicobacter pylori has oft en been a subject of investigation, with studies showing confl icting results. A small study investigated ocular rosacea, and clinical and serological evidence of H. pylori infection showed signifi cant improvement of rosacea symptoms, with ocular disease responding better than cutaneous rosacea (Daković, Vesić, Vuković et al., 2007 ). An older study from Poland on the treatment of H. pylori infection, in 60 patients with rosacea having erythema and fl ushing on the face with visible papules and pustules, was compared to 60 age and gender matched patients without any skin diseases (Szlachcic, 2002 ). Th e eff ect of treatment on plasma interleukin (IL-8) and tumor necrosis factor alpha (TNF-α ) was also determined aft er 1 week of Principles of Integrative Gastroenterology 97 omeprazole 20 mg, clarithromycin 500 mg, and metronidazole 500 mg, all twice daily. Th e H. pylori prevalence in rosacea patients was about 88% , compared to 65% in control patients. Th ere was twice the incidence among rosacea patients of a more virulent form of H. pylori (cytotoxin-associated gene A [CagA] positive). Aft er antibiotics, 51 out of 53 treated rosacea patients became Hp negative. Within 2 to 4 weeks, the symptoms of rosacea disappeared in 51 patients, markedly declined in one, and remained unchanged in one other subject. Plasma TNF-α and IL-8 were reduced signifi cantly aft er the therapy in both groups of patients (72% and 65% , respectively).

Rosacea could be considered as one of the major extragastric symptoms of H. pylori infection cytotoxins and cytokines.

SIBO

Italian investigators recently discovered the link between rosacea and small intestinal bacterial overgrowth (Parodi, Paolino, Greco et al., 2008 ). Of 113 consecutive rosacea patients, 52 had a positive breath test (versus 3 of 60 controls). Aft er SIBO eradication by rifaximin, as determined by reversal of the breath test, cutaneous lesions cleared in 20 of 28, and greatly improved in 6 of 28 patients, whereas patients treated with placebo remained unchanged (18/20) or worsened (2/20) (P<0.001) (Figure 7.8). Th e patients who were given placebo were subsequently switched to rifaximin. In these patients, SIBO was eradicated in 17 of 20 cases. Fift een of these patients had a complete resolution of rosacea. Th irteen of 16 patients with negative breath tests for SIBO remained unchanged, and this result diff ered from SIBO-positive cases (P<0.001). Eradication of SIBO induced an almost complete regression of their cutaneous lesions for at least 9 months. Th e authors of the study suggested that chronic systemic infl ammation causes infl ammation of the skin. Figure 7.8 shows the clinical outcome in SIBO-positive and SIBO-negative rosacea patients treated with rifaximin.

1. Myth: Syndromes are all “in your head” and are due to “stress.” 2. Restless legs syndrome is caused by central nervous system iron deﬁ - ciency and altered dopamine interactions. Evidence is growing for the role of small intestinal bacterial overgrowth. 3. The real name for “leaky gut” is increased intestinal permeability . 98 INTEGRATIVE GASTROENTEROLOGY

Summary

1. Integrity of the gut mucosa is essential for good health. 2. Imbalance of bacteria plays a role in many disorders. 3. A shift of colonic type bacteria into the small intestine results in infl ammation as well as fermentation, with subsequent gas production. 4. Treatment with special antibiotics, motility medicine, and probiotics may provide benefi ts to those suff ering from “syndromes.” 5. Syndromes do not exist in a vacuum. Th e high prevalence of these idiopathic conditions in the population, and the overlapping of symptoms from one condition to another, suggest that a central cause could be a signifi cant factor (Figure 7.9 ). 8 The Skin and the Gastrointestinal Tract

ANDREW G. FRANKS , JR.

key concepts

■ Th e neutrophilic dermatoses are a spectrum encompassing four distinct diseases characterized by sterile neutrophilic cutaneous infi ltrates, and include erythema elevatum diutinum, pyoderma gangrenosum, Sneddon-Wilkinson syndrome, and Sweet’s syndrome. ■ Bowel stasis, which promotes bacterial overgrowth, with either disease or surgically induced blind loops, can cause a bowel- associated dermatosis-arthritis syndrome. ■ Acanthosis nigricans is arguably also the most well-recognized cutaneous sign of internal malignancy. ■ Peutz-Jeghers syndrome is a dominantly inherited polyposis syndrome, characterized by hamartomatous polyps of the gastrointestinal tract, and mucocutaneous pigmentation and melanin spots. ■

Introduction

he skin and the gastrointestinal tract are both covered or lined by epithelium, and both communicate with the external environment. T Th erefore, it is not surprising that diseases that primarily aff ect the gastrointestinal tract oft en have cutaneous manifestations as well. Th ese cutaneous

99 100 INTEGRATIVE GASTROENTEROLOGY fi ndings frequently provide clues to the diagnosis of the underlying gastrointestinal disease (Gregory & Ho, 1992a , 1992b ). Th ere are a vast number of associations, from extremely rare genetic disorders to more common illnesses, both benign and malignant. Th ese more common associations, which are most likely to be encountered in clinical practice, are the focus of this review. Of the benign disorders, the following will be reviewed:

• IBD and the neutrophilic dermatoses • Bowel bypass syndrome • Erythema nodosum • Acrodermatitis enteropathica • Dermatitis herpetiformis • Pancreatic panniculitis • Hepatitis C • Helicobacter pylori

Of the malignancy-associated disorders, examples of the following will also be reviewed:

• Glucagonoma syndrome • Bazex’s syndrome • Palmar-plantar hyperkeratosis • Acanthosis nigricans • Gardner’s syndrome • Peutz-Jeghers syndrome • C o w d e n d i s e a s e

The Neutrophilic Dermatoses and Other Benign Disorders

Th e neutrophilic dermatoses are a spectrum encompassing four distinct diseases characterized by sterile neutrophilic cutaneous infi ltrates. Th e etiology of these disorders is not well understood, but is thought to be related to deposition of immune complexes in dermal vessels, resulting in complement fi xation and leukocytoclastic vasculitis, as well as altered neutrophilic chemotaxis. Th e neutrophilic dermatoses include erythema elevatum diutinum, pyoderma gangrenosum, Sneddon-Wilkinson syndrome and Sweet’s syndrome. The Skin and the Gastrointestinal Tract 101

ERYTHEMA ELEVATUM DIUTINUM

Erythema elevatum diutinum (EED) is characterized by multiple symmetric papules, plaques, nodules, vesicles, or bullae on the extensor surface of joints, particularly the elbows, knees, hands, and feet. Th e lesions usually are initially red to purple in color, some becoming yellowish-brown. Many patients are asymptomatic, but pruritus, tenderness, and pain may occur. Th ey may be cold-induced, and also demonstrate Koebnerization. Constitutional symptoms may include arthralgias and fever. Th e course of the disease is chronic and frequently relapsing, though it may spontaneously remit. Lesions heal with residual atrophic patches, with loss of collagen in the dermis. EED has been associated with a variety of underlying autoimmune, gastrointestinal, and hematopoietic disorders, including Crohn’s disease (Evans et al., 1999 ; Walker & Badame, 1990 ). Skin biopsy is not specifi c, and usually reveals a dense perivascular neutrophilic infi ltrate involving the superfi cial and mid dermis, with leukocytoclastic vasculitis, fi brin deposition, and endothelial swelling. An interstitial infi ltrate of lymphocytes, neutrophils, eosinophils, plasma cells, and histiocytes may be observed. Features of older lesions include perivascular fi brosis, intracellular lipid deposition, and capillary proliferation.

PYODERMA GANGRENOSUM

Pyoderma gangrenosum (PG) usually begins as painful papules/pustules, which rapidly expand into painful burrowing ulcers with undermined borders and/or raised violaceous rims. Th e pretibial areas of the legs are the most frequent site, but any location may be involved. Diff erent clinical presentations of PG include: ulceration with rapidly evolving purulent wound; discrete pustules, commonly associated with infl ammatory bowel disease; superfi cial bullae with development of ulcerations; and vegetative erosions and superfi cial ulcers. An oral form of the disease, known as pyostomatitis vegetans, occurs primarily in patients with infl ammatory bowel disease (Yasuda et al., 2008 ). Oft en the lesions heal, leaving a cribriform-shaped scar. Ulcerations of pyoderma gangrenosum may occur aft er trauma or any injury to the skin, and the term pathergy is used to describe the process. PG occurs most oft en in association with infl ammatory bowel disease (Crowson et al., 2003 ), but also with any of the connective tissue diseases, Monoclonal gammopathy of undetermined signifi cance (MGUS), myeloma, myelodysplastic syndrome 102 INTEGRATIVE GASTROENTEROLOGY

(MDS) leukemia and lymphoma. Culture-negative pulmonary infi ltrates are the most common extracutaneous manifestation. Histopathologic changes vary where the biopsy is taken in relation to the lesion. Lymphocytic vasculitis is found in the area of erythema peripheral to the central ulceration, whereas neutrophilic infi ltrates and abscess formation are identifi ed more centrally.

SNEDDON-WILKINSON SYNDROME

Sneddon-Wilkinson syndrome, or subcorneal pustular dermatosis, is a recurrent pustular disorder that may mimic pustular psoriasis, and presents with bilateral crops of lesions on the fl anks, trunk, and proximal extremities with a fl exural tendency. Th e primary lesions are pea-sized sterile pustules and papulovesicles, oft en described as half-pustular (bottom) and half-clear (top), or “half & half blister.” Sometimes, burning, pain, and tenderness of the aff ected areas of the skin may occur. Subsequently, the lesions may coalesce and form annular polycyclic rings, which eventually crust and erode. Th e histopathology reveals a subcorneal pustule fi lled with polymorphonuclear leukocytes, with only occasional eosinophils, and absence of spongiosis and acantholysis. Constitutional features may not be prominent, but generalized arthralgias and arthritis may occur. It is frequently associated with an MGUS, particularly IgA, less commonly IgG. Multiple myeloma and other lymphoproliferative disorders are sometimes found, and an association with pyoderma gangrenosum and infl ammatory bowel disease has been noted (Delaporte et al., 1992 ; Garcia-Salces et al., 2008 ).

SWEET’S SYNDROME

Th e combination of high fever, leukocytosis, boggy, red, painful papules and plaques with dense neutrophilic dermal infi ltrates, without evidence of vasculitis on skin biopsy, is characteristic of Sweet’s syndrome, or acute febrile neutrophilic dermatosis. Soft , pea-sized papules and papulovesicles grouped within boggy violaceous plaques are very suggestive of the diagnosis. If the plaque is squeezed between the thumb and forefi nger, a grey-yellow coloration may be noted within the papules. Lesions tend to occur on the extremities more so than the trunk. Sweet’s syndrome may be associated with hemato- logical malignancy, especially acute myelogenous leukemia, as well as infl ammatory bowel disease, particularly Crohn’s disease (Burrows, 1995 ; Mustafa & Lavizzo, 2008 ). Th e initial episode is oft en thought to be cellulitis or erysipelas. Patients are placed on antibiotics empirically and, as spontaneous remission The Skin and the Gastrointestinal Tract 103 occurs, this reinforces the misdiagnosis. Patients may become secondarily infected, further causing confusion.

Bowel Bypass Syndrome

Bowel bypass syndrome refers to a constellation of cutaneous and arthritic symptoms related to, but not exclusively associated with, bypass surgery. Although this procedure is not routinely performed today, patients with its complications are still seen by physicians. Interestingly, a similar clinicopatho- logical syndrome has been reported in patients without surgery but with other bowel conditions, particularly infl ammatory bowel disease. Th erefore, the term bowel-associated dermatosis-arthritis syndrome has been proposed, to include patients without bowel bypass surgery for obesity. Th e common risk factor appears to be bowel stasis, which promotes bacterial overgrowth with either disease, or surgically induced blind loops. Th e bowel bypass syndrome consists clinically of a characteristic, intermittent neutrophilic dermatosis, oft en associated with polyarthritis, tenosynovi- tis, malaise, and fever. Cryoglobulinemia is commonly found. Th e syndrome oft en mimics gonococcal sepsis. Skin manifestations consist of characteristic lesions that are erythematous macules, oval in shape, ranging from 3 mm to 10 mm in diameter. Th e skin lesions consist of sweeps of neutrophils, very much like Sweet’s syndrome. Th e formation of vesicles become pustular, and may appear similar to disseminated gonococcal disease. Th ey may become painful, and last for up to a week but remain sterile on culture.

Erythema Nodosum

Erythema nodosum accompanied by gastrointestinal complaints includes infl ammatory bowel disease, Behcet’s disease, bacterial gastroenteritides, pancreatitis, celiac disease, and Whipple’s disease (Schwartz & Nervi, 2007 ). Erythema nodosum is the most common form of septal panniculitis, and the most frequent skin manifestation associated with infl ammatory bowel disease. Since the development of erythema nodosum is closely related with a variety of disorders and conditions, it can serve as an important early sign of systemic disease. Aphthous stomatitis and pyoderma gangrenosum, along with erythema nodosum, are the most common skin disorders related to infl ammatory bowel disease (Farhi et al., 2008 ). Erythema nodosum clinically presents as multiple, bilateral, painful, non-ulcerating, subcutaneous nodules that undergo characteristic color changes commencing with bright erythema, and ending in 104 INTEGRATIVE GASTROENTEROLOGY bruise-like areas. It occurs most commonly on the extensor surface of the shins, and is less common on the thighs and arms. It usually subsides in 3 to 6 weeks without scarring or atrophy, but may be chronic.

Acrodermatitis Enteropathica

Acrodermatitis enteropathica is most oft en a hereditable disease of infancy or childhood, related to the malabsorption of zinc (Maverakis et al., 2007 ). Zinc defi ciency can be an acquired condition in adults as a result of infl ammatory bowel disease, or as a result of nutritional deprivation of zinc. Eczematous, psoriasiform, and vesicular lesions have been described, most of which occur in acral locations and, sometimes, on the face as well. Th e same process may be associated in adults with niacin defi ciency and the glucagonoma syndrome (Teixeira, Nico, & Ghideti, 2008 ).

Dermatitis Herpetiformis

Dermatitis herpetiformis (DH) is an autoimmune blistering skin disease associated with a gluten-sensitive enteropathy. Gluten sensitivity usually presents as celiac disease in infancy and childhood, and DH later in life. It is associated with IgA antibody formation and gluten-sensitive enteropathy, but 90 % if patients have no gastrointestinal symptoms (Oxentenko & Murray, 2003 ). Skin lesions are extremely itchy groups of vesicles, most oft en found on extensor surfaces. Th ere is burning, stinging, and intense pruritus. Erythematous vesicles are symmetrical over the extensor surfaces, including elbows, knees, buttocks, shoulders, and neck. Th ere may be associated crusts and erosions. Patients oft en complain of stinging or burning of the skin before the appearance of new lesions (Nicolas et al., 2003 ). Th e oral mucosa is usually not involved, nor are the palms or soles. Biopsy is required for diagnosis. Light microscopy alone is oft en inadequate, and direct immunofl uorescence is usually necessary to confi rm the diagnosis. Granular IgA deposits in dermal papillae of perilesional skin, observed by direct immunofl uorescence, are diagnostic (Kárpáti, 2004 ).

Pancreatic Panniculitis

Pancreatic panniculitis is an uncommon cutaneous eruption that is associated with disorders of the pancreas, both benign and malignant (García-Romero & Vanaclocha, 2008 ). Th e most common disorders associated with pancreatic The Skin and the Gastrointestinal Tract 105 panniculitis are acute or chronic pancreatitis, especially the alcohol-related types, and pancreatic carcinoma. Although the underlying pancreatic pathologic conditions vary, the clinical features of pancreatic panniculitis are similar (Sagi et al., 2008 .). Th e legs are the most commonly aff ected area, but the lesions can also occur on the arms, thighs, and trunk. Th ey begin as erythematous or red-brown subcutaneous nodules, with a tendency to central soft en- ing. In the mild form, they may involute within weeks and leave an atrophic hyperpigmented scar. If the fat necrosis is severe, individual nodules may break down and ulcerate (Shehan & Kalaaji, 2005 ).

Hepatitis C

Hepatitis C may be associated with a number of cutaneous disorders, but classically with mixed cryoglobulinemia (Agnello & Romain, 1996 ). Cryoglobulins are abnormal immunoglobulins that form complexes and precipitate out of serum at low temperatures, and redissolve upon warming or returning to room temperature. Cryoglobulins are made up of monoclonal antibodies of IgM or IgG, rarely IgA. Types II and III cryoglobulinemia (mixed cryoglobulinemia) contain rheumatoid factors (RFs), which are usually IgM and, rarely, IgG or IgA. Th ese RFs form complexes with the Fc portion of polyclonal IgG. Th e actual RF may be monoclonal (in Type II cryoglobulinemia) or polyclonal (in Type III cryoglobulinemia) immunoglobulin. Types II and III cryoglobulinemia represent 80 % of all cryoglobulins. Th e cryoglobulin concentration is usually low, just above 1mg/ml. Types II and III are called mixed cryoglobuline- mias, and are associated with chronic infl ammatory states, such as systemic lupus erythematosus (SLE), Sjögren’s syndrome, and viral infections, particularly HCV (Della Rossa et al., 2001 ). Cutaneous vasculitis associated with cryoglobulinemia and hypocomplementemia is not uncommon in the course of chronic active hepatitis C infection. Th e triad of necrotizing vasculitis, chronic hepatitis C infection, and cryoglobulinemia, occurs late aft er initial infection with hepatitis C (La Civita et al., 1996 ). In these disorders, the IgG fraction is always polyclonal, with either monoclonal (Type II) or polyclonal (Type III) IgM (rarely IgA or IgG), and RF activity. Cutaneous fi ndings in cryoglobulinemia include erythematous to purpuric macules, papules and urticarial plaques, livedo, acral necrotic infarction, hemorrhagic erosions, painful distal ulcers, and extensive postinfl ammatory hyperpigmentation. Skin biopsy most oft en reveals small-vessel leukocytoclastic vasculitis and, less frequently, infl ammatory or noninfl ammatory purpura, noninfl ammatory hyaline thrombosis, and postinfl ammatory sequelae. HCV virus has also been identifi ed in vessel walls (Schott, Hartmann, & Ramadori, 2001 ). 106 INTEGRATIVE GASTROENTEROLOGY

Helicobacter pylori

Th ere is increasing evidence for systemic eff ects of gastric H. pylori infection, which may result in extragastrointestinal disorders (Rojo-García et al., 2000 ). Th ere is some evidence for a potential link of H. pylori infection and chronic urticaria, although the data are still confl icting. Th us, the search for H. pylori should be included in the diagnostic management of chronic urticaria. With regard to other skin diseases such as rosacea, a higher prevalence of H. pylori infection in rosacea patients than in healthy controls has been reported, and may be worth evaluation (Buechner, 2005 ).

Malignancy-Associated Disorders

GLUCAGONOMA SYNDROME

Glucagonoma syndrome is a paraneoplastic phenomenon characterized by an islet alpha-cell pancreatic tumor, necrolytic migratory erythema on the skin, diabetes mellitus, weight loss, anemia, stomatitis, thromboembolism, and gastrointestinal and neuropsychiatric disturbances. Th ese clinical fi ndings, in association with hyperglucagonemia and demonstrable pancreatic tumor, establish the diagnosis. Glucagon itself is responsible for most of the observed signs and symptoms, and its induction of hypoaminoacidemia is thought to lead to necrolytic migratory erythema. Liver disease, and fatty acid and zinc defi ciency states, may also contribute to the pathogenesis of the eruption in some cases (Chastain, 2001 ). At diagnosis, most glucagonomas are malignant and oft en metastatic (Chen et al., 2005 ). Th e diagnostic features of necrolytic migratory erythema include a chronic migratory cutaneous eruption with advancing borders, which oft en contain vesicopustules. Patients also usually have glossitis, angular cheilitis, blepharitis, weight loss, and abnormal glucose tolerance.

BAZEX’S SYNDROME

Acrokeratosis paraneoplastica (Bazex’s syndrome) is a rare paraneoplastic dermatosis characterized by psoriasiform and erythematous plaques, typically aff ecting hands, feet, nose, and earlobes. Th e condition almost exclusively aff ects Caucasian men older than 40 years. It is usually associated with primary The Skin and the Gastrointestinal Tract 107 malignant neoplasms of the upper digestive tract, especially esophageal carcinoma, as well as cervical lymph node metastases from an unknown primary tumor. Other rare associations include adenocarcinoma of the stomach or uterus, anaplastic small-cell carcinoma of the lung, Hodgkin’s lymphoma transitional-cell carcinoma of the bladder, adenocarcinoma of the colon, and squamous cell carcinoma of the lower leg (Rao & Shenoi, 2004 ). In most cases, the skin changes precede the clinical manifestation of the underlying neoplasm. Th e dermatosis can be cured only by removal of the underlying carcinoma (Sator, Breier, & Gschnait, 2006 ).

PALMOPLANTAR KERATODERMAS

Palmoplantar keratodermas are a heterogeneous group of disorders characterized by diff use, abnormal thickening of the palms and soles, with autosomal recessive and dominant, X-linked, and acquired forms, all having been described. Some hereditary types, as well as some acquired forms, have been associated with pancreatic carcinoma, as well as other carcinomas (Kaur, Sarkar, & Kanwar, 2002 ).

ACANTHOSIS NIGRICANS

Although acanthosis nigricans is a skin condition that occurs most oft en with insulin resistance associated with obesity, particularly with Cushing’s syndrome or Type 2 diabetes, it is arguably also the most well-recognized cutaneous sign of internal malignancy. Acanthosis nigricans is characterized by hyperpigmentation, velvety cutaneous thickening, and intensifi ed skin mark- ings, oft en with the development of verrucous or skin-tag-like excrescences typically involving the intertriginous areas, but may also be found on the lips and within the mouth (Kaminska-Winciorek et al., 2007 ). It has been reported with many kinds of cancer, but the most common underlying malignancy is an adenocarcinoma of gastrointestinal origin, usually a gastric adenocarcinoma (Bohm, Luger, & Metze, 1999 ).

GARDNER’S SYNDROME

Gardner’s syndrome is the association of multiple colonic and rectal polyps with sebaceous cysts and jaw osteomas (Parks, Caldemeyer, & Mirowski, 2 0 0 1 ) . Th e signifi cance of this dominantly inherited condition is that the 108 INTEGRATIVE GASTROENTEROLOGY polyps usually undergo malignant change by the fourth decade, and the extraintestinal lesions may be apparent before those in the bowel. Th erefore, early detection of multiple jaw osteomas and/or multiple sebaceous cysts, particularly on the scalp, may lead to appropriate further investigation and treatment prior to malignant transformation (Basaran & Erkan, 2008 ). Gardner described the occurrence of familial adenomatous polyposis, with the extracolonic manifestations of desmoids, osteomas, and epidermoid cysts in the skin and the gastrointestinal tract. Th e number of polyps can range from no detectable polyps at colonoscopy, to more than 7,000 seen on resected specimens of bowel. Th e polyposis predominantly aff ects the left colon (Bilkay et al., 2004 ).

PEUTZ-JEGHERS SYNDROME

Peutz-Jeghers syndrome is a dominantly inherited polyposis syndrome characterized by hamartomatous polyps of the gastrointestinal tract, and mucocutaneous pigmentation and melanin spots. Th ey appear as small, fl at, brown or dark blue spots with the appearance of freckles, most commonly in the perioral area. Th ey may be present on the fi ngers and the toes, on the hands and the feet, and around the anus and genitalia. Of note, the lesions may fade considerably aft er puberty (Giardiello & Trimbath, 2006 ). Since its description, much debate has centered on the true malignancy risk of Peutz-Jeghers syndrome, including malignancy within and outside the gastrointestinal tract. Although the intestinal lesions are hamartomas, patients with Peutz-Jeghers syndrome are generally considered to have a 15-fold increased risk of developing intestinal cancer compared to that of the general population (Homan, Strazar, & Orel, 2005 ). Rare tumors such as adenoma malignum of the cervix occur in Peutz-Jeghers syndrome. Likewise, more common cancers occur at younger ages. Children may manifest symptoms of this disease, including gastrointestinal complications and malignancy (Brichard et al., 2005 ).

COWDEN SYNDROME

Cowden syndrome is an autosomal dominant disorder characterized by multiple hamartomas and a high risk of development of breast, thyroid, endometrial, and other cancers (Schrager et al., 1998 ). Th e classic features of the disease include mucocutaneous papillomatous papules and trichilemmomas on the malar area of the face (Kovich & Cohen, 2004 ). Most aff ected people develop these characteristic lesions by their early twenties. At least one of four types of skin lesions is present in nearly all cases. Facial papules are fl esh-colored, The Skin and the Gastrointestinal Tract 109 fl at-topped, dry or warty 1mm to 5mm papules around the mouth, nostrils, and eyes. Oral lesions are numerous 1mm–3mm smooth white spots on the gums and palate that create a cobblestone appearance known as papillomatosis (Jornayvaz & Philippe, 2008 ). Acral keratoses are fl esh-colored or slightly pig- mented smooth or warty papules on the upper surface of hands and feet. Palmoplantar keratoses are scaly spots on the palms and soles that also may occur. Noncancerous breast and thyroid diseases are also common.

Conclusions

Integrative practitioners should become aware of the various systemic manifestations of gastrointestinal disease. Dermatological conditions can precede, coincide, or occur aft er the underlying digestive disorder. Early recognition of dermatoses that underlie digestive health problems can lead to early diagnosis a n d t r e a t m e n t . 9 Premenstrual and Menstrual Exacerbation of IBS: An Integrative Medicine Analysis of the Bi-Directional Connection between Female Hormones and Gut Health

JOEL M. EVANS

key concepts

■ IBS symptoms oft en have premenstrual and menstrual exacerbations. ■ Progesterone dominance in the second half of the menstrual cycle explains the observation that constipation as an IBS symptom is more frequent in reproductive-aged women than in men. ■ S t r e s s i s p r o i n fl ammatory and known to exacerbate IBS. ■ Th e perimenstrual release of proinfl ammatory cytokines contributes to the observed increase in IBS symptoms during menstruation. ■ H e a l t h y g u t fl ora and overall gut health have a direct relationship to female hormonal health. ■ An integrative treatment plan for IBS includes normalizing hormone levels, as well as reducing stress and infl a m m a t i o n . ■

Introduction

omen have long been aware of the relationship of their menstrual cycle to nongynecologic health complaints. However, because W up to 75 % of women experience some recurrent premenstrual 110 Premenstrual and Menstrual Exacerbation of IBS 111 symptoms, there has been disagreement among medical authorities on whether to classify these nongynecologic health complaints as normal (physiologic) or abnormal. Th e premenstrual symptoms germane to IBS are the changes in bowel habits (abdominal pain, bloating, diarrhea and constipation) described by many healthy women, as well as those diagnosed with IBS.

Background: Menstrual Symptoms and IBS

In 1990, the medical literature began to address the connection between the menstrual cycle and IBS symptoms, when Whitehead et al. (1990 ) reported an increase in fl atulence, diarrhea, and constipation during menstruation. Th ese fi ndings were confi rmed by Heitkemper and Jarrett (1992 ) two years later. In 1998, Kane, Sable and Hanauer found that a high percentage of healthy women have a premenstrual change in many bowel symptoms, but this change is more pronounced in women with IBS. Interestingly, the authors also found that patients with IBS have more extraintestinal premenstrual and menstrual complaints than controls. Th is is an important fi nding when discussing possible emotional (neurochemical) factors underlying the physiologic mechanisms for the premenstrual worsening of IBS, including changes in serotonin levels, progesterone levels, and prostaglandin production. Women with an IBS diagnosis also report a fl uctuation in symptoms related to their menstrual cycle (Heitkemper & Jarrett, 2008 ).

EMOTIONAL FACTORS

Like PMS, the extent of the contribution of emotional factors to IBS has also been the subject of debate, with some authors even describing IBS as part of the spectrum of purely depressive disorders (Kovacs & Kovacs, 2007 ). In fact, stress is well known to both exacerbate symptoms of IBS in humans, and cause increased intestinal permeability in rodents (Gareau et al., 2008 ).

Stress itself can cause increased intestinal permeability.

However, even though stress itself increases infl ammation (Miller et al., 2002 ), when describing the premenstrual and menstrual exacerbations of IBS it is most accurate to classify stress and emotions as contributing factors, rather than the predominant factor, to the other, more signifi cant underlying mechanisms mentioned earlier. Th ese mechanisms will now be discussed in further 112 INTEGRATIVE GASTROENTEROLOGY detail, to better understand the basis for an integrative approach to premen- struation- and menstruation-exacerbated IBS.

HORMONES AND IBS

Th e second half, or luteal phase, of the menstrual cycle is associated with progesterone dominance relative to estrogen, with a sharp decrease of both hormones at the end of the luteal phase causing a destabilization of the endometrial lining, ending in menstruation.

Because progesterone is known to have the effect of decreasing gut motility (Gonne et al., 2006 ), the hormonal milieu of progesterone dominance explains the clinical observation that women with IBS, as opposed to men, frequently present with constipation as the dominant IBS complaint (IBS-C).

It also explains why symptoms associated with increased motility occur immediately before and during menstruation, when progesterone levels are at their nadir. In addition, as women go through the age-related spectrum of hormonal transition of reproductive age to menopause, the hormonal shift that occurs fi rst is a drop in luteal phase progesterone levels (Lipson et al., 1992 ). Th e gynecologic literature is fi lled with research attempting to explain the hormonal imbalances associated with premenstrual syndrome (PMS), and a recent Cochrane literature review on the subject (Ford et al., 2006a ), found some evidence for relief with progesterone administration. Th is would help support the progesterone hypothesis, which states that decreasing levels of progesterone are responsible for the myriad symptoms associated with PMS. However, the trials referenced in the Cochrane review diff ered in route of administration, dose, and duration of treatment, as well as selection of participants. Although still a theory at this point, the progesterone hypothesis is a plausible explanation for the observed worsening of IBS symptoms seen in women with PMS (Altman et al., 2006 ).

INFLAMMATION AND IBS

Th e fi nal mechanism to explain menstrual exacerbation of IBS is the proinfl ammatory state associated with menses. While all clinicians are familiar with Premenstrual and Menstrual Exacerbation of IBS 113 the therapeutic effi cacy of antiprostaglandin medications in the treatment of dysmenorrhea, further research (Wander et al., 2008 ) has shown that menstruation is associated with a 17 % increase in C-reactive protein, a biomarker of infl ammation. Th is shows that menstruation induces a systemic infl ammatory state. Additionally, there is a documented local and systemic infl ammatory cytokine release that is associated with both the tissue breakdown and progesterone withdrawal that accompanies menstruation (Critchley et al., 2 0 0 1 ) .

The systemic increase in proinﬂ ammatory cytokines serves as a further explanation for the observed increase in IBS symptoms during menstruation (O’Mahony et al., 2005 ).

Gynecological Manifestations of IBS

So far, the discussion has centered on the exacerbations of IBS that accompany the premenstrual and menstrual phases of a woman’s hormonal cycle. However, practitioners that are active in caring for women are likely to note that their patients suff ering from endometriosis, chronic pelvic pain, and dysmenorrhea are more likely to also have IBS symptoms or an IBS diagnosis. In fact, one out of three women with chronic pelvic pain has IBS symptoms (Zondervan et al., 2 0 0 1 ) .

Anti-Inﬂ ammatory Therapeutic Options to Improve Gynecological Health

Th e common underlying pathophysiologic mechanism of infl ammation is the link between all of these conditions, and serves as the basis for using a broad anti-infl ammatory approach (supplementing with fi sh oil, hops, rosemary, bromelain, turmeric, quercetin) to address both menstrual and gut symptoms (De Giorgio & Barbara, 2008 ). In addition, treating the underlying abnormalities in the gut— for example, by avoiding foods that create an infl ammatory reaction, and supplementing with anti-infl ammatory probiotics (such as Lactobacillus plantarum 299v, Lactobacillus acidophilus NCFM® , and Bifi dobacterium lactis ), in order to decrease gut induced infl ammation — will oft en dramatically decrease the severity of gynecologic symptoms. 114 INTEGRATIVE GASTROENTEROLOGY

The Gut–Gynecological Axis of Health

All of the preceding relationships can be summarized as showing that hormonal changes aff ect gut function, both directly (progesterone mediated eff ects) and indirectly (infl ammation mediated eff ects). However, the relationship between the gut and female hormonal milieus is really bidirectional. In other words, it is not just that hormonal health aff ects gut health, but also that gut health infl uences hormonal health. It is crucial for practitioners treating bowel dysfunction to be aware of this bidirectionality, because by ensuring optimal gut health in their female patients, they are not only helping them lead more comfortable lives but also helping prevent and treat common estrogen- related disorders (endometriosis, fi broid tumors, breast cancer).

The Gut and Gynecological Hormonal Health

Th e connection between gut health and hormonal health has its basis in the way estrogen is eliminated by the body. All of a woman’s circulating estrogen that does not bind to an estrogen receptor in estrogen-sensitive tissue (such as breast and endometrium) must be eliminated through the liver via the Phase I and Phase II detoxifi cation pathways. It is then secreted into the bile, and dumped into the gut for elimination via stool.

Any process that impairs Phase I or Phase II detoxiﬁ cation, whether genetic (CYP 450 polymorphisms), environmental (increased toxic burden), or nutritional (decreased micronutrient or protein intake), will decrease estrogen elimination.

Nutritional Interventions to Improve Gynecological and Gut Health

Phase II detoxifi cation of estrogen involves the attachment, or conjugation, of other compounds to enable the estrogen molecule to be excreted in the bile and then into the gut for elimination. Th e most important conjugation reaction for estrogen elimination is glucuronidation, whereby a glucuronide molecule is attached to estrogen to form an estrogen glucuronide. Th is relates to Premenstrual and Menstrual Exacerbation of IBS 115 gut health, in that the most common reason for impaired glucuronidation (and, therefore, reduced estrogen elimination) occurs when abnormal or unhealthy gut fl orae are present, as they secrete an enzyme called beta- glucuronidase. Th is enzyme cleaves the glucuronide molecule from the estrogen-glucuronide that was sent to the gut through the bile, leaving free estrogen to be reabsorbed systemically via enterohepatic recirculation. Interventions that have been shown to improve glucuronidation include a low-animal-fat diet, and supplementation with probiotics and calcium-D-glu- carate (Walaszek et al., 1997 ). Th us, eliminating constipation and ensuring regular bowel movements in patients with IBS now has a whole new level of importance.

Conclusions

In summary, the physiological mechanisms described in this chapter associated with the luteal phase of the menstrual cycle, PMS, and menstruation, explain the observed phenomenon of IBS exacerbation during those periods. Th e systemic infl ammation associated with chronic pelvic pain and other gynecologic disorders explains the observation of increased in IBS in those patients. Lastly, the connection between gut health and estrogen elimination demonstrates the importance that gut health has in estrogen related disorders. Th erefore, a truly integrative approach to managing IBS in women, in addition to therapies targeting the gut, addresses all of these additional factors. Helping women with IBS assess and normalize hormone levels, reduce systemic and gastrointestinal infl ammation, ensure healthy gut fl ora, and identify their stressors and resolve their interpersonal confl icts, will not only improve their IBS but will also help decrease the symptoms and incidence of the disorders associated with excess estrogen, allowing women to experience healthier and happier lives. Th is is the true defi nition of a holistic approach, and is exactly what brings joy and fulfi llment to the busy lives of integrative practitioners. 1 0 Fibromyalgia and Gastrointestinal Disorders

DAVID M. BRADY AND MICHAEL J. SCHNEIDER

key concepts

■ Fibromyalgia syndrome (FMS) does not appear to be a disorder of peripheral tissues, including muscle, but a dysfunction within the central nervous system (CNS) that involves the processing of sensory stimuli. ■ Dysfunction of CNS processing of pain, and overactivity of the hypothalamic-pituitary-adrenal (HPA) axis and sympathetics, are likely the root causes of classic FMS. ■ 5-hydroxytryptophan, a serotonin precursor, is eff ective in improving the symptoms of FMS. ■ Many studies have demonstrated a common association (comorbidity) between IBS and FMS, ranging from 30% to more than 80 % . ■ Patients with FMS frequently have nonspecifi c bowel complaints similar to those with small intestinal bacterial overgrowth (SIBO). ■ S i g n i fi cant improvement in IBS symptoms has been reported aft er antibiotic treatment, including rifaximin, typically used to t r e a t S I B O . ■

Introduction

ibromyalgia syndrome (FMS) remains an elusive condition of unknown etiology, with a strong prevalence of overdiagnosis, in which patients F report chronic widespread pain (allodynia or hyperalgesia) and a variety of other complaints, including fatigue, sleep disorders, cognitive defi cit, irritable

116 Fibromyalgia and Gastrointestinal Disorders 117 bowel and bladder syndrome, headache, Raynaud’s syndrome, bruxism, atypical patterns of sensory dysesthesia, and other symptoms suggestive of autonomic nervous system or neuroendocrine dysregulation (Fitzcharles & Boulos, 2003 ; Wolfe, Smythe, Yunus et al., 1990 ; Wolfe, 2003 ; Staud, Cannon, Mauderli et al., 2003 ; Gracely, Petzke, Wolf, & Clauw, 2002 ; Jacobsen, Danneskiold- Samsoe, & Lund, 1993 ; Jain, Carruthers, & van de Sande, 2003 ; Abeles, Pillinger, Solitar, & Abeles, 2007 ). Despite the name of the condition— “fi bro-myalgia” — there are no data to support the hypothesis that FMS is a distinct pathological disorder of the soft tissues. More recent data tends to support the notion that FMS is a disorder of the central nervous system (CNS) pain- processing pathways, and not some type of primary rheumatologic disorder (Jacobsen et al., 1993 ; Jain, Carruthers, & van de Sande, 2003 ). It has been well established in the literature that FMS patients are predominantly female (female to male ratio of 10–20:1), typically report nonrefreshing sleep, general fatigue, low energy and vague gastrointestinal complaints, and experience concomitant anxiety and depression disorders. In true fi bromyalgia, there are physical symptoms suggestive of an underlying psychological disorder, mediated by overactivity of the limbic system and hypothalamic-pituitary-adrenal (HPA) axis, causing the multiple symptoms seen in the “classic” cases of FMS in rheumatology clinics. Th ese classic cases probably represent the somatic manifestations of extreme emotional stress and/or psychological illness, yet are distinct from a true somatization disorder in which there is no real physical illness. It is too simplistic to state that all cases of classic FMS merely represent a somatic manifestation of clinical depression or anxiety, because not all patients with depression or anxiety disorders experience the symptom of widespread allodynia with multiple tender points. Yet, it has been known for almost 20 years that FMS patients oft en respond well (at least in the short term) to low doses of antidepressant medications, suggesting that there is signifi cant overlay between mood disorders and FMS. Recent studies are starting to implicate the role of the limbic structures (hippocampus, amygdala, and hypothalamus) and neuroendocrine system in the production of FMS symptoms. One study showed diff erences in circadian cortisol release in FMS versus healthy controls, suggestive of overactivity of the HPA axis in these patients (Croff ord, Young, Engleberg et al., 2004 ). Various types of thermal, mechanical, and electrical modalities have been applied to FMS and healthy controls, and consistently the FMS group shows signs of central sensitization (Desmeules, Cedraschi, Rapiti et al., 2003 ). PET scans and fMRI studies of the brain activity of FMS subjects versus healthy controls, while they receive innocuous sensory stimulation, have shown that FMS patients’ limbic structures are activated by nonpainful stimuli, which only activate the sensory cortex in healthy controls (Gracely, Petzke, Wolf, & Clauw, 2002 ). 118 INTEGRATIVE GASTROENTEROLOGY

It is not currently known exactly why certain patients with emotional illnesses or mood disorders will develop the characteristic symptoms of what is termed FMS, and why others with the same level of psychopathology do not experience these symptoms. Th ere could be a combination of factors, including genetic predispositions that may, in future research, be shown to be associated with the production of FMS symptoms. A recent study of family members and probands of FMS patients showed that reduced pressure-pain thresholds aggregate in families, and that FMS co-aggregates with major mood disorders in families (Arnold, Hudson, Hess et al., 2004 ). Th e relevance for the physician seeing these patients is the recognition that mental health and mood disorders may be the root cause of the symptoms of widespread pain, allodynia, sleep disorders, and cognitive defi cit that could easily be misdiagnosed as a purely physical disorder. It would seem appropriate for the primary care physician to refer these patients for cognitive behavioral therapy or other forms of psychological counseling, rather than for physical therapy. A recent systematic review of the literature has shown that cognitive behavioral therapy is an eff ective treatment strategy for FMS patients, along with mild exercise and low-dose antidepressant medication (Sim & Adams, 2002 ). More recent studies have supported the use of serotonin and norepinephrine reuptake inhibitors (SNRIs), such as duloxetine and milnacipran, and alpha-2 delta ligands, such as pregabalin, in the treatment of FMS (Arnold, 2006 ). Th is makes sense, in light of the fact that serotonin and norepinephrine are the key neurotransmitters released at the synapses between the limbic system interneurons and the brainstem nuclei that control the descending antinociceptive system (DANS). Other studies have supported the use of natural serotonin precursors, such as 5-hydroxytryptophan, as well as nutraceuticals that have a calming eff ect on the CNS, such as phosphytidylser- ine, in the complementary treatment of FMS (Caruso & Puttini, 1992 ; Caruso et al., 1990 ; Manteleone P et al., 1992 ). However, before any diagnosis of FMS is rendered and treatment initiated, great attention must be paid to adequate diff erential diagnosis and assurance of the existence of a central pain processing disorder (Schneider & Brady, 2001 ; Schneider, Brady, & Perle, 2006 ; Dadabhoy & Clauw, 2006 ).

• The diagnosis of ﬁ bromyalgia syndrome should not be used to categorize all patients with widespread pain and fatigue of unknown origin. • Many other medical conditions can be misdiagnosed as ﬁ bromyalgia syndrome, including hypothyroidism, anemia, Lyme disease, dysglycemias, metabolic abnormalities, mitochondrial dysfunction, myofascial pain syndrome and many other musculoskeletal disorders (Schneider & Brady, 2001 ; Schneider, Brady, & Perle, 2006 ; Dadabhoy & Clauw, 2006 ). Fibromyalgia and Gastrointestinal Disorders 119

Fibromyalgia and Irritable Bowel Syndrome

Irritable bowel syndrome (IBS) aff ects approximately 11 % to 14 % of the population. It is a condition with multiple models of pathophysiology, including altered motility, visceral hypersensitivity, abnormal brain–gut interaction, autonomic dysfunction, and immune activation (Lin, 2004 ). Th is chronic functional bowel disorder, characterized by both visceral and somatic hyperalgesia, produces eff ects similar to those seen with the central hypersensitivity mechanisms in FMS (Frissora & Koch, 2005 ; Moshiree, Price, Robinson, Gaible, & Verne, 2007 ). Many studies have demonstrated a common association or comorbidity between IBS and FMS, ranging from 30 % to more than 80 % (Riedl, Schmidtmann, Stengel et al., 2008 ; Garcia, 2007 ; Cole, Rothman, Cabral et al., 2006 ; Kurland, Coyle, Winkler, & Zable, 2006 ; Wallace & Hallegua, 2004 ; Verne & Price, 2002 ; Whitehead, Palsson, & Jones, 2002 ; Lubrano, Iovino, Tremolaterra et al., 2001 ; Sperber, Carmel, & Atzmon, 2000 ; Sperber, Atzmon, Neumann et al., 1999 ; Price, Zhou, Moshiree et al., 2006 ). Prevalence rates reported by Kurland et al. (2006 ) of IBS in FMS patients (n=105) was 63% by Rome I and 81% by Rome II criteria, compared to the prevalence of IBS in controls (n=62) of 15% by Rome I and 24% by Rome II criteria (FM vs. control; p<0.001). Lubrano et al. (2001 ) reported a prevalence of FMS in approximately 20% of IBS patients. However, since the commonly used diagnostic criteria of FMS include IBS, the relationship of the two syndromes is diffi cult to analyze (Azpiroz, Dapoigny, Pace et al., 2000 ). A female predominance has been reported in both IBS and FMS. It has been suggested that the female predominance in IBS patients may result mainly from coexisting FMS (Akkus, Senol, Ayvacioglu et al., 2004 ). Visceral hypersensitivity, measured by decreased pain thresholds to gut distension, is considered a biological marker of IBS. However, patients with IBS also have many extraintestinal symptoms consistent with hyperalgesic states, and they may also exhibit cutaneous hyperalgesia similar to that seen in other chronic and global pain disorders, including FMS (Verne & Price, 2002 ). Th is suggests not only comorbidity between IBS and FMS, but some shared mechanisms of central nociceptive pathophysiology. It has been hypothesized that the visceral and cutaneous hyperalgesia seen in IBS is likely to be at least partly related to sensitization of spinal cord dorsal horn neurons and, in this respect, may be similar to other persistent pain conditions such as FMS (Price, Zhou, Moshiree et al., 2006 ). Patients with IBS and FMS show greater thermal hypersensitivity compared to patients with IBS alone, while IBS patients exhibit higher pain ratings to rectal distension compared to those with both 120 INTEGRATIVE GASTROENTEROLOGY

IBS and FMS. Th is suggests that the regions of primary and secondary hyperalgesia are dependent on the primary complaint (Moshiree et al., 2007 ). Current research appears to indicate that, although they share a common hypersensitivity background, multiple mechanisms may modulate perceptual somatic and visceral responses in patients with IBS and FMS (Caldarella, Giamberardino, Sacco et al., 2006 ). Whitehead et al. (2002 ) conclude that, “Multivariate statistical analyses suggest that these are distinct disorders, but their strong comorbidity suggest a common feature important to their expression, which is most likely psychological.” High rates of psychiatric comorbidity have been reported in patients with IBS and FMS. One of the psychiatric comorbidities associated with FMS is post-traumatic stress disorder (PTSD). However, studies have shown a lower-than-expected prevalence of PTSD among IBS patients (Cohen, Jotkowitz, Buskila et al., 2006 ). Patients with coexisting IBS and FMS have worse scores on the health-related quality of life (HRQOL) indices than patients with either disorder alone (Sperber et al., 1999 ). In summary, the underlying pathophysiological mechanisms of IBS and FMS have much in common, and strong comorbidity certainly exists, but they do not necessarily appear to be the same disorder. Patients who exhibit both disorders fare worse symptomatically, and may have greater over- a l l m o r b i d i t y .

Fibromyalgia and Small Intestinal Bacterial Overgrowth

Patients with FMS frequently have nonspecifi c bowel complaints similar to those with small intestinal bacterial overgrowth (SIBO; see Wallace & Hallegua, 2004 ). SIBO is a condition in which colonic aerobic and anaerobic bacteria are overrepresented in the small intestine. Th ere is a growing body of evidence suggesting that SIBO may play a signifi cant role in a wide range of gastrointestinal disorders, including Crohn’s disease and IBS (Funayama, Sasaki, Naito et al., 1999 ; Pimentel., Park, Mirocha, Kane, & Kong, 2006 ; Pimentel, Chow, & Lin, 2003 ; Sharara, Aoun, Abdul-Baki et al., 2006 ).

Recent studies indicate that up to 84 % of patients with IBS have an abnormal lactulose breath test result, suggesting small bowel bacterial overgrowth. (Pimentel et al., 2006 )

Pimentel et al., (2001 , 2004 ) using lactulose hydrogen breath testing (LHBT), reported that of 123 subjects with FMS, 96 (78 % ) were found to have SIBO. (Pimentel et al, 2001 ; 2004 ). Of these 123 subjects with FMS, 87% also met the Fibromyalgia and Gastrointestinal Disorders 121

Rome I criteria for IBS. Of 25 subjects who returned for follow-up LHBT, 11 achieved complete eradication and 14 achieved incomplete eradication of their SIBO with antibiotic therapy. Improvement in GI symptoms, including bloating, gas, diarrhea, constipation, and abdominal pain, as well as general symptoms of pain, fatigue, and sleeplessness, were also reported via follow-up patient questionnaires. Better clinical results were clearly observed with complete eradication. Antibiotics, such as neomycin, seem to improve symptoms in many subjects, but eff ectively eliminate SIBO in only about 25 % of patients, and side eff ects limit their use (Pimentel et al., 2006 ). Rifaximin is a gut- selective antibiotic with negligible systemic absorption (<0.4% ), minimal side eff ects [similar to placebo], and broad-spectrum activity in vitro against Gram- positive and Gram-negative aerobes and anaerobes. It results in eff ective eradication of SIBO in up to 70% of cases (Jiang & DuPont, 2005 ; Di Stefano, Malservisi, Veneto, Ferrieri, & Corazza, 2000 ). Rifaximin also has known activity against Clostridium diffi cile (Marchese, Salerno, Pesce, Debbia, & Schito, 2000 ). Traditionally, small bowel aspirate (> 10 5 cfu/ml) has been accepted as the gold standard for SIBO diagnosis. However, breath testing and urinary markers, including cholyl-PABA and indican, have frequently been used due to their convenience and noninvasive nature. However, a systematic review by Khoshini et al. ( 2008 ) concluded that there is no well-validated test or gold standard for the diagnosis of SIBO. A better method for accurately identifying SIBO is needed, and quantitative bacterial polymerase chain reaction (PCR) may serve this role for the future. According to Khoshini, the most practical current clinical method may be a test, treat, and outcome technique. Animal models have suggested that SIBO results in bacterial translocation to mesenteric lymph nodes, and can produce systemic eff ects possibly mediated by Gram-negative endotoxins, which could explain the soft tissue hyperalgesia seen in some subjects labeled, incorrectly or not, with FMS (Berg, Wommack, & Deitch, 1988 ; Wells, Barton, Jechorek et al., 1991 ; Guarner, Runyon, Young et al., 1997 ; Nieuwenhuijs, Verheem, van Duijvenbode- Beumer et al., 1998 ; Lichtman, Keku, Clark et al., 1990 ; Lichtman, Sartor, Keku et al., 1990 ; Riordan, Melvor, & Williams, 1998 ; Maier, Wiertelak, Martin D et al., 1993 ; Watkins, Wiertelak, Goehler et al., 1994 ; Watkins, Wiertelak, Furness et al., 1994 ; Wiertelak, Smith, Furness et al., 1994 ; Kanaan, Saade, Haddad et al., 1996 ; Cahill, Dray, & Coderre, 1998 ; Walker, Dray, & Perkins, 1996a , 1996b ). Lin ( 2004 ) concludes that, “Th e gastrointestinal and immune eff ects of SIBO provide a possible unifying framework for understanding frequent observations in IBS, including postprandial bloating and distension, altered motility, visceral hypersensitivity, abnormal brain–gut interaction, autonomic dysfunction and immune activation.” 122 INTEGRATIVE GASTROENTEROLOGY

Conclusions

Fibromyalgia syndrome (FMS) consists of dysfunction within the central nervous system that involves the processing of sensory stimuli, overactivity of the hypopituitary-adrenal (HPA) axis and sympathetics, and dysfunction of the descending antinociceptive system, resulting in altered pain perception, fatigue, mild depression, vague gastrointestinal complaints, and a host of other symptoms. A strong association exists between FMS, irritable bowel syndrome (IBS), and small intestinal bacterial overgrowth (SIBO), which may involve some common mechanisms of pathophysiology and provide a framework for common treatment. Th e gut-selective antibiotic rifaximin has been shown to have negligible systemic absorption, minimal side eff ects, and results in eff ective eradication of SIBO in up to 70% of cases. Improvement in GI symptoms, including bloating, gas, diarrhea, constipation, and abdominal pain, as well as general symptoms of pain, fatigue, and sleeplessness, has been reported with successful eradication of SIBO. Serotonin appears to be a key neurotransmitter involved in altered pain perception and sleep disturbances observed in FMS, and may also play a critical role in functional bowel disorders, including IBS. Th e use of serotonin and norepinephrine reuptake inhibitors, such as duloxetine and milnacipran, and alpha-2 delta ligands such as pregabalin, as well as the serotonin precursor 5-hydroxytryptophan, have demonstrated eff ectiveness in improving the symptoms of FMS. Oral administration of phosphatidylserine may counteract stress- induced activation of the HPA axis, as is commonly found in FMS subjects. Management of each of these elements of the FMS patient’s possible clinical presentation is essential to achieve comprehensive and successful outcomes. 1 1 Acupuncture for Digestive System

SANGHOON LEE AND TA-YA LEE

key concepts

■ Acupuncture is a modality that can channel energy and blood fl ow to infl uence digestive function. ■ Acupuncture has been shown to be benefi cial for a number of gastrointestinal motility disorders. ■ Stimulating PC6 point (located on the forearm) has been most frequently applied for nausea and vomiting. ■ Electro-acupuncture may increase the threshold of rectal sensitivity in irritable bowel syndrome patients. ■ Acupuncture has been shown to benefi t irritable bowel syndrome and infl ammatory bowel disease patients; however, sham-controlled studies have been inconsistent and lack u n i f o r m i t y . ■

Introduction

cupuncture (from Lat. acus, “needle,” and pungere, “to prick”) (Mayor, 2006 ) is a technique of inserting and manipulating fi ne needles into A specifi c points on the body, with the aim of relieving pain, and for therapeutic purposes. According to traditional Chinese acupuncture theory, these acupuncture points lie on meridians along which qi, the vital energy, fl ows. Th ere is no generally accepted anatomical or histological basis for these concepts, and modern acupuncturists tend to view them in functional rather than structural terms. Acupuncture originated in China and is most commonly associated with traditional Chinese medicine (TCM). Diff erent types of

123 124 INTEGRATIVE GASTROENTEROLOGY acupuncture (Classical Chinese, Korean, Japanese, Tibetan, and Vietnamese acupuncture) are practiced and taught throughout the world.

What Is Energy Flow?

Energy, or qi, fl ows up and down the meridians. Sometimes the energy is blocked, defi cient, excessive, or unbalanced. Th is throws Yin and Yang out of balance, which in turn causes illness. Acupuncture restores the balance, thus encouraging healing.

Why Needles?

Acupuncture is performed using very fi ne needles, which are applied to promote healing. Overall, defi ciencies are tonifi ed or reinforced, and excesses will be dispersed or reduced. In addition to using needles, acupuncturists may also use heat, pressure, friction, or impulses to stimulate specifi c acupuncture points. Most practitioners currently use prepackaged, sterilized, one-time use, disposable needles. Electro-acupuncture is another example of a 20th century adaptation, a mix of ancient and modern technology.

Which Conditions Is Acupuncture Used For?

Acupuncture is used to treat many types of conditions, the most common of which is pain. According to the American Academy of Medical Acupuncture, acupuncture may be considered as a complementary therapy for the conditions listed here (Braverman, 2004 ). Th e conditions labeled with an asterisk are also included in the World Health Organization (WHO) list of acupuncture indications (WHO, 1979).

• Abdominal distention/fl atulence ∗ • Acute and chronic pain control ∗ • Allergic sinusitis∗ • Anesthesia for high-risk patients or patients with previous adverse responses to anesthetics • A n o r e x i a • Anxiety, fright, panic∗ • Arthritis/arthrosis∗ • Atypical chest pain (negative workup) Acupuncture for Digestive System 125

• Bursitis, tendinitis, carpal tunnel syndrome ∗ • Certain functional gastrointestinal disorders (nausea and vomiting, esophageal spasm, hyperacidity, irritable bowel) ∗ • Cervical and lumbar spine syndromes∗ • Constipation, diarrhea∗ • Cough with contraindications for narcotics • Drug detoxifi cation ∗ • Dysmenorrhea, pelvic pain∗ • Frozen shoulder∗ • Headache (migraine and tension), vertigo (Ménière’s disease), tinnitus ∗ • Idiopathic palpitations, sinus tachycardia • In fractures, assisting in pain control and edema, and enhancing healing process • Muscle spasms, tremors, tics, contractures∗ • Neuralgias (trigeminal, herpes zoster, post-herpetic pain, other) • Paresthesias ∗ • Persistent hiccups∗ • Phantom pain • Plantar fasciitis∗ • Post-traumatic and postoperative ileus∗ • Selected dermatoses (urticaria, pruritus, eczema, psoriasis) • Sequelae of stroke syndrome (aphasia, hemiplegia) ∗ • Seventh nerve palsy • S e v e r e h y p e r t h e r m i a • Sleep disorders (Gooneratne, 2008 ) • Sprains and contusions • Temporomandibular joint (TMJ) syndrome, bruxism∗ • Urinary incontinence, retention (neurogenic, spastic, adverse drug eff ect)∗ • Weight loss ( http://www.nature.com/ijo/journal/v27/n4/pdf/08022 54a.pdf

How Does Acupuncture Work?

Currently there is no concrete, identifi able way to prove if acupuncture indeed works, and it is still diffi cult to standardize the quality and quantity of treatments since acupuncture usually has a patient-centered individualized approach. But, there are several theories that attempt to explain the benefi ts of t r e a t m e n t . 126 INTEGRATIVE GASTROENTEROLOGY

Table 11.1. The Proposed Mechanism of Action for Acupuncture

Theory Proposed mechanism of action

Augmentation of By some unknown process, acupuncture raises levels of Immunity Th eory triglycerides, specifi c hormones, prostaglandins, white blood counts, gamma globulins, opsonins, and overall antibody levels.

Endorphin Th eory Acupuncture stimulates the secretions of endorphins in the body (specifi cally, enkephalins).

Neurotransmitter Certain neurotransmitter levels (such as serotonin and Th eory noradrenaline) are aff ected by acupuncture.

Circulatory Th eory Acupuncture has the eff ect of constricting or dilating blood vessels; this may be caused by the body’s release of vasodilators (such as histamine), in response to acupuncture.

Gate Control Th eory Th e perception of pain is controlled by a part of the nervous system that regulates the impulse, which will later be interpreted as pain. Th is part of the nervous system is called the “gate.” If the gate is hit with too many impulses, it becomes overwhelmed and closes, preventing some of the impulses from getting through. Th e fi rst gates to close would be those that are the smallest. Th e nerve fi bers that carry the impulses of pain are rather small nerve fi bers called “C” fi bers. Th ese are the gates that close during acupuncture.

Safety and Risks

Because acupuncture needles penetrate the skin, many forms of acupuncture are invasive procedures, and therefore not without risk. Injuries are rare among patients treated by trained practitioners (Lao, Hamilton, Fu, & Berman, 2003 ). In most jurisdictions, needles are required by law to be sterile, disposable, and used only once.

Common, Minor Adverse Events

A survey by Ernst et al. (2003 ) of some 400 patients receiving more than 3,500 acupuncture treatments found that the most common adverse eff ects from acupuncture were:

• Minor bleeding aft er removal of the needles, seen in roughly 3 % of patients. (Holding a cotton ball for about one minute over the punctured site is usually suffi cient to stop the bleeding). Acupuncture for Digestive System 127

• Hematoma, seen in about 2% of patients, which manifests as bruises. Th ese usually go away aft er a few days. • Dizziness, seen in about 1% of patients. Some patients have a kind of needle phobia, which can produce dizziness and other symptoms of anxiety. Patients are usually treated lying down, in order to reduce the likelihood of fainting.

Th e survey concluded: “Acupuncture has adverse eff ects, like any therapeutic approach. If it is used according to established safety rules and carefully at appropriate anatomic regions, it is a safe treatment method.”

Serious Injury

Other serious, but rare, risks of injury from the insertion of acupuncture needles include:

• Nerve injury, resulting from the accidental puncture of any nerve. • Brain damage or stroke, which is possible with very deep needling at the base of the skull. • Pneumothorax from deep needling into the lung (Leow, 2001 ). • Kidney damage from deep needling in the low back. • Hemopericardium, or puncture of the protective membrane surrounding the heart, (Yekeler et al., 2006 ) which may occur with needling over a sternal foramen (a hole in the breastbone that occurs as the result of a congenital defect. • Risk of terminating pregnancy with the use of certain acupuncture points that have been shown to stimulate the production of adrenocorticotropic hormone (ACTH) and oxytocin.

Risks from Omitting Conventional Medical Care

Receiving any form of alternative medical care without also receiving conventional biomedical care can be oft en risky, since an undiagnosed disease may go untreated and worsen. For this reason, interdisciplinary collaboration is strongly recommended.

Historical/Theoretical Basis

Acupuncture as part of TCM dates back more than 2,000 years. It originates from China, but was infl uenced by surrounding Asian countries like Korea 128 INTEGRATIVE GASTROENTEROLOGY and Japan. One of the earliest texts is the Yellow Emperor’s Classic of Internal Medicine , which laid out the essential theoretical foundation of TCM and acupuncture as we know it today. Th e text describes the fundamental theories of TCM, including Yin/Yang, the Five Elements, Meridians, Qi, Spirit, Blood, etiology of disease, pathologies, and diagnostic methods, as well as a basic knowledge concerning acupuncture points and needling techniques. Th e understanding of exactly how this knowledge base had come about from ancient times is still one of the underlying mysteries surrounding the development of TCM.

Technique

Classical acupuncture is used to stimulate specifi c points in the body with very fi ne needles (normally 0.16 mm to 0.30 mm diameter). Many types of modifi ed applications are available, such as acupressure, electro-acupuncture, stud, laser, magnet, etc. Traditionally, acupuncture has been applied to various gastrointestinal disorders, from short-term acute symptoms (e.g., abdominal discomfort, indigestion) to chronic disorders such as infl ammatory bowel disease. In addition, many clinical trials and basic studies have been performed to verify the eff ectiveness of acupuncture and to investigate its mechanisms.

Table 11.2. Acupuncture Effects on Gastrointestinal Function or Disorders

Clinical beneﬁ ts

Nausea and • Acupuncture, electro-acupuncture and acupressure can be vomiting benefi cial for nausea and vomiting induced by surgery, chemotherapy, pregnancy, etc. (Streitberger, Ezzo et al., 2006 )

Gastric secretion • Electro-acupuncture may inhibit acid secretion. (Tougas, Yuan et al., 1992 ; Lux, Hagel et al., 1994 )

Gastric motility • Electro-acupuncture or acupuncture either inhibits or excites gastric motility. (Sato, Sato et al., 1993 ; Shiotani, Tatewaki et al., 2004 ; Noguchi, 2010 )

Irritable bowel • Inconclusive. Quality of life and symptoms were improved aft er syndrome acupuncture compared to baseline, but no group diff erence with placebo or sham. (Forbes, Jackson et al., 2005 ; Schneider, Enck et al., 2006 )

Infl ammatory bowel • Acupuncture improved disease activity compared to sham; disease improved quality of life compared to baseline. (Joos, Brinkhaus et al., 2004 ; Joos, Wildau et al., 2006 ) Acupuncture for Digestive System 129

Table 11.3. Possible Acupuncture Mechanism for Gastroenterology

• Stimulating PC-6 point (located on the forearm) has been most frequently applied for nausea and vomiting. • Various mechanisms have been proposed: neurotransmitters (endogenous opioids and serotonin), Nausea and vomiting smooth muscle of the gut, somatovisceral refl ex, sensory input inhibition, somatosympathetic refl ex, vagal modulation, and cerebellar vestibular neuromatrix. (Streitberger, Ezzo et al., 2006 )

• Electro-acupuncture may inhibit acid secretion via somatic aff erent–visceral refl ex mechanism (Zhou and Gastric secretion Chey 1984 )11 , releasing beta-endorphin and somatostatin (Jin, Zhou et al., 1996 ) and opioid neural pathways (Tougas, Yuan et al., 1992 ).

• Acupuncture may induce gastric relaxations via somatosympathetic refl ex and enhancement of c-Fos cells at ventrolateral medulla (Tada, Fujita et al., 2003 ).13 Abdominal pain • Electro-acupuncture may modulate pain via central opioid pathway (Gao, Wang et al., 1997 ; Iwa, Strickland et al., 2005 ).

• Needling on the abdomen may inhibit gastric motility via sympathetic and spinal refl exes, while needling on the limbs may excite gastric motility via vagal and supraspinal Gastric and duodenal refl exes (Sato, Sato et al., 1993 ). motility • Electro-acupuncture may induce response of duodenal motility similar to that of gastric motility induced by acupuncture (Noguchi, Ohsawa et al., 2003 ).

• Electro-acupuncture may increase the threshold of rectal sensitivity in IBS patients (Xing, Larive et al., 2004 ). • Electro-acupuncture attenuated chronic visceral Irritable bowel syndrome hypersensitivity in correlation with decrease of phosphorylation of spinal cord N-methyl-D-aspartic acid (NMDA) receptors in IBS rats (Tian, Wang et al., 2008 ).

Th e most frequently used acupuncture points for gastrointestinal disorders are Zusanli point (Stomach36;ST36) of the lower limb, and Neiguan point (Pericardium-6;PC6) of the forearm (Takahashi, 2006 ). It is reported that acupuncture is generally very safe if it is performed by a credentialed practitioner (Lao, Hamilton, Fu, & Berman, 2003 ). 130 INTEGRATIVE GASTROENTEROLOGY

Table 11.4. Contraindications and Precautions to Acupuncture Treatment

Contraindications

• P l a t e l e t < 50,000/mm3 • Abnormal PT, PTT Bleeding • Anticoagulant therapy • H e m o p h i l i a

• A N C < 500 mm (Menten K, 2008 ) • No needles in skin lesions Infection • Other severely immunosuppressed c o n d i t i o n

Cardiac disorder (especially for • P a c e m a k e r electro-acupuncture) • O t h e r i m p l a n t a b l e e l e c t r i c a l d e v i c e

CNS disorder • Seizure

A l l e r g y • M e t a l a l l e r g y

Precautions

• P r e g n a n c y • Unstable vital signs • Unstable diabetes • Sensory disorder • Needle phobia • S e v e r e f a t i g u e • S e v e r e h u n g e r

(modifi ed from Menten K. et al., 2008 )

Conclusions

Acupuncture is a very old, but still practical, “ancient healing art.” It has been applied for diverse symptoms or diseases, including gastrointestinal problems. Extensive data support that acupuncture can relieve nausea and vomiting from various causes. Several mechanisms are suggested for how acupuncture stimulation may modulate gastric secretion and motility, which can be important for many functional problems. On the other hand, it seems promising but not conclusive whether acupuncture can be useful to improve the quality of life and relieve symptoms for irritable bowel syndrome and infl ammatory bowel disease patients. Further high quality, well designed studies are necessary to establish strong evidence of acupuncture for gastrointestinal disorders. 1 2 Ayurveda and Digestive Health

DAVID SIMON AND VALENCIA PORTER

key concepts

■ Patients with digestive illness should be educated about eating with awareness in a quiet, settled environment, paying attention to their body’s signals. ■ Patients with digestive illness should become familiar with their mind-body connections and be educated about how diet relates to body constitution type. ■ Patients with stagnant digestion can ignite their digestive fi re by including ginger and lemon, and by reducing foods that are diffi cult to digest (i.e., ama -reducing program). ■ Herbs can be utilized when needed, to enhance the processes of digestion, assimilation, and elimination. ■

General Ayurvedic Principles

yurveda is an ancient traditional medical system from India that emphasizes health as a balance of body, mind, and spirit. Th is balance A can be achieved through healthy lifestyle in accordance with nature and one’s own body-mind constitution. Th e preventive practices of proper nutrition and exercise, nourishing relationships, good emotional health, and a regular daily routine contribute to the maintenance of health, which, according to Ayurveda, is not simply the absence of disease. Digestive health is a key principle in Ayurvedic practice. Acknowledging the multitude of functions of the digestive tract— extracting nourishment,

131 132 INTEGRATIVE GASTROENTEROLOGY nervous system feedback and peptide messengers, and immune system interactions — Ayurveda states that digestive and metabolic fi re maintains one’s span of life, vitality, and natural resistance. Th e Sanskrit term agni, which has a common root with the English word ignite, refers to this metabolic fi re, with the primary function being digestion, absorption, assimilation, and transformation of food and sensations into energy. When our digestive fi re is strong, and metabolism is balanced, we experience health. An imbalance of agni can manifest as a number of physical conditions. People can have problems with either too little or too much digestive fi re, resulting in delicate digestion on the one hand, and heartburn or acid indigestion on the other. In addition, when digestion is poor, internal metabolic waste, called ama, may accumulate, leading to generalized symptoms such as fatigue and body ache. According to Ayurveda, treatment of the condition is of equal importance to eliminating the cause, rebuilding the body, and continuing support through rejuvenative practices.

Mind-Body Interactions in Digestion

Th e gastrointestinal system is truly remarkable. Th rough it, we ingest energy and information from the environment to create both our physical form and the energy we need to support our activities. Th is may be the most convincing expression of the Vedic understanding that the environment is our extended body. Nature has packaged her biological energy and information in the form of food that contains the basic substrates needed to create and replenish our cells. Th rough the process of digestion, basic codes of intelligence are exchanged between our individual and our environmental physical sheaths. Ayurveda describes the physical body as anna maya kosha, which means “the layer made out of food.” In its essence, the body really is the intelligence carried on our DNA molecules, wrapped in food. Th e key to good health is the ability to fully digest the experiences presented to us at any moment. When we are able to extract the nourishment we need and leave the rest behind, we create balance and integrity in mind and body. Under ideal circumstances, this beautiful and dynamic process occurs spontaneously. When the mind is balanced and integrated, our appetites are strong and appropriate. Th e gastrointestinal system receives healthy messages from the brain, and is able to extract the elements necessary for maintaining structure and energy. Eating with awareness is great practice for living with awareness. When we are fully present while enjoying a meal, we effi ciently extract the available nutrition and spontaneously avoid consuming that which is toxic. Ayurveda and Digestive Health 133

Th e Body Intelligence Techniques (see text box) are cues to bring us back to present-moment awareness.

Body Intelligence Techniques

• Include all six tastes (sweet, sour, salty, pungent, bitter, astringent) at every meal. • Eat in a quiet, settled, comfortable environment. • Eat only when you feel hungry. • Do not eat when you are upset. • Always sit down to eat. • Reduce ice-cold food and beverages. • Eat at a comfortable pace; stay conscious of the process. • Reduce talking while chewing and keep to lighthearted conversations. • Wait until one meal is fully digested before eating the next. • Sip warm water with your meals to avoid diluting digestive acids. • Eat freshly prepared foods. Lightly sautéed or steamed foods are preferable to raw or overcooked. • Do not cook with honey; use maple syrup. Honey is best as a condiment. • Drink milk separately from meals, preferably warm, and either alone or with other sweet foods. • Do not overeat. Leave 1/4 to 1/3 of your stomach empty to aid digestion. • Sit quietly for a few minutes after your meal. Focus your attention on the sensation in your body, then take a short walk.

If one is having symptoms of digestive imbalance, such as heartburn, bloating, or discomfort, use attention and intention to reestablish balance. Aft er a quiet meditation, localize attention to the alimentary system and visualize comfortable, smooth, eff ortless, balanced digestion. Eating and digesting are such primordial processes that simply remembering how natural they are can improve their function. Nature’s gift s can be used to enliven healthy digestion. Enhance digestive power with spices that stimulate metabolic fi re, such as pepper, ginger, asafetida, wild celery seeds, cardamom, cayenne, and cloves. Simplify the diet when digestion is delicate, pay attention to appetite signals, and ensure regular elimination, using gentle, natural agents to restore balance when necessary.

Use of Ayurvedic Herbs

According to Ayurveda, three essential elements make up a healthy digestive system: digestion, assimilation, and elimination. Th e mind–body practices 134 INTEGRATIVE GASTROENTEROLOGY described help to maintain all of the processes, and particular herbs may also be used to aid each of these processes.

AYURVEDIC HERBS FOR ENHANCING APPETITE AND DIGESTION

Herbs to stimulate the digestive fi re are generally spicy in nature, and best taken immediately prior to or with a meal. Ginger, black pepper, cayenne, wild celery seeds, and long pepper contain essential oils that have eff ects at several levels of the digestive process.Ginger ( Zingiber offi cinale), known in Ayurveda as the universal remedy, has long been used in many cultures for its culinary and medicinal properties. Classically used to treat nausea and vomiting in a number of conditions, it stimulates the release of salivary enzymes and enhances stomach emptying when taken orally. According to Ayurveda, ginger works on all three phases of gastrointestinal function and, as part of an herbal aperitif, the pungency of ginger can kick-start the digestive process. Th ere are no documented problems with taking ginger in normal doses; however, it appears to have mild anti-platelet-forming eff ects, and thus should be used with caution by those who are on prescribed blood thinners. Bitter herbs can also enhance the fi rst stage of digestion by way of a neural refl ex. Th e classic bitter is gentian, which enhances stomach emptying and stimulates the secretion of enzymes by the stomach, gallbladder, and pancreas. Other bitter herbs that are useful in small quantities include dandelion, orange peel, aloe vera, and chamomile.

AYURVEDIC HERBS FOR QUIETING EXCESSIVE DIGESTIVE FIRE

Hyperacidity, heartburn, gastroesophageal refl ux, and peptic ulcers are expressions of an ineffi cient digestive fi re that is imbalanced in both location and quantity. Cooling herbs that pacify the excessive heat, and encourage a cleaner digestive fi re, can help reduce heartburn and improve digestion. Th ese include cumin, coriander, fennel, and licorice, as well as amalaki and shatavari. Th ey are generally taken aft er a meal, or when the symptoms of acid indigestion are prominent. Shatavari ( Asparagus racemosus ), also known as Indian asparagus, is one of the prime rejuvenating herbs in Ayurveda. While particularly helpful in supporting the female reproductive system, it is also eff ective in relieving infl ammatory conditions and in soothing irritated tissues, and has a traditional role as a digestive aid. Th is herb cools off an irritated digestive system that manifests as heartburn, diarrhea, or irritable bowel syndrome. In men with a history Ayurveda and Digestive Health 135 of heartburn and indigestion aft er meals, shatavari was found to be as eff ective as metoclopramide (Dalvi, Nadkarni, & Gupta, 1990 ). Shatavari also has an established history as an antidiarrheal agent, although not formally studied for this purpose. In studies, shatavari has been demonstrated to have immune- modulating properties (Rege & Dahanukar, 1993 ; Dhuley, 1997 ; Th atte & Dahanukar, 1988 ; Rege et al., 1989 ). To treat digestive distress, one teaspoon in one-half cup of warm milk is taken aft er each meal. It mixes well with equal parts of amalaki and licorice for symptoms of heartburn or indigestion. Amalaki ( Emblica offi cinalis), also known as Indian gooseberry, is considered the best herbal medicine for rejuvenation in Ayurveda. It is one of the richest natural sources of antioxidant vitamins, possessing almost 20 times as much vitamin C as orange juice. Used alone or in combination with many other herbs, it has wide traditional uses, including the treatment of skin diseases, lung conditions, diabetes, and indigestion. Amalaki is one of the three ingredients in triphala, the most important Ayurvedic bowel tonic. Mostly studied in the areas of cancer inhibition, lowering cholesterol, and decreasing platelet aggregation, amalaki has also traditionally been used in the treatment of heartburn, and a few scientifi c studies have supported this use (Chawla et al., 1982 ). In a clinical trial on a series of 27 patients with duodenal ulcer, and 12 with nonulcerative dyspepsia, a signifi cant decrease in acid and pepsin secretion, with marked symptomatic relief, was found aft er 3 months of using amalaki (Varma et al., 1977 ). A recent study has shown that it has a role in mucin protection and regeneration, in the healing of ulceration related to nonsteroidal anti-infl ammatory drug use (Bhattacharya et al ., 2 0 0 7 ) . I t a l s o h a s a reputation for the treatment of liver and pancreatic conditions, and in an animal study was shown to reduce the extent of tissue damage caused by experimental pancreatitis (Th orat et al., 1995 ). Amalaki can be taken as the traditional rejuvenative jam, Chavan Prash , one teaspoon twice daily, either straight or mixed in juice or warm milk. Amalaki in triphala can help those with chronic constipation, as well as those with irritable bowel syndrome. Mixed with shatavari, fennel, and turmeric, it can be eff ective in reducing hyperacidity. To improve colon function, 1 to 2 grams daily in divided doses is recommended. Owing to its laxative qualities, amalaki should be used carefully in people with a tendency toward loose bowels. Licorice (Glycyrrhiza glabra) is another herb that has been used among many cultures, with a number of therapeutic eff ects. Used cautiously and with respect, licorice is a valuable healing plant, but at excessive levels it can cause potentially dangerous side eff ects. One of its traditional uses has been in the treatment of peptic ulcers, and animal studies have shown that licorice stimulates the production of protective mucus in the stomach lining (Nadar & Pillai, 1989 ). Most complications occur in people taking excessive doses of 136 INTEGRATIVE GASTROENTEROLOGY licorice with the component glycyrrhizic acid, which causes retention of sodium and elevated blood pressure. It is advised not to take more than 100 mg of glycyrrhizic acid per day, which would be approximately 2.5 grams of dried licorice root. In addition, the German Commission E recommends limiting use to no longer than 6 weeks at a time. It is possible to obtain and use DGL (deglycyrrhizinated licorice), which contains less than 3% glycyrrhizic acid and is considered quite safe. For hyperacidity, take licorice 30 minutes before a meal or 1 hour aft er the meal.

AYURVEDIC HERBS FOR ENHANCING ABSORPTION

Problems with this phase of digestion result in gas, bloating, and heaviness aft er a meal. People with assimilation diffi culties oft en report that even though they are eating healthy foods, they do not feel they are being adequately nourished. Nutmeg, chamomile, peppermint, and lemon verbena are herbs traditionally used to reduce abdominal spasms and bloating. Cinnamon, cardamom, and bay are known as the “three carminatives,” meaning that they dispel con- gested intestinal gas. Other culinary herbs useful in reducing bloating include basil, oregano, thyme, coriander, cumin, dill, and fennel. Ayurvedic herbs useful in reducing gas that are not as well known in the West include wild celery seeds ( Apium graveolens) and long pepper ( Piper offi cinarum ). Cooking beans or legumes with asafetida ( Ferula asafoetida), also known as hing, can improve digestive ability and reduce bloating and gas.

AYURVEDIC HERBS FOR ENCOURAGING ELIMINATION

A fi ber-rich diet that includes plenty of fresh fruits, vegetables, and whole grains is the most important contributor to daily elimination. When necessary, adding fi ber in the form of psyllium or fl axseed can invigorate sluggish bowels. A classic Ayurvedic formula called triphala consists of three fruits— amalaki, bibhitaki ( Terminalia belerica) and haritaki ( Terminalia chebula). Like psyllium, the fi ber in triphala can help enhance elimination in people whose bowels are slow, and normalize bowel movements in people who tend toward loose stools. Amalaki is discussed above. Bibhitaki has a strong purgative action, and is also an excellent rejuvenative. Recent studies have also shown antiviral and lipid-lowering eff ects (Shaila et al., 1995 ; Xu et al., 1998 ). Haritaki is called “king of medicines” in Tibet, and recent studies have shown its promise as an antioxidant, anti-diabetic, antimicrobial, and anti-cholesterol agent (Lee et al., 2005 ; Gao et al., 2008 ; Murali et al., 2007 ). One animal study showed Ayurveda and Digestive Health 137 that haritaki was comparable to metoclopramide in increasing gastric emptying (Tamhane et al., 1998 ). When taken in larger doses at night, triphala can be helpful in relieving constipation. Triphala can also be used as a daily rejuvenative formula, and prolonged use is safe and non-habit forming. Herbal stimulant cathartics should only be used rarely. Castor oil, cascara sagrada, senna, and aloe are the most common plant-based laxatives that act by stimulating the nerve fi bers to the colon, and by causing the accumulation of salts and water in the intestines. Th ese laxatives can cause abdominal cramping, with cascara the mildest and castor the strongest. Th e main problem with repeated use of these herbal stimulants is that one can become dependent on their use to stimulate bowel movements. Using these tools, to restore our digestive power to its natural state of health, supplies us with our energy and physical needs. Listening to our body–to our

Table 12.1. Ayurvedic Herbs

Ayurvedic Herbs for Enhancing Digestion

Ginger Dandelion

Black pepper Orange peel

Cayenne Aloe vera

Wild celery seeds Chamomile

Long pepper Gentian

Ayurvedic Herbs for Reducing Excess Acidity

Amalaki Cumin

Shatavari Coriander

Licorice Fennel

Ayurvedic Herbs for Reducing Gas and Bloating

Nutmeg Basil Wild celery seeds

Chamomile Oregano Long pepper

Peppermint Th yme Asafetida (Hing)

Lemon verbena Coriander

Cinnamon Cumin

Cardamom Dill

Bay Fennel

(Continued) 138 INTEGRATIVE GASTROENTEROLOGY

Table 12.1. (Continued)

Ayurvedic Herbs for Enhancing Elimination

Triphala (Amalaki, Bibhitaki, Haritaki)

Stimulant Cathartics:

• Castor oil

• Cascara sagrada

• Senna

Aloe (latex portion)

gut–allows us to tune into our innate intelligence, which can guide us along the path of greater well-being.

Mind-Body Prescription for Digestive Health

1. Follow the Body Intelligence Techniques at every meal. 2. Follow dietary recommendations specifi c to your mind–body constitution. 3. Pay attention to your appetite level and only eat when you are really hungry, stopping when you are comfortably full. 4. Similarly, pay attention to the natural urge to defecate. 5. Eat an occasional meal in silence. 6. If your digestion is delicate, follow an ama -pacifying program for a couple of weeks. 7. If your appetite is weak, eat a mixture of fresh grated ginger, lemon juice, and rock salt (1/2 tsp. fresh ginger, 1/2 tsp. lemon juice, a pinch of salt) to stimulate agni, one-half hour before meals. 8. If you tend to get heartburn aft er meals, chew a quarter-teaspoon of roasted fennel seeds or a pinch of fresh coriander leaves. Cook with cumin and coriander, which are also cooling herbs. 9. To decrease gas or bloating, add cinnamon, cardamom, and bay to your cooking. 10. Ayurvedic herbs traditionally used to enhance appetite and digestion include sunthi (ginger), maricha (black pepper), pippali (long pepper) and ajwan (wild celery seeds). Ayurveda and Digestive Health 139

11. Ayurvedic herbs traditionally used to quiet excessive digestive fi re include shatavari (Indian asparagus), amalaki (Indian gooseberry), and yasthi madhu (licorice). 12. Ayurvedic herbs traditionally used to enhance absorption include jatiphala (nutmeg), haritaki ( Chebulic myrobalan ) and musta (nut grass). 13. Celebrate eating! Don’t strain.

Ama-Pacifying Program

1. Follow the Body Intelligence Techniques . 2. Eliminate/reduce foods that increase ama — fried foods, heavy and oily foods, aged cheeses, meats, rich foods, and anything that is diffi - cult to digest. 3. Stimulate your digestion with ginger tea. 4. Eat warm, freshly cooked whole foods that are light and easy to digest, such as rice, soups, lentils, freshly steamed or lightly sautéed v e g e t a b l e s .

Table 12.2. Dietary Recommendations for your Mind-Body Constitution (adapted from Chopra, 2000 )

Mind–Body type Favor Reduce/Avoid

Vata Warm food, moderately heavy Cold salads, raw vegetables and textures greens Added butter and fat Iced drinks Salt, sour and sweet tastes Dry, salty snacks (nuts are fi ne in Sweet fruits small amounts) Soothing and satisfying foods Dried fruits Dairy Beans (except chickpeas, mung beans, pink lentils, tofu) Astringent and bitter tastes

Pitta Cool or warm, but not steaming- Excessive salt, sour or spicy tastes hot foods (pickles, yogurt, sour cream, Moderately heavy textures cheese, processed and fast foods) Bitter, sweet and astringent tastes Red meat and seafood such as salads and legumes Fried foods Less butter and added fat Sour or unripe fruits Milk, grains, vegetables Nuts and seeds (except coconut, Sweet, ripe fruits pumpkin seeds, sunfl ower seeds)

(Continued) 140 INTEGRATIVE GASTROENTEROLOGY

Table 12.2. (Continued)

Mind–Body type Favor Reduce/Avoid

Kapha Warm, light food Sweet, rich and salty foods Dry food, cooked without much Cold foods water Dairy products (especially butter, Raw fruits, vegetables, salads, ice cream, cheese) legumes Oil (small amounts of corn, Pungent, bitter and astringent almond and sunfl ower oils tastes Red meat and seafood Stimulating foods Sweet and juicy vegetables and fruits 1 3 Osteopathic Medicine

DIANE CLAWSON

key concepts

■ Osteopathic Medicine is not merely a combination of traditional Western medicine and osteopathic manipulation (DiGiovana, 1997 ). It is based on a philosophy of health that considers the whole patient —mind, body and spirit. ■ Th e evaluation and treatment of the musculoskeletal system is used for diagnosis and treatment of systemic disease, as well as musculoskeletal complaints. ■ Doctors of Osteopathic Medicine (DOs) are fully licensed physicians, practicing all specialties of medicine. Th e profession has overcome many obstacles to achieve equal practice rights with their Medical Doctor (MD) counterparts. ■ Th e focuses for osteopathic treatment of gastointestinal disease are the viscerosomatic refl exes occurring with the sympathetic nervous system, the parasympathetic nervous system, and lymphatics. ■ Osteopathic treatment is most commonly used in conjunction with the standard of care for each particular disorder. In mild cases, osteopathic manipulative medicine (OMM) may be the only treatment needed. ■

141 Introduction to Osteopathic Medicine

steopathic Medicine was founded in 1874 by Andrew Taylor Still, MD. In the 1800s, physicians were trained primarily through appren- O ticeships, and Dr. Still was no exception. Th e training was frequently inadequate, and the treatments of the day included bloodletting, mercury, alcohol, morphine, laxatives, and purgatives. Still watched his brother become addicted to morphine through medical treatment, and he lost three of his children to meningitis, unable to help them with the medical practices of the time. He became increasingly dissatisfi ed with allopathic medicine, and began to develop a method of treatment that would bring health without the oft en disastrous eff ects of the then-current practices. Still identifi ed the musculoskeletal system as a key element of health, recognizing the importance of unobstructed circulation and innervation in maintaining health. He believed that the body has its own “pharmacy” and an innate capacity for self-healing. He stressed prevention, healthy eating, and exercise as necessary components of health. Osteopathic Medicine is based on a philosophy, of which there are four basic tenets. Th ese are:

1. Th e body functions as a whole — mind, body, and spirit. 2. Th e body is self-regulating and self-healing. 3. Structure and function are interrelated. 4. Rational treatment is based on the above principles.

Through a combination of intense study of anatomy and philosophical enlightenment, “Still came to see humans as marvelous machines, created and sustained by laws of nature” (Ward, 1997 ). This became the basis for his new brand of medicine called “Osteopathy.”

Today, DOs have the same practice rights as MDs, and both are seen working together in the same hospitals, the same clinics, and the same branches of the military. Th is, however, was not always the case. It has been a long and arduous process to achieve equal practice rights. Th e American School of Osteopathy in Kirksville, Missouri, was the fi rst school to open in 1892. In 1910, the Flexner report was published and harshly condemned both osteopathic Osteopathic Medicine 143 and allopathic medical schools. 1 As a result, all of the osteopathic schools and 122 of the MD schools were closed. During World War I, the fi rst eff orts to obtain federal recognition were undertaken so that DOs could become commissioned as military offi cers. Instead, the DOs were required to serve as regular soldiers, despite their medical training. In 1941, the Military Appropriations Act was passed, which allowed for recognition of DOs in the military. However, during World War II, DOs were deferred rather than draft ed. Th e DOs were left to care for the thousands of patients left by the MDs serving in the war. Th is ultimately proved to be a positive development for the DOs, by enhancing the public’s view of them as full-service physicians. Finally, in 1966, DOs were accepted as physicians and surgeons in the military. Th e darkest days of osteopathy occurred in 1962, when there was an eff ort to abolish the DO licenses in California. Th ere was a merger between the California Osteopathic Association and the California Medical Association. DOs were able to obtain an MD degree for a small fee. Th e degree was not recognized outside of California, but 85% of the DOs became MDs during this time. Th e proposed referendum was passed, and the licensing of DOs in California was discontinued. In 1974, the referendum was overturned and DOs could once again become licensed in California.

Vermont was the ﬁ rst state to grant full practice rights to DOs in 1896. The last state to recognize DOs as fully licensed physicians was Louisiana in 2001.

Today, there are 25 osteopathic schools in 31 locations, and approximately 60,000 DOs who are licensed to practice all phases of medicine in all 50 states, the District of Columbia, and U.S. territories. In addition to a holistic philosophy, DOs use structural diagnosis and manipulative treatment, along with all

1 Th e Flexner Report is a book-length study of medical education in the United States and Canada, written by the professional educator, Abraham Flexner, and published in 1910 under the aegis of the Carnegie Foundation. Many aspects of the present-day American medical profession stem from the Flexner Report and its aft ermath. Th e report (also called Carnegie Foundation Bulletin Number Four) called on American medical schools to enact higher admission and graduation standards, and to adhere strictly to the protocols of mainstream science in their teaching and research. Many American medical schools fell short of the standard advocated in the report and, subsequent to its publication, nearly half of such schools merged or were closed outright. 144 INTEGRATIVE GASTROENTEROLOGY of the other, more traditional, forms of diagnosis and treatment, to provide comprehensive medical care to their patients.

With a renewed interest in osteopathic manual medicine, a mechanism has been instated that will allow MDs to train and become certiﬁ ed in OMM. Additional coursework is required.

Application of Osteopathic Concepts to Digestive Issues

At the core of osteopathic treatment for digestive issues is a comprehensive knowledge and understanding of the segmental and autonomic innervation of the gastrointestinal tract itself. Th ere is a refl ex arc between the viscera (internal organs of the body, especially of the abdomen and thorax) and the segmen- tally related musculoskeletal region. (Table 13.1 ) When there is pathology or dysfunction, the viscera and soma become linked in a cycle of aff erent and eff erent impulses, which can sustain and even exacerbate the problem. With increased and prolonged visceral input, the spinal cord region becomes facilitated. As a result, there are palpatory tissue changes, joint somatic dysfunction, and tenderness to palpation in the corresponding segments on exam (Figure 13.1 ). Th e osteopathic term for this is viscerosomatic refl ex . Th ese refl exes are also responsible for what are known as “Chapman’s Refl exes.” Th ey are defi ned as “a system of refl ex points that present as predictable anterior and posterior fascial tissue texture abnormalities assumed to be refl ections of visceral dysfunction or pathology.” (Figure 13.2 .)

Table 13.1. Segmental Arrangement of the Sympathetic Chain

T6 Esophagus

T6-T9 Lower Esophagus and Stomach

T6-T9 (right) Liver and Gallbladder

T6-T9 (left ) Spleen and Pancreas

T7-T9 Small Intestine

T10-L1 (right) Ascending and Transverse Colon

T12-L2 (left ) Descending Colon and Rectum

(Adapted from DiGiovana, 1997 ) Osteopathic Medicine 145

Facilitated segments secondary to systemic disease do not respond well to a type of treatment known as high-velocity, low-amplitude (“cracking” technique associated mostly with chiropractors). If a lesion recurs repeatedly, it is a sign that systemic issues may be present (Kuchera & Kuchera, 1994 ).

In the OMM model, the end result of these refl exes is increased sympathetic tone, which causes vasoconstriction and alteration of the bicarbonate and mucous buff ers (Kuchera & Kuchera, 1994 ). Th e mucosal defenses against digestive acids and enzymes are reduced, and believed to be a factor for infl ammation and ulceration in the upper GI system. Th e goal of treatment is to normalize the facilitated segments, thereby normalizing the sympathetic input. In addition to normalizing sympathetic input, attention must also be paid to the parasympathetic branch of the autonomic nervous system. Th e parasympathetic input is provided by the vagus nerve and the pelvic splanchnic nerves. Th e right vagus nerve innervates the lesser curvature of the stomach, liver, gallbladder, small intestine, and right half of the colon. Th e left vagus supplies the greater curvature of the stomach to the duodenum. Th e pelvic splanchnic nerves, which originate from cord segments S2, S3 and S4, inner- vate the left half of the colon and the pelvis. (Figure 13.3 ) When there is hyperactivity of the parasympathetic input, there are increased bowel motility and glandular secretions oft en associated with diarrhea (Kuchera, 1994 . Conversely, constipation is a likely manifestation of hypoactivity (Kuchera, 1994 ). Irritable bowel syndrome results when there is uncoordinated hyperactivity of both the parasympathetic and sympathetic systems (Kuchera, 1994 ). Lastly, with dysfunction and disease, increased demands are placed upon the lymphatic system. Lymphatic fl ow can be hindered by a fl attened diaphragm (which acts as an extrinsic pump) or torsed fascia, which can greatly reduce the body’s ability to recover from a disease process (Kuchera, 1998). Lymphatic drainage of the abdomen is an important consideration in the treatment of an ileus or infl ammatory bowel disease.

Conclusion

Osteopathic medicine off ers a holistic philosophy and unique approach to medical treatment. Th ere is recognition that the musculoskeletal system, which comprises 60% of our body mass, is interrelated with all other body systems. Dysfunction in one system causes altered function in others. Osteopathic manipulative treatment of gastrointestinal issues requires extensive knowledge of anatomy, and an appreciation of the autonomic nervous system and lymphatics in maintaining or achieving health. 1 4 Gastroenterology and an Integrative Chiropractic Approach

LOREN MARKS AND DAVID M. DURKIN

key concepts

■ A historical review of chiropractic. ■ Human beings are made up of a web of structural, emotional, and biochemical components. ■ Th e integration of these systems within us cannot be entirely divided by subspecialties. ■ Th e Integrative Assessment Technique [IAT] is methodologies for both— the chiropractic profession (and other practitioners) who wish to have a more comprehensive alternative approach bridging together the three worlds of structure, emotions, and biochemistry. ■ It is the very essence of this text to embrace and understand contextually where and how the alternative medicine models fi t into the evaluation and management of gastroenterology. ■ Th e future belongs to those willing to lay new track, and not merely adhering to the continuance of the status quo. ■

146 A Brief History of Chiropractic

r. D.D. Palmer 1 Dr. Daniel David (D.D.) Palmer, a Canadian-born teacher and healer, founded chiropractic in 1895. A man with a unique D perspective, he was very inquisitive and determined to understand health and promote wellness by trying to work with the body’s innate life force. Dr. Palmer, having studied anatomy and physiology in his search to become a healer, had developed a very in-depth knowledge of these topics by the late 1800s and, as a result, had been using magnets to try to infl uence his patients’ life force. Harvey Lillard 2 One day, a janitor in Dr. Palmer’s offi ce building named Harvey Lillard, who had lost his hearing some seventeen years earlier, following feeling a “pop” in his back while in a stooped position, was working near Palmer’s offi ce when D.D. asked the man if he could evaluate his condition. Dr. Palmer (1910 ) later recounted this story in Th e Chiropractor’s Adjuster. Palmer noticed a protru- sion in the janitor’s back and asked him to lie down on a bench, at which time Dr. Palmer applied a gentle manual force to his spine, which subsequently restored his hearing following several such treatments. With this vantage point, Palmer continued studying the relationship of each spinal segment and its corresponding organ, as well as evaluating the overall health of the local townspeople and trying to relate their overall health to their spinal function. Th is type of study became his passion, and ultimately was the start of our present-day chiropractic profession. Dr. B.J Palmer1 D.D.’s son, B.J. Palmer, is attributed with developing the art, science, and philosophy of chiropractic. B.J. raised the standards of the chiropractic educational system, to its present doctoral level. He understood, as did physicians practicing medicine, that without knowledge of such things as microbial invasion and a continued growth in the sciences, health care would be limited. However, it has been only a decade or so that chiropractors and medical physicians have been communicating at a higher level, to help ensure an integrative

1 Pictures of D.D. Palmer and B.J. Palmer originally appeared in Th e Subluxation Specifi c ∼ Th e Adjustment Specifi c , Davenport: Palmer College of Chiropractic, 1934; Reprinted 1995. (p.2). Available at: http://www.cafeofl ifepikespeak.com/tribute_DD.htm , and http://www.cafeofl ife pikespeak.com/tribute_BJ.htm 2 Picture of Harvey Lillard from Chiropractic History, WikipediaOnline Encyclopedia 2008, http://en.wikipedia.org/wiki/Chiropractic_history . 148 INTEGRATIVE GASTROENTEROLOGY healthcare model for the future. Today’s chiropractic physicians are more dedicated than ever to learning from and educating other healthcare providers, and to promoting integration of all healthcare modalities to help ensure a truly integrative medical model. An interesting point for practitioners to focus on is that all healthcare practitioners work in their chosen fi eld for the love of their specialty, and for the benefi ts of contributing to the health and/or wellness of their patients. If we understand this, then it is easy to overlook some small philosophical diff erences, as long as the patient’s best interest is kept in focus when delivering care.

Integration or Separation

On the fi rst look at a topic of “gastroenterology and chiropractic,” one may wonder how chiropractic treatment can be integrated into the treatment of gastroenterological disease or disorders. Th ese are the type of questions that have been asked of the chiropractic profession for over one hundred years. However, when the nervous system is evaluated further, the possibilities and the resulting impact of a properly functioning nervous system become more evident for even a layperson. In fact, it is not uncommon for chiropractic patients to have questions about changes with their bowel function, as well as other organs, following chiropractic care. How can this be? To help in the initial process of understanding the chiropractic paradigm, a brief overview of some of the basic chiropractic models is needed.

The Vertebral Subluxation Complex

Vertebral Subluxation Complex (VSC) is a theoretical model of motion segmental dysfunction (subluxation) that incorporates the complex interaction of pathologic changes in nerve, muscle, ligamentous, vascular and connective tissues (Gatterman, 1995 ). Th ese aberrations of the nervous system can result in:

• Loss of sensory information: Causing inappropriate nerve responses; and • Altered states of function in other areas of the nervous system: Causing changes in body functions (Hughes & Rousso, 2004 ). Gastroenterology and an Integrative Chiropractic Approach 149

Th ese changes are explained with several chiropractic models, two of which will be our focus here to help us understand the link between musculoskeletal changes and an overall improvement in the global health of a patient.

• Mechanical or Mechanistic Abnormal changes in weight bearing, movement, or the spinal curves (alignment or structure). • Neurological or Vitalistic Interference in the normal physiological function of the nervous system, aff ecting every tissue, organ and system in the body.

Chiropractic physicians are trained to locate and treat these mal-positioned vertebrae or subluxations. Patients enter chiropractic offi ces daily wanting to know how this type of physical medicine can help treat, correct, and heal the host of symptoms that are talked about in chiropractic testimonies and in alternative literature. Such patients need to understand that chiropractic physicians are trained to diagnose illness, much like family physicians, but there is a diff erence: Chiropractic physicians primarily treat subluxations. Subluxations cause altered nerve function inducing a nerve impingement syndrome , which causes a mechanistic (alignment and structure) and a vitalistic change (altered normal function) to the exiting nerves of the spinal cord. Th is causes a potential alteration to all the areas that that specifi c nerve travels (organs, tissues, and cells) throughout the entire body. Restoring normal motion of a spinal segment can eliminate nerve impingement syndrome and restore proper function, which helps lead to a restoration of health and wellness.

The Autonomic Nervous System

Patients need to realize that they must also exercise, eat well, and reduce emotional stress to promote total wellness. Th ese topics are now generally addressed in most chiropractic offi ces. Furthermore, revolutionary changes in the chiropractic profession have evolved through the use of computerized analysis, followed by spinal correction with some of these same computerized instruments. Such changes in many offi ces have helped develop not only the traditional art of locating subluxations, but have created a more scientifi c analysis for locating spinal hypomobility and, additionally, have standardized the correction of subluxations. 150 INTEGRATIVE GASTROENTEROLOGY

Instruments such as the ProAdjusterTM from Sigma Instruments and Pro- Solutions and the Insight Subluxation StationTM from the Chiropractic Leadership Alliance have given the chiropractic profession an increased level of certainty, improving the objective data to help locate and defi ne the degree, as well as the location of vertebral segmental dysfunction or subluxation. Th is, coupled with the traditional art and science of chiropractic, yields the practicing chiropractor a pool of information from which to draw upon to help reestablish the normal balance (homeostasis) of the nervous system and thus the body as a whole. If structural changes are not corrected, spinal or joint degeneration will begin and symptoms may develop and/or progress. Loss of structural integrity can cause a progression toward illness, and can even cause disease (i.e., degenerative disc disease, neuritis, neuropathy, gastritis, gastro-paresis, allergies, fatigue, sleep, various sinus conditions, colds and fl u (neuro-immunology) due to the resulting nerve impingement. Structural changes are easier to identify and understand for the average patient, and for that reason is usually the focus of education in a chiropractic offi ce. Th ese structural changes can eventually lead to the neurological changes described in the more complicated vitalistic model of chiropractic. All types of physicians must keep in mind that a subluxation cannot be diagnosed by decreased spinal motion (hypomobility) alone, but must possess a neurological fi nding such as pain, weakness, and/or sensory changes. However, such changes may be diffi cult to detect without advanced testing like magnetic resonance imaging (MRI), electromyography (EMG) or nerve conduction velocity (NCV) tests. Th is is the reason many chiropractic physicians are now using more advanced instrumentation as discussed above, (ProAdjuster and Subluxation Station) to confi rm their working diagnoses of subluxation. Spinal hypomobility alone would be considered only a spinal fi xation, which is a precursor to subluxation but not synonymous with it. Both conditions can be treated in chiropractic offi ces, but the latter is more serious and includes mechanistic and vitalistic alterations. Th is is a common error seen when evaluating physician reports and literature on the topic of segmental dysfunction. An evolution of chiropractic has continued over the years and today’s chiropractic practices are now more geared toward total wellness than at any other time in the history of the profession. Due to the level of education available, the chiropractic educational standards, and the in-depth training of today’s chiropractors, the chiropractic profession is moving toward being trusted advisors to their patients, as opposed to treating only musculoskeletal conditions — a “wellness advisor,” if you will, that can assist patients with health issues including diet, sleep, nutritional supplementation, weight loss and stress management which support healthy lifestyle behaviors. Today’s chiropractors Gastroenterology and an Integrative Chiropractic Approach 151 develop relationships with many medical physicians in allied fi elds such as orthopedic surgeons, physiatrists, neurologists and radiologists. Chiropractor’s who practice via a more holistic or wellness based model, develop relationships with all types of physicians and routinely refer to these doctors to support the overall wellness of there patients. More education and a greater focus are needed in our society on the benefi ts of preventative medicine and wellness care. Th is is a responsibility that must be embraced by all entry-level practitioners (traditional and alternative), if we are to establish a healthier society. Embracing such standards would help decrease chronic illness and human suff ering. Promoting “wellness care” would decrease the practice of treating so much disease at such a huge expense to our society. Such education would allow us to help our patients understand the consequences of their lifestyle choices, reducing illness and promoting health. Wellness is a product of normal physiology and disease is a product of altered physiology. Oft en, delayed intervention promotes disease (longstanding altered physiology), which mandates costly allopathic intervention. If we reestablish a healthier physiological state early on, a disease that may have occurred may be prevented prior to its development, and those that do occur gain the advantage of improved and less invasive allopathic treatment. It is the opinion of the authors that the health of our society can best be obtained by all practitioners working together for the benefi t of patients.

Medicine and Disease

If we take a retrospective review of the early beginning of medicine, we fi nd that some of the foundational principles were based upon Pasteur’s original doctrines, notably his view of microbes and the isolation of them as a primary cause of disease. Even though we have scientifi cally documented the phylogenic and taxo- nomic identifi cation of microbial species, there remains, in many aspects of modern medicine, too strong a practice of “isolate and eradicate” without addressing lifestyle and dietary behaviors. Th is is evidenced by the over- prescribing of antimicrobials in the United States. Pasteur’s successor, Beauchamp, points out that it is the terrain that has been compromised, not the invading germs. Th is requires a more common practice — to defi ne etiologic mechanisms when patients are not in acute states of illness. Integrative practitioners are embracing this model, and it is the hope of these authors that we might all come to an enhanced understanding of human health through the various forms and legitimate practices that have been developed over time to address the ills of mankind. 152 INTEGRATIVE GASTROENTEROLOGY

Th is text is a body of knowledge comprising an integrative approach to gastroenterology. It is a groundbreaking attempt to look at the various mechanisms and alternative healing practices that exist, contributing to the betterment of gastrointestinal health. Th e purpose of the opening of this text was to establish a template for the contextual nature of where chiropractic care and GI disturbances meet. Indeed, no double-blind peer reviewed studies have been performed to substantiate the relationship of chiropractic care to GI health, as the dynamic nature of vitalistic changes are diffi cult to quantify between patients, but an established hypothesis has been utilized over the years and has been outlined above. Empirical knowledge— through neural segmental enervation of the autonomic nervous system (ANS) to each organ system, diet and lifestyle, and refl ex testing — is the experiential substitute for the “evidence-based medicine model” that exists for the doctor of chiropractic pertaining to gastroenterology. Case studies and reviews of GI disturbances, such as childhood colic, ileocecal valve disturbances, and hiatial hernias do exist in the literature. Th is hardly equates to a database from which to draw. It is fair to say that the funding of research for the chiropractic profession to study the relationship of GI health to spinal manipulative therapy (SMT) has been very diffi cult to achieve, since the pharmaceutical industry’s model for health dominates the current terrain. While not an excuse, it is a consideration that has limited the direction of dollars allocated for non-allopathic models. Unquestionably, doctors of chiropractic have been treating patients since 1895, receiving feedback from patients stating that they came for low back pain or neck pain, and since beginning care, their constipation, intestinal cramping, or lower quadrant pain have been relieved or resolved. Th is empirical evidence provides a basis, albeit far from the rigors set forth in scientifi c methodology, for an evidence-based approach. You may ask where does this relationship originate? Th e nervous system, being the supreme controller and coordinator of physiologic function in the human body, is the template upon which chiropractic care is based. Th e enervation of spinal nerves to the somatic structures of the body has A well-documented structure–function relationship. Pain and its dermato- mal, motor, and sensory aspects are all functions of neural tissue, and the resultant compromise that can occur when the vertebral segments encroach the spinal cord or spinal nerve roots. A further review of the nervous system may be helpful at this point: At the same time, a relationship exists of neuronal enervation of the peripheral nervous system (sensory-somatic and the autonomic nervous system) that enervate the viscera, infl uencing their function through the sympathetic and parasympathetic nervous system. Gastroenterology and an Integrative Chiropractic Approach 153

Sensory stimuli elicit changes in the nervous system. Segmental aberrations (subluxations) cause a host of neural activations, from nociception at the local tissue to autonomic responses occurring peripherally and aff ecting a myriad of physiologic responses. Interestingly, all segmental dysfunction does not originate at the spinal level aff ecting target tissues (somatovisceral reactions). Many segmental disruptions (subluxations) occur as a result of viscerosomatic responses. Aberrations in neural transmission derived from overstimulation in the viscera results in autonomic nervous system (ANS) activation, with a resultant eff ect at the segmental level of enervation from that respective organ, i.e.,T9 (see Figure 14.2) and the adrenal glands. Th e surrounding musculature can then become hypertonic and induce a biomechanical change at that segmental level. We are a complex organism responding to a host of stimuli at all times, in our attempt to adapt. Ultimately, our ability to interpret human physiology must derive from a comprehensive review of systems that has no boundaries set by current standards. We are a web of structural, emotional, and biochemical components. Th e integration of these systems within us cannot be entirely divided by subspecialties. It is true that the knowledge of each respective specialty in health care is required, due to the vast amount of data and its application that exists today. Th e observed compromise is, “ the isolation of information derived from each respective specialty is applied through exclusive and narrow parameters that are dictated by the specialty, as opposed to how the data relates to the organism as a whole .”

Integrative Assessment Technique (IAT) – Contributing to Integration

Th e Integrative Assessment Technique (IAT) was created by Dr. Loren Marks to establish an assessment methodology for the chiropractic profession, as well as other practitioners who wish to have a more comprehensive alternative approach bridging the three worlds of structure, emotions, and biochemistry. Th is muscle response technique utilizes refl exes located on the surface of the body that can be challenged by a doctor skilled in the art of this application, to read these responses and derive not only a cross-referenced capacity with known diagnostics, but also an ability to assess rapid integration of one body system over another in an attempt to derive causation. Th is technique is not intended to replace any known standards, but to enhance the role that integrative care can provide, while off ering natural solutions where applicable. Such muscle testing has been extensively tested and validated by David Hawkins, MD, PhD, following his observation of George J. Goodheart, Jr, DC, who was 154 INTEGRATIVE GASTROENTEROLOGY utilizing such testing in his work in the 1960s. Dr. Hawkins has written several books explaining his research, the most notable being Power Vs. Force (Hawkins, 1995 ). Gastroenterology is a perfect example of the benefi ts of an integrated mechanism. Let’s take a patient with chronic GI complaints of gas, bloating and bowel irregularities. Th e IAT model would begin with a thorough consultation, history, and review of any applicable studies that might have been previously performed, assuming the patient has seen either a primary care physician or gastroenterologist and continues to have unresolved complaints despite standard therapeutic intervention. Th e IAT model challenges the broad categories of structure, emotions, and biochemistry to identify which system is the primarily, secondary, and tertiary driver involved in contributing to disease. Th is prioritization is the key in identifying and allowing intervention from an etiologic perspective/paradigm. No one questions the resultant eff ect that patients present with, especially on an acute basis, but an example might be if mental and emotional perpetuators are the driving force of gut disturbances in a given case, and management from this vantage point will bring the patient to a quicker resolve, and if this was known with reasonable certainty before a trial of many other therapeutics, then we could accomplish improved outcomes and lower healthcare costs. Alternatively, a patient may present with a biochemical priority. Navigation through the refl exes helps to assess organ involvement, followed by various GI metabolic functions such as HCL output, biliary involvement, gut Ph, microbial overgrowth, or the presence of heavy metals, etc., as a functional medicine doctor might proceed. Here, the model allows for a unique process of reasoning, followed by diagnostic tests to confi rm or rule out their presence. Chiropractic assessment of segmental dysfunction is an integral part of this process to determine if there are spinal aberrations that are either “caused by or the result of” the metabolic imbalance in the gut (viscerosomatic response). What is so interesting is that these seemingly two worlds— a bioenergetic muscle response-testing model, and the biochemical realm of blood, urine and other diagnostic testing to validate and cross-reference its fi ndings— have met. Without a doubt, nothing can replace the quantifi cation of some known standards such as lipid analysis, WBC, and RBC levels. It is the rapid determination and level of integration that the IAT model purports. It seems incomprehen- sible in our modern scientifi c state that a doctor can learn the standards of IAT muscle response testing from the mapped refl exes on the surface of the skin, and accurately assess from such parameters whether a viral, bacterial, fungal, or parasitic infestation exists. Indeed, this level of accuracy is possible when one masters the fundamentals of IAT combined with one’s knowledge of biochemistry, anatomy and the Gastroenterology and an Integrative Chiropractic Approach 155 physiologic pathways being reviewed. Th e application of this model is well suited to the gastrointestinal system, providing numerous avenues of proper identifi cation, from the segmental dysfunctions that arise from viscerosomatic reactions to various states of microbial dysbiosis, infl ammatory cascades, enzymatic insuffi ciencies and bowel toxicities that present to clinicians daily. Th e future belongs to those willing to lay new track, and not merely adhering to the continuance of the status quo. Integration between the various medical practitioners will ultimately be needed to accomplish this feat and reach new frontiers. A reality that is already becoming more common in today’s atmosphere, with such books and literature as this. Th e future of integration is b r i g h t . 1 5 Energy Medicine and Gastrointestinal Disorders

ANN MARIE CHIASSON

key concepts

■ Energy Medicine is based on the concept that there is an underlying energy body within the physical body that aff ects health; energy medicine therapies are focused on shift ing this energy body. ■ Th e National Center for Complementary and Alternative Medicine (NCCAM) divides the fi eld of energy medicine into measurable and non-measurable energies. ■ Non-measurable energies are the current focus of controversy in energy medicine. ■ A Cochrane review concludes that energy medicine touch therapies may reduce pain and analgesic use. ■ Th ere is no evidence for or against energy medicine in GI disorders, as there is a paucity of research in this area. ■

D e ﬁ nition and Prevalence of Energy Medicine

nergy Medicine is a newer term coined to refer to healing modalities that work with the underlying energy or vital force of the body: “In Eaddition to a system of physical and chemical processes, the human being is made up of a complex system of energy” (Hurwitz, 2001 ). Th is energy system, called the energy body, biofi eld or subtle body, is housed within the physical body, and is considered fundamental to the functioning of the

156 Energy Medicine and Gastrointestinal Disorders 157 physical body. Energy medicine refers to any modality that aff ects the underlying energy or vital force of the body. Th e National Center for Complementary and Alternative Medicine (NCCAM) provides a comprehensive defi nition of energy medicine and the scope of modalities included in this paradigm. Th e concept that human beings are infused with a subtle form of energy has been around for 2,000 years, and has many names, “such as Qi in traditional Chinese medicine (TCM), ki in the Japanese Kampo system, doshas in Ayurvedic medicine, and elsewhere as prana, etheric energy, fohat, orgone, odic force, mana, and homeopathic resonance” (NCCAM, 2003 ). How the energy body and the physical body interact is described diff erently depending on the tradition.

Energy medicine may be a resurgence of “vitalism,” or the belief that an underlying vital force exists in the body and is central to health. This concept predates Hippocrates, who espoused that the vital force was dependent on balance of the four humors. More recently, Mesmer also promoted this concept and called it magnetism . When medicine shifted to organ-based systems, with the rise of the Paris Clinics in the early 1800s, the importance of the body’s vital energy lost its importance in modern medicine. The resurgence of energy medicine is actually an integration of prior views of health and healing, with conventional medicine, and may end up augmenting our current views of health and how we treat illness.

Certainly, therapies that employ electromagnetic forces are used in modern medicine. At present, the fi eld of energy medicine deals with both measurable and non-measurable energy fi elds. NCCAM recognizes two types of energy fi elds, veritable and putative. Th e veritable energies are those that are measurable (through wavelengths and frequencies) and “employ mechanical vibra- tions (such as sound) and electromagnetic forces, including visible light, magnetism, monochromatic radiation (such as laser beams), and rays from other parts of the electromagnetic spectrum” (NCCAM, 2003 ). Medical interventions that employ electromagnetic fi elds include magnetic resonance imaging, cardiac pacemakers, radiation therapy, ultraviolet light for psoriasis and laser keratoplasty, and more (NCCAM, 2003 ). Putative energy fi elds, according to NCCAM, are those that “have defi ed measurement to date by reproducible methods. Th erapists claim that they can work with this subtle energy, see it with their own eyes, and use it to eff ect changes in the physical body and infl uence health” (NCCAM, 2003 ). Currently, when practitioners and research studies discuss energy medicine (EM), they are not discussing conventional medical treatments that employ forms of energy; most are referring to therapies that work with the putative fi eld. 158 INTEGRATIVE GASTROENTEROLOGY

Th e belief in an underlying vital force or subtle body is present in cultures worldwide. Ninety-four cultures have a documented concept that describes the underlying energy of the body; it is alternately characterized as spiritual healing, EM, and includes aspects of TCM, mind–body medicine, and even manual medicine therapies. Some nurses use EM, both in their usual work and as a separate modality; Healing Touch was developed by a nurse, specifi cally for nurses, as adjunct therapy for hospital patients. Th e defi nition of the scope of EM is up for debate. Since many EM practitioners postulate that everything is energy, one can place much of CAM within the EM paradigm. Table 15.1 gives a brief overview of some popular energy

Table 15.1. Common Energy Medicine Techniques (adapted from Baggot, 1999 )

Technique Theory underlying the paradigm

Acupuncture Inserts needles or pressure to stimulate energy fl ow at meridian points on the body

Healing Touch Based in the chakra system; transfers energy by laying hands onto the body

Homeopathy Uses highly diluted substances that would cause symptoms in undiluted quantities to stimulate increased immunity at the level of the energy body

Joh Rei Detoxifi es the energy body by sending universal energy to the patient from the healers hands across a short distance

Polarity Th erapy A touch therapy that balances positive and negative energy fl ows in the body

Qi Gong Uses movement and laying on of hands to cultivate balanced energy fl ow throughout the body

Reiki Channels universal energy into the patient’s body through the hands of the healer

Sound Th erapy Uses vibration through sound to aff ect the energy body

Tai Chi A series of movements and postures to stimulate and increase energy fl ow and restore balance

Th erapeutic Touch Transfers energy by placing the hands into the patient’s electromagnetic fi eld around the body

Yoga Philosophy, poses and breathing techniques to promote energy fl ow and balanced energy

Zero Balancing A gentle touch and movement therapy that balances energy at the zero-point fi eld of the body Energy Medicine and Gastrointestinal Disorders 159 modalities, and the underlying conceptual framework of each modality. While there is research on the eff ectiveness for some EM techniques, many of these modalities fall into other paradigms, such as TCM and physical exercise. Th e research available to date on EM therapies is primarily on therapeutic touch, Reiki, and healing touch, and therefore will be the focus of this chapter. Currently, gas discharge visualization (GDV, which measures biophoton emissions), superconducting quantum interference devices (SQUID), and low-frequency pulsed electromagnetic fi eld (PEMF) are being explored to measure the electromagnetic fi eld of the body (Di Nucci, 2005 ). Yet, until a method is devised to accurately measure the body’s subtle fi eld, the confusion about the defi nition and scope of EM will likely continue. Despite the defi ni- tional uncertainty, EM modalities are being used in the United States. Th e 2000 National Health Interview Survey study on CAM revealed that at least 1 % of people in the US use Reiki or another form of EM, and this number is growing (CDC, 2004). Th e percentage increases to 45% to 50% in persons with chronic pain and chronic illness (Rao et al., 1999 ). Overall, women use EM modalities more than men. Most patients used EM as an adjunct for symptom relief rather than cure (Rao et al., 1999 ). As of 2002, more than 50 hospitals and clinics in the United States provide EM as an adjunct (Di Nucci, 2005 ).

Anatomy, Development of Illness, and Healing

Th e anatomy of the underlying energy fi eld varies according to the tradition. One Qi Gong system (there are multiple of forms of Qi Gong) describes one basic energy center; the Hindu tradition introduced the chakra system, with its 7 energy centers; and TCM describes energy fl ows called meridians . Conceptually, the relationship between these anatomies can be seen as layers. Th e deepest layer is the primary energy center, the next layer houses the 7 chakras and, fi nally, at the interface with the organs, is the meridian system. A simple map of these layers is presented in Figure 15.1 . Diff erent EM techniques work at diff erent layers of the biofi eld. For example, healing touch works at the chakra layer, while TCM works at the most superfi cial layer. Healers tend to perceive the energy fi eld of the system they have been trained in, although some are able to perceive and work in multiple systems and layers. In the natural history of a disease, the energy body is postulated to be out of balance fi rst; then pathology develops, and fi nally symptoms appear. Major cellular pathology develops months to years aft er a block in the natural fl ow of energy, although pain, which is also considered blocked energy, can occur right away. Factors that contribute to or cause a block include genetic or hereditary causes, outside insults, and physical or emotional trauma. Treatment is based 160 INTEGRATIVE GASTROENTEROLOGY on transferring energy to remove blocks and to restore the body’s normal energy fl ow. Keeping the energy fi eld clear, and the energy fl owing, promotes health and healing (University of Arizona, 2007 ). Energy medicine therapies shift or change the underlying energy fi eld of the body. Th e most common technique involves laying the hands on or over the patient’s body. Other techniques employ vibration, light, sound, movement, magnets, or direct current. Movement is extremely important, as it promotes energy fl ow. Th e patient can continue to “balance” himself or herself through movement or self-administered EM techniques, thus reducing the frequency of visits with an EM practitioner.

Research Evidence for Energy Medicine

While there is a paucity of well-done studies on EM, evidence is emerging. In 2003, NCCAM concluded that signifi cant scientifi c evidence exists for veritable EM, including studies on magnet therapy, millimeter wave therapy, sound energy therapy, and light therapy. NCCAM also concluded that the data for putative forms of EM are scant and of poor quality (NCCAM, 2003 ). While this is true, there are studies and reviews worthy of consideration. In 2008, Cochrane published a review of touch therapies (healing touch, Reiki, therapeutic touch), which concluded that touch therapies may have a modest eff ect on pain relief and may decrease analgesic use. Th ey found pain was decreased overall by 0.85 pts (1.16–0.5,) on a scale of 1–10. However, they noted a greater reduction in pain with more experienced practitioners (So, 2008 ). Th is review is in agreement with most claims by the specifi c modalities that they decrease pain, anxiety, and healing times. In the 1970s, Dr. Herbert Benson’s research demonstrated the eff ect of relaxation on the body. He documented shift s in blood pressure, heart rate, and brain wave activity, as well as improvements in immune system, peristalsis, and kidney function (Benson, 1976). Similar physiological changes have been found in studies of EM treatments. For example, Wetzel demonstrated signifi - cant increases in hemoglobin and hematocrit levels in healthy persons learning Reiki (Miles & True, 2003 ), and Movaff aghi et al. ( 2006 ) demonstrated elevation of hemoglobin and hematocrit levels in healthy students treated with therapeutic touch (TT); the same decrease was found in the mock TT group, and no changes were found in the control group. Meehan (1985 , 1993 ; Meehan et al., 1990 ) performed three studies demonstrating that therapeutic touch reduces pain aft er surgery and decreases the time between request for as-needed analgesic dosing (p<.01). Wardell (2001 ) illustrated signifi cant decreases in anxiety and blood pressure, increased salivary IgA, increased skin temperature and Energy Medicine and Gastrointestinal Disorders 161 decreased EMG during a Reiki treatment. Similar fi ndings were demonstrated by Manville ( 2008 ) with healing touch; he reported statistically signifi cant decreases in pretreatment versus post-treatment systolic and diastolic blood pressure, heart rate, skin conductance level, EMG, and trait anxiety.

Placebo effects, relaxation, the effects of human touch, and the healer/ patient relationship are all potentially important factors in EM treatments. The effect on the autonomic nervous system during an EM session, which is typically an hour long, can help patients cope more effectively with their symptoms and illness. Notably, the patient’s breath shifts during a healing session to slower, deeper, abdominal breathing. While the data on the effects of EM on the immune system are scant, it is possible that EM treatments to the belly may affect the gut immune system. I have seen a decrease in reported symptoms with inﬂ ammatory bowel disease, although I have not seen a complete remission from EM alone.

Systematic reviews of EM in various settings reveal a broad range of rigor, and approximately half of them show benefi t. Jonas ( 2003 ) reviewed 19 randomized controlled trials, most on therapeutic touch, and found 11 of 19 showed statistically signifi cant treatment eff ects with a mean eff ect size of 0.60. He concluded that the evidence for EM modalities for relieving pain and anxiety was “level B,” or poor to fair. Astin (2000 ) reported the mean eff ect of therapeutic touch was 0.63 in a systematic review of 11 TT studies. He found that 7 of 11 studies showed a positive eff ect on at least one outcome. When all healing trials (including prayer and distant healing) were reviewed, the mean eff ect size was 0.40. Th e mean eff ect score for distant healing, which included Reiki, was 0.38. Finally, Abbot ( 2000 ) reviewed 22 trials of EM healing. His review concluded that of 22 trials reviewed, 10 had a signifi cant positive outcome for healing, 11 had no signifi cant outcome, and 1 study was indeterminate due to poor study design. Five out of the eight studies with a Jadad score of 5 showed signifi cant diff erences between the EM treatment group and the control group. Further, EM has also been used for more than 20 years as an adjunct to cancer treatment to help alleviate side eff ects (Stephen et al., 2007 ).

Evidence for Energy Medicine in Gastrointestinal Disease

Published studies report that the prevalence of CAM use ranges from 35% to 52 % in infl ammatory bowel disease patients, functional bowel disorder 162 INTEGRATIVE GASTROENTEROLOGY patients, and gastroenterology patients (Ganguli et al., 2004 ; Joos et al., 2006 ; Quattropani et al., 2003 ). However, none of these studies asked specifi cally about EM modalities, such as healing touch or Reiki. Th ere is emerging evidence to support the successful use of mind–body techniques (including hypnotherapy), acupuncture, and relaxation training as adjunctive treatment to standard therapy in infl ammatory and functional bowel disorders (Forbes et al., 2000 ; Keefer & Blanchard, 2002 ; Spanier, Howden, & Jones, 2003 ; Tan, Hammond, & Joseph, 2005 ; van der Veek, Rood, & Masclee, 2007 ; van Tilburg et al., 2008 ; Wilson et al., 2006 ). As already discussed in this chapter, these paradigms can be categorized under the broad concept of EM, but are addressed in other chapters of this book. While there is a strong possibility that EM therapies may have a similar eff ect to these evidenced therapies, this needs further research with regard to GI disorders and specifi c EM techniques. Th ere is one study worth noting for GI functional and infl ammatory disorders, by Wilkinson. He demonstrated that healing touch (HT) positively aff ected sIgA levels, decreased pain, and decreased patient perception of stress. Experience of the HT practitioner was proportional to the eff ect experienced (Wilkinson et al., 2008). Further, while there is a paucity of studies with positive evidence specifi cally for gastrointestinal disease and EM, it is important to note that there are no negative studies published, either.

Side Effects and Consideration for Referral

When properly used, EM has negligible negative eff ects. Practitioners report there may be an increase in pain in long-term chronic pain patients aft er the fi rst few treatments. Th is is understood by the practitioners to represent the release of blocked energies, and is expected to diminish and dissipate with subsequent treatments. Patients who are seeking adjunctive therapies for their pain or related symptoms, with a belief, openness, or cultural alignment to EM, may be appropriate for referral. Matching the patient’s belief system to the available modalities is useful. Patients with longer duration of illness and more severe pain are good candidates. EM can be a useful adjunct to their medical management, with few side eff ects. If a patient does not experience positive physical or mental eff ects within a few visits, it may be more appropriate for the patient to use his or her resources on another modality. Most EM modalities have websites with certifi cation guidelines and lists of practitioners; e.g., www.iarp.org (Reiki), www. healingtouchinternational.org (Healing Touch), www.barbarabrennan.com , and www.zerobalancing.com , (Zero Balancing.) Energy Medicine and Gastrointestinal Disorders 163

When choosing a pracitioner for referral, I have a few considerations. I choose practitioners that do not “hex” or put down conventional medicine. I tend to choose practitioners that have more experience — at least 3 years, and preferably more than 10 years of experience. Experience is not equal to expertise, yet I ﬁ nd healers who have been doing it longer are, as a group, better. I try to visit the healer myself prior to referring. I often do this anonymously, so I can have a “standard” session to see what my patients will experience.

Conclusion

EM techniques arise from the ancient concept of a primary vital force within the body aff ecting the health of the physical body. While research is limited, EM appears to be most helpful for increasing relaxation and decreasing pain and anxiety. It may also have a role in increasing sIgA levels. It can facilitate a healing relationship between practitioner and patient, which in itself is therapeutic. Women tend to seek out EM practitioners more than men, and EM may be a useful adjunct for chronic functional and infl ammatory gastrointes- t i n a l d i s e a s e . 1 6 Guided Imagery and Gastroenterology

MARTIN L. ROSSMAN

key concepts

■ Imagery is a natural way the human nervous system stores, accesses, and processes information. ■ Guided imagery is a mind–body technique to channel information that may aff ect physiology and the way patients care for themselves. ■ Indications for guided imagery include stress-related conditions (e.g., anxiety), preparation for invasive procedures, chronic illness, pain, relaxation, and symptom reduction. ■ Guided imagery can be learned from trained practitioners; this training may be supplemented by books, CDs, or audio downloads. ■ Guided imagery should be used to augment healing as an adjunct to conventional therapies, not as a standalone modality for chronic diseases. ■ Patients who are psychotic or who are on the verge of psychotic breaks, who have dissociative disorders, or who have borderline personality disorders or post-traumatic stress disorder, must be handled with care. ■

he highly innervated gastrointestinal system is oft en a sensitive responder to mental and emotional infl uences. Most of the mind/body T phenomena we see as clinicians are responses to stress and worry, unintentional eff ects that in themselves illustrate the powerful eff ects of mental imagery on GI function.

164 Guided Imagery and Gastroenterology 165

Mental imagery, which is simply thinking sensory-based thoughts, is the natural language of the unconscious. It is the language in which we represent our worlds to ourselves and to each other in art, poetry, music, and drama, and it is the internal language of dreams, daydreams, memory, and future planning. Th e most common form of mental imagery is worry. As our minds frequently return to, or are even dominated by, recurrent images and thoughts of undesirable, fearful events, our bodies respond with physiologic stress reactions. Because the GI system is a delicate network of target organs, we may suff er GI symptoms from indigestion, nausea, refl ux, diarrhea, constipation, or abdominal pain. Th e importance of this common clinical observation is that learning to use our imaginations in more skillful ways can help us relax, manage stress, and relieve many GI symptoms.

Research shows that relaxation, hypnosis, and guided imagery are the most effective known treatments for IBS.

Even patients with physiologic bowel disease may suff er exacerbations in response to stressful situations, and may fi nd some symptom relief through guided imagery. Th e eff ects of the mind on physiologic function has been described in the West by physicians going back to the time of Hippocrates, and much earlier in ancient treatises on Oriental medicine. In 1823, U.S. Army surgeon William Beaumont treated a patient, Alexis St. Martin, who had been shot in the stomach, leaving a nonhealing fi stula into which Beaumont could see. Beaumont observed that the lining of the stomach would turn red and dry when the patient was angry, and pale from vasoconstriction when the patient was frightened. Modern research shows that when people use imagery to stimulate relaxation responses instead of stress responses, they can reduce or even eliminate stress-induced GI symptoms, and reduce the amount of symptom amplifi cation that can occur when sympathetic and adrenergic stimulation are layered on top of GI illness. Using guided imagery allows people to develop ways to manage stress more eff ectively, so they are better able to stop using alcohol, tobacco, or excessive eating to reduce perceived stress.

Guided imagery has also been shown to reduce anxiety before and during endoscopy and colonoscopy, and has been shown to signiﬁ cantly reduce postoperative pain and complications in patients having GI surgery. 166 INTEGRATIVE GASTROENTEROLOGY

WHAT IS IMAGERY?

Imagery is a natural way the human nervous system stores, accesses, and processes information. It is the coding system in which memories, fantasies, dreams, daydreams, and expectations are stored. It is a way of thinking with sensory attributes. Functional MRI shows that, in the absence of competing sensory cues, the brain and the body tend to respond to images in the same way that they do to actual events. Imagining stressful events, or worrying, tends to stimulate stress physiology, while imagining peaceful or comforting settings or events tends to stimulate relaxation physiology. Th e applications of guided imagery are shown in Table 16.1 .

Table 16.1. Applications of Guided Imagery

Relaxation training and stress reduction

Pain relief

Management of chronic illness and prevention of acute exacerbations

Preparation for surgery and medical procedures

Medication compliance and adherence issues

Cancer treatment and life-threatening illnesses

Terminal illnesses and end-of-life care

Fertility, birthing, and delivery

Grief therapy

Post-traumatic stress disorder

Anxiety disorders

Depression

Imagery has been shown in dozens of research studies to affect almost all major physiologic control systems of the body, including respiration, heart rate, blood pressure, metabolic rates in cells, gastrointestinal mobility and secretion, sexual function, and even immune responsiveness. Guided Imagery and Gastroenterology 167

Imagery is also a rapid way to access emotional and symbolic information that may aff ect physiology and the way the patient cares for himself or herself. For instance, a patient may talk at length about the nature of her GI symptoms, yet we may appreciate something more when we invite her to allow an image to form for her symptoms. A 33-year-old patient with ulcerative colitis described his image of his colon as “red, angry, and very irritated.” Not only does this give us a graphic, sensory description of the symptom, it may also lead to important psychosocial information involved in the perception of the pain — in this case, asking him to say more about anger and irritation.

Is Guided Imagery the Same as Hypnosis?

Guided imagery and hypnosis are closely related, and the practitioner who uses either should be skilled in both. I think of hypnosis as the state of relaxed, alert, attention, and imagery as the contents that most eff ectively create physiologic eff ects and insight. You can’t accomplish much in hypnosis without using imagery-based suggestion, and when people engage in guided imagery, they spontaneously go into the relaxed state of attention that is usually termed “hypnosis.” One advantage of using the term guided imagery is that it frees the patient from fears, realistic or not, that many people have of hypnosis. It also encourages people to learn how to use their minds better, rather than placing them in the role of passive recipient.

How Does Guided Imagery Work?

Imagining something, especially with multiple senses, tends to create an inner experience that the brain and body react to as if the actual event were happening. A common example is sexual fantasy, which has profound infl uences on physiology and behavior. Since the invention of the functional MRI (fMRI), we know that when people imagine visual objects or experiences, they activate the occipital cortex, where visual information is processed. In the same way, imagining music or conversation activates the temporal cortex, and imagining movement activates the premotor cortex.

Imagery activates the parts of the cortex that process real events, and sends signals to the limbic and sub-limbic structures that regulate or express emotions and physiologic responses, modulating autonomic response, endocrine response, circulation, digestion, rest and sleep cycles, and sexuality, among other functions. 168 INTEGRATIVE GASTROENTEROLOGY

Cultivating a regular process of physiologic and mental relaxation through relaxation techniques, meditation, self-hypnosis, or self-suggestion, allows people to develop the skill of calming the GI system, which can have positive, rather than negative, eff ects. Imagery, guided toward these ends, is oft en the simplest, easiest, and least challenging approach for most people to learn.

What Are its Applications in Gastroenterology?

Since imagery is a way of thinking, it has widespread applications in clinical medicine, ranging from simple relaxation techniques to preparation for procedures and surgery, treatment adherence, reducing convalescent time, changing lifestyle behaviors, and fi nding meaning in illness. Guided imagery is essentially a way of working with the patient, rather treating particular disease entities. However, it is especially eff ective in the areas listed below, which are common issues with patients with GI illness:

• Relaxation Training and Stress Reduction Imagery is the easiest way to teach relaxation: Simply invite someone to daydream themselves to a place that is beautiful and safe, where they love to be. Ask them to notice what they imagine seeing, hearing, feeling, what the temperature is like, what time of day it is, and what time of year. Th eir immersion in the sensory cues will elicit a relaxation response. • P a i n R e l i e f From a safe place of relaxation (see above) invite the person to imagine something soothing, comforting, or healing coming to any areas that are uncomfortable, breathing easily and regularly while doing so. • Adapting To and Managing Chronic Illness In a relaxed state, invite the patient to allow an image to form that represents the illness. Have him describe it, its qualities and how he feels about it. Ask him to imagine that the image can respond in a way he can understand, and facilitate an imaginary dialogue, ultimately aiming for a way they can better coexist or “help each other.” • Preparation for Surgery and Endoscopic Procedures Many guided imagery CDs are available that lead people through relaxation and imagery, focusing on the ideal outcomes they desire. Guided Imagery and Gastroenterology 169

Th is gives people a sense they are participatory rather than help- less, reduces anxiety, and reduces postoperative complications and discomfort. • Medication Compliance and Adherence Issues Asking patients to imagine medications working exactly like they’d want them to work encourages adherence and compliance.

Imagery in the context of counseling or psychotherapy is especially effective when working with grief, post-traumatic stress disorder, anxiety disorders, and depression, all of which are frequently coexistent with GI illnesses.

How Is Guided Imagery Used and Taught?

Th e basic self-care skills of relaxation and guided imagery can be taught easily and inexpensively through the use of books, CDs, or audio downloads from the sites listed in the resource section. Classes, groups, or individual instruction are also available in many areas. Th e questions and techniques used in a typical interactive guided imagery session are illustrated in Tables 16.2 and 16.3 .

Table 16.2. A Typical Guided Imagery Session

1. Assessment (foresight):

a. Ask what symptom, illness, or thoughts the patient would like to explore.

b. Ask what the patient wants to get out of the session.

c. Ask patient to narrow down the problem to a short phrase or question.

d. Formulate a one-sentence summary of goals.

e. Obtain patient’s consent.

2. Imagery process (insight):

a. Relaxation:

(1) Ask how the patient best relaxes.

(2) Use the patient’s best method, or teach him/her one.

b. Imagine a beautiful, safe place:

(Continued) 170 INTEGRATIVE GASTROENTEROLOGY

Table 16.2. (Continued)

(1) “Allow yourself to imagine a comfortable and peaceful place. It might be a place that you have been before, or something that’s just coming into your imagination now. If several places come to mind, allow yourself to pick just one to explore now.”

(2) Ask the patient to describe the place in regard to sensations (“What do you see, hear, smell, feel and taste? What makes you feel comfortable there?”).

(3) Invite the patient to fi nd a comfortable place to settle down.

c. Imagery dialogue:

(1) Invite the patient to form an image that represents the illness, symptom or issue.

(2) Ask the patient to describe the image in detail. (Have him/her describe at least three things, such as appearance, character, and emotions of the image.)

(3) Ask the patient to describe the qualities that the image portrays.

(4) What feelings does the patient have about the image?

(5) Invite the patient to express these feelings to the image and allow it to respond.

(6) “Imagine that it can communicate with you in a way you can easily understand.”

(7) Facilitate the imaginary conversation as needed, using “content-free” questions and suggestions such as:

(a) “Do you have any questions you would like to ask the image?”

(b) “How does it respond?”

(d) “What does it want you to know?”

(e) “What does it need from you?”

(f) “What does it have in common with you?”

(g) “What does it have to off er you?”

(h) Ask the image what it can tell you about the problem, so you can better understand.

(i) Ask the image what it can tell you about the solution, so you can better understand.

(j) Go back to the safe place, and return from the inner place. Guided Imagery and Gastroenterology 171

Table 16.2. (Continued)

d. When the image communicates, you might ask the patient how he/she feels about that or wants to respond, then encourage the patient to respond and let the image respond to that. Your role is to facilitate the dialogue, not provide the answers.

e. If the patient appears frightened, ask whether he/she feels safe; if not, have the patient go back to the safe place, or ask what he/she needs to feel safe.

3. Evaluation (hindsight):

a. Ask the patient what he/she felt was interesting or signifi cant about the dialogue.

b. Ask the patient whether he/she learned anything from or about the image and/or the symptom.

c. Ask the patient whether the information changes his/her perspective, or how he/ she wants to respond.

d. Ask the patient what he/she would do next with what he/she learned.

Table 16.3. Common Interactive Guided Imagery Suggestions and Questions

• Allow an image to form. • What do you notice about it? • What are you aware of? • What are you experiencing? • What would you like to notice yourself having? • What would you like to say to it? • What sensations are you aware of? • Let me know when you are ready to move on.

Interactive Guided Imagery sm (IGI) includes techniques that are applicable in the course of brief medical offi ce visits, or in longer counseling or psychotherapy formats. Physicians who are trained may practice it themselves, or employ an ancillary health professional to off er longer sessions or work with patients with more complex issues.

Is There Any Risk in Referring a Patient for Guided Imagery?

Th e primary danger in using guided imagery to augment healing in medical situations is when it is used in lieu of appropriate medical diagnosis and/or treatment. We emphasize the necessity of an accurate diagnosis, so that the 172 INTEGRATIVE GASTROENTEROLOGY

Table 16.4. Contraindications to Guided Imagery

• Strong religious beliefs proscribing the use of imagery • Disorientation, dementia, or impaired cognition due to pharmacologic or other agents • Inability to hold a train of thought for at least 5 to 10 minutes • Potential litigation. Guided imagery may be considered a form of hypnosis, which aff ects the legal status of information obtained with its use

patient can also be made aware of the medical options for treatment. When you refer a patient for IGI aft er evaluating his or her medical condition, this risk is eliminated. Patients who are psychotic, or who are on the verge of psychotic breaks, who have dissociative disorders, or who have borderline personality disorders or post-traumatic stress disorder must be handled with care. While these diagnoses do not represent absolute contraindications for imagery work, they require that health professionals who use imagery have expertise in these areas.

Conclusion

Guided imagery is a method of tapping into the mind’s resources to alter physiology favorably, reducing stress and improving physiology. Given the mind– gut connection infl uences on many digestive conditions, guided imagery should be considered as an adjunct to conventional therapy when stress reduction is needed. Abundant resources are available for practitioners and patients to apply guided imagery to self-care. Caution should be exercised not to use guided imagery in lieu of conventional therapies, or to use it in situations where dissociative disorders, borderline personalities, psychosis, or post- traumatic stress disorder are suspected.

Resources

GUIDED IMAGERY SELF-CARE BOOKS AND TAPES

Th e Healing Mind www.thehealingmind.org Books and home-study audio programs from Martin Rossman, MD, Jeanne Achterberg, PhD, Kenneth Pelletier, PhD, Rachel Remen, MD, Emmett Miller, MD, and more. Research reviews and professional community resources listed. Guided Imagery and Gastroenterology 173

PROFESSIONAL TRAINING AND REFERRALS

Academy for Guided Imagery www.acadgi.com Provides professional training and certifi cation in Interactive Guided Imagery,sm and referrals to certifi e d p r a c t i t i o n e r s . 1 7 Hypnosis and Gastrointestinal Disorders

ANASTASIA ROWLAND-SEYMOUR

key concepts

■ Hypnosis has long been used to treat chronic medical illnesses. ■ Recent research supports the view that hypnotic suggestions eff ectively change aspects of the person’s physiological and neurological functions. ■ Th e possible mechanism of hypnotic eff ects is still unclear. ■ Th ere is a large body of literature on the use of gut-directed hypnotherapy suggesting that hypnosis has a role in treating refractory irritable bowel syndrome. ■ A few trials suggest that hypnosis may have a role in functional dyspepsia, and that propose a mechanism of action. ■ Some preliminary data suggest a short-term eff ect of hypnosis on infl ammatory markers in infl ammatory bowel disease, although this data set has not been validated. ■ M o r e r i g o r o u s t r i a l s a r e r e q u i r e d t o d e fi nitively say that hypnosis produces long-lasting eff ects in gastrointestinal disorders. ■ Prior studies have hinted that hypnosis may actually not be cost-prohibitive; however, trials on its cost eff ectiveness need to b e c a r r i e d o u t . ■

174 Introduction

DEFINITION OF HYPNOSIS

here is a great deal of variation in the defi nitions of hypnosis. According to the American Society of Clinical Hypnosis, the largest and most T respected association for medical professionals using hypnosis, “hypnosis is a state of inner absorption and focused concentration.” Th e American Psychological Association’s defi nition of hypnosis notes that “[hypnosis] procedures traditionally involve suggestions to relax, though relaxation is not necessary for hypnosis and a wide variety of suggestions can be used including those to become more alert.” Many mind–body techniques aim to induce relaxation, and thereby upregulate the parasympathetic system, in an eff ort to decrease sympathetic drive and induce the relaxation response to achieve symptom control. Hypnosis does not require one to be relaxed; rather, it requires one to be distracted and absorbed in one’s thoughts. Part of the hypnotic procedure oft en induces relaxation; however, the ultimate goal of hypnosis is focused concentration. Th is allows hypnosis to be used for multiple outcomes. Hypnosis is most oft en used in one of three ways. Th e fi rst is to induce the imagination to take hold, correlating mental images with illness and health; this aspect of the technique can be very similar to guided imagery. Secondly, hypnosis allows the practitioner to give a subject direct suggestions aimed at changing behaviors or improving health. Lastly, hypnosis can be used to explore the psychological reasons for particular behaviors that aff ect health.

POSSIBLE MECHANISMS OF HYPNOSIS

While there is general agreement that hypnosis may have clinical eff ects for some conditions, there are diff erences of opinion within the research and clinical communities about how hypnosis works. Recent research supports the view that hypnotic suggestions eff ectively change aspects of the person’s physiological and neurological functions. One way of thinking about hypnosis is that it changes the associations between occurrences and our perceptions of them. Some describe it as “reshuffl ing our mental fi ling cabinet.” By uncou- pling associated responses or emotions from life events, one can then interpret new data diff erently and create new associations between events and thoughts. Researchers at Penn State have been using hypnosis as a tool to better understand the brain. Th ey have done a number of EEG studies, looking at 176 INTEGRATIVE GASTROENTEROLOGY pain response. One such study suggests that hypnosis can remove the emotional experience of pain, while allowing the sensory sensation to remain. Th us, one notice might notice that one was touched, but not that it hurt (Ray et al., 2002 ). An emerging body of literature suggests that hypnosis may cause physiologic changes in the brain. We know from studying positron emission tomography (PET) scans in people who have undergone hypnotic relaxation that they experience increased regional cerebral blood fl ow in the anterior cingulate cortex, the thalamus, and the midbrain. (Rainville, Hofb auer, Bushnell, Duncan & Price, 2002 ) Subjects who were experiencing increased mental absorption, rather than relaxation, as part of their hypnotic experience, were found to have increased regional cerebral blood fl ow in a distributed network predominately ranging over the prefrontal cortices. Th is is very similar to the patterns of activation that have been associated with tasks involving visual, auditory, and somatosensory stimulation (Rainville et al., 2002 ; Peyron et al., 1999 ). Hypnosis has long been studied in medical conditions and has been shown to have wide-ranging eff ects. Th ere are studies documenting its usefulness in many illnesses, ranging from managing acute and chronic pain, decreasing presurgical anxiety, acting as sole or adjuvant analgesia during surgical procedures, promoting healing from burns, and managing nausea and vomiting, dermatologic disorders, and gastroenterologic disorders.

Hypnosis in Gastrointestinal Disorders Literature

Hypnosis has been studied in several gastrointestinal disorders, most notably irritable bowel syndrome. It has also been studied in functional dyspepsia and, most recently, in ulcerative colitis.

IRRITABLE BOWEL SYNDROME

A large number of trials have used gut-directed hypnotherapy in subjects with irritable bowel syndrome (IBS). While these studies are of varying quality, the preponderance of data suggests a positive eff ect of this modality in IBS. Th e fi rst published trial using hypnotherapy in IBS was a small but well-designed placebo-controlled trial by Whorwell, Prior, and Faragher ( 1984 ). In this study, hypnosis was compared to psychotherapy plus a placebo medication. Th e hypnosis group was found to have fewer symptoms, including abdominal pain and distention, than the control group (Figure 17.1 ). Hypnosis and Gastrointestinal Disorders 177

Th e authors noted that, although the mechanism by which hypnotherapy works is uncertain, its results might be mediated by some psychological eff ect or by direct-action gut motility. Th e researchers favored the latter, because a pilot study suggested that hypnosis that emphasized general relaxation did not improve irritable bowel symptoms until sessions were directed specifi cally at controlling intestinal function. A follow-up noted that these results were maintained for a 2-year period post-treatment (Whorwell, Prior, & Colgan, 1987 ). Th ese results have been validated in several studies by the same group (Gonsalkorale, Houghton, & Whorwell, 2002), as well as by several other investigators. It has been suggested that individual hypnotherapy is impractical for most practice settings, given the cost and access to appropriately trained hypno- therapists. Harvey et al. (1989 ) compared individual gut-directed hypnotherapy to group sessions, with up to 8 subjects per group, in a small trial of 33 subjects. For subjects with refractory IBS who underwent individual versus group gut-directed hypnotherapy, improvement in symptoms was comparable. While the results were not as robust as those noted in the Whorwell trials, these results were sustained for 3 months aft er the trial ended, without formal intervention (Table 17.1 ).

Table 17.1. Patient Characteristics and Response to Hypnotherapy

No improvement Less symptoms Symptom free — (n=13) (n=9) (n=11)

Sex 3M, 10F 2M, 7F 3M, 8F

Hypnotherapist A 6 8 3

Hypnotherapist B 7 1 8

Group Th erapy 5 6 6

Individual Th erapy 8 3 5

Severe symptoms at start 4 5 2 (total symptom score ≥ 35)

Psychological Problems 5∗ 3 0∗ (GHQ score ≥ 5)

Age > 50 yr 4 2 1

∗p<0.05 for diff erence between symptom-free and no-improvement groups. Th ere were no other signifi cant diff erences between response groups. Adapted from Harvey et al. (1989 ). Lancet , 1, 424–425. Reprinted with permission. 178 INTEGRATIVE GASTROENTEROLOGY

Table 17.2. 14-Day Diary Symptom Scores at Each Assessment Time in Study II∗

Time 1 Time 2 Time 3

Immediate group (N =15) Pretreatment Posttreatment 4 mo follow-up

Abdominal Pain 23.9 (2.5) 12.9 (3.2)† 12.5 (3.4)†

Bloating 20.3 (3.1) 15.1 (2.7)† 11.1 (3.3)†

Proportion of hard/loose stools 0.25 (0.04) 0.10 (0.03)† 0.23 (0.05)†

Bowel movements per day 3.1 (0.7) 2.3 (0.5) 2.3 (0.5)

Delayed group (N =9)

Abdominal Pain 16.00 (1.9) 16.8 (1.2)‡ 10.2 (1.8)†

Bloating 13.6 (2.1) 11.67 (1.7)‡ 9.0 (1.48)‡

Proportion of hard/loose stools 0.27 (0.06) 0.26 (0.06)‡ 0.8 (0.03)‡

Bowel movements per day 2.2 (0.4) 2.1 (0.4) 1.7 (0.2)

∗ Th e immediate group received hypnosis treatment between time 1 and 2, whereas the Delayed group received hypnosis between time 2 and time 3. Boxes delineate pre-versus posttreatment contrast. † Signifi cantly diff erent from pre-treatment values in this group, P < 0.05 . ‡ Signifi cantly diff erent from Immediate Group values at the same time point P <0.05 . Reprinted with permission from Palsson O et al. ( 2002 ). Digestive Diseases and Sciences, 47 (11), 2605–2614.

In an uncontrolled prospective cohort trial, Palsson and Whitehead ( 2002 ) noted that there was signifi cant improvement in irritable bowel symptoms (see Table 17.2 ). However, improvements were unrelated to the physiologic changes that were measured. In particular, there was no change in rectal pain thresholds, rectal smooth muscle tone and autonomic functioning, except sweat gland reactivity (Table 17.3 ). A systematic review by Wilson et al. ( 2006 ) included 18 trials, four of which were randomized, 2 of which were controlled and 12 of which were uncontrolled. Th ese trials tended to demonstrate that hypnotherapy was eff ective in managing IBS. However, the number of subjects per trial was small. Th e majority of the studies suggested possibilities for bias, and only one of the trials (Roberts et al., 2006 ) scored well with respect to internal validity. Th e subsequent Cochrane review (Webb et al., 2007 ) included only the four randomized controlled trials; all other studies were discarded as methodologically fl awed. Th e study designs were suffi ciently varied to preclude the Hypnosis and Gastrointestinal Disorders 179

Table 17.3. Physiological Parameters Before and After Hypnosis Treatment in Study II (N = 24)

Measure Pretreatment Posttreatment P (mean + / -SE) (mean + / - SE)

Skin conductance (μ mhos) 1.45 ± 0.29 1.11 ± 0.16 NS

Skin conductance stress change (μ mhos) 1.41 ± 0.18 1.01 ± 0.19 0.01

Heart rate (bpm) 66.1 ± 1.8 67.2 ± 1.9 NS

Heart rate stress change (bpm) 3.1 ± 1.5 4.83 ± 1.5 NS

Systolic BP (mm Hg): 123.6 ± 2.3 121.1 ± 2.9 NS

Systolic BP stress change (mm Hg) 5.2 ± 1.5 1.4 ± 4.8 NS

Diastolic BP (mm Hg) 70.8 ± 2.5 70.9 ± 2.4 NS

Diastolic BP stress change (mm Hg) 3.3 ± 1.5 3.5 ± 1.0 NS

Finger skin temperature (° F) 86.7 ± 1.7 86.9 ± 1.4 NS

Finger temperature stress change ( °F) —2.2 ± 1.0 —2.1 ± 0.4 NS

Baseline EMG ( μ v) 4.1 ± 0.6 3.5 ± 0.5 NS

Stress-related increase in EMG (μ v) 3.8 ± 1.0 3.2 ± 0.9 NS

Reprinted with permission from Palsson O et al. (2002 ). Digestive Diseases and Sciences, 47 (11), 2605–2614. possibility of a meta-analysis. Nonetheless, the authors did fi nd that hypnosis appeared to be a safe intervention and could be tried in individuals who have failed conventional treatment for IBS. Further, they concluded that even though there was the suggestion of a benefi cial eff ect in the short term, this fi nding has not been convincingly proven by high-quality studies. Th e suggestion of persistent long-term benefi ts of hypnotherapy in IBS has been noted in several studies; however, each of these studies is methodologically challenged. Only one primary-care-based study measured long-term (12 months) outcomes in a systematic method, and no benefi t was found (Roberts et al., 2 0 0 6 ) .

FUNCTIONAL DYSPEPSIA

More recently, hypnosis has been looked at in the setting of functional dyspepsia. In 2002, the same Manchester group of Whorwell et al. created a three- arm trial designed to explore what, if any, eff ect hypnosis would have on 180 INTEGRATIVE GASTROENTEROLOGY functional dyspepsia. One arm of this trial was a hypnotherapy group, another arm was a psychotherapy plus placebo-medication group, and both were compared to standard medical therapy. Th ere was a 59% reduction in quality of life measures, which continued to improve aft er treatment, reaching a 73 % reduction in symptom severity at one year (Calvert et al., 2002 ; see Figure 17.2 ). Prior analyses have suggested that hypnotherapy was not economically fea- sible because a standard course of treatment typically requires 12 sessions with a single hypnotherapist. Others have observed, however, that once treated with hypnosis, patients with IBS oft en require minimal further intervention. Th is trial noted a statistically signifi cant decrease in medication usage and healthcare utilization (Table 17.4 ). More recent functional studies have looked at possible mechanisms for hypnosis’ usefulness in GI disorders. Chiarioni et al. (2006 ) noted in a small trial that patients with functional dyspepsia who underwent hypnosis had a

Table 17.4. Medication Use and Consultation Rate of Patients During Long-term Follow-up

40 Week follow-up

Hypnotherapy Supportive Medical (n = 26) (n = 24) (n = 29)

Number taking medication 0 20 26

% taking medication 0 81.8 89.7

PPI 0 6 15

H2 antagonists 0 8 8

Prokinetics 0 0 0

Antacids 0 4 3

Antidepressants 0 5 0

None 26 4 3

Total number of consultations 1 (0–2) 4 (1–10)∗ 4 (0–9) ∗ median (IQR)

Number of GI consultations 0 (0–0) 3.5 (0–10)∗ 3 (0–9) ∗ median (IQR)

NOTE. Expressed as median (interquartile range). ∗ P <0.001 vs. hypnotherapy. Reprinted with permission from Department of Medical Illustration, Withington Hospital, Manchester, England. Reprinted with permission from Calvert et al. (2002 ). Gastroenterology, 123, 1778–1785. Hypnosis and Gastrointestinal Disorders 181 shortened gastric emptying time as compared to cisapride and usual care. Th is shortened gastric emptying time was also noted in the control group of normal subjects who underwent hypnosis.

INFLAMMATORY BOWEL DISEASE

Hypnosis may have some eff ect on infl ammation and immune response in a number of diseases. Th ere are anecdotal reports of improvement in infl ammatory bowel disease with the use of hypnosis. Th ere are, however, few studies of hypnosis in infl ammatory bowel disease. In a small controlled trial by Mawdsley et al. (2008 ), subjects with ulcerative colitis underwent one session of hypnosis. Systemic infl ammatory markers were measured with interleukin-6 (IL-6) and interleukin-13 (IL-13) serum levels, and rectal mucosal infl ammation was assessed by mucosal release of substance P, histamine, and IL-13. One session of hypnosis reduced serum IL-6 concentrations by 53% , and reduced rectal mucosal release of substance P by 81% , histamine by 35% , and IL-13 by 53% . While this is data from a single time point, and in no way can it be extrapo- lated as to whether the results would be sustained with repeated interventions, it is interesting to note that hypnosis has a clear physiologic eff ect that could explain some of the anecdotal reports of improvement with its use in infl ammatory bowel disease.

Conclusion

Th ere are signifi cant data to support the use of clinical hypnosis in functional gastrointestinal disorders. Although well-designed trials are few in number, reviews suggest that hypnosis may be eff ective in functional disorders that are refractory to conventional medical approaches. Similarly, while there is not suffi cient data to be conclusive, there is the suggestion of a possible improvement in infl ammatory bowel disease. A growing body of literature details the neuroscience of hypnosis, and literature substantiates the organ-specifi c physiologic changes that may account for the eff ects of hypnosis in GI disorders. Clearly, further well-designed trials are needed to fully understand the eff ects that hypnosis has on gastroenterologic disorders. Additionally, it would be extremely useful to address the perceived issues of fi nancial nonviability. Prior studies have suggested not only that self-hypnosis pays for itself in the long run by decreasing healthcare utilization, but also that accessibility can be increased, while still maintaining effi cacy, with group hypnotherapy. Th ese questions need to be answered with the help of well-designed trials. 1 8 Homeopathy Origins and Therapeutic Principles

SAVELY YURKOVSKY

key concepts

■ Homeopathic remedies are representatives of a matter–energy duality phenomenon, and are the extracts of the underlying information content of a substance from which the remedy is prepared. ■ Th erapeutic prescription of classical homeopathy is based on the laws of totality and complexity, which operate in humans both in health and disease. ■ For true health progress, symptoms of chronic disease, which are refl ections of underlying etiologic agents, must not be suppressed just for the sake of palliation but must be allowed to manifest themselves and exit from the body according to Hering’s Law of Cure. ■ Causative homeopathy renders novel means and remedies that endow the body with great therapeutic potential to rid itself of a variety of environmental pollutants and other morbid agents, including carcinogens, which are ubiquitous in our daily environment. ■ Th e pathogenicity of these agents in chronic degenerative diseases is in accord with the accepted tenets of the science of toxicology. Both classical and causative homeopathy represent a strictly individualized and novel paradigm in viewing illness as individual disease states versus approaching these as generically classifi e d d i s e a s e s . ■

182 Classical Homeopathy

THE LAW OF SIMILARS

n 1796, Samuel Hahnemann, of Germany, published the paper, “A New Principle of Healing,” which he named homeopathy (Schmidt, 1988 ; I Schmidt, 1994 ). Th e name denotes “similar disease,” based on the Greek term, homoion pathos, or the Latin term, “like cures like” ( similia similibus curentur ), and is referred to as “Th e Law of Similars.” Th e principle itself had been known and applied through various therapeutics, from Egyptian alchemists to Hippocrates and Paracelsus. However, both Hahnemann’s pharmacopeia and methodology were truly innovative. Th e remedy preparation involved serial dilutions of the original, or any substance (plant, mineral, toxicological or infectious agents, etc.), along with succussions — the parallel and repetitive mechanical impacts delivered to the solution against the bottom of a glass bottle, even far beyond Avogadro’s number, 6.02 × 1023 . Th ese remedies, then, would be administered to the sick who display symptoms similar to those elicited by the same remedies, in healthy volunteers, in the process of proving, or eliciting remedy-induced symptoms. Th e picture for prescribing would include not only localized pathology — e.g., headache, diarrhea, vomiting, etc. — but a very detailed qualitative analysis of these and, strangely enough, a broad range of concomitant complaints, including mental, emotional, and general symptoms nonspecifi c for disease, per se. Even more novel, the therapeutic rating of these other symptoms — and particularly those that were considered peculiar and seemingly unrelated to the main pathology; for example, ear itch, claustrophobia, or testicular pain in a colitis case — would oft en prevail over the therapeutic rating of the local disease. It was observed that the remedies that encompassed these other and especially peculiar symptoms yielded greater therapeutic success than those focused on disease, per se. Th e rationale for the emphasis on other and peculiar symptoms was that they were more refl ective of the state of the body’s defense force on the total, complex level that the remedies aimed to stimulate in order to elicit more specifi c and intense response of that defense force against any morbid factors behind an illness. Th is approach was deemed to be based on the law of totality and was referred to as classical homeopathy . Another unique property of homoeopathy has been formulated as Hering’s Law of Cure, summed up by Constantine Hering in the nineteenth century (Treuherz, 2005 ). It is based on countless clinical observations that in any set 184 INTEGRATIVE GASTROENTEROLOGY of pathologies, in order for true healing to take place, the pathology in the course of the therapeutic process must move in a downward anatomical direction from head to toe, from inside out, and in reverse order of the time of onset of pathological symptoms. Th e fi rst two rules underscore a priority in protecting more physiologically important organs, while the third rule implies the process of peeling off morbid layers of disease in the corresponding chrono- logical order of their original aggregation. It is of interest that the latter rule is deemed to be placebo-proof since, in the majority of cases and only upon the return of old and oft en forgotten symptoms by patients, did the patients make their homeopaths aware of those symptoms’ past existence. On the whole, neglect of Hering’s Law via mere suppression of local pathological symptoms, without cure through conventional or alternative means, has been observed to be followed by progressive disease with the passage of time. Th is sequence was encountered particularly in cases with suppressed bodily discharges, either via skin, respiratory, gastrointestinal, or urogenital outlets. More impartial evidence for the confi rmation of this tenet is based on the successful experiences of homeopathic treatment where regression of chronic diseases was followed by the return of the original suppressed discharges, or other old symptoms. Th is phenomenon presupposes the existence of some property of cellular memory in the tissues in relation to unresolved pathogenic layers, accrued over time. Homeopathy also seeks to address a person’s inherited systemic weaknesses through the prescription of certain constitutional or miasmatic remedies. It has been observed that these were oft en followed by copious discharges or skin outbreaks, as if some underlying morbid agents were indeed being released while, in their wake, progress in health would ensue. Th is is the main reason why homeopathy favors centrifugal therapeutic action versus a centripetal, s u p p r e s s i v e o n e .

Mechanism of Action

Th e main objection of critics of homeopathy is primarily based on the tenets of chemistry, where the remedy solution, due to successive dilutions, oft en exceeds Avogadro’s number and renders its composition void of the original substance and, presumably, of therapeutic action. Th is argument has been negated by data from science that is well recognized as ontologically more fundamental than chemistry — materials science (Roy et al., 2005 ). Th e epistemological data considered in this context includes many pertinent sciences and phenomena that fall outside the scope of chemistry. Homeopathy Origins and Therapeutic Principles 185

Among these are physics, quantum chemistry, quantum physics, weak quantum theory, and the science of colloids and crystals. Th ese and other authors emphasize the diff erence between the structure of substance, which largely controls its physicochemical properties, versus simply a molar composition. Other authors cite other phenomena, including: epitaxy, pressure, nanobub- bles and hydrogen bond networks, electromagnetic coherent forces, reduplica- tion of original information of a solute (Roy et al., 2005 ; Smith, 1994 ; Del Giudice et al., 1988 , 1998 ), and even remedy information storage in the coarse layers of a vacuum (Tiller, 1997 ). Based on this data, homeopathic remedies are deemed to be energy medicines capable of not only retaining, but exponentially expanding the information content of the original substance through the succussive cycles of their preparation. Repetitive succussions are being singled out as playing a crucial role in this process.

Clinical Studies and Scientiﬁ c Conﬁ rmation

Two major reviews of all clinical trials on homeopathy have confi rmed the positive biological action of homeopathic remedies (Kleijnen et al, 1991 ; Linde et al., 1997 ). Th e more recent meta-analysis of homeopathic studies yielded a negative report (Shang et al., 2005 ). However, it was deemed by its critics to be seriously fl awed(Walach et al., 2005 ; Bell, 2008). A broad review analysis of the homeopathic studies and related topics, including those concerning gastrointestinal disorders, was published recently (Walach et al., 2005 ). Th e authors, considering nonlinear action of homeopathic remedies and other peculiar factors involved in homeopathic practice, challenge the standard clinical effi cacy assessment methods as suboptimal for both conventional pharmacology and, especially, for homeopathy.

Complex Homeopathy

Complex homeopathic remedies consist of a number of remedies, each with a known affi nity for certain organs or related conditions such as headaches, diarrhea, allergies, etc. Experientially, these have been found to have some palliative eff ect in acute ailments In chronic diseases, due to the fact that complex homeopathy is too non-specifi c either in relation to true etiologic agents of chronic diseases or to patient totality of symptoms, their eff ectiveness seems marginal and of limited potential, overall. 186 INTEGRATIVE GASTROENTEROLOGY

Causative Homeopathy

Prescribing in causative homeopathy is based on the principle, exact treats exact. Unlike classical homeopathy, which treats based on the totality of a patient’s symptoms or responses as an adaptional reaction to some (usually unknown) morbid agents, causative homeopathy uses remedies — the exact counterparts of the morbid agents themselves— deemed to be the causative agents of pathology. Th e remedies are prepared from infectious, toxicological, radioactive, or any pathogenic agents themselves, or the patient’s own bodily fl uids, including pathological discharges or abscesses containing these agents, and are administered with a therapeutic or prophylactic purpose. A rather recent striking case of homeoprophylaxis of Leptospirosis involving as many as 2.3 million people took place in Cuba and yielded a signifi cant reduction in morbidity and mortality in the treated population (Bracho et al., 2010 ). Th e homeopathic vaccine was prepared out of actual circulating strains of Leptospirosis and was administered in homeopathic dilutions far exceeding Avogadro’s number. Th e study was conducted by the mainstream major medical research institute that also oversees production and administration of conventional Leptospirosis and other vaccines on a national level. Besides homeopathic vaccination showing somewhat superior protection over conventional vaccination, 84 % versus 78.1 %, respectively, in the annual reduction of Leptospirosis, the study authors have emphasized the advantage of homeoprophylaxis in costs, facility in production, availability and accessibility, particularly in the face of suddenly arising circumstances of emergency.

Samples of Remedies and their Prescribing Keynotes for Common Gastrointestinal Ailments

Constipation (Kratz, 2001 ) • B r y o n i a a l b a • C a l c a r e a C a r b o n i c a • Lycopodium clavatum Diarrhea (Lilienthal, 1996 ) • A l o e s o c o t r i n a • Argentum Nitricum • Arsenicum Album • B r y o n i a a l b a Homeopathy Origins and Therapeutic Principles 187

• H y o s c y a m u s n i g e r • Oxalicum acidum • Podophyllum peltatum • Zincum Metallicum Gallbladder Disorders (Kruzel, 1988 ) • B e r b e r i s v u l g a r i s • C a l c a r e a c a r b o n i c a • C a r d u u s m a r i a n u s • C h e l i d o n i u m m a j u s Nausea and Vomiting • C o c c u l u s I n d i c u s • C r o t a l u s H o r r i d u s • G l o n o i n u m • Ipecacuanha (Cephaëlis ipecacuanha) • K r e o s o t u m • Nux Vomica (Strychnos nux vomica) • R h u s To x i c o d e n d r o n • Tabacum (Nicotiana tabacum) • Z i n c u m m e t a l l i c u m

Summary

Since its inception, homeopathy has remained a poorly understood medical system. Th e main arguments: the remedies defy accepted chemistry rules, utilize implausible therapeutic principles based on the law of similars, treats morbid stressors via near or identical morbid stressors, or via an approach of totality by addressing seemingly unrelated symptoms. However, mounting evidence from multidisciplinary sciences over recent decades continues to yield copious supporting data on behalf of the tenets of homeopathy. Among these are laws of complexity applicable to living systems, information and chaos theories (Bellavite & Signorini, 2002 ; Bell & Koithan, 2006 ), the phenomena of quantum physics (Smith, 1998 ; Wolkowski, 1994 ) and cellular memories (Miller, 1978 ; the discovery of DNA and related disease predispositions, and even the theory of evolution, which emphasizes adaptation of species to stressors via exposure to the identical stressors (Darwin, 1859 ). Not surprisingly, Th e Law of Similars has been in extensive use in conventional medicine through such practices as vaccinations, allergy desensitization, and botulin administration in neurological diseases. Another example, 188 INTEGRATIVE GASTROENTEROLOGY the newly emerging fi eld of psychoneuroimmunology, has substantiated — via experiments involving the peptide systemic network— interconnections among multiple systems and their functions as including those of emotions and nervous systems, as well as endocrine and immune systems (Pert, 1997 ). Modern technologies using spectral analysis obtained with the Raman laser, infrared absorbance, and nuclear magnetic resonance (NMR), have all confi rmed the diff erence in emission patterns between homeopathic remedies and a placebo. In addition, each homeopathic remedy was found to exhibit a unique NMR emission pattern. Furthermore, substances that were both diluted and succussed to 30X potency, according to the full homeopathic method, exhibited a specifi c band pattern in their emission spectra that was absent when the substances were merely diluted but not succussed. (Barros et al., 1984 ; Smith & Boericke, 1966 ; Young, 1975 ; Lasne et al., 1989 ; Smith & Boericke, 1968 ; Sacks, 1983 ; Demangeat et al., 1992 ). All this evidence does supports the scientifi c foundation of homeopathy and provides a safe and at times cost-eff ective option to patients and practitioners for a number of gastrointestinal tract ailments. 1 9 Massage for Digestive Health

STEPHANIE PORCARO AND GERARD E. MULLIN

key concepts

■ Massage can calm patients with underlying anxiety disorders. ■ Massage can infl uence gastrointestinal physiology. ■ Th ere is data to support its use for patients who are constipated. ■ Contraindications to massage exist, and practitioners need to be aware of the potential risks and benefi t s o f m a s s a g e . ■

A Brief History of the Beneﬁ ts of Massage

assage is one of the most ancient forms of healing. Th e fi rst writings on massage emerged around 2000 BC. Th e ancient Greeks and M Romans used massage to maintain health and promote healing. As early as the fourteenth century, Guy deChauliac was noted to have written a book on surgery, and bodywork was mentioned as an adjunct to surgery. During the sixteenth century, Ambroise Pare, a French barber surgeon, was said to have mentioned the many benefi ts of massage. It was Lord Francis Bacon who observed that massage enhanced circulation. During the 1850s, scientifi c massage therapy was introduced in the United States by two New York physicians, brothers George and Charles Taylor. (Calvert, 2002 )

189 190 INTEGRATIVE GASTROENTEROLOGY

Beneﬁ ts of Massage that May Improve Digestive Illness

• Relieves stress and promotes an overall feeling of relaxation • Alleviates pain and tension • Decreases infl ammation • I m p r o v e s c i r c u l a t i o n • Improves and strengthens immune system • Reduces anxiety and promotes an overall feeling of well-being • Increases body awareness (Takeda et al., 2008 ; Lee, 2006 )

Effect of Massage Therapy on Related Conditions

Aside from being very eff ective in relieving stress, there is evidence that massage can help with a variety of health conditions that may be linked to digestive disorders (Lee, 2008 ; Chen et al., 2008 ; Garner et al., 2008 ; Piovesan et al., 2007 ; Tso, 2007 ; Field, 2002 ), including:

• Anxiety • A r t h r i t i s • Chronic and acute pain • Circulatory problems • D e p r e s s i o n • F i b r o m y a l g i a • H e a d a c h e s • Sleep disorders • S t r e s s

Massage and Digestive Disorders

Th ere is a paucity of medical literature on the potential health benefi ts of massage for digestive disorders. Utilization data exists for usage of complementary and alternative medicine (CAM) modalities; however, massage was not specifi cally addressed (Burgmann, Rawsthorne, & Bernstein, 2004 ; van Tilburg et al., 2008 ). Massage therapy has been studied for its potential to promote gastrointestinal motility and ameliorate constipation in patients with spinal cord injury (Ayaş et al., 2006 ; Albers et al., 2006 ). Massage for Digestive Health 191

Gastric motility has also been shown to improve in preterm neonates aft er abdominal massage. Compared with preterm neonates receiving sham massage, those receiving massage therapy exhibited greater weight gain and increased vagal tone and gastric motility during, and immediately aft er, treatment. Gastric motility and vagal tone during massage therapy were signifi - cantly related to weight gain. Postoperative motility has been shown to improve aft er acupressure massage (Chen et al., 2003 ; Daletskaia, Ekisenina, & Lorie , 1988 ). Th ermovi- bromassage of the right hypochondrium area, for biliary dyskinesia, has been reported to promote normalization of biliary system motility (Matveeva, Kuz’menko, & Kirillova , 1997 ). Remission persisted for 6 to 8 months in patients with biliary dyskinesia. Th us, massage may in part reset enteric nervous system electromyographic rhythms, as suggested by human and animal studies (Koizumi, Sato, & Terui, 1980 ; Liu et al., 2005 ). Abdominal massage to relieve constipation is a palliative type of care that used to be a commonly practiced therapy. Massage to promote movement of fecal wastage has been well documented and should be considered in patients with functional constipation (Di Lorenzo, Ordein, & Hyman, 1993 ; Culbert & Banez, 2007 ; Harrington & Haskvitz, 2006 ; Preece, 2002 ; Ernst, 1999 ; Jeon, & Jung, 2005 ; Kim et al., 2005 ). One study showed massage to provide a benefi t for relief of symptoms of irritable bowel syndrome (Bosseckert, 1982 ).

Massage and the Digestive Tract Technique for Patients

Abdominal massage relaxes and tones the organs, muscles, and fascia of the abdomen, while providing overall relaxation and stress relief. Abdominal massage is eff ective and fast. Some people feel the urge to eliminate during or just aft er the massage itself, when well hydrated. In this section, we assume that individuals are working with a partner, although most techniques described can be performed during self-massage. Th e abdominal area is highly sensitive. Approach it with respect and positive intention. Begin with a gentle opening hold, slowly bringing your hand down to rest in the center of your partner’s abdomen just below the navel. Allow your partner to become comfortable with the sensation of being touched there. Encourage deep, relaxed breathing during the massage. Open the area with slow stretches between the fl oating ribs and iliac crest, reaching for the side of the body opposite you and pulling up and toward the navel in a sweeping motion. Th is technique addresses the obliques and transverse abdominis. Next, effl eurage the rectus abdominis in a sweeping motion, creating clockwise 192 INTEGRATIVE GASTROENTEROLOGY circles with your hands around the center of the abdomen. Abdominal massage always proceeds in a clockwise motion, reinforcing the clockwise passage of waste through the large intestine. Working in a counterclockwise direction may harm the intestines and intensify existing fecal impaction. Now that the superfi cial abdominal tissue is relaxed, it is possible to perform intestinal massage. Please refer to the diagram (Figure 19.1) for assistance with the anatomy. Depending on the size of the individual, and whether he or she is constipated and remains relaxed during the session, you may actually feel the intestines themselves. Even if you do not palpate the structures, work in the area where they are located, with the intention of massaging them. Start at the upper left -hand quadrant of the abdomen just below the ribcage. Sink in deeply and travel with circular friction, 2 to 4 inches down the line between the navel and the anterior superior iliac spine (the pointy part of the front of the hip). Repeat 2 to 5 times. Next move across to the right ribcage area and sink into the tissue, massaging across the transverse colon to the left side. Avoid deep pressure over the fascia of the midline of the body, which you will cross while massaging the transverse colon. Repeat 2 to 5 times. Now move to the area between the right anterior hip and navel, and massage up the ascending colon with circular friction. Repeat 2 to 5 times. Put the three parts of the massage together — starting again at the ascending colon, moving to the transverse and to the descending— in one fl uid motion. Imagine your hands pushing out the waste for elimination. Return back to the lower right abdomen, at the point between the navel and the hipbone. Th is locates the ileocecal valve (ICV). Gently push down at this point to feel the valve and the connection between the small and large intestine. Th en massage up an inch toward the left shoulder, palpating the ICV. If this area is sore or uncomfortable, the valve fl ap may be stuck open. When this occurs, waste backs up into the small intestine, causing small intestinal bacterial overgrowth. Repeat the massage, starting at the ileocecal valve, continuing to use small clockwise circles overlapping the entire pattern as before. Each circle or pass, aft er that, allows the circular massage to close in around the navel. Finish the massage by placing your hand fl at over the abdomen. Turn your whole hand — fl at, and with equal pressure on the fi ngers and heel of the hand— in a clockwise direction. Th is is calming and reinforces the direction of the deeper work. Th ere are many massage therapy modalities that focus on core work and digestive health. For further exploration, see videos available on the Internet, on Maya Abdominal Massage, Ayurvedic, and Tuina. Massage for Digestive Health 193

Abdominal Massage Don’ts

• Abdominal massage should not be done if a person has infl ammation of the uterus, bladder, ovaries, or fallopian tubes. • Abdominal massage should not be done if a person has stones in the kidneys, bladder or gallbladder, or ulcers of the stomach or intestines. • Abdominal massage should not be done aft er a heavy meal. • Th e bladder should be emptied before the massage. • Since blood pressure increases during abdominal manipulation, patients with hypertension should avoid abdominal massage. • Massage should also be avoided in cases where there has been recent bleeding in the lungs, stomach, or the brain. 2 0 Mindfulness Based Stress Reduction for Health and Diseases

PADMINI D. RANASINGHE

key concepts

■ Mindfulness-based stress reduction (MBSR) is gaining popularity as a stress reduction technique for healthy adults and adolescents, as well as for patients with various chronic conditions. ■ Th e purpose of MBSR is to allow participants to cultivate moment-to-moment awareness in order to facilitate reduction of stress and stress-related symptoms. ■ Physiological changes follow sustained activity, and MBSR and mindfulness meditation are known to produce physiological and anatomical changes in bodily systems over time. ■ MBSR triggers changes in the cardiovascular system, respiratory system, neurological system, endocrine and immune system. ■ Stress, anxiety, and depression play a role in formation and exacerbation of common GI diseases like IBS, IBD, PUD, GERD and most other chronic diseases. MBSR may be highly benefi - cial for patients with these conditions. ■

Introduction: Stress and Health

tress is a complex phenomenon that occurs in humans, with multiple sequences of events aff ecting short-term to long-term health, ranging S from endocrine to neuronal systems. Within seconds following a stress-causing stimulus, catecholamines from the sympathetic nervous system

194 Mindfulness Based Stress Reduction for Health and Diseases 195 are released. Corticotropin-releasing hormone (CRH) secretes from the hypothalamus, along with enhanced secretion of adrenocorticotropic hormone (ACTH). Th en gonadotropin-releasing hormone (GnRH) decreases pituitary gonadotropins and increases secretion of prolactin and glucagon. Th ese neuro- humoral changes lead to various clinical reactions. Based on the intensity and duration of these reactions, stress can adversely aff ect physical and psychological health. With the growing realization of the role played by stress in a wide array of medical conditions, stress reduction is now widely acknowledged to be important in the treatment and prevention of chronic illnesses. Mindfulness-based stress reduction is receiving attention in the medical community as an eff ective method for reducing stress.

Stress and GI Disease

Physiological changes in the gastrointestinal (GI) tract can aff ect mood and psychological health, and cause physical ailments. It has been documented that stress plays a role in the causation and exacerbation of common GI diseases like IBS, IBD, PUD and GERD (Whitehead et al., 1992 ; Bennett et al., 1998 ; Hertig et al., 2007 ; Maunder & Levenstein., 2008 ; Levenstein et al., 1999 ; Davidson et al., 2007 ). Th ere is a heightened response to CRH by patients with IBS compared to healthy people (Fukudo et al., 1998 ). Stress reduction techniques may be benefi cial in treating some chronic gastrointestinal disorders.

What Is MBSR?

Mindfulness-based stress reduction (MBSR) methods are gaining widespread popularity as stress reduction techniques for healthy adults and adolescents, as well as patients with various chronic conditions. Th e purpose of MBSR practice is to allow participants to cultivate moment-to-moment awareness of bodily functions in order to facilitate reduction of stress-related symptoms. Since it was described by Kabat-Zinn in 1989, MBSR practice has been used in various populations in multiple healthcare and non health care settings. As described elsewhere, conscious management of attention by selectively focusing on breathing or other physical sensations is the foundation of any MBSR practice. Mindfulness meditation practice, a source of inspiration for MBSR, traces its origins to the Buddhist traditions of the East, but the practice itself can be adopted for strictly secular use stripped of any religious or philosophical restrictions. Due to this methodological commonality, MBSR and mindfulness meditation will be used interchangeably in the scope of this chapter. 196 INTEGRATIVE GASTROENTEROLOGY

Mindfulness meditation is a reﬂ ective practice followed by various Buddhist traditions.

Th is chapter describes some of the evidence available in the literature of the use of MBSR practices in healthy adults and populations with certain clinical conditions. MBSR has been studied and shown some benefi ts in conditions, such as chronic pain, cancer, psychiatric conditions, and some chronic diseases. Physiological changes follow any sustained activity. MBSR and mindfulness meditation are known to produce physiological and anatomical changes in bodily systems over time, some of the changes are in the cardiovascular system, respiratory system, neurological system, endocrine system and immune system.

A decrease in cardiac pre-ejection period, increase in cardiac output, and decrease in diastolic blood pressure (BP) were observed during mindfulness meditation (Ditto et al., 2006 ).

Practice of long term meditation, not necessarily MBSR, has shown to produce some structural and functional changes in the brain. A small study showed that long-term meditators had structural changes in the brain compared to controls, such as increased gray matter density in lower brainstem regions and increases in the left prefrontal cortex and right anterior insula (Vestergaard-Poulsen et al., 2009 ; Lazar et al., 2005 ). Expert meditators who practiced concentration meditation showed a signifi cant activation of brain regions associated with sustained attention as captured by functional MRI (Brefczynski-Lewis et al., 2007 ). As examined by fl ashlight test and visual sensitivity test, mindfulness meditation increased attention and changed perception at 3month follow up of 16hour/day meditation. (Brown et al., 1984 ).Th ere are also changes in immune cells, mediators, and hormones levels with MBSR related practices.

MBSR in Practice

MBSR has been used in various patient populations and healthy adults to promote physical, social, and psychological health. MBSR techniques may help a broad range of individuals to cope with clinical and nonclinical problems, and Mindfulness Based Stress Reduction for Health and Diseases 197 are shown to be eff ective as an interventions in a variety of healthcare settings (Praissman, 2008 ; Grossman, Niemann et al., 2004 ; Williams, Kolar et al., 2001 ). In some healthcare settings MBSR technique has been taught in weekly group sessions, usually lasting 8 to 10 weeks with video-assisted homework assignments. Other adapted methodologies also have been used in research settings. Group mindfulness meditation techniques have been shown to be benefi cial immediately, as well as one year aft er intervention, in several physical, psychological and social parameters (Reibel et al., 2001 ). It has been shown that MBSR may be eff ectively taught by video-conferencing in patients with chronic pain (Gardner-Nix et al., 2008 ).

HEALTHY ADULTS

Most MBSR-related studies were conducted among healthy adults. Mindfulness meditation has been shown to play a role in cognitive fl exibility, stress reduction, increased relaxation, and decreased overall psychological symptoms, while promoting an overall sense of control in adult volunteers (Agee et al., 2009 ; Moore & Malinowski, 2009 ; Astin, 1997 ). Experienced meditators showed increasing introception awareness and heartbeat detection (Khalsa et al., 2008 ).

MBSR has been shown to improve sleep quality, improve night-time symptoms of insomnia and decrease pre-sleep arousal, sleep effort and dysfunctional sleep-related cognition (Klatt et al., 2008 ; Winbush et al., 2007 ; Ong et al., 2008 ).

MBSR related practices have demonstrated eff ectiveness among a wide range of populations. While both MBSR and cognitive-based stress reduction were eff ective in reducing perceived stress and depression, MBSR is more eff ective in increasing mindfulness and energy, reducing pain, psychological distress and reported medical symptoms in adults (Smith, Shelley et al., 2008 ; Carmody, Reed et al., 2008 ). A sample drawn from the general population, as well as hospital staff , who participated in an MBSR program, had a higher quit rate of smoking in smoking cessation intervention studies (Davis et al., 2007 ; Michalsen et al., 2002 ). Meditation has shown to lower stress and support forgiveness among college students, and to lower distress and improve mood in medical students (Oman et al., 2008 ; Rosenzweig et al., 2003 ). In an earlier study MBSR also has been shown to be effi cacious in decreasing stress and anxiety and increasing empathy in medical students (Shapiro, Schwartz et al., 1998 ). 198 INTEGRATIVE GASTROENTEROLOGY

Nurses who participated in a short MSBR program experienced reduced burnout symptoms, increased general relaxation and satisfaction with life compared to a wait listed control group (Mackenzie et al., 2006 ). It also had shown to be benefi cial to improve self-care, decrease tendencies to take on others’ negative emotions, lower burnout, and improve well-being among nurses and nursing students (Cohen-Katz et al., 2004 , 2005 ; Beddoe & Murphy, 2004 ).

PAIN

MBSR techniques have been used to assist individuals with chronic pain in diff erent clinical conditions. Women with fi bromyalgia showed a decrease in their basal sympathetic activity, and a improve in psychological health such as changes in depressive symptoms, anxiety and coping skills aft er receiving MBSR (Grossman, Tiefenthaler-Gilmer et al., 2007 ; Sephton et al., 2007 ; Lush et al., 2009 ). A randomized clinical trial of 30 patients with chronic musculoskeletal pain showed that MBSR was more eff ective and longer lasting in mood improvement than massage therapy (Plews-Ogan et al., 2005 ). In an early study of 90 patients with chronic pain, a 10-week stress reduction and relaxation program was associated with improvement in present-moment pain, negative image, mood disturbances, and other psychological symptoms like anxiety and depression and these benefi ts lasted 15 months except for present movement pain (Kabat-Zinn, Lipworth et al., 1985 ). In older patients with lower back pain, MBSR has been used to increase physical function and quality of life, decrease pain, and support mood elevation, and sleep (Morone, Greco et al., 2008 ; Morone, Lynch et al., 2008 ).

CANCER

For oncology patients, MBSR is gaining recognition as a credible and benefi - cial intervention to be incorporated in to the treatment. A review study has shown that the patients with cancer who received MBSR training had a positive change on psychological functioning, stress reduction and increased coping skills and well-being (Ott et al., 2006 ). Cancer patients who participated in an MBSR program had increased quality of life, less stress, and fewer physical symptoms (Kieviet-Stijnen et al., 2008 ). Another review article found a potential benefi t for MBSR in cancer patients for sleep, mood, and reduction in stress (Smith, Richardson et al., 2005 ). In a small study, cancer patients who underwent hematopoietic stem cell transplant showed a statistically signifi cant decrease in heart and respiratory Mindfulness Based Stress Reduction for Health and Diseases 199 rates, and improvements in physical and psychological symptoms immediately before and aft er each MBSR session suggesting potential benefi ts and feasibility of MBSR in hospitalized cancer patients (Bauer-Wu et al., 2008 ). Similarly studies involving breast and prostate cancer patients showed that an MBSR program was resulted in positive benefi ts, such as increased quality of life and sleep, decreased stress symptoms and cortisol level, as well as immune patterns consistent with less stress and mood disturbance, and decreased blood pressure (Carlson, Speca et al., 2004 , 2007 ; Carlson & Garland, 2005 ). MBSR may also have positive eff ects on the quality of sleep in breast cancer patients whose sleep disturbances were associated with stress (Shapiro, Bootzin et al., 2003 ).

Studies have also shown psychological beneﬁ ts for MBSR in patients diagnosed with cancer.

A randomized, controlled clinical trial showed that patients diagnosed with breast cancer had lower depression scores, less anxiety, and less fear of recurrence, in addition to improved energy and physical function aft er MBSR intervention (Lengacher, Johnson-Mallard et al., 2009 ). MBSR programs have been shown to reduce mood disturbance and symptoms of stress, and increase well-being and the ability to handle stress in adult patients with various cancers (Carlson, Ursuliak et al., 2001 ; Speca, Carlson et al., 2000 ). A meta-analysis has shown that MBSR has the potential to improve psychosocial adjustment to the disease in cancer patients (Ledesma & Kumano 2008 ). Some other benefi ts of 8 weeks of MBSR in patients diagnosed with breast cancer include an increase in serum immune markers: regained peripheral blood mononuclear cell NK cell activity (NKCA) and IFN-gamma production, decreased IL-4, IL-6, and IL-10 production, and decreased plasma cortisol levels, in addition to improved quality of life and coping (Witek-Janusek et al., 2008 ). In patients with breast and prostate cancer who received MBSR training, had decreased in pro-infl ammatory immune cells and cytokines steadily over 1 year In addition to improving symptoms stress, quality of life and mood and they concluded that these shift s in immune parameters are associated with the resolution of depressive symptoms (Carlson, Speca et al., 2 0 0 3 ) .

PSYCHIATRIC CONDITIONS

Another major area where MBSR has been widely studied is in psychiatric conditions like depression, anxiety, and stress. 200 INTEGRATIVE GASTROENTEROLOGY

In one study, 28 patients with chronic recurrent depression with protracted course and current symptoms of depression were randomized to receive mindfulness-based cognitive therapy or usual treatment. Th ere was a decrease in symptoms from severe to mild levels of depression in patients who were assigned to the mindfulness-based cognitive therapy group (Barnhofer et al., 2009 ). Mindfulness has been shown to be benefi cial in relapse prevention in patients with depression aft er adjusting for other variables at 12 months follow-up (Michalak et al., 2008 ). Small study with 11 participants with generalized anxiety disorder who received 8 week mindfulness-based cognitive therapy showed that there was a signifi cant reduction in anxiety, depressive symptoms, and worry, from baseline to end of intervention (Evans, Ferrando et al., 2008 ). Eight week MBSR practice as an intervention has been shown to decrease perceived stress and vital exhaustion, and is strongly associated with positive aff ect and quality of life and well-being in adult patients with distress from the community and mindfulness mediated eff ect on stress and quality of life (Nyklicek & Kuijpers, 2008 ;) Another study of 174 adults in a clinical mind- fuleness progam has shown that 8 week MBSR had increased mindfulness, wellbeing and decreased stress. Th is imporvement was singinifantly related to the time spent on MBSR related activities and minfulness was found to be a mediator for some outcomes. (Carmody & Baer, 2008 ). It also has been shown that patients with chronic physiological and psychological stress would benefi t from an 8-week MBSR program to improve their well-being and quality of life (Majumdar et al., 2002 ). In a study involving both cognitive behavioral therapy (CBT) and MBSR, for patients with DSM-IV generalized social anxiety disorder receiving CBT showed a greater improvement in social anxiety disorder related symptoms than MBSR group, but an equally comparable improvement was recorded in mood, disability and quality of life from both interventions. (Koszycki et al., 2 0 0 7 ) . Th ree-year follow-up study of patients with anxiety has shown that there were long-term benefi ts of mindfulness meditation in the treatment of anxiety disorder (Miller et al., 1995 ). Kabat-Zinn et al. (1992 ) have shown that MBSR with group mindfulness meditation training is benefi cial in reducing symptoms of anxiety and panic and to maintain those low levels in patient with generalized anxiety disorder. It has been shown in small studies that MBSR-related techniques may also be benefi cial in treating other psychiatric conditions like obsessive-compulsive disorder and ADHD in adults — possibly by letting go, and improving behavioral and neurocognitive impairment, respectively (Hanstede et al., 2008 ; Zylowska, Ackerman et al., 2008 ). A small study has shown that patients with bipolar disorder who received mindfulness-based cognitive therapy did better Mindfulness Based Stress Reduction for Health and Diseases 201 with anxiety symptoms specifi c to bipolar disorder than those who did not receive it (Williams, Alatiq et al., 2008 ). Th ere appear to be some promising results with MBSR techniques for younger women with bulimia nervosa and and women with sexual dysfunction (Proulx, 2008 ; Brotto, Basson et al., 2008 ). A study of patients, 1-year aft er mild to moderate brain injuries, who received MBSR showed an improvement in quality of life, cognitive aff ect, domain of Beck Depression Inventory, and positive distress inventory of SCL- 90R (Bedard et al., 2003 ).

OTHER CHRONIC DISEASES

Type 2 Diabetes

An MBSR program for 14 patients with Type-2 diabetes has shown a positive impact on HbA1C, blood pressure, body weight, anxiety, depression, somatization, and psychological distress at 1-month aft er the intervention (Rosenzweig, Reibel et al., 2007 ).

Transplant Patients

It has been shown in an 8-week MBSR program, transplant patients have experienced an improvement in sleep, positive mental health, anxiety score, and overall well-being at 3months and for sleep even at 6 months aft er the intervention (Kreitzer, Gross et al., 2005 ; Gross, Kreitzer et al., 2004 ).

Heart Disease

Small and short duration 2 studies with 8-week MBSR practice show some benefi ts in patients with heart disease. One study has shown a reduction in anxiety score in patients with heart disease. Another study has shown a positive trend for changes in resting levels of cortisol, physical function and, signifi - cantly diff erence in pattern of breathing during exercise in women with heart disease who received MBSR (Robert-McComb et al., 2004 ; Tacon et al., 2003 ).

Congestive Heart Failure

Prospective cohort study of heart failure (NYHA 11) patients who underwent a MBSR program in addition to medications had a lower anxiety score, 202 INTEGRATIVE GASTROENTEROLOGY less depression, and improved symptoms as measured by Kansas City Cardiomyopathy questionnaire symptom scale and clinical scale, but there was no treatment eff ect on death/rehospitalization at one year (Sullivan et al., 2009 ).

HIV

A single-blinded, randomized, controlled study of 48 HIV patients who received 8-week MBSR intervention showed that CD4 + count was not decreased from baseline compared to a control group in whom there was reduction in CD4+ count, independent of antiretroviral therapy (Creswell et al., 2009 ). Among HIV patients, natural killer cell activity and number increased, suggesting that MBSR may play a role in improving immunity in this population (Robinson et al., 2003 ).

Other Conditions

Th irty seven patients with psoriasis who received brief MBSR delivered by audiotape during ultraviolet phototherapy or photochemotherapy showed an increased rate of resolution of psoriatic lesions compared to who didn’t receive the MBSR intervention (Kabat-Zinn, Wheeler et al., 1998 ). MBSR techniques may be used as a complementary therapy in rheumatoid arthritis, by improving psychological distress and well-being as shown in a randomized control study with 8-week MSBR and waitlisted control group (Pradhan et al., 2007 ). Small Studies have shown that this technique may also be potentially benefi cial to improve severity and frequency of hot fl ushes in women and also patients with symptoms of tinnitus. (Carmody, Crawford et al., 2006 , Sadlier et al., 2008 ). Currently studies are underway to further explore MBSR and related techniques as interventions for healthy adults and populations with various diseases.

HEALTHCARE UTILIZATION

Th ere is some evidence to suggest that MBSR interventions may decrease healthcare utilization and chronic care visits in addition to improving self- esteem and decreasing medical and psychological symptoms, in an inner-city English and Spanish speaking population (Roth & Stanley, 2002 ; Roth & C r e a s e r , 1 9 9 7 ) . Mindfulness Based Stress Reduction for Health and Diseases 203

Limitations

Because of the nature of MBSR interventions and the diversity of practices that use MBSR as a common approach, the true range of therapeutic possibilities and limitations of MBSR are not yet clearly established. At a minimum, MBSR may be a safe and eff ective technique, but requires practice to experience full benefi ts. Th ere are multiple studies looking at application of MBSR and related techniques as an adjunctive treatment option for people with chronic diseases and for healthy individuals, but there are some common limitations of these studies. Most of these are small-scale studies with short-term follow-up. Only some studies were conducted in randomized control fashion and those trials also have used waitlisted control subjects. Th ere are multiple limitations with waitlisted control comparison groups. As MBSR techniques require individual motivation and time commitment, attrition rate is also higher before and aft er completion of the program. It is important to have well-conducted, large-scale, randomized, controlled trials with long-term follow-up - to facilitate incorporating MBSR into mainstream treatment. Finally, it is apparent that MBSR may be more attractive for people who are very motivated and committed to these kinds of interventions, as well as to positive behavioral changes (Robinson et al., 2003 ).

Conclusion

MBSR may be a safe and eff ective technique for patients to resolve certain symptoms (anxiety, depression, fear, stress, and pain) those oft entimes incite digestive tract and other chronic diseases. It also has been shown to improve general wellbeing and quality of life in healthy adults and patients with certain chronic conditions. Laboratory studies have shown an improvement in proinfl ammatory cytokine profi les, with reduction in stress-related hormones and symptoms, as a consequence of MBSR. MBSR techniques have been studied to some extent among healthy adults, patient with cancer, psychiatric conditions, chronic pain and certain other conditions. It is possible most of the benefi ts we see with this intervention may be explained by the fact MBSR and similar practices help to alleviate stress and related symptoms. Although there is paucity of data on specifi cally examining MBSR for symptoms of gastrointestinal diseases, these techniques may be benefi cial as an adjunctive treatment for this patient population where stress plays a role in causation and exacerbation. Active trials are underway to examine MBSR for this population. 204 INTEGRATIVE GASTROENTEROLOGY

(Gaylord S.A. Whitehead W et al., and David Kearney) Finally although there is a lack of studies favoring the use of MBSR in the prevention and treatment of digestive disturbances and other chronic diseases, practitioners may educate patients about its potential benefi ts, given the lack of adverse eff ects. 2 1 Naturopathic Medicine and Digestion

JOSEPH PIZZORNO

key concepts

■ Naturopathic medicine prioritizes supporting the body’s innate healing processes. ■ Th is is primarily achieved by normalizing physiological function. ■ Digestive system dysfunction not only causes acute and chronic symptoms, but can contribute to, and even cause, both local and systemic disease. ■ Disorders of digestion and nutrient absorption, such as hypochlorhydria, pancreatic exocrine insuffi ciency, and excessive bowel permeability, are common. ■ Relatively simple interventions can have dramatic impacts on patients’ health. ■

Naturopathic Medicine

aturopathic medicine is a distinct system of health-oriented medicine that stresses promotion of health, prevention of disease, support N for the body’s own healing systems, patient education, and self- responsibility. However, naturopathic medicine symbolizes more than simply a healthcare system; it is a way of life. Unlike most other healthcare systems, naturopathy is not identifi ed with any particular therapy, but rather a way of thinking about life, health, and disease. It is defi ned not by the therapies it uses, but by the philosophical principles that guide the practitioner.

205 206 INTEGRATIVE GASTROENTEROLOGY

Seven concepts provide the foundation that defi nes naturopathic medicine, and create a unique group of professionals practicing a form of medicine that is fundamentally diff erent from the disease-centric approach of conventional medicine. Armed with a strong belief in the inherent ability of the body to heal — if just given the chance — the profession developed these principles as a guide to developing a curative relationship with patients.

The seven core principles of naturopathic medicine are as follows, with “wellness and health promotion” emerging into the forefront of the scholarly discussion of naturopathic clinical theory: 1. The healing power of nature ( vis medicatrix naturae ) 2. First do no harm ( primum non nocere ) 3. Find the cause ( tolle causam ) 4. Treat the whole person (holism) 5. Preventive medicine 6. Wellness and health promotion (emerging principle) 7. Doctor as teacher ( docere )

As an outcome of the above principles, the profession has developed specifi c guidelines to assist in providing patient care, beginning at the least invasive and, as necessary, utilizing progressively more invasive procedures. Naturopaths are not against drugs or other conventional therapies and prescribe— or, depending on state licensure statues, refer for— drug or other conventional treatments when necessary.

7 NATUROPATHIC GUIDELINES

1. Reestablish the basis for health. 2. Stimulate the vital force. 3. Tonify and nourish weakened systems. 4. Correct structural integrity. 5. Prescribe speciﬁ c substances and modalities for speciﬁ c conditions and biochemical pathways (e.g., botanicals, nutrients, acupuncture, homeopathy, hydrotherapy, counseling). 6. Prescribe pharmaceutical substances. 7. Use radiation, chemotherapy, and surgery. Naturopathic Medicine and Digestion 207

Because of its eclectic nature, the history of naturopathic medicine is by far the most complex of any healing art. Naturopathic medicine traces its philosophical roots to many traditional world medicines, and its body of knowledge derives from a rich heritage of writings and practices of Western and non- Western nature doctors since Hippocrates. Naturopathy became a formal profession in the United States aft er its founding by Benedict Lust, in 1896.

A Physiological Systems Approach to Healing

While the foundation of patient care is education and counseling in diet and lifestyle, much of naturopathic intervention centers on normalizing system function.

The naturopath asks basically 5 questions: 1. What is the system supposed to be doing? 2. What signs, symptoms, and lab tests indicate the system is dysfunctional? 3. Why is the system dysfunctional? 4. What is the least invasive way to restore function? 5. If function cannot be restored, how can the functions be simulated?

Dealing with the disorders of the digestive system is an excellent way to demonstrate the applications of the principles of naturopathic medicine. Th e old naturopathic adage, “disease begins in the bowel,” which sounded quaint to new students 35 years ago, is now recognized as wise clinical insight. Th e GI system is the primary gateway by which the external environment interacts with the body (Sult, 2006 ). Th e basic physiology of digestion and absorption is well understood, although digestive disturbances remain unresolved in a signifi cant portion of the population. Viewing digestion as a physiological process, the food must be broken into its components by mechanical homogenization and chemical breakdown, followed by absorption of the smaller carbohydrates, lipids, proteins, vitamins, minerals, and other nutrients, through a variety of passive and active processes. In addition to the digestion and absorption of food, the GI tract must also defend against pathogens and toxins that we are exposed to on a continuous basis. It has a number of protective mechanisms, including a low pH in the stomach, coverage of the complete GI tract with a mucus layer, a diverse array of immune cells that lie beneath this mucus layer, and the presence of 208 INTEGRATIVE GASTROENTEROLOGY commensal microbes that abundantly colonize the GI tract (Zoetendal, Rajilic- Stojanovic, & de Vos, 2008 ). Th ere are many ways in which one or more of these critical processes can break down. Rather than focus on what specifi c digestive disease a patient may have, the naturopath instead focuses on restoring normal function of all digestive processes.

Restoring Physiological Function

Th e largest survey of GI symptoms to date (Camilleri et al., 2005 ) found an overall prevalence of at least one upper GI symptom (during the previous 3 months) of 45 % those surveyed (including heartburn, early satiety, loss of appetite and postprandial fullness). A smaller survey of Canadian adults found a prevalence of lower GI symptoms of 5.2 % (abdominal pain/bloating, constipation, diarrhea) (Hunt et al., 2007 ). More recent studies in the United States suggest bloating is as common as 19% to 21% among U.S. adults (Jiang et al., 2008 ; Tuteja et al., 2008 )

In as many as half of the symptomatic patients seen by gastroenterologists, a cause (i.e., disease) is not found, and they are often given a diagnosis of unclear etiology, such as functional dyspepsia or irritable bowel syndrome (IBS). (Geeraerts & Tack, 2008 )

In reality, these symptoms indicate one or more disruptions in gastrointestinal function that will usually, eventually, result in diagnosable pathology. For example, recent research has found the prevalence of celiac disease to be much greater than assumed, aff ecting up to 1 % of the U.S. population. For example, a recent report from the United Kingdom estimated that only 1 out of every 9 cases has been diagnosed (van Heel & West, 2006 ), and the average time of delayed diagnosis is 4.5 to 9 years (Hopper et al., 2007 ). An earlier study suggests that in some patients with IBS, celiac disease may be the underlying cause, with an odds ratio (OR) of 7.0 for those with IBS (Sanders et al., 2001 ). Indeed, a screening of over 13,000 individuals found that those with digestive complaints such as constipation, diarrhea, and/or abdominal pain had a 1:56 chance of having celiac disease— a risk increase of more than twofold what was found in the general population (Fasano et al., 2003 ). Space limitations do not allow consideration of all gastrointestinal dysfunctions, such as hypochlorhydria, hyperchlorhydria, pancreatic insuffi ciency, Naturopathic Medicine and Digestion 209 excessive bowel permeability, imbalanced microbial fl ora, malabsorption, reduced bile salt secretion, overgrowth of bacteria in the small bowel, food intolerance/allergy, etc.

Hypochlorhydria

Lack of suffi cient stomach acid has been associated with reduced vitamin and mineral absorption (Hershko et al., 2005 ; Hirschowitz, Worthington & Mohnen, 2008 ), incomplete protein digestion, and subsequent food allergy (Untersmayr & Jensen-Jarolim, 2006 , 2008 ), bacterial infections of the GI tract, and a large number of chronic diseases. Th e incidence of hypochlorhydria is controversial, ranging from 10 % to 50 % (Huritz et al., 1997 ; Rafsky & Weingarten, 1946 ). Much of this is likely due to the diversity of testing methodologies and age of the participants. Testing only resting pH will provide a much lower incidence than testing the ability to acidify a standard meal or bicarbonate challenge.

DIAGNOSIS

• Laboratory diagnosis. Heidelberg pH capsule gastric analysis, gastric tube, serum pepsinogen I (S-PGI) and serum gastrin-17 (S-G-17). • Clinical diagnosis. High predictability factors include the H. pylori

infection, use of antacids, H2 blockers and proton-pump inhibitors (PPIs), and pernicious anemia. Medium predictability factors include age greater than 60, acne rosacea, and rheumatoid arthritis. Lower predictability factors include nausea, abdominal gas, belching, constipation, chronic diarrhea, dyspepsia, weak/cracked/peeling fi nger- nails, osteoporosis, asthma, gastric ulcer, and decreased ferritin.

CAUSES

Acid Secretion-Suppressing Drugs. Th e use of acid-suppressing drugs has increased the incidence of problems associated with the stomach. For example, a study of nearly 1,700 cases of C. diffi cile infection and acid suppression found that the adjusted rate ratio of infection was 2.9 for the use of PPIs, and 2.0 with H2 receptor antagonists (Dial et al., 2005 ). Th e frequency of B12 defi ciency 210 INTEGRATIVE GASTROENTEROLOGY among long-term users of PPIs was recently found to be 29% , though it is oft en missed by serum cobalamin evaluation alone.10 Th e increasing incidence of C. diffi cile infection has been proposed due to the increased use of acid suppressing drugs (Dial, Delaney, Barkun, & Suissa, 2005 ). Age . Th e acidity of the stomach declines with age, and may contribute to the associated nutrient defi ciencies and greater infection risk. For example, the incidence of C. diffi cile is higher among the elderly (Kelly & LaMont, 2008 ). In a sample of nearly 250 patients aged 65 or greater, only 67 % had consistent acid secretion, while 22 % had intermittent secretion and 11% were consistent hyposecretors. Th is study likely underestimated the incidence of hypochlorhydria, as a pH less than 3.5 was defi ned as acidic and no challenge testing was done; i.e., determining if a standardized meal is acidifi ed (Hurwitz, Brady, & Schaal, 1997 ). H. pylori . Th irty to forty percent of the U.S. population is infected with H. pylori , with an increasing prevalence associated with age (Chey & Wong, 2007 ). Data from more than 7,000 adults in the NHANES study (1988–1991) found a seroprevalence of 16.7 % for persons 20 to 29 years old, to 56.9 % for those 70 or more years old (Everhart et al., 2000 ). Although mostly known as the primary cause of peptic ulcers, especially duodenal, H. pylori also causes chronic gastritis leading to atrophy and loss of parietal cells, and thus reduced gastric acidity. Th e pepsinogen I/II ratio is oft en used as a marker for gastric atrophy, and correlates well with gastric pH (Kato et al., 2008 ).

INTERVENTION

Th e basic clinical strategy is as follows:

1. Stop acid secretion-inhibiting drugs if they are being used, and instead treat the causes of the GERD. 2. Eradicate the H. pylori ; make conditions inhospitable for its return. 3. Stimulate regeneration of the gastric mucosa and parietal cells. 4. If HCl production has not returned, stimulate with herbal bitters. 5. If still no HCl production, emulate with oral supplementation.

H. pylori. A recent study found that eradication of H. pylori was associated with a return to normal gastric acidity (Kato et al., 2008 ). Th is is supported by an earlier study, monitoring pepsinogens and gastrin, in 172 patients that underwent eradication therapy; at 12–15 months the results were comparable to those without previous infection (Ohkusa et al., 2004 ). Th e most reliable Naturopathic Medicine and Digestion 211 intervention is with triple drug therapy (two antibiotics and an H2 inhibitor); see Chapter 39 by Minocha. Eff ective natural therapies include:

• C o n c u r r e n t Lactobacillus GG supplementation makes standard drug therapy more eff ective, and reduces adverse drug reactions (Armuzzi et al., 2001 ). • Vitamin C at 5 g/d for 4 weeks eliminates H. pylori in 30% , and long- term (5-year) use inhibits H. pylori growth and reverses gastric atrophy as measured by pepsinogen secretion (Zhang, Wakisaka, Maeda, & Yamamoto, 1997 ; Sasazuki et al., 2003 ). • Curcuma longa has great potential, as it is both bactericidal to H. pylori and, in an animal model, decreases the infl ammation associated with the infection (De et al., 2009 ). Human research is, however, limited. One study concluded that since curcumin only eradicated H. pylori in 12% of the participants, it was not successful. However, treatment was only 7 days in duration and combined with other nutrients. Th e patients showed signifi cant improvement in dyspeptic symptoms and reduction in serological signs of gastric infl ammation 2 months aft er the end of the short therapy (Di Mario et al., 2007 ). Th e inhibition of H. pylori and anti-infl ammatory eff ects may help explain curcumin’s anti-gastric cancer eff ects (Cheng et al., 2001 ).

Deglycyrrhizinated licorice (DGL). Th e fl avonoids found in Glycyrrihiza glabra impair H. pylori growth (including antibiotic-resistant strains; see Fukai et al., 2002 ). It has a long history of use in the successful treatment of gastric ulcers (Doll et al., 1962 ), and has been shown to stimulate regeneration of the gastric mucosa (van Marle, Aarsen, Lind, & van Weeren-Kramer, 1981 ). Glycyrrhizin is removed to allow long-term use, as it can cause pseudohyper- aldosteronism. Acid secretion-suppression drugs. Rather than treat symptoms, deal instead with the causes of GERD. While these drugs in the short run decrease symptoms and may prevent sequelae, the long-term eff ects of maldigestion, impaired B12 absorption, etc., are serious and underappreciated (see Chapter 37). Herbal bitters. Herbal bitters (sometimes known as Swedish bitters) have a centuries-old tradition of use for digestive disorders. While they are claimed to increase stomach acid secretion, there is actually no apparent objective research. In fact, some constituents of bitters, such as aloe, have actually been shown to suppress gastric acid secretion, although it does protect the gastric mucosa (Yusuf, Agunu, & Diana, 2004 ). 212 INTEGRATIVE GASTROENTEROLOGY

HCl supplementation. Oral HCl supplementation has long been used by the CAM community to treat patients with hypochlorhydria if the eff orts to regenerate HCl production fail.

The following are directions provided to patients for assessing HCl supplementation requirements: 1. Begin by taking 1 HCl capsule (10 grains) at your next large meal. At every meal after that, of the same size, take 1 additional capsule (1 capsule at the next meal, 2 at the meal after that, then 3 at the next meal, and so on). 2. Continue to increase the dose until you reach 7 capsules, or you feel a warmth in your stomach, whichever occurs ﬁ rst. A feeling of warmth in the stomach means that you have taken too many capsules for a meal of that size. Take 1 less capsule the next time. However, it is a good idea to try the larger dose again at another meal to make sure that it was the HCl that caused the warmth and not something else. 3. After you have determined the largest dose that you can take at your large meals without feeling any warmth, maintain that dose at all meals of similar size. Take fewer capsules with smaller meals. 4. When taking several capsules, it is best to take them throughout the meal rather than all at once. 5. As your stomach begins to regain the ability to produce the amount of HCl needed to properly digest your food, you will notice the warm feeling again. This is the time to start decreasing the dose level. 6. Every 3 days, decrease by 1 capsule per meal. If the warmth continues, decrease more rapidly. If maldigestion symptoms return, add capsules back until digestion improves again.

Exocrine Pancreatic Insufﬁ ciency

Inadequate pancreatic enzyme and bicarbonate secretion impairs the breakdown of food entering the small intestine, resulting in incomplete digestion and, most consequentially, malabsorption of a variety of nutrients. Fat malabsorption occurs initially, and defi ciencies of vitamins A, E, and K, as well as essential fatty acids, are common. Markers of pancreatic insuffi ciency have been found recently in patients with osteoporotic fractures, and the data suggests that vitamin D defi ciency also occurs frequently, due to poor pancreatic output (Mann et al., 2008 ). While generally thought to occur as a later symptom, reduced circulating levels of amino acids among patients with chronic pancreatitis suggest that protein digestion and absorption are also impaired (Schrader et al., 2009 ). Naturopathic Medicine and Digestion 213

DIAGNOSIS

• Laboratory diagnosis: Although most direct tests are generally accurate, they are usually invasive and expensive. For this reason, pancreatic elastase 1 (PE1) is typically used (normal > 200 ug/g; see Naruse et al., 2006 ). • Clinical diagnosis. Although most clinicians use the presence of oily, foul-smelling and buoyant stool (due to the increased fat content) as an indication of pancreatic exocrine insuffi ciency, measurable dysfunction can occur before these stool changes are observed. Further complicating the issue is that the various exocrine functions can become dysfunctional independently (Owyang, 2003 ). Other symptoms, such as abdominal pain, are more likely in acute or chronic pancreatitis, not necessarily due to insuffi ciency, and gas and bloating are likely but not very specifi c .

CAUSES

Chronic pancreatitis (CP) : One of the most well-established causes of pancreatic insuffi ciency is chronic pancreatitis, for which alcohol use is the major risk factor. About 70% of CP is caused by alcohol. Smoking is also a signifi cant risk factor, with an odds ratio of 7.8 for current smokers, and a greater risk with an increasing cumulative amount of smoking (Lin et al., 2000 ).38 Cystic fi brosis (CF): Approximately 90% of people with CF have pancreatic insuffi ciency, particularly those of Northern European descent, where a more severe genetic mutation predominates (Rovner et al., 2007 ). Celiac disease. Chronic immunological reaction to wheat is also thought to be a cause of exocrine pancreatic insuffi ciency, with at least 20% estimated to have a defi ciency (Freeman, 2007 ). Although the removal of gluten from the diets of these patients improves pancreatic function in some, those with chronic diarrhea despite gluten avoidance are more likely to have reduced pancreatic function (Leeds et al., 2007 ). Recent research suggests that celiac is seriously underdiagnosed. Diabetes mellitus: Diabetes mellitus is a signifi cant cause of pancreatic insuffi ciency, and although it is more common in Type 1, patients with either type of diabetes may be aff ected. Overall, 27% of patients with diabetes (n=2001) had a fecal elastase 1 < 100ug/g, a marker of severe pancreatic insuffi ciency, while only 58% had a level > 200ug/g (Hardt et al., 2008 ). 214 INTEGRATIVE GASTROENTEROLOGY

Infl ammatory bowel disease: Compared to control subjects, patients with Crohn’s disease were found to have more than an eightfold risk for a FE1 < 200 μg/g, and those with ulcerative colitis had nearly a 13-fold risk.

INTERVENTION

1 . Eliminate contributing factors .

Although not always causative, patients should avoid alcohol and smoking, particularly those with chronic pancreatitis. Additionally, avoidance of gluten in those with celiac disease may improve the pancreatic insuffi ciency in some cases (Carroccio et al., 1991 ).

2. Pancreatic enzyme replacement.

Complete replacement should include proteolytic enzymes, lipase, as well as enzymes that digest carbohydrate. Th e supplement should be taken during or immediately aft er meals for the greatest effi cacy (Domínguez-Muñoz et al., 2 0 0 5 ) .

3. Correct related nutrient defi ciencies.

Fat soluble vitamins, (A, D, E, and K) are likely to be defi cient in patients with poor pancreatic exocrine function, along with essential fatty acids (Peretti et al., 2005 ; Dodge &Turck, 2006 ).

4. Potential therapies.

Although clinical research is lacking, melatonin appears to have an important role in pancreatic function. Th e concentration of melatonin in the GI tract is 10 to 100 times higher than in the plasma, and the total amount of melatonin is around 400 times higher than the amount of melatonin in the pineal gland (Bubenik, 2008 ). Melatonin has been shown to have some protective function for the pancreas, and to strongly stimulate pancreatic amylase secretion (Jaworek et al., 2007 ).

INCREASED INTESTINAL PERMEABILITY

Abnormal permeability refers to a measurable increase in fl ux of small water- soluble compounds across the paracellular pathway of the small intestine. Naturopathic Medicine and Digestion 215

Intracellular enterocyte and tight junction proteins regulate the rate of movement and permeability through this pathway. Th e infl ammation typically associated with altered permeability is not restricted to the gut. For example, animal models of Type 1 diabetes have shown that intestinal permeability, with resultant infl ammation, plays a role in the autoimmune destruction of pancreatic islet cells. Recent research suggests that the same is true for Type 1 diabetes in humans. Increased lactulose permeability (with normal mannitol) precedes detectable clinical onset of impaired glucose regulation, suggesting that the small intestine participates in the pathogenesis of the disease (Bosi et al., 2006 ).

Loss of intestinal barrier function may also be associated with other autoimmune diseases, such as multiple sclerosis, ankylosing spondylitis, IgA neph- ropathy, and nonalcoholic steatohepatitis (NASH), as well as digestive autoimmune processes, such as Crohn’s disease and celiac disease (Fasano & Shea-Donohue, 2005 ).

DIAGNOSIS

• Laboratory assessment is done primarily with the lactulose/mannitol test (see Chapter 5).

CAUSES

A number of factors can alter the normal permeability, including food allergy, food intolerance, infection, infl ammatory cytokines, nutrient transporter activation, noxious environmental toxins, toxic— not infectious— bacteria, and unknown causes. Evolving research is showing that altered intestinal permeability plays a role in a number of digestive diseases, including celiac, IBD, IBS and food allergy, and may precede the illness (Meddings, 2008 ). NSAIDs are a well-accepted cause of increased intestinal permeability in both the short term and long term, causing signifi cant morbidity and mortality (Bjarnason & Takeuchi, 2009 ). Aspirin was recently shown to increase the susceptibility to “gut leakiness” in patients with non-alcoholic steatohepatitis (NASH), although lactulose/mannitol was not modifi ed by aspirin, the urinary sucralose increased only in patients with NASH, suggesting a colonic permeability increase (Farhadi, Gundlapalli, & Shaikh, 2008 ). 216 INTEGRATIVE GASTROENTEROLOGY

INTERVENTION

Th e strategy to facilitate repair of the damaged intestinal mucosa entails 3 steps:

1. Stop the damage. 2. Reestablish a healthy microbial fl ora. 3. Stimulate regeneration.

Th e intestinal mucosa is damaged by allergenic foods, commonly consumed chemicals such as alcohol, NSAIDs and some food additives, cytotoxic drugs, and toxic microbial fl ora. Food allergy/intolerance. A recent trial found that, in subjects with adverse reactions to food, the severity of clinical symptoms correlated with the degree of intestinal permeability, as measured by lactulose/mannitol (Ventura, Polimeno, & Amoruso, 2006 ). An immune-mediated reaction to foods can cause increased intestinal permeability, as is well documented in celiac disease, and proper treatment results in restoration of intestinal integrity (Vilela et al., 2008 ). Th e basic approach is to determine and eliminate the foods that induce an immunological reaction. Unfortunately, there is no gold standard to achieve this. Th e author prefers challenge testing. Once the worst allergenic foods are eliminated, a 4-day rotation diet is recommended until proper digestive function is reestablished and the intestines healed. Surprisingly, this may take only a few weeks. However, this does not mean the allergenic foods can be immediately reintroduced, and some patients appear to have a lifelong reaction to some foods. Bowel microbial fl ora . Th e increased permeability caused by bacterial and viral infections is well known. Less well appreciated is the chronic subclinical infl ammation and intestinal damage caused by commensal microbial agents that do not cause overt infection (Tlaskalová-Hogenová, 2004 ). 55 Also underappreciated are the diverse roles a healthy microbial balance plays in the maintenance of healthy digestion, as well as disease prevention. Th ese include the production of essential vitamins and cofactors, cidal activity against pathogenic bacteria, enhancement of intestinal barrier function through modulation of cytoskeletal and tight junctional protein phosphorylation, metabolism of toxins, reduction of GI infl ammation, and help maintaining immune homeostasis within the gut-associated lymphoid tissues (GALT; see Ng, Hart & Kamm, 2009 ). Naturopathic Medicine and Digestion 217

Th e clinical approach is to use low-toxicity antimicrobial agents to kill the unwanted bacteria and to then reseed with preferred strains. Th is author has seen considerable success using Hydrastis canadensis (goldenseal), which has been shown to be active against many of the undesirable intestinal microfl ora (Scazzocchio, Cometa, Tomassini, & Palmery, 2001 ). Many probiotics and prebiotics have been used to reseed the intestines. 8 One of the most researched strains is Lactobacillus rhamnosus (Hawrelak, 2006 ). Probiotics that support Bifi dobacteria spp. growth include fructooligosaccharides (asparagus, onion, leek, garlic, artichoke, Jerusalem artichoke, chicory root); galactooligosaccha- rides (cow’s milk, yogurt, human milk); xylooligosaccharides (oats); and galactosyl lactose (human milk). Lactobacillus spp. are supported by β -glucooligomers (oats) and raffi nose (legumes, beets). Cabbage juice and glutamine. More than 50 years ago, daily consumption of 1 quart of cabbage juice was found to repair gastric ulcers, which was confi rmed radiologically (Cheney, 1949 ). Follow-up research unoffi cially dubbed the unknown factor in cabbage juice “vitamin U” (Cheney, Waxler, & Miller, 1 9 5 6 ) . Th is factor was later determined to be glutamine, and subsequent research (with a few exceptions) has clearly documented the effi cacy of 500 mg three times a day in repairing a damaged intestinal mucosal barrier (Li et al., 2006 ). Several other natural agents have been shown to decrease excessive gastrointestinal permeability, including quercetin, glutathione, omega-3 fatty acids, and Aloe vera (Rosella, Sinclair, & Gibson, 2000 ; Lash, Hagen, & Jones, 1986 ; Kim et al., 2005 ).

• High predictability factors include IBS, Type 1 diabetes, migraine, celiac disease and food allergies. • Medium predictability factors include Type 2 diabetes, inﬂ ammatory bowel disease, use of ibuprofen, indomethacin, naproxen or aspirin, Giardia , Blastocystis hominis , Entamoeba histolytica , Candida albicans , atopic dermatitis, psoriasis, asthma, hypochlorhydria, abdominal bloating, aphthous stomatitis, and chronic stress. • Lower probability factors include taking Vioxx or Feldene, and essential fatty acid deﬁ ciency.

Conclusion

Disorders of digestive function are surprisingly common, and oft en aggra- vated by conventional drug interventions. Th ese disorders not only cause signs and symptoms of digestive distress, but they also cause a diverse range of 218 INTEGRATIVE GASTROENTEROLOGY systemic diseases from chronic nutrient defi ciencies, increased production and transport of infl ammatory mediators, immune complex deposition from food allergies, and absorption of toxins from aberrant microbial fl ora. Restoration of normal digestive function not only relieves symptoms, but oft en results in widespread improvement in health and decreased disease burden. Finally, as amply demonstrated in the example of vitamin D defi ciency secondary to subclinical pancreatic exocrine defi ciency, nutrient defi ciencies can occur with digestive dysfunctions that are not clinically overt. Th is requires a high level of clinical awareness of the many ways digestion become disordered. 2 2 Taiji, Qigong, and Digestive Health

YANG YANG AND BOB SCHLAGAL

key concepts

■ Research points to the value of exercise and diet in maintaining digestive health. ■ Research supports a role for stress reduction techniques in limiting digestive distress. ■ Carefully conducted studies of tai chi verify a cascade of exercise and stress reduction benefi ts stemming from its practice. ■ Focus on two core components of tai chi practice, form and Qigong, appears to produce the greatest health and stress reduction benefi ts. ■ C a r e f u l l y c o n d u c t e d s c i e n t i fi c studies have verifi ed many of the benefi ts of tai chi that have long been claimed by practitioners. ■ Tai chi’s focus on deep relaxation and gentle exercise promotes improved everyday physical functioning, and should assist in regulating the brain–gut axis. ■

Stress Reduction and Exercise

unctional GI disorders are extremely common in the general population. Th ey are not caused by the kinds of organic diseases readily F assessed by standard diagnostic procedures (x-rays, blood tests and the like). Instead, these diseases present themselves as abnormally functioning digestive tracts, and are identifi ed by process of elimination and reported symptoms of distress. Th e most common of these is the irritable bowel syndrome.

219 220 INTEGRATIVE GASTROENTEROLOGY

Experts estimate that 50 % to 80% of those suff ering from abnormal functioning of the GI tract do not seek medical help and, instead, use over-the- counter prescriptions and/or a variety of complementary and alternative therapies (Mullin, Pickett-Blakely & Clarke, 2008 ). 1

The Foundation of the American Gastroenterological Association, among many other medical associations, makes a variety of nonmedical recommendations for maintaining GI tract health. These include recommendations about diet, but also stress reduction and regular exercise.

Th e presence or absence of stress and/or physical fi tness is seen to play a role in the onset, mitigation, or prevention of GI disorder symptoms. Stress is known to produce wearing eff ects on the immune, circulatory, and nervous systems. By contrast, deep relaxation has been shown to produce benefi ts in these systems (Barnes, Treiber, & Davis, 2001 ; Carlson, Speca, Pate, & Faris, 2007 ; Jones & Heymen, 2008 ; Kjaer, Bertelsen, Piccini et al., 2002 ; Sakakibara,Takeuchi, & Hayano, 1994 ; Travis & Wallace, 1999 ; Young & Taylor, 1998 ). 2,3,4,5,6,7,8 . Training in some form of stress reduction tends to produce not only benefi ts to these systems, but also assists in preparing individuals to encounter stresses at a lower level of anxious arousal. Th is can assist in improving symptoms and in managing digestive distress (Keefer & Blanchard, 2001 ; To n e r , 2 0 0 5 ) . 9,10

Regular exercise is not only important for overall health, but also plays an important role in digestion.

Exercise assists in regulating the rhythms of digestion and, according to the Center for Colon and Digestive Disease, quiets the bowel: “If exercise is used regularly and if physical fi tness or conditioning develops, the bowel may tend to relax even during non-exercise periods” (Drossman & Swantkowski, 2008a ). 11 Exercise can also strengthen abdominal muscles, improving their ability to push material through the intestines. Addressing GI health through stress reduction and regular exercise means addressing the “brain–gut axis” of digestive health. It has been argued that functional GI disorders should be understood as a dysregulation of brain–gut functioning (Drossman & Swantkowski, 2008b ). 12 Improved regulation of brain–gut or mind–body connections through regular exercise and cultivated relaxation should, therefore, play an important role in attaining GI health. Taiji, Qigong, and Digestive Health 221

Components of Tai Chi Practice

Tai chi (also known as t’ai chi chuan, taiji, or taijiquan) is an ancient Chinese martial art that has long been associated with health promotion. It is practiced in slow, even, and relaxed movements, with an emphasis on diaphragmatic breathing and the goal of circulating energy effi ciently and thoroughly throughout the body. It also emphasizes stable, relaxed postures and dynamic balance. Carefully conducted scientifi c studies have verifi ed many of the benefi ts of tai chi that have long been claimed by practitioners. Th ese include positive eff ects on blood pressure, oxygen uptake, cardiovascular fi tness, bone density, strength, balance, and agility, as well as improved immune function and enhanced self-effi cacy (Yang & Grubisich, 2008 ; Yang, 2005 ; Yang et al., under review) To date, there appear to be no studies of tai chi exercise in relation to GI health, though this is also one of the benefi ts that Chinese masters have long believed results from this practice.

Training the mind–body connection (by combining exercise and meditation) is the heart of traditional tai chi training.

Th is connection is made holistically, in a variety of mutually reinforcing ways. Th is is accomplished most obviously through the complementary practices of Qigong and form. Form consists of a choreographed sequence of movements derived from various Chinese martial arts. Th ese are meant to improve effi ciency of movement (balance, strength, and agility) and to nurture energy and stamina while improving the mind–body connection. Th is is the most visible and characteristic aspect of tai chi training.

QIGONG

Qigong, however, holds an equal if not more central role. Qigong (energy cultivation) is exercised through both static and dynamic methods. Static Qigong includes standing, sitting, and lying-down meditation. Standing involves holding specifi c postures and relaxing into a calm, meditative state. Th is is one of the ways that tai chi players cultivate the deep relaxation and strong natural structures that are to be used while executing form practice. Although holding a particular posture can be initially somewhat demanding, the muscles are 222 INTEGRATIVE GASTROENTEROLOGY progressively loosened and the mind is settled on the dantian , the area that radiates from the naval upward to the lower ribs and downward to the pelvic fl oor. (Th e dantian is understood to be the center for cultivating and storing energy). In this way, breathing relaxes, deepens, and becomes diaphragmatic. It is through practice in this way that qi (internal energy) is cultivated. With continued exercise, one can enter a state of great calm during static Qigong. (Sitting and lying-down meditation are also central, and used to attain deep calm and relaxation). An old saying ( taiji tai he) holds that “peacefulness is a requisite of tai chi” (Yang & Grubisich, 2008 ). It is also said (Qì gōng néng qū bìng, yuán yóu zài sōng jìng) that “relaxation and tranquility/quietness are the reasons why Qigong can heal you” (Yang & Grubisich, 2008 ). Lastly, it is oft en said ( Yào bŭ bù rú shí bŭ, shí bŭ bù rú qì bŭ, qì bŭ bù rú shén bŭ), “To improve your health, medicine is not as good as food/nutrition; food/nutrition is not as good as Qi(gong); Qi(gong ) is not as good as spiritual nourishment” (Yang & Grubisich, 2008 ). Th e “spiritual” component— an important facet of stress reduction — is nurtured in tai chi during static Qigong through the use of positive and tranquil imagery.

DYNAMIC QIGONG

In dynamic or moving Qigong, one focuses on circulating qi, or energy, through the body by coordinating slow, relaxed, outward movements with movements of the dantian, using reverse breathing. In reverse breathing one inhales slowly and gently, drawing the abdominal area (including the pelvic fl oor) gently inward; in exhalation, the diaphragm relaxes and moves outward. Th e purpose of reverse breathing is to gather, guide, and release the energy cultivated through static Qigong. Th is pattern of breathing massages and conditions the internal organs, as well as the diaphragmatic musculature. As with static Qigong, moving Qigong is used to cultivate energies (skills) to be used during the more complex and dynamic demands of form practice. In particular, dynamic Qigong helps to activate the movement of the dantian, from which all movement in tai chi form must emanate. An example of such an exercise is called “gathering qi (energy) from nature.” In this exercise, one exhales while slowly reaching out the arms horizontally and open-handed; while inhaling, one pulls the hands back toward the dantian, at the same time gently closing the fi sts. (Illustrations of this and other important dynamic Qigong exercises can found in Yang (2007 ), and an explanation of the physiological eff ects of core tai chi/Qigong practices can be found in Yang and Grubisich ( 2008 ). Taiji, Qigong, and Digestive Health 223

TAI CHI FORM

In tai chi form, one incorporates and extends what is developed through Qigong into a more complex arena of activity. Th e slow, gracefully executed choreography of form further helps to nurture and build energy, to improve the mind–body connection, and to train effi cient body movement. Again, each movement in the form originates in the dantian and extends from there (in coordination with breathing) into the outer limbs. And, through the more complex expressions of form practice, the dantian rotates in all dimensions of movement in order to extend energy/movement in the various required directions.

IMPROVING BRAIN-GUT FUNCTION THROUGH TAI CHI

As stated above, tai chi has long been viewed in China as a tool for recovery and health. It appears that the core practices of this art might play a likely role in moderating some of the discomfort of functional GI disorders, and might contribute to healing and promoting general GI health. Th e focus on deep states of relaxation, the gentle exercise of the diaphragmatic terrain, and the extension of these into complex actions, may allow for the reregulation of dys- regulated brain–gut function. In their comprehensive review of the therapeutic benefi ts of tai chi, Klein and Adams ( 2004 ) found that research confi rms a variety of therapeutic benefi ts of tai chi practice with respect to improved physical functioning and quality of life.

Tai chi leads to improvements in cardiovascular function, strength, balance, agility, ﬂ exibility, and kinesthetic sense, as well as pain reduction and enhanced immune response.

Further, a recent article on the Mayo Clinic’s online “Stress Reduction” portion of their website points to the support that scientifi c study has given to many of tai chi’s ancient claims. Summarized in Table 22.1 , it underscores the depth and variety of tai chi’s health benefi ts, ones that reach well beyond stress reduction alone. 224 INTEGRATIVE GASTROENTEROLOGY

Table 22.1. Mayo Clinic Summary of Tai Chi’s Empirically Supported Health Beneﬁ ts

• Reducing anxiety and depression • Improving balance, fl exibility and muscle strength • Improving sleep quality • L o w e r i n g b l o o d p r e s s u r e • Improving cardiovascular fi tness in older adults • Relieving chronic pain • Increasing energy, endurance and agility • Improving overall feelings of well-being

We contend that relieving pain and the improved overall physical functioning implied across other categories would account for the potential eff ect of tai chi on functional GI disorders. We also note that for all of the benefi ts the research has documented, the vast majority of studies on tai chi have been based on tai chi form practice alone. We might expect to see evidence of more profound benefi ts when future tai chi research incorporates Qigong — especially static Qigong.

Conclusion

No carefully controlled scientifi c studies have yet examined the eff ect of a traditional tai chi curriculum on the mitigation of functional GI disorders. Nonetheless, it is our experience that integrating Western medical approaches with Eastern methods of health cultivation, like tai chi, holds signifi cant potential for improved regulation of the brain–gut axis. Th is belief has been shared by generations of tai chi practitioners based on sustained anecdotal evidence. (Yang & Grubisich, 2008 ) Further, tai chi off ers an approach to a variety of health issues, has no undesirable side eff ects, is cost eff ective, and has com- paratively low post-intervention dropout rates. (Yang et al., 2008 ) 2 3 Digestive Health and Reiki Energy

BETH NOLAN

key concepts

■ Reiki is an energy-based touch therapy that rebalances the human energy fi elds. ■ Reiki may improve digestive health by focusing on the energetic origins of disease and discomfort in the physical body. ■ Reiki has been shown to reduce stress, rebalance the autonomic nervous system, relieve acute and chronic pain, and ameliorate anxiety and depression, which may benefi t patients with stress- related functional digestive disorders. ■

eiki improves digestive health in several key ways. Despite their diff erences, each of the following modalities promotes relaxation, improves R circulation, calms the nervous system, and helps balance mind, body and spirit, while complementing the others. In this section, we will explore these modalities and focus on practical techniques for improved intestinal health. Abdominal massage therapy techniques stimulate peristaltic contractions, helping push waste through the intestines. In this way, massage manually moves waste out of the body. Many yoga postures are a form of self-massage: by doing twisting poses and compressing the torso, one indirectly massages the intestines and digestive organs, improving blood and oxygen fl ow to these areas. Finally, Reiki— an energy-based touch therapy— may improve digestive health by focusing on the energetic origins of disease and discomfort in the physical body. Th ese techniques all help eliminate toxins and release chronic patterns in muscle tissue and the energetic body.

225 226 INTEGRATIVE GASTROENTEROLOGY

Reiki

Reiki is the Japanese term for universal life energy, a visible and palpable energy that infuses and permeates all living forms (Usui & Petter 2003 ; Bohm, 1980 ; Z u k a v , 1 9 8 9 ) . Reiki as a healing technique is an energy-based touch therapy that allows life force energy, or chi , to recharge, realign, and rebalance the human energy fi elds (Honervogt, 1998 ). Similar to other touch therapies, such as therapeutic touch and healing touch, Reiki involves the use of energy directed by the practitioner’s hands to strengthen the recipient’s ability to heal. It also involves a mind–body connection. Reiki is an ancient energetic healing practice believed to have originated thousands of years ago in the Tibetan sutras, and then lost. It was rediscovered in the 1800s by Dr. Mikao Usui, a Japanese monk (Zukav, 1989 ). Nurses and others have observed that Reiki may have relaxation and stress-management benefi ts, and may lessen pain and promote inner healing. However, there is little empirical evidence to show just how it works (Miles & True, 2003 ; Bullock, 1997 ; Nield-Anderson & Ameling, 2000 ). Within the last 10 years, the use of Reiki has increased among nurses, physicians, and rehabilitation therapists, and is practiced in hospitals, hospice care, emergency departments, psychiatric settings, nursing homes, operating rooms, family practice, and many other settings (Barnett & Chambers, 1996 ). A review of the medical literature fails to produce any published evidence that Reiki can benefi t digestive health or disease. However, studies of its ability to reduce stress, rebalance the autonomic nervous system, relieve acute and chronic pain, and ameliorate anxiety and depression have been published (Shifl ett, Nayak, Champa, Miles, & Agostinelli, 2002 ; Wardell & Engebretson, 2001 ; Olson, Hanson, & Michaud, 2003 ; Mackay, Hansen, & McFarlane, 2004 ). Functional digestive disorders (IBS, non-ulcer dyspepsia, non-cardiac chest pain, etc.) and infl ammatory bowel disease are chronic illnesses characterized by acute and chronic pain, stress-provoking fl ares, frequent psychopathology, and improvement of intestinal symptoms in response to mind–body therapies. Th us, Reiki, which has been shown to improve these core imbalances of pain and dysfunction, is likely to benefi t patients with many digestive illnesses. 2 4 Self-Care Journaling for Digestive Health

DANNA M. PARK

key concepts

■ Journaling is a cost-eff ective therapy that improves immune system function and aids in “brain–gut axis” regulation. ■ Journaling may be used as an adjunctive therapeutic tool in treating a variety of GI conditions, including IBD, IBS, and functional abdominal pain. ■ Expression of emotions, such as fear or stress, through writing can lead to improvement in GI symptoms and well-being, most likely via neurotransmitter eff ects. ■ Journaling may be taught to patients quickly and easily in the offi c e s e t t i n g . ■

Self-Care Journaling: Theory

ournaling is the process of self-exploration and expression via writing. Although keeping a diary is oft en used in gastroenterology for the elucida- J tion of connections between foods, emotions, events, and symptoms, the modality of journaling, also called expressive writing , may be underused. Journaling can not only help establish and verify connections between stressors/situational events and GI symptoms, it can also be a therapeutic tool in its own right, allowing the patient to express emotions in a safe, secure, and private environment. Although we use lay language frequently to express the

227 228 INTEGRATIVE GASTROENTEROLOGY mind–body connection between the gut and the brain (for example, “I knew it was OK because I could feel it in my gut,” or “It was such a shock, I felt as if someone had kicked me in the stomach”), there is now no doubt about the physiologic connection between the brain and GI tract. Th is connection provides the theoretical evidence for using a therapy such as journaling. Th e “brain–gut axis” defi nes the endocrinologic links between the brain and the GI tract. Numerous neurotransmitters and neuropeptides are involved, including serotonin (95 % of the body’s serotonin is in the GI tract, whereas 5 % is in the brain), norepinephrine, dopamine, cortisol-releasing hormone (from both the hypothalamus and the enterochromaffi n cells in the colon), interferon gamma, substance P, VIP, and many others. Imbalances in these neurotransmitters can lead to GI symptoms. For example, in the diarrheal form of irritable bowel syndrome (IBS), high levels of serotonin inhibit norepinephrine, thereby increasing acetylcholine levels and causing increased gut motility. Conversely, a high adrenergic state with elevated levels of norepinephrine decreases serotonin levels, inhibits acetylcholine, and decreases GI motility and tone, consistent with the constipation form of IBS (Crowell, Schuster, & Talley, 2000).

Journaling: Summary of Medical Literature

Th e implication of psychosocial factors, emotional and physical abuse, coping skills, and stress in relation to exacerbations of IBS and infl ammatory bowel disease (IBD) has been researched. In children with functional abdominal pain, accommodation to the pain by responding to it as a challenge, with determination to continue normal activities as much as possible, resulted in positive coping mechanisms that strengthened their internal and external coping skills Conversely, those who responded to the pain with fear were more likely to limit their daily activities due to their pain, which propagated a cycle of pain anticipation, focus on pain, limitation of activities, loss of psychosocial developmental milestones, and eventually the likelihood of serious anxiety and clinical depression (Walker & Jones, 2005 ). Patients with high levels of prolonged stress who have infl ammatory bowel disease have more relapses in their disease (90 % ) as opposed to those who have lower stress levels (relapse rate 40% ; see Levenstein et al., 2000 ). Stress aff ects intestinal permeability, decreasing the barrier function of the gut mucosa, which may hasten infl ammatory GI problems in patients who are susceptible, or trigger a relapse in patients who already have such illnesses (Hollander, 2003 ). Literally Self-Care Journaling for Digestive Health 229

“swallowing emotions” and keeping them inside may be a trigger for IBS in women, as in one study where women with IBS had higher rates of emotional abuse, self-blame, and self-silencing (Ali et al., 2000 ). Expression of emotions such as fear or stress through journaling has shown to decrease disease severity in conditions such as post-traumatic stress disorder (PTSD; see Davidson & Robison, 2008 ), rheumatoid arthritis, and asthma (Smyth et al., 1999 ). Physical health benefi ts include improved immune system function, indicating some kind of eff ect in the hypothalamus-pituitary- adrenal axis and/or the sympathetic-adrenal-medullary axis. Improved mood and aff ect, and a feeling of higher psychological well-being, may implicate eff ects in neurotransmitters such as serotonin and dopamine (Baikie and Wilhelm, 2005 ). Given these fi ndings, there may be a strong role for journaling as a component of a treatment plan for a variety of GI illnesses, especially in functional abdominal pain, IBD, and IBS.

Summary: Journaling Clinical Practice and Guidelines

Journaling is a simple, cost-eff ective adjunct to a GI treatment plan, and can be introduced to the patient as a therapy that improves and regulates the immune system and may help “rebalance” the brain–gut axis. Instructions to the patient should include emphasis that their writing is for him or her alone, and does not need to be shared with anyone unless he or she chooses to. Patients should be counseled to fi nd a quiet place where they will not be disturbed, and to pick a situation that is “emotionally charged” for them, such as an upsetting or troubling experience in their life. In whatever form they choose (prose, poetry, free-form without punctuation, etc.), the patient should write continuously about the experience for 20 minutes, expressing his or her deepest feelings about it and about any insights he or she has had as a result of their experiences. Patients are encouraged to write for 20 minutes each day, for at least 4 days (the topic they choose may be diff erent each time), and to note any change in their physical and/or emotional state. If helpful, this is a practice that can be continued on a daily basis. Potential adverse eff ects of journaling include emotional distress from the experience of remembering upsetting experiences, and patients should be asked to contact their healthcare provider if they experience such distress— the processing of emotional events may also require mental health counseling and support. An excellent patient handout with journaling instructions is reproduced in Table 24.1 , from David Rakel’s textbook Integrative Medicine (Second Edition; 2007). 230 INTEGRATIVE GASTROENTEROLOGY

Table 24.1. Patient Handout

Using journaling to aid digestive health

What Is Journaling?

Journaling is the process of writing about times in our lives that were stressful or traumatic. It provides an avenue for the expression of thoughts and memories that may have been internalized. Th ese repressed emotions can oft en lead to a worsening of physical symptoms. William Boyd, a pathologist at the turn of the 19th century, described this process well; he wrote, “Th e sorrow that hath no vent in tears, may make other organs weep.” Journaling is one type of therapy that can be used to aid this process.

How Does It Work?

Studies have found that if we express feelings about a time in our lives that was very traumatic or stressful, our immune function strengthens, we become more relaxed, and our health may improve. Writing about these processes helps us organize our thoughts and create closure to an event that the mind has a tendency to want to suppress or hide. Th is can be done in the privacy of your home and requires only pen and paper.

Does Anybody Need to Read It?

No. You can share your writings with others if you desire, but no one needs to read what you write. Th e most benefi t comes from writing the document, and the words can be thrown away if you desire. In fact, some people fi nd that burning or destroying the document can add ceremony to the process. Letting the wind carry away the smoke can act as a positive metaphor that helps them let go, forgive, and heal. Others prefer to keep their writings private, so they can look back on them and see how they have grown from the events.

Are Th ere any Side Eff ects or Th ings I Should Be Aware Of?

Recalling stressful memories can make you feel uncomfortable for a few days. If this were not the case, the body would not use so much energy trying to repress them. Th e benefi ts of journaling become most apparent weeks to months aft er writing.

Th is process can bring back into mind some frightening events for which you may need the help of a licensed counselor. Please notify your medical practitioner if you develop feelings that would benefi t from further discussion. Th is is oft en the fi rst step toward creating an environment that will promote healing from within.

How Is It Done?

Th ere are many diff erent ways to express emotions. Journaling is simple and inexpensive, and can be done independently. It would be benefi cial to keep a regular journal to write about events that bring anger, grief, or joy. But if that is unlikely, and you just want to deal with a specifi c event or see whether this technique will help your condition, follow these steps: Self-Care Journaling for Digestive Health 231

Table 24.1. (Continued)

Using journaling to aid digestive health

1. Find a quiet place where you will not be disturbed. 2. Using pen, pencil, or computer, write about an upsetting or troubling experience in your life, something that has aff ected you deeply and that you have not discussed at length with others. 3 . First describe the event in detail. Write about the situation, surroundings, and sensations that you remember. 4. Th en describe your deepest feelings about the event. Let go and allow your emotions to run freely in your writing. Describe how you felt about the event then, and how you feel now. 5. Write continuously. Do not worry about grammar, spelling or sentence structure. If you come to a “block,” simply repeat what you have already written. 6. Before fi nishing, write about what you may have learned or how you may have grown from the event. 7. Write for 20 minutes for at least 4 days. You can write about diff erent events, or refl ect on the same one each day. 8. If the process proves helpful, consider keeping a journal regularly.

How Can I Learn More?

An excellent resource for more information on this subject can be found in Opening Up: Th e Healing Power of Expressing Emotions by James Pennebaker (Guilford Press, 1997).

Th ere is also a comprehensive web site on the subject: www.journaltherapy.com

Th is article was published in Integrative Medicine, Second Edition . David Rakel, Chapter 98, page 1043. Copyright Elsevier 2007. 2 5 Spirituality

FREDERIC C. CRAIGIE , JR .

key concepts

■ Spirituality has to do with what is “vital and sacred” in people’s lives. It may or may not be expressed in religious involvement. ■ Spiritual care begins with the healing intention and compassionate presence of clinicians. ■ Spiritual care may also take the form of supportive and encouraging conversations with patients about what gives their lives meaning and purpose, and in identifying particular spiritual practices that bring patients peace and comfort. ■ Chaplains and other spiritual care professionals help patients and families to address especially painful spiritual issues and needs. ■

pirituality frames a broad and central aspect of human experience having to do with meaning and purpose, life force, and enlivening and sustain- S ing relationships with spirit. (Craigie, 2010 ) Former Surgeon General C. Everett Koop, for instance, has defi ned spirituality as “the vital center of a person; that which is held sacred.” (Koop, 1994 ) Spirituality is not synonymous with religion. For some people, “the vital center” and “sacredness” are expressed in the context of religious traditions and communities; for other people, spirituality is a more personal journey, or one that is not aligned with a particular religious faith. Th ere has been lively interest in the interface of spirituality with medicine (e.g., Levin, 2001 ) and with integrative medicine (Craigie, Silverman & Maizes, 2007 ) in recent years. Th e emerging literature suggests that spirituality is important in healthcare for a variety of reasons. First, the spirituality of

232 Spirituality 233

clinicians— variously framed as “healing presence” (McDonough-Means, Kreitzer & Bell, 2004 ), “compassionate presence” (Puchalski, Lunsford, Harris, & Miller, 2006 ), “intention,” (Shealy & Church, 2006 ), “mindfulness” (Schmidt, 2004 ), and even “love” (Levin, 1999 ) — plays a substantial role in the healing process. A sample of family physicians, for instance, expressed the view that their own centeredness and grounding helped them have a more peaceful presence and be more available as instruments of healing in other people’s lives. (Craigie & Hobbs, 1999 ) Second, the spirituality of patients is important because there are strong epidemiological relationships between spiritual and religious beliefs and practices, and a variety of outcomes in the arenas of subjective well-being, coping, mental health, and health. (Miller & Th oresen, 2003 ; Tsuang, Simpson, Koenen, Kremen & Lyons, 2007 ) Spirituality promotes wholeness, energizes positive lifestyle changes, and provides a source of strength and solace in adversity. Literature exploring connections between spirituality or spiritual practices and gastroenterological disease is sparse. One may argue, however, that the spiritual journey toward peacefulness and meaning: (a) speaks to the frequently implicated relationship between stress and GI disease (Bhatia & Tandon, 2005 ), and (b) may underlie some of the benefi ts of psychosocial interventions in this arena, such as the eff ects of cognitive-behavioral therapy on symptoms and quality of life in patients with irritable bowel syndrome. (Lackner et al., 2007 ; 2008 ) A recent review has proposed incorporating con- structs of mindfulness and acceptance — both of which have deep traditional and Eastern spiritual roots — into mind–body treatment protocols for irritable bowel syndrome. (Naliboff , Fresé & Rapgay, 2008 )

Spiritual Care in Integrative Medicine

Spiritual care begins with compassionate presence (Puchalski, 2004 ), and with the ways compassion and healing intention are embodied in the clinician. (Craigie, 2010 ) A family physician describes this well:

“Before I go in a room, I stand briefl y outside the door, feet fl at on the fl oor, and remind myself why I want to be there for the patient I am about to see.” (Interview notes from Craigie and Hobbs, 1999 )

Healthcare practitioners may pursue many approaches, such as meditation, prayer, affi rmations, and devotional or inspirational readings, to cultivate a spirit of compassion, mindfulness, and healing intention as they move through their days. 234 INTEGRATIVE GASTROENTEROLOGY

Clinically, spiritual care is less defi ned by specifi c techniques than it is by conversation with patients about what matters to them— what is “vital” and “sacred.” (Craigie, 2010 ) Organizational consultant Margaret Wheatley observes that “real change begins with the simple act of people talking about what they care about.” (Wheatley, 2002 ) Providing the opportunity for patients to talk about their hopes, their suff ering, their dreams and values— wanting to do an honest day’s work, wanting to show courage and grace to a beloved child in facing serious illness, wanting to work their way through forgiveness and reconciliation with an abusive parent — helps patients be affi rmed, focused, and empowered in their spiritual journeys. Th ere are many ways of joining this conversation. Th ere are a number of templates for spiritual assessment (with subsequent conversation) in healthcare; two of the more prominent are FICA (Puchalski, 2006 ) and HOPE. (Anandarajah & Hight, 2001 ) Both these frameworks pose four questions (e.g., the “I” from FICA: “What importance does faith or belief have in your life?”) for effi ciently surveying a person’s spirituality and how it relates to his or her health and medical care. Clinicians may also utilize single-item, open-ended conversation starters, such as “Do you have any religious or spiritual beliefs or practices that you would like me to know about?” (Astrow, Puchalski & Sulmasy. (2001 ) As an alternative, clinicians may also join the conversation with language of meaning, purpose and passion: “What keeps you going? What sustains you? Where do you fi nd strength? What are the things that are really important to you? What do you take pride in? What do you hope for? What helps you to be more peaceful and centered? What do you hope the legacy of your life will be? What are you really passionate about? When do you feel most alive?” As patients talk about hopes and values, and how they want to live their lives, the “intervention” is to support and encourage them to do so: “We’ve talked about some of the uncertainties in the future for you with stomach cancer, and you’re saying today that it’s really important for you to have a better relationship with your son in Minnesota. Where do you see yourself going with that, and what would some next steps be?” Physicians and other healthcare professionals can eff ectively pursue many such conversations. As patients raise more serious spiritual struggles and issues, however (“Why would the God I have served all my adult life visit me with this terrible disease?”), referral to spiritual care professionals such as chaplains, clergy, and spiritual directors is oft en helpful. In terms of specifi c spiritual techniques, patients oft en take the lead when they are asked. Patients oft en report particular practices like prayer or devotional reading, for instance, when they are asked about where they fi nd strength and what helps them be more peaceful and centered. Clinicians can be aware Spirituality 235 of a range of practices and pursuits as they speak with patients, and may make their own suggestions. Examples include mindfulness and meditative practices (Kabat-Zinn, 2005 ), rituals, ceremonies and sacraments (Hammerschlag & Silverman, 1997 ), participation in religious or spiritual communities, service or volunteer work, and creating or journeying to sacred places.

Summary

Spiritual beliefs and practices are strongly associated with well-being and health. Clinicians incorporate spirituality in healthcare by cultivating their own centeredness, intention, and compassionate presence with patients. Clinicians also support patients’ spiritual resources by encouraging patients to express the values and activities that are “vital and sacred” in their lives. While spirituality in medicine is not defi ned by specifi c techniques, there are oft en particular practices, such as meditation, prayer, forgiveness, devotional reading, and community gatherings that draw upon patients’ spirituality as a healing force. Chaplains and other spiritual care specialists can oft en be very helpful clinical partners when patients are particularly distressed and bur- dened by spiritual issues. 2 6 What Patients Want from Their Doctors

DONNA JACKSON NAKAZAWA

ft er my book, Th e Autoimmune Epidemic, came out, I heard from thousands of people from every conceivable background who suf- A fered from a wide range of diseases. In conversations and emails, they shared with me their experiences of illness and treatment, their hopes, disap- pointments, and lessons gleaned. At the heart of each of their stories is the tale of a patient’s relationship with his or her doctor and how it helped — or hindered— the patient’s journey toward wellness. Th eir stories, along with the experiences of patients I interviewed while researching Th e Autoimmune Epidemic, and my own decade-long journey as a patient in the American medical system, have taught me what American patients want — and desperately need — from their doctors. Patients love to tell “doctor stories”; the good, the bad, and the unfortunate. Oft en, those suff ering from illness want to tell me stories about the fi rst doctor who really (fi nally) listened to them, that compassionate healer who went the unexpected extra mile to help solve the mystery of their illness. Th ey want to share the tale of the practitioner who gave them a clear message of hope— a conviction that they could be well — which became a mantra that settled somewhere in their psyche and played a part in nudging them toward recovery. But, more oft en, the stories they tell me are about doctors who didn’t listen, or didn’t seem to care, or dismissed them as malingerers; practitioners whose obvious condescension still rankles them to this day. Th is concern with what makes a good doctor isn’t surprising when you consider recent statistics that 133 million Americans suff er from a chronic disease, be it heart disease, cancer, severe back pain, arthritis, autoimmunity, or a plague of other challenging ailments that derail normal life. Th ese chronically ill patients oft en traipse from one healthcare professional to the next in search of answers and relief — a process that can take years. Indeed, the average autoimmune disease patient, of whom there are now 24 million in the United States alone, sees four doctors over four years before receiving a proper diagnosis. Th is search for a good doctor can be emotionally arduous. Recent surveys

236 What Patients Want from Their Doctors 237 conducted by the American Autoimmune Related Diseases Association reveal that 45% of patients with diagnosed autoimmune diseases were told that they were hypochondriacs at some point in their medical care. Increasingly, patients who feel they need more than what traditional medicine can off er go “off the reservation,” seeking help from holistic and alternative healthcare specialists as well. Whether a patient seeks the help of traditional or alternative/complimentary practitioners (or, as a majority of patients now do, both) all “healer stories” really contain the same key themes. If the good healthcare practitioner were a recipe, the four integral ingredients would be these: 1) Compassion. Patients know whether healthcare professionals have it or they don’t. Doctors who express compassion for their patients’ pain and circumstances stand out immediately. I know a well-known transverse myelitis and multiple sclerosis specialist at a major medical institute who, when he diagnoses a patient, feels so deeply for them that he always hands them his cell phone number, because he knows there will be “dark moments” where they will have “sudden, urgent questions” that can’t wait for the next clinic visit. And I have heard his voice crack when he talks about the loss of a young patient he could not save. Another physician revealed the strength of his character when, aft er diagnosing me with Guillain Barre Syndrome, a disease in which the body becomes increasingly paralyzed degree by steady degree, he sat with me in a small, white exam room at Johns Hopkins, talking with me quietly for an hour and a half, while my mother and husband rushed to arrange admission to the hospital, collected my bags from home, and arranged for child care. He stayed with me, he said, because he didn’t want me to wait alone aft er the devastating news he’d just delivered — even though nurses were rapping on the exam room door, and his patient waiting room was near to overfl owing, and it no doubt meant he would go home much later that night to his family than he might like. He is a very decent man, a good man, and the numerous patients I know who see him use those words to describe him whenever they mention his name. On the other hand, there are doctors and practitioners who make it clear that you are taking up too much or their time, or wearing their patience thin with your illness— mentally placing you, perhaps unconsciously, somewhere in the category of the famous Freudian hysterics (especially if you are a woman). Th ey don’t respect their patients. I can’t help but think of the story of one young woman, now president of a large advocacy group for autoimmune disease, who was in her early 30s when she began suff ering from severe muscle fatigue and disabling weakness. Her doctor, whom she’d seen eight times, was unable to come up with a diagnosis. “We’ve given you every test known to man but an autopsy,” he said. “Would you like one of those, too?” She was later 238 INTEGRATIVE GASTROENTEROLOGY diagnosed with myasthenia gravis by a doctor who took time to understand the complex portrait presented by her symptoms and lab work. I recall, in my own health tribulations, seeing a doctor who, despite my history of severe autoimmune issues, paralysis, and other complications, yelled at me in his offi ce: “Yesterday you came in here saying you were nauseated, and now today you say you have diarrhea! Make up your mind, which one is it?” Th e next day I ended up in the emergency room and was hospitalized. While I was there I was treated by a GI specialist who came into my hospital room on several diff erent occasions at the end of the day and sat down, his briefcase on his lap, to talk to me about pursuing wellness strategies outside the box. Th e hospital by that hour was growing quiet and dark, he had already seen me earlier in the day during the requisite rounds, and his day was now done. Yet, he had enough compassion for a mom with two young children to take time to educate me about how to approach my GI problems more holistically— advice which, over the next two years, would lead to turning around my GI symptoms. Of course, delivering compassion means building time into the patient–doctor relationship to allow for that extra, meaningful exchange— a conundrum in a healthcare climate that has shaved the average doctor’s visit down to a mere matter of minutes. I would bet that a doctor who has been consistently stripped of time has also been stripped of compassion. Th e question healthcare professionals need to ask themselves is this: which type of practitioner would you prefer to see? Th e one who gives you their cell number, or sits with you aft er a tough diagnosis, or the one who speaks to you disrespectfully or impatiently? Granted, most practitioners fall somewhere in between, but patients search hard and long for the former, and never forget them when they are lucky enough to fi nd them. Compassionate doctors emerge as central fi gures when patients share their healing stories. 2) A Deep and Growing Fund of Knowledge. Of course, compassion alone hardly makes for a good healer. If a healthcare specialist doesn’t possess a deep fund of knowledge — and the curiosity to constantly keep abreast in their fi eld to extend their acumen — all the compassion they can muster can’t make up for what they just don’t know. One woman consulted three local doctors, several times each, over eight months; they all missed her multiple sclerosis. She then saw a university hospital specialist who suspected MS in the fi rst visit, ordered a series of tests, and diagnosed her disease that same week. “Why didn’t those other three doctors even know enough to suspect MS?” she asks. Another young woman described suff ering from severe thirst, dizziness, fatigue, and a 20-pound weight loss over three weeks, but the doctor she was seeing dismissed her complaints and told her, “You just need to gain some weight. Go have a banana split and you’ll be fi ne.” A few hours aft er that appointment, a friend found her in a near-diabetic coma on her sofa and rushed her to the What Patients Want from Their Doctors 239 emergency room, where she was diagnosed with Type 1 diabetes. “How did he miss it, given the state I was in?” she asks. Th ese stories become the doctor- who-didn’t-get-it lore that patients so oft en vent about with each other. But patients also share positive stories about practitioners who, although they may not have ready-made answers, commit time and energy to solve their patient’s case. One patient suff ering from severe fatigue and poor appetite for half a year told me of his relief in fi nding such a doctor. He had already been to two doctors who “couldn’t fi nd anything” (one of whom handed him antidepressants). A third physician confessed that he, too, was perplexed, but he took a diff erent approach. He put his hand on his patient’s shoulder and reas- sured him, “I don’t know what’s causing this, but I promise you we’re going to fi gure this out together.” It took several weeks and much diligence to determine that he was suff ering from an uncommon parasite infection. Likewise, another patient talks about meeting a doctor who surprised and moved her by asking her to “start by telling me about the last time you were well.” Th is patient confesses, “No one had ever asked me anything like that before.” Indeed, this doctor’s narrative approach to obtaining her patient’s medical history was just the fi rst of many ways in which she showed her commitment to helping this patient toward recovery. 3) Open to Complementary Approaches. In a healthcare world in which the majority of patients now use alternative medicine, it’s a given that patients want physicians whose fund of knowledge includes being well-versed in complementary medicine. Patients seek doctors who are able to off er advice on food as medicine, safe supplements, exercise, stress management, and who are willing to move beyond disease labels to delve into what combination of factors may lead to a patient to falling ill in the fi rst place. But this kind of physician can be tough to fi nd. Hundreds of patients (including many with infl ammatory bowel disease, a disease whose course is known to be infl uenced by diet) have told me that the physician or specialist they see never mentions diet or supplements to them at all. Yet, by working with a nutritionist whom they seek out, or by researching the role of nutrition in their ailments on their own, they are able to help turn their disease around. When patients fi nd the rare physician who competently blends Western and complementary approaches, they stick with them, and they refer other patients to them as well. One young woman with rheumatoid arthritis told me about her relief in fi nding a doctor who not only helped her sort out the side eff ects among her choices of medications, he also emailed her recent groundbreaking studies to convince her to make dietary changes that would improve her health. Patients today take a proactive role in their own wellness journeys — and they view allopathic physicians who rely solely on drugs as being out of touch with the growing data that exists on how lifestyle factors 240 INTEGRATIVE GASTROENTEROLOGY impact one’s well-being. Of course, offi ce visits that allow time for discussions of diet and lifestyle, as well as writing prescriptions, take longer — and patients are choosing healthcare practitioners who have built that buff er time into their patient schedule. 4) A Champion of Hope. Patients seek healthcare specialists who avoid focusing on negative outcomes and referring to diseases as “degenerative” or “progressive,” and who, instead, off er as part of their Rx the conviction that their patient can and will have a hopeful, positive outcome. Indeed, patients love to tell stories about how their practitioners’ encouraging statements of hope and healing, statements that emphasize the miracles the human body is capable of, oft en become the patient’s own inner affi rmation that they can and will be well. One woman’s doctor told her, during a particularly diffi cult time in her battle with cancer, “You are going to beat this and you are going to live a totally normal life.” Th is doctor couldn’t know that to be true, but by saying it with conviction, she helped her patient to believe it too, and might just have helped to save her patient’s life. At least her patient — ten years later — believes that her doctor’s faith helped to pull her through. In my own health history, this certainly has been the case. Th e neurologist who sat beside me those long hours aft er diagnosing me with Guillain Barre later saw me through a repeat episode of the disease. Th e second time Guillain Barre strikes (and it is rare for it to strike twice) it is much more damaging. It took me fi ve months to learn to walk unaided again. During this time, several other neurologists at the hospital where I was being treated made it clear that they were dubious that I would ever regain my mobility. I asked my neurologist, “Why are they all warning me to prepare for the worst?” He shook his head. “Don’t listen to that,” he said. “I’m your doctor and I know you. Patients have recovered and been able to walk again aft er having Guillain Barre twice. I know you. Th ey don’t know you. And I know that if it can be done, if it is possible, then you will do it.” Could he have known, as he said these words, that his reply would stay with me day in, day out, that long, hard summer, as I spent hours in grueling physical therapy, fi rst learning to walk to the door of my bedroom, then fi nally— fi ve months later— down the steps and out the door? Healthcare professionals who off er up compassion, a deep fund of knowledge of both Western and complementary treatments, and a heartfelt prescription for hope, facilitate better patient outcomes. But that’s not the only good news. In my work, I also talk to and hear from numerous doctors and healthcare practitioners who tell me that when they off er this “recipe” to their patients, their lives as healers become imbued with greater meaning, and their own work lives are all the more joyful and rewarding. 2 7 The Value of Support Groups

PEARL L. LEWIS AND GERARD E. MULLIN with a foreword by Bernie Siegel

key concepts

■ Community support for restoring the health of ill individuals has been an ancient tradition in the healing arts. ■ Individuals with support have better outcomes for many illnesses. ■ Isolation is associated with increased all-cause mortality. ■ Th e physiologic mechanisms for group support in benefi ting ill individuals include improved markers of stress (cortisol, IL-6, etc.). ■ Numerous support groups exist for digestive tract and liver diseases. ■

Foreword by Dr. Bernie Siegel, author of Love, Medicine and Miracles

Support groups are of value because “natives” (patients) understand the experience of their disease — they are not tourists — while many doctors treat the disease and not the patient’s experience. Group members listen to each other, help each other, and ﬁ nd what is right for them. Members are active and responsible participants in their care. In the process, a new family is created— one that is able to support and listen to each other, banishing the loneliness and fear that negatively affect immune function.

241 242 INTEGRATIVE GASTROENTEROLOGY

If I were a quadriplegic, I’d want another quadriplegic to talk to, who could give me hope and teach me practical things I could do, such as using a motorized wheelchair, using a telephone, and painting with my mouth. I’d want to hear about what is possible, not what is impossible. Life without hope is bleak; it is hope that fuels the engine of life.

Overview

Illness represents an imbalance between the individual and society, and requires participation of the patient’s family and community members to restore balance. In many ancient traditions (e.g., Celtic, Native American Indian), community members contribute to the healing of the sick. In Western medicine, these traditions are oft en substituted with isolation and separation of the sick from society, resulting in concomitant depression, disability, and despair. However, groups of patients have rallied by organizing support systems that work in concert with special-interest medical societies (e.g., Crohn’s and Colitis Foundation of America). Th e concept of group support in the healing practice of Western medicine evolved from the success of Alcoholics Anonymous in the 1930s. Today, support group members provide each other with various types of help for a particular shared, usually burdensome, illness. Th e help may take the form of providing and evaluating relevant information, relating personal experiences, listening to and accepting others’ encounters, providing sympathetic understanding, and establishing social networks. A support group may also work to inform the public or engage in advocacy. A variety of studies support the idea that social isolation is associated with adverse health outcomes and that self-expression, education, and sense of community can lower levels of stress hormones, improve quality of life, and enhance immune function (Gordon, 2006 ). Key studies are summarized below:

1. All-Cause Mortality. Social isolation itself has been identifi ed as an independent major risk factor for all causes of mortality (House, Landis, & Umberson, 1988 ). Being well integrated socially reduces all- cause, age-adjusted mortality by twofold— about as much as having low versus high serum cholesterol levels or being a nonsmoker (House, Landis, & Umberson, 1998 ). The Value of Support Groups 243

2. Social Support and Disease Outcome. a. Social Support and Depression. Depression is linked with multiple diseases, such as cancer, sudden death, and coronary artery disease CAD. Nancy Frasure-Smith has demonstrated in multiple studies that social support ameliorates this eff ect in heart patients. Social support does not necessarily eliminate depression, but it does eliminate the adverse health outcomes of depression (Frasure- Smith et al., 2000 ). b . Social Support and Cardiac Disease. Family and friends questioned 149 men and women, who were set to undergo cardiac catheteriza- tion, about how loved and supported they felt. Th e number of blockages found on subsequent angiograms correlated positively with the degree of reported love and support (Seeman & Syme, 1987 ). c . Social Support and Death Rate. Researchers surveyed 6,900 participants about their contact with friends and relatives, church membership, membership in clubs or groups, and marriage, and then followed them for 17 years. Th ose without close ties or frequent social contact had an overall death rate 3.1 times higher than those who did have these contacts. Both men and women in the low-connection category had higher rates of death from cancer. An analysis of breast cancer patients found that those with low connection had twice the death rate, regardless of race (Kaplan, Seeman, Cohen, Knudsen, & Guralnik, 1987 ). d . Social Support and Disease Susceptibility. In this study, 276 healthy volunteers were given doses of internasal rhinoviruses until they shed virons. Th e participants were also questioned about 12 types of relationships, such as those with their parents, children, friends, and social groups. Each positive relationship was scored as one point. Participants with fewer than 3 points developed cold symptoms at a rate 4 times greater than those with higher scores.

Th ese studies and others indicate that social isolation, a perceived lack of connection, is a signifi cant risk factor for coronary artery disease (CAD), cancer, and all-cause mortality. It is important to note that social isolation reported in these studies is self-reported, and this risk may therefore be related to the individual’s perception of isolation. Th us, perception likely contributes to health outcomes, together with interpersonal connection and community support. 244 INTEGRATIVE GASTROENTEROLOGY

1. Connection in the Community (Egolf, Lasker, Wolf, & Potvin, 1 9 9 2 ) . A 50-year observational study followed the health of residents of the towns of Roseto, Bangor, and Nazereth, Pennsylvania. In the 1930s and 1940s, it was noted that the town of Roseto had a signifi cantly lower rate of acute myocardial infarctions (MIs) than its neighboring communities, despite equal prevalence of diabetes, obesity, and high- fat diet in the three towns. During the follow-up in the 1970s, the rates of MI and overall mortality substantially increased in Roseto, but not the other towns. When health behaviors were analyzed, there were still no signifi cant diff erences in the three communities as to smoking, weight, diet, diabetes, or other risk factors. What had changed, however, was the social structure of Roseto, whose close family ties and community practices (mainly religious) in the 1930s and 1940s began to disintegrate in the late 1960s. At the same time, the rates of MI and mortality began to rise. Th is is the longest of multiple studies of communities that show a clear relationship between community activity, social structure, and the rates of disease. It also points toward the role of community practice and its eff ect on disease prevalence. 2. Support Group Connection as Intervention: Benefi ts of Support Groups. During the last 30 years, researchers have shown great interest in the phenomenon of social support, particularly in the context of health. Prior work has found that those with high quantity or quality of social networks have a decreased risk of mortality, compared with those who have low quantity or quality of social relationships, even aft er statistically controlling for baseline health status (Westaway, Seager, Rheeder, & Van Zyl, 2005 ). In fact, social isolation itself has been identifi ed as an independent major risk factor for all-cause mortality (Fischer Aggarwal, Liao, & Mosca, 2008 ). Current research has focused on expanding several areas of knowledge in this fi eld. Th ese include social support infl uences on morbidity, mortality, and quality of life in chronic disease populations, understanding the mechanisms responsible for such associations, and understanding how we might apply such fi ndings to design relevant interventions.

In researching the topic of the value of social support in various chronic diseases, we found that support was valuable, no matter what the disease. One study demonstrated that: (1) socio-emotional and tangible support were the underlying dimensions of social support; (2) socio-emotional support is an important determinant of health and well-being; and (3) social support is benefi cial for one aspect of diabetes mellitus management, namely, blood pressure control (Eisenberger, Taylor, Gable, Hilmert, & Lieberman, 2007 ). The Value of Support Groups 245

In an ethnically diverse population, emotional social support was linked to higher high-density lipoprotein cholesterol levels, through increased physical activity and wine intake, suggesting possible mechanisms through which social support may reduce cardiovascular disease risk (Shepp, Chase, & Rawls, 1999 ).

1. Key studies in which a psychosocial “connection” intervention altered disease outcomes for diseases not generally considered psychosomatic diseases: Metastatic Breast Cancer (Spiegel, Bloom, Kraemer, & G o t t h e i l , 1 9 8 9 ). In this study, women with metastatic breast cancer attended a weekly 90-minute group support session for one year. Follow-up occurred over 5 years. Th e initial hypothesis was that group support would help these women adjust to their disease, as well as help with anxiety, depression, and other psychosocial issues. Th e outcomes supported this hypothesis. A more dramatic and surprising outcome was that the group-support patients lived twice as long as the control group (18 months versus 9 months on average). Malignant Melanoma (Fawzi, Fawzi, & Hyun, 1993 ). In this study, patients who had undergone local resection of malignant melanoma were placed in a 6-week support group. Th ey were then followed for 5 to 6 years. No other intervention was used. Th ere were 13 recurrences and 10 deaths in the control group, compared with 7 recurrences and 3 deaths in the support group, results that were statistically signifi cant. Th e Ornish program for reversing heart disease (Ornish et al., 1983 , 1990 , 1998 ; Ornish, 1998 ). Th is series of studies has followed up to 477 patients. Th e intervention includes a low-fat vegetarian diet, exercise, yoga, and group support. Th ese trials have had remarkable success in reversing CAD and diminishing adverse events, procedures, and cost of care. Individuals in groups that bond well and interact well in their group sessions tend to have greater improvements on subsequent angiograms, and fewer adverse outcomes than those in groups that become dysfunctional. Th e group model of intentional connected- ness is clearly one of the most powerful tools we have to combat illness-related depression and anxiety. It is also one of the most potent eff ectors of behavioral change, as documented in chemical depen- dency programs. Even venting itself appears to impact the outcome of illness (Spiegel, 1999 ). Th e above studies (and others) show that group support signifi cantly aff ects the clinical course of a person with an illness. 2. Th e healing physiology of support group connection: underlying mechanisms. 246 INTEGRATIVE GASTROENTEROLOGY

It is well established that a lack of social support constitutes a major risk factor for morbidity and mortality, comparable to risk factors such as smoking, obesity, and high blood pressure. Although it has been hypothesized that social support may benefi t health by reducing physiological reactivity to stressors, the mechanisms underlying this process remain unclear. Cormier (2005 ) reported that individuals who interacted regularly with supportive individuals across a 10-day period showed diminished cortisol reactivity to a social stres- sor. Moreover, greater social support and diminished cortisol responses were associated with decreased activity in the dorsal anterior cingulate cortex (dACC) and Brodmann’s area (BA) 8, regions previously associated with the distress of social separation. Lastly, individual diff erences in dACC and BA 8 reactivity mediated the relationship between high daily social support and low cortisol reactivity, such that supported individuals showed reduced neurocognitive reactivity to social stressors, which in turn was associated with reduced neuroendocrine stress responses. Th is study is the fi rst to investigate the neural underpinnings of the social support–health relationship, and provides evidence that social support may ultimately benefi t health by diminishing neural and physiological reactivity to social stressors. Other mechanisms may explain the health benefi ts of support group connection. Intentional connection (group support), interpersonal connection (marriage, friendship, and pets), and community connection (participation in church groups and social groups), have all been shown to decrease life stress. Life stress is internally mediated through the release of catecholamines, cortisol (if chronic), and probably other neurohormonal mechanisms. Social isolation is associated with elevated catecholamines and cortisol. Catecholamines and cortisol contribute directly to disease susceptibility through the following mechanisms: increased blood pressure, increased blood viscosity, increased platelet adhesion, increased endovascular reactivity and endothelial infl ammation, increased production and release of proinfl ammatory cytokines. For example, IL-6 has been found to be inversely associated with social integration in men (Loucks et al., 2006 ). Social support predicted lower stimulated levels of IL-8, IL-6, and tumor necrosis factor (TNF-α) (Marsland, Sathanoori, Muldoon, & Manuck, 2007 ). Immunologic Mechanisms (Kiecolt-Glaser & Glaser , 1 9 9 3 ) . Th e healing benefi ts of group support connections occur through immunologic mechanisms as well. Cortisol suppresses immune function. Group support has been shown to be eff ective in the treatment of autoimmune diseases. Psychosocial factors have been shown to aff ect the susceptibility to, or the progression of, autoimmune diseases, infection, and cancer. Immunologic reactivity is altered by stress. Findings for people under stress include: decreased NK cell activity Gamma interferon levels decreased by 90 percent, decreased T-cell responsiveness, decreased immune responsiveness, increased The Value of Support Groups 247 upper respiratory infections. Social connection for caregivers was correlated directly with immune function. Th e most convincing research backing the use of support groups appears in Current Opinion in Psychiatry (Remblin & Unchino, 2008 ). Th e researchers postulate that the acts of giving and receiving support have unique pathways to stress reduction: Giving is mediated by increased effi cacy, leading to lower stress, while receiving support has a direct eff ect on stress. Taken together, studies such as these suggest that there is something potentially unique about the act of giving support. It may be that people experience positive aff ect while helping others, which may improve their health. Or it may be that benefi ts occur in the context of a high-quality relationship in which one feels valued and can reciprocate by providing support. In isolation, there is no hope; without hope, life can be bleak. By referring your patient to a support group, and participating with a support group yourself, you can give your patient the most valuable of gift s — one that complements and assures compliance with your medical treatment.

From Where I Stand: Gerard Mullin

As a digestive healthcare practitioner, I oft en detect that social isolation and disconnection from society are major infl uences in a patient’s illness. Facilitating the restoration of health in digestive disease patients requires guidance and support. Th ere are dozens of national and local support foundations to help the more than 60 to 70 million digestive disease patients become “unstuck.” Many digestive care specialist physicians participate in these patient- oriented support groups, in activities ranging from educational symposia to group activities (e.g., 5K walks, etc.). Another possible opportunity for the physician to facilitate healing is to serve as a group leader for workshops geared toward mind–body skills. Training and certifi cation is available through the course taught by James S. Gordon, MD, at the Center for Mind–Body Medicine: http://www.cmbm.org .

From Where I Stand: Pearl Lewis

Chronic digestive disease brings with it, besides physical symptoms, a host of psychological and emotional issues that can have negative eff ects on one’s family life, education, and progress in the work force. Th e path to a correct diagnosis is oft en long. During this time, the patient may be told his or her condition is either stress-related or “all in your head.” As a result, painful 248 INTEGRATIVE GASTROENTEROLOGY symptoms such as depression, anxiety, and isolation can dash one’s hopes for the future. In the most severe cases, income from work is replaced by Social Security Disability; health benefi ts are replaced by Medicare— aft er a 24-month waiting period without access to healthcare.

Group Support Related Speciﬁ cally to Digestive Disease1

Most people are familiar with the Crohn’s and Colitis Foundation of America. Th is organization has existed since the 1970s and has provided education, support, and research funds for Crohn’s disease and ulcerative colitis. During the last several decades, however, there has been a proliferation of support groups for almost every digestive disease (refer to the list in the appendix). One of the newest members of the digestive healthcare team originated at a 550-bed tertiary care center in the Southeast, which created an interactive, educational patient and family support group for people with pancreatitis. No previous support groups for this population could be located in the United States, even though pancreatitis may progress to include chronic pain, frequent hospitalizations or emergency room visits, narcotic dependence, and depression. Th e group used a partnership model as a basis for helping empower patients and their family members to have more understanding of, adaptation to, and participation in the treatment choices and responsibility for managing symptoms of their chronic illness. Facilitated by a multidisciplinary team, this is the fi rst group of its kind in the United States and was enthusiastically received by those who participated. “Abundant research supports the premise that social support facilitates patient well-being and contributes to health and health promotion through interpersonal interactions,” write Klytta and Wiltz (2007 ). “Gastroenterology nurses are well positioned to facilitate improved outcomes in patients with chronic hepatitis C virus by initiating interventions designed to enhance existing sources of social support or to promote new ones. Development of psychosocial interventions, such as support groups, aimed at maintaining or fostering social support, may improve health outcomes and promote a higher health- related quality of life for persons living with chronic hepatitis C virus.” Whether one has irritable bowel syndrome, hepatitis A, B, or C, clostro- dium diffi cile, gluten intolerance, celiac sprue, or an ostomy, there are support groups for it online or located in a town nearby.

1 See Directory of Digestive Diseases Organizations for Patients in Appendix B. The Value of Support Groups 249

Conclusion

Self-help groups have developed into an established pillar within the health system. It has been shown that the patients involved benefi t from such groups in terms of both secondary and tertiary prevention. Physicians, too, can profi t from the wealth of experience gained by self-help groups. From this source, they can obtain useful insights into patients’ problems that go well beyond what is possible in the offi ce setting. Self-help group members have been shown to diff er from patients in outpatient psychotherapy by expressing a more positive opinion of group work, and higher openness to new experiences. Additionally, they discuss the topic of self-help groups more frequently with their therapists. Th is may be a starting point for promoting more self-help activities of patients in the future. Th e February 2008 issue of American Psychologist reports that more Americans are trying to change their health behaviors through self-help than through all other forms of professionally designed programs (Davison, Pennebaker, Dickerson, 2000 ). Th e Internet has become a source of education and support for almost every known disease. When diagnoses have not been forthcoming, many people have found theirs on the Internet. Kathryn P. Davison, of Th e Human Asset in Dallas, Texas, and her colleagues looked at support-group participation for 20 disease categories in four metropolitan areas (New York, Chicago, Los Angeles, and Dallas) and in nationwide online discussion groups (Davison, Pennebaker, & Dickerson, 2000 ). “Support seeking was highest for diseases viewed as most stigmatizing, including alcoholism, AIDS, breast cancer and anorexia,” they write. “Support seeking was lowest for less embarrassing but equally devastating disorders, such as heart disease, hypertension, migraine, ulcer, and chronic pain.” Digestive diseases that cause diarrhea and incontinence certainly fi t into this category. Online support groups, which involve a relative amount of anonymity, allow people to confi de in each other without experiencing immediate social repercussions. Yet, attendance is also high in local support groups for conditions associated with embarrassment. “Th ese groups,” according to Davison et al., “are populated by individuals whose illnesses, either by their very nature or as a result of treatment, have forced them to experience embarrassment and social stigmatization. Th e seriousness of their conditions, the weight of their illness’ impact, and the degree of readjustment required under the circumstances, set them apart from their immediate social setting and propel them toward others who have been similarly marked.” 250 INTEGRATIVE GASTROENTEROLOGY

An important fi nding of the study, say the authors, is that more than 60% of groups describing themselves as self-help are professionally facilitated. “Self-help and professional help are oft en perceived as mutually exclusive, but the data indicate that such perceptions are misleading,” write the researchers. “Group participants may not be resistant to professional input; rather, they may need to speak and be heard about issues not addressed within the healthcare setting.” As for the eff ectiveness of self-help groups, the researchers say prior investigations have yielded positive results overall. Th e self-help movement, they add, has tremendous therapeutic potential, especially in the current culture of institutional healthcare, which is still far from incorporating psychological support into healthcare delivery. Just as the Internet has become a lifeline for those living with myriad chronic, life-threatening diseases, it also provides a wealth of information. Th e vast majority of articles and information used here to back the use of support groups came from MedScape. What did not come from professional sources was derived from more than 25 years of creating and participating in support groups. Th is experience has convinced me that the best healthcare puts the patient at the center of his or her entire healthcare team. Th is team oft en includes a primary-care physician, specialists, nutritionists, nonprofi t health agencies, support groups, and other paraprofessionals, and even the patient’s loved ones, who all join together to create a supportive, healing family.

2 8 Overview of Visceral Manipulation for the Integrative Gastroenterologist

JEAN-PIERRE BARRAL AND GAIL WETZLER

key concepts

■ An organ in good health has physiologic motion. ■ Th e interrelationship of structure and function among the internal organs is interdependent. ■ Mobilizing the organs increases proprioceptive communication in the body and enhances internal mechanisms for better health. ■ R e s e a r c h d e m o n s t r a t e s t h a t t h e b e n e fi cial eff ects of visceral manipulation are due to the return of normal organ mobility and pressure, rather than the return of normal anatomical position. ■ Current evidence suggests that during functional gastrointestinal disease, organs lose their mobility and inherent tissue motions. Visceral manipulation is the primary modality used to explore these fi xations, and restore heir natural rhythm and motion for better function. ■

What Is Visceral Manipulation?

isceral Manipulation (VM) is a manual therapy consisting of gentle yet specifi cally placed manual forces that encourage normal mobility, V vascularity, tone, pressure, and inherent tissue motion of organs, their connective tissues, and their relationship to other areas of the body where physiologic motion has been impaired. Th e central premise of VM is that an organ in good health requires physiologic motion (Barral, & Mercier, 1988 ).

251 252 INTEGRATIVE GASTROENTEROLOGY

Table 28.1. Visceral Manipulation (VM) Parameters

Visceral Manipulation is a modality concerned with the 3-dimensional dynamics of organ biomechanics and how they relate to the body (including connective tissue structures, vascular, nervous, and musculoskeletal systems).

Visceral Manipulation Parameters:

• Are derived from the concept that good health is not a state, but a search for equilibrium. • Healthy organs have an axis of motion in which mobility and motility are the same. • Structure and function are interrelated. Movement and function are interdependent. • Movement within the organs, such as secretions, absorption, blood and lymph circulation, peristalsis, respiration, nutrition and immune mechanisms, creates physiological effi ciency.

When an organ loses its mobility or its inherent tissue motion (motility), suboptimal physiological function of the body can develop. VM is the primary modality used by manual therapists to explore and correct these tensions. Once movement is restored, and communication between organs is more effi - cient, fl uid circulation and drainage are improved and irritating signals are reduced. Overall, the body’s homeostatic mechanisms can operate more eff ectively, thus restoring health and better function (Table 28.1 .). Visceral mobility is tested by evaluating the sliding surfaces between one organ and another, or between the organ and body wall or musculoskeletal system. Th e study of visceral motion is now becoming more relevant to the medical fi eld, and increasing research is being conducted on the normal physiological patterns of visceral movement (Table 28.2 .). With the use of X-rays and echograms, studies have shown that an organized and repetitive dynamic does exist on the visceral level (Finet & Williame, 2000 ). Visceral support is provided by connective tissues that hold the viscera in a 3-dimensional, vertically oriented column, and by tension (tensegrity model) within the body cavities (Canadas et al., 2002 ). Connective tissues are known to facilitate communication between organs. Th is phenomenon is referred to as mechanical dialogue (Barral, 1989 ). Th e interrelationship of structure and function among the internal organs is interdependent. When a fi xation within the visceral system occurs, manual therapy treatment focuses on removing the strain on the connective tissues surrounding and within the viscera. Th is is where mechanical strains can develop into deformation, with an extensive loss of organ fl exibility. Th ese restrictions alter the physical properties of connective tissues, aff ecting characteristics such Overview of Visceral Manipulation for the Integrative Gastroenterologist 253

TABLE 28.2. Inﬂ uences of Visceral Mobility

Central nervous system Voluntary movement of musculoskeletal system

Autonomic Nervous System Diaphragm motion Peristalsis Refl ex activity in the CNS and PNS

Articulations Relative position and shape of each organ, membranous sliding surfaces, orientation to blood vessels, and proximity of supportive tissues

Pressures Subatmospheric Tugor Gravity as mobility, deformation, compressibility, viscoelastic compliance, elongation, and organ secretion of fl uids (Stone, 2007 ). Th e goal of mobilizing the organs is to facilitate their ability to move when stimulated by central nervous system (CNS), autonomic nervous system (ANS) or enteric nervous system (ENS) activity, and to respond to fl uid dynamics (Table 28.3 ; see Stone, 2007 ; Barral, 1989 ; Allison, Dhillon, Lewis and Pounder, 1998 ). Further research on how manual therapy aff ects the ANS is currently being conducted at the University of North Texas Health Science Center (Osteopathic Research Center, 2008 ). Th ree major processes have been identifi ed as being potentially infl uenced by manual therapy (Barral, 1988 ):

(a) repair process, (b) fl uid fl ow dynamics, and (c) adaptation process (length; see Lederman, 2005 )

Table 28.3. The Goals of Visceral Manipulation Treatment

1 . Restore functional mobility 2 . Restore motility 3 . Restore soft tissue elasticity 4 . Restore fl uid exchange 5 . Restore pressure systems between the cavities and inside the organs 6 . Restore physiologic function 7 . Relieve pain 8 . Resolve the mechanical link compensation 9 . Restore proprioceptive communication 10. Restore local and systemic responsiveness 1 1 . Restore viscerosomatic relationship 12. Restore visceral-emotional relationship (Barral, 1988 ; Stone, 2007 ) 254 INTEGRATIVE GASTROENTEROLOGY

Clinical Relevance

INFLAMMATORY BOWEL DISEASE

It is our expert opinion that many functional digestive disorders have vascular origins. Manual treatment of the mesenteries that house blood vessels is necessary to improve functional digestive illness. Since these membranes are highly refl exogenic, if they contain abnormal tension, vasoconstriction may result (Barral, 1989 ). Th e literature reports that infl ammatory bowel disease is associated with vasomotor instability, congestive regional lymph nodes, mucosal ulcerations/scarring, infl ammation of the intestinal wall, and abnormal tonus and extensibility of the colon (Pounder, 1998; Hudson et al., 1992 ; Sankey et al., 1 9 9 3 ) . Th e entire gut should be treated because it can lose elasticity easily, create multiple adhesions, and go into more frequent spasm with ANS and vagus nerve infl uences (Table 28.4 .).

IRRITABLE BOWEL SYNDROME

Diseases within the internal organs manifest themselves as alterations in the musculoskeletal system, frequently in the form of pain. (Greenman, 1996 )

Pain, like that of irritable bowel syndrome (IBS), can be caused by edema- tous distention of the serosa, and spreads gradually to the visceral peritoneum

Table 28.4. Treatment Considerations for Inﬂ ammatory Bowel Disease

1. Intestinal function depends on diaphragmatic mobility and intestinal peristalsis 2. Hepatic and splenic fl exures are suspended from the diaphragm 3. Transverse colon is subject to diaphragm attraction 4. Greater omentum as it links the stomach to the transverse colon and connects laterally on the diaphragm 5. Dysfunctional sphincters disrupt the pressure diff erentials 6. Vagus Nerve and ANS techniques for abnormal tonus and peristalsis 7. Infl uence of urogenital system restrictions 8. Colon, duodenum and jejunoileum mobility and motility Overview of Visceral Manipulation for the Integrative Gastroenterologist 255 and ultimately to the parietal peritoneum, causing a mechanical chain of fascial pain (Steer et al., 2003 ). Th e fascial coverings of organs limit expansion and increase internal pressure, which further compromises the neural tissue. Th e pain pathways barrage the area of synapse within the cord, promoting viscerosomatic disorders. In IBS, it is important to know how to manipulate the colon at junctions and sharp angles (fl exures), as these are areas of lesser circulation where there can be risk of ischemia and infl ammation (Steer et al., 2003 ; Barral & Mercier, 1988 ).

DYSPEPSIA

Th e pain associated with dyspepsia can be of muscular origin (causing a dull pain), mucosal origin (burning pain), nervous system origin (sharp pain from the celiac plexus), or a combination of any of these origins (Michallet, 1989 ). Mechanoreceptors in the stomach, when dysfunctional, can promote an increase or decrease of secretions (HCl) for gastric function. VM aff ects these receptors by creating movement within the muscular walls of the stomach, decreasing viscerospasm, increasing the stomach dilatation refl ex, and increasing the interchange of appropriate secretions. Th e mucosal pain can be caused by a decrease of mobility and motility of gastric propulsion. Gastric evacuation is increased when the ileum is active or externally stimulated (disinhibi- tion of the ileal brake), which allows us to apply certain techniques to the ileum for treatment of the stomach. (Barral, 1989) Th e specifi city of a VM evaluation allows for the practitioner to locate the point of origin for gut dysfunction. Points of origin can include an associated organ, such as the duodenum, nerve (celiac versus vagus), supportive structures (gastrophrenic ligament versus greater omentum), or be located within the organ itself.

GERD

When refl ux occurs due to a dysfunctional hiatal zone, the visceral practitioner will evaluate for the dominant mechanical cause of the symptoms (Table 28.5 ). Th e manual technique for gastric ptosis, or loss of elasticity in the organ ligaments, has been checked several times with fl uoroscopy. Th ese studies showed the pyloric antrum had moved upward by as much as 5 cm. (Dr Searge Cohen) Manipulations of the hiatus can facilitate resolution of gastroesophageal refl ux disease (GERD; see Michallet, 1989 ). (17) 256 INTEGRATIVE GASTROENTEROLOGY

Table 28.5. Structural Causes of GERD That Can Be Addressed by VM

• R/O cervical or brachial plexus problems that can provoke phrenic nerve irritation • Diaphragmatic hypertonicity • Th oracic or abdominal scarring • Esophagus/stomach immobility • Fascial restrictions of surrounding tissues/organs • Gastrophrenic ligament and upper fundus restrictions • T 5, T6 viscerosomatic restrictions • T 12–L3 spinal mechanical restrictions • Gastric ptosis (loss of elasticity in the organ ligaments)

Experiments • Alain Crobier, DO, J.P. Barral, DO. (2007–2008). Effects of manual therapy on the vascular system of 200 different people using the Doppler for pretreatment and post-treatment evaluations. Dissections • During 1970–1974, more than 100 cadavers were dissected with Dr. Barral and Professor Arnaud in Grenoble, France, to better understand anatomy and its interrelationships. Video • Visceral Manipulation by Jean Pierre Barral, 2005, Coproduction of Eastland Press, Inc., and the Verlag fuer Ganzheitliche Medizin, Dr. Erich Wuehr, GmbH Website • www.barralinstitute.com

SUMMARY

Based on the central premise that organs in good health require physiologic motion, mobilizing the viscera can be benefi cial in the treatment of internal organ dysfunction. We have treated more than 104,000 patients with visceral manipulation, providing us with expert evidence and real-life clinical experience. We fi rmly believe that manipulations should be precise, with the goal of a whole-body response and for the achievement of homeostasis. Visceral manipulation should be considered as part of an integrative approach to diges- t i v e d i s o r d e r s . 2 9 Probiotics in the Prevention and Treatment of Gastrointestinal Disease

GERALD FRIEDMAN

key concepts

■ Probiotics are “live microbial feed supplements that benefi cially aff ect the host animal by improving its intestinal microbial balance.” ■ Prebiotics are “non-digestible food ingredients that benefi cially aff ect the host by selectively stimulating the growth and/or activity of one or a limited number of bacteria in the colon.” ■ Clinical situations where probiotics may play a role in the alleviation of disease include lactose intolerance, infantile necrotizing enterocolitis, antibiotic-associated diarrhea and clostridium diffi cile colitis, irritable bowel syndrome, traveler’s diarrhea, ulcerative colitis, Crohn’s disease, bacterial overgrowth syndromes, colon carcinoma, food allergy, and gut-origin septicemia. ■ Th ere are a limited number of well-regarded, randomized, placebo-controlled, double-blind trials on the eff ects of probiotics on antibiotic-associated diarrhea, pouchitis, and irritable bowel syndrome. Probiotics appear to be most effi cacious in the prophylaxis of disease, and as maintenance therapy. ■ Probiotics are derived from “normal” commensal bacteria and, as such, are generally safe for short-term use. Caution should be used with severely immune-compromised subjects, patients with central vein catheters, and patients with valve replacements. ■ Future research using single-strain or multi-strain probiotics in humans will provide further supporting evidence for the value of probiotics. ■

257 Introduction

robiotics have been in vogue intermittently since the turn of the century, when Eli Metchnikoff received the Nobel Prize for observations P on the value of lactic acid-producing bacteria in enhancing health and longevity (Metchnikoff , 1910 ). Presently, there is renewed interest in the contributions of commensal bacteria to human health. Major advances in defi ning the quality, quantity, and physiologic activity of the intestinal microbiota were enabled by the conversion of culture-based techniques to genetic analysis. Now, DNA sequences can defi ne the profi les and functions of microorganisms inhabiting the GI tract (Schloss & Handelsman, 2005 ). To better understand the critical value of commensal microbiota, it is important to know the nature, number, anatomic distribution, and development of these hollow- tract bacteria.

Commensal Bacteria

Th e adult human intestinal tract contains approximately 100 trillion microbial organisms known as microbiota (Backhed et al., 2005 ). Th ese essentially anaerobic organisms contain more than 500 species. Th e longitudinal distribution of intestinal microorganisms increases in density, progressing from the small bowel to the colon. In the duodenum and jejunum, aerobes and facultative anaerobes contain 10 3 to 105 organisms/gram luminal contents. Th e terminal ileum contains approximately 107 to 10 8 organisms/gram luminal contents, and the colon contains 1010 to 1011 organisms/gram luminal contents (Berg, 1996 ). Th e microbiota benefi t the host by performing metabolic functions, including energy-producing fermentation of malabsorbed carbohydrates, producing short-chain fatty acids, adding to trophic action on the epithelium, producing vitamins (B vitamins and vitamin K), and playing a pivotal role in the development of the immune system.

Development of Intestinal Microbiota

Th e initial manner of acquisition of intestinal microbiota aff ects the rate and the nature of the development of the immune system. Th e host genotype and birth environment are important in determining populations of intestinal organisms (Palmer et al., 2007 ). Fetuses are sterile in utero. Vaginal delivery Probiotics in the Prevention and Treatment of Gastrointestinal Disease 259 allows infant exposure to maternal bacteria; the longer the birth process, the greater the exposure. Infants born by Cesarean delivery acquire bacteria by nonvaginal maternal exposure, as well as isolates transferred by nursing staff , other infants, air, and equipment. Following birth, oral and cutaneous bacteria from the mother are mechanically transferred to the infant by suckling, kiss- ing, and caressing. Breastfeeding exposes the infant to bacteria, especially bifi - dobacteria from milk ducts, nipple, and surrounding skin. Breast milk contains antimicrobial and growth factors that stimulate the development and maturation of the intestinal mucosa (Mackie, Sghir, & Gaskins, 1999 ). Infants born by Cesarean section may experience a delay in the development of a full complement of commensal bacteria. Some suggest that this delay presents an opportunity for the development of certain allergic-related illnesses such as atopic dermatitis, allergic bronchitis, and certain autoimmune diseases. Aft er introduction of solid food, by the fi rst two years of life, the bacterial profi les of breastfed and formula-fed infants are similar to those of adults.

D e ﬁ nitions of Probiotics, Prebiotics, and Synbiotics

Probiotics are “live microbial feed supplements that benefi cially aff ect the host animal by improving its intestinal microbial balance” (Fuller, 1989 ). Prebiotics are “non-digestible food ingredients that benefi cially aff ect the host by selectively stimulating the growth and/or activity of one or a limited number of bacteria in the colon” (Gibson & Roberfroid, 1995 ). Examples of prebiotics include fructooligosaccharides, inulin and psyllium. “Synbiotics” is the term used when a product contains both probiotics and prebiotics.

How Do Probiotics Act?

Most probiotics are obtained from normal human commensal bacteria. Predominant species include lactobacilli, bifi dobacteria, E. coli and Strepto- myces . Th e exception is a yeast, Saccharomyces boulardii , obtained from the lychee plant. Experimental data gleaned from actions of single-strain and multi-strain bacteria reveal three groups of biologic eff ects of probiotics. Th e fi rst includes modulation of the immune system, by increasing total and specifi c IgA secretion, downregulation of T-cell responsiveness, alteration of cytokine profi les, and induction of oral tolerance. Th e second group includes enhancement of intestinal barrier function by increasing mucous production, promoting tight cellular junctions and epithelial restitution. Th ird, probiotics prevent invasion of pathologic bacteria by bacteriocin production, prevent 260 INTEGRATIVE GASTROENTEROLOGY adhesion of pathologic organisms, increase colonizing resistance, and decrease luminal pH through the formation of organic acids (Fedorak & Madsen, 2 0 0 4 ) .

Clinical Applications of Probiotics

Clinical situations in which probiotics play a role in the alleviation of disease include:

1. Lactose intolerance 2. Infantile necrotizing enterocolitis 3. Antibiotic-associated diarrhea and Clostridium diffi cile colitis 4. Irritable bowel syndrome 5. Traveler’s diarrhea 6. Infl ammatory bowel diseases, including Crohn’s disease, ulcerative colitis, and pouchitis 7. Bacterial overgrowth syndromes 8. Colon carcinoma 9. Food allergy 10. Gut-origin septicemia

A brief review of selected clinical applications follows. Th e review includes a description of the clinical entity, the rationale for the use of probiotics, and an analysis of available clinical trials supporting its use.

Lactose Intolerance

Lactose intolerance is a problem worldwide, its prevalence varying from 7% to 20% among Caucasians, 50% among Hispanics, 75 % among Africans and African-Americans, and more than 90 % in Asian populations. Clinical symptoms include diarrhea, abdominal pain, and fl atulence following the ingestion of milk or milk products. Th e reduced amount of lactase enzyme in the glycocalyx of the proximal small bowel fails to hydrolyze lactose to glucose and galactose. As a result, the poorly absorbed lactose passes into the colon where it is metabolized by colonic microbiota, producing short-chain fatty acids and an excess of hydrogen, methane, and carbon dioxide gases, resulting in the symptom complex noted above. Symptoms vary based upon the dose of lactose ingested, and the concomitant dilutional eff ect of the accompanying meal. Treatment involves reducing lactose intake, using enzyme substitutes Probiotics in the Prevention and Treatment of Gastrointestinal Disease 261

(e.g. Lactaid tablets), or probiotics (He et al., 2008 ). In my personal experience, combining a probiotic ( Lactobacillus GG) and a prebiotic (fructooligosaccha- ride) eff ectively ameliorates symptoms of patients with hydrogen-breath-test proven lactose intolerance (Friedman, 2008 ).

Necrotizing Enterocolitis

Necrotizing enterocolitis is the most common gastrointestinal emergency in neonates, particularly aff ecting premature infants, with an increased risk for males and black infants. Clinically, infants present with gastrointestinal and systemic signs including feeding intolerance, delayed gastric emptying, abdominal tenderness and distention, occult or gross blood in the stool, leth- argy, and respiratory distress. Treatment consists of bowel decompression, broad-spectrum antibiotics, and careful monitoring. Up to 20 % to 40 % of patients may require surgery. Probiotics reduce the risk of necrotizing enterocolitis, reduce the risk of death, and shorten time to full feeds (Deshpande, Rao, & Patole, 2007 ).

Irritable Bowel Syndrome

Irritable bowel syndrome is one of the most common syndromes seen by primary care physicians and gastroenterologists, with a prevalence of 10% to 15 % . It is characterized by chronic, intermittent, and recurring abdominal pain in association with altered bowel function (diarrhea, constipation, or alternating diarrhea and constipation) occurring longer than three to six months. Symptoms are more common among young to middle-aged females; female to male ratio 2:1. Etiological factors include psychologic and stress features, altered gut motility and hypersensitivity, dysregulation of gut-based serotonin, altered immune function, postinfectious bowel dysfunction, and bacterial overgrowth. Predominant complaints of most patients with IBS involve “gas syndromes,” increased fl atulence, abdominal distention, and bloating. Increased gas production is related to fermentation of malabsorbed carbohydrates, swallowed air, delayed small bowel and/or colonic motor function, or altered bacterial fl ora. A unifying framework for understanding irritable bowel syndrome has been off ered by Dr. Henry Lin (2004 ), who identifi es distal small bowel bacterial overgrowth as its central feature. Th is model then accounts for both intestinal and extraintestinal IBS symptoms. Further support is given to small intestine bacterial overgrowth (SIBO) in a subset of patients with IBS (Pimentel, Chow, & Lin, 2000 ), and evidence exists that IBS 262 INTEGRATIVE GASTROENTEROLOGY symptoms can be ameliorated with poorly absorbed antibiotics (Pimentel, Chow, & Lin, 2003 ). Indeed, there are some physicians who use a nonabsorb- able antibiotic (rifaximin) as therapy for IBS patients suspected of SIBO (Pimentel et al., 2006 ).

Postinfectious Irritable Bowel Syndrome (PI-IBS)

Patients experiencing infectious diarrhea may be predisposed to IBS symptoms. Postinfectious IBS develops in 3 % to 30% of individuals following bacterial or viral gastroenteritis. Major risk factors include the severity of the initial illness, female gender, prior anxiety/depression, and other psychological factors (Spiller & Campbell, 2006 ). Symptoms may be sustained by immunologic factors (Dupont, 2007 ). Various histologic changes include increased intraepithelial and lamina propria lymphocytes, as well as increased intestinal permeability. Cytokine profi les reveal increased expression of interleukin (IL)-1b, a proinfl ammatory cytokine. Treatment and prognosis are similar to that of other IBS patients. Special attention should be given to the elimination of nutrients that contribute to the patient’s symptoms (reduction of lactose, sor- bitol, fructose). Antidiarrheals for diarrhea, bulk laxatives for constipation, low-dose anticholinergics, or selected antidepressant medications for abdominal pain or cramps should be used.

Probiotics and Irritable Bowel Syndrome

Th e goal of probiotic therapy is to benefi cially alter the microbial fl ora by ame- liorating the symptom complex associated with IBS. More than 15 randomized, double-blind studies of probiotics have been published, using single or multiple bacterial strains. Th ese studies generally reveal methodologic design limitations, lack of comparative standardizations, variations in dosages, lack of dose-response curves, diff erent durations of study, and use of small patient numbers (Borowiec & Fedorak, 2007 ; Guslandi, 2007 ; Jonkers & Stockbrugger, 2007 ; Camilleri, 2006 ). However, it is apparent from these studies that the symptoms in common — fl atulence, bloating, distention, abdominal pain, and altered bowel function, as measured by patient’s global assessment — are completely or partially ameliorated. Th us, in concert with Dr. Lin’s assessment noted previously, it is this author’s belief that the commensal bacteria remain a central focus. Probiotics can replace the diminished concentrations of lactobacilli and bifi dobacteria noted in IBS patients, thus counteracting the proinfl ammatory cytokines interleukin-12 (IL-12.) Abnormal colonic fermentation Probiotics in the Prevention and Treatment of Gastrointestinal Disease 263

(King, Elia, & Hunter, 1998 ) may be ameliorated, reducing the short-chain fatty acid contractile propulsive activity. Increased deconjugation of bile acids by lactobacilli and bifi dobacteria can reduce the bile acid load, and diminish colonic mucosal secretion, which contribute to diarrheal symptoms. Two randomized controlled studies deserve mention: one with a single strain probiotic, and the other a multi-strain. A four-week, multicenter study with a large number of female IBS patients used Bifi dobacteria infantis compared to placebo in a dose-ranging study. Statistical improvement was demonstrated in composite global symptom scores and bloating (Whorwell et al., 2006 ). Th is author’s four-week, multicenter randomized placebo-controlled study used a multi-strain probiotic ( Lactobacillus acidophilus LA-5, Bifi dobacterium BB-12, Lactobacillus paracasei CRL-431 and Streptococcus thermophilus STY-31), with diarrhea as the primary end point, and demonstrated statistical reduction of diarrheal episodes, as well as decreased bloating (Friedman & Biancone , 2008 ).

Traveler’s Diarrhea

Interest in traveler’s diarrhea is prompted by the frequency of global vacations and business travel. Highest risk areas ( > 30% ) are Mexico, South and Central America, Asia, and Africa. Th e most common causative bacterial organism is enterotoxigenic E. coli (ETEC). Th e possible progression of this illness to postinfectious IBS is a matter of concern. Dupont has summarized recommendations for prevention and treatment.

1. Bismuth subsalicylate, (2.1 g/day–two tablets with meals and at bedtime): 65% eff ective 2. Levofl oxacin, one 500 mg tablet once daily: 80 % eff ective 3. Rifaximin, one 400 mg tablet twice daily: 75 % eff ective 4. Probiotics, Lactobacillus GG, one capsule twice daily: 40% eff ective (Hilton et al., 1997 )

Antibiotic-Associated Diarrhea (AAD)

Antibiotic-associated diarrhea occurs in 5% to 25% of patients receiving antibiotics, with increased risk in the aged, immunosuppressed, and GI surgery patients. AAD extends hospital stays by 8 to 20 days, causes higher medical care costs, and places patients at higher risk for acquiring other nosocomial infections. Agents most likely to cause diarrhea include cephalosporins, clindamycin, 264 INTEGRATIVE GASTROENTEROLOGY and broad-spectrum penicillins. Antibiotics alter epithelial barrier defense, allowing insurgence of pathogens. Clostridium difi cile is the most severe form of AAD, and accounts for 15% to 25% of hospital cases. Th is is a toxin-mediated illness with characteristic clinical and pathologic features (Bartlett, 2002 ). Diagnosis is confi rmed by assay of toxins A & B. Probiotics prevent mucosal barrier disruption and restore normal commensal bacteria. Saccharomyces boulardii has been eff ective in reducing AAD, and as adjunctive therapy for C. diffi cile infection (McFarland, 2006 ). Mechanisms of action include inactivation of toxins A & B, stimulation of host immune system, and trophic eff ects on intestinal mucosa (Buts & Bernasconi, 2005 ). Th e dosage is 250 mg twice daily for prevention, and four times daily to prevent recurrent C. diffi cile colitis, in concert with either metronidazole or vancomycin. Lactobacillus GG has been extensively studied as eff ective treatment of acute diarrhea in infants and children, dosage being one capsule twice daily. Th is Gram-positive rod has powerful adhesive properties, modulates antigen transport, augments immune responses, and increases IgA secretion (Doron, Snydman, & Gorbach, 2 0 0 5 ) .

I n ﬂ ammatory Bowel Diseases

Causative elements of infl ammatory bowel diseases are genetic predisposition, altered immune response, environmental factors (diet, smoking, stress), and commensal bacteria. Commensal bacteria have been implicated in the pathogenesis of IBD because the areas of infl ammation involved have a high density of luminal bacterial organisms, the continuity of the fecal stream is linked with disease activity, surgical interruption of the stream results in diminished infl ammatory activity, and restoration results in renewed infl ammation. Th ese concepts have been supported by the creation of a colitis-like disease in genetically altered animals, in which colitis only occurs when microbiota are added to the germ-free animal. Pouchitis is a nonspecifi c infl ammation of the ileal reservoir following ileal pouch–anal anastomosis for ulcerative colitis. Approximately half of all pouch patients experience infl ammation at some time aft er the operation. Th ere are diminished amounts of lactobacilli and bifi - dobacteria in the pouch contents. Most patients respond to antibiotic therapy (metronidazole or ciprofl oxacin). Recurrent or refractory infl ammation occurs in 10 % to 15 % of patients. Aft er suppression of the infl ammation with antibiotics, maintenance therapy is needed. Probiotics have been successfully used in place of further antibiotic therapy. Probiotic treatment of pouchitis was the fi rst major randomized controlled trial for IBD demonstrating prophylactic Probiotics in the Prevention and Treatment of Gastrointestinal Disease 265 effi cacy for recurrent disease (Gionchetti et al. , 2000 ). Gionchetti et al., randomized 40 patients and compared 20 patients on VSL3 (3 g twice daily; four strains of Lactobacillus [ casei, plantarum, acidophilus, and delbruckii subsp bul- garius ]; three strains of Bifi dobacterium [ longum, breve, and infantis ]; and one strain of Streptococcus [salivarius subsp thermophilus]) with 20 patients on placebo for nine months. In the VSL3 group three (15% ) patients relapsed compared with 20 (100 %) in the placebo group (P=0.001). Within four months aft er discontinuation of therapy, 100 % of responding patients relapsed. All of the responding patients on VSL3 showed an increase in the concentrations of lactobacilli and bifi dobacteria. Two years later, a similar study confi rmed these results (Mimura et al., 2004 ). Administering 6 g/day immediately aft er operation as a prophylactic to pouch patients for one year prevented recurrent pouchitis in 90 % of subjects, compared to 60% recurrence on placebo (Gionchetti et al., 2003 ).

Ulcerative Colitis

Ulcerative colitis is a mucosal infl ammatory disease that may aff ect the rectum (proctitis), rectosigmoid (proctosigmoiditis), extend to the splenic fl exure (left -sided colitis), or involve the entire colon (pancolitis). Most human trials have assessed the effi cacy of probiotics on sustaining remission following suppression by anti-infl ammatory agents (steroids, immunosuppressive agents, biologic agents, mesalamine). Th e reason for treating quiescent disease rather than active colitis is related to rapid passage of the probiotic through the GI tract secondary to diarrhea, disallowing adequate time for nidation and proliferation of the probiotic. Open label studies using much larger doses of probiotics have shown some success. Equivalency studies, comparing remission rates of E. coli Nissle strain 1917 with mesalamine, have been reported (Kruis et al., 1997 ; Rembacken et al., 1999 ). Th ese studies are interesting, but not per- suasive. In an open label, two-center trial by Fedorak and Madsen ( 2004 ), 30 patients with mild to moderate ulcerative colitis who failed mesalamine therapy were treated with VSL3 (1 x 10 12 CFU daily) for 4 months with a remission rate of 63% . Another open label study using Saccharomyces boulardii treated 25 mild to moderate colitis patients who failed mesalamine therapy (Guslandi, Giollo, & Testoni, 2003 ). Th ese investigators used 750 mg daily for one month, with a response rate of 68% . In summary, the use of probiotics in both the acute phase and maintenance of ulcerative colitis are suggestive, but inconclusive. Large, randomized, double-blind, placebo controlled trials are needed. 266 INTEGRATIVE GASTROENTEROLOGY

Crohn’s Disease

Crohn’s disease is a chronic infl ammatory bowel disease that can aff ect any part of the GI tract from mouth to anus, with a predominance of small bowel and colonic involvement. Pathologically, it is transmural, aff ecting mucosa, submucosa, muscularis and serosal surfaces. Crohn’s disease trials are divided into three areas: (1) treatment of acute, active disease; (2) maintenance aft er medically induced remission; and (3) maintenance aft er surgically induced remission. Th ere are no randomized, controlled trials of patients with acute, active Crohn’s disease. In the maintenance phase of medically induced remission, a double-blind study by Malchow ( 1997 ) with 28 patients, randomized to receive E. coli Nissle l917 compared to placebo for one year, revealed a relapse rate of 30% in the E. coli group compared to 70 % in the placebo group. An open label maintenance study by Guslandi et al. ( 2003 ) compared Saccharomyces boulardi 1000 mg/day + mesalamine 2 g/day with mesalamine 3 g/day for six months. Th e remission rate was 94% with the former and 38% with the latter. A randomized, controlled trial of maintenance aft er surgical resection by Campieri et al. (2000 ) treated 40 patients for one year, comparing rifaximin l.8 g/day for 3 months followed by VSL3 for 9 months with mesalamine 4 g/day. Endoscopic remission was noted in 80 % versus 60 % of patients on mesalamine alone. Overall, published results do not support the use of probiotics in the treatment of active Crohn’s disease, or as maintenance therapy for medical or surgically induced remission.

Safety Issues

Th e safety of the microbes traditionally used as probiotics has been confi rmed through experience. Th e use of non-sporing LAB in fermented foods is widespread. Th ere have been reports associating LAB and S. boulardii with clinical infection in immunosuppressed, severely debilitated patients (Gasser, 1994 ; Schlegel, Lemerle, & Geslin, 1998 ). Probiotics should not be used in severely immunocompromised patients, patients with synthetic valves, or patients with indwelling central venous catheters (Hennequin et al., 2000 ). Capsules should not be broken in patients’ rooms for use in enteral tube feedings. Probiotics in the Prevention and Treatment of Gastrointestinal Disease 267

Summary

In the past decade there has been a dramatic resurgence of interest in commensal bacteria related to improved genetic analysis of intestinal microbiota. Th ese bacteria benefi t the host by performing metabolic functions, including energy-producing fermentation of malabsorbed carbohydrates that produce short-chain fatty acids, adding to trophic action on the epithelium, producing vitamins, and playing a pivotal role in the development of the immune system. Probiotics are live microbial feed supplements that benefi cially aff ect the host animal by improving its intestinal microbial balance. Selected clinical studies demonstrate that probiotics play a role in the alleviation of such illnesses as lactose intolerance, infantile necrotizing enterocolitis, AAD and C. diffi cile colitis, IBS, traveler’s diarrhea, IBD, and pouchitis. Th ere are a limited number of well-regarded, randomized, placebo-controlled double blind trials available. Such trials have focused on pouchitis, AAD, and IBS. Future research using single strain and multi-strain probiotics in humans and animals will provide further supporting evidence regarding the value of probiotics. 3 0 The Role of Nutritional Genomics and Functional Medicine in the Management of Crohn’s Disease

SHEILA G. DEAN AND KATHIE M. SWIFT

key concepts

■ Diet and nutritional intervention for gastrointestinal health may be personalized to the individual’s genetic uniqueness. ■ Multiple risks have been identifi ed that can increase the risk for Crohn’s disease; however, research strongly supports genetic susceptibility and a leaky gut as predisposing factors. ■ Functional clinical tests to assess intestinal infl ammation, such as fecal calprotectin, are useful diagnostic tools. ■ Certain nutrients such as antioxidants and polyphenols can provide protection of the gut mucosa, and functional foods, including prebiotics and probiotics, support function of the gut immune system. ■ A “4R” GI restoration program that involves removing toxic substances, replacing digestive factors, reinoculating with commensal bacteria, and regenerating the GI integrity, may have signifi cant impact in infl ammatory bowel disease, and merits f u r t h e r s t u d y . ■

268 Introduction to Nutritional Genomics

utritional genomics is an emerging fi eld that is now defi ned as the interface between genes and nutrition. It addresses the concept of N one’s biochemical and genetic uniqueness, and how this interaction then gives rise to outward, physical traits known as the phenotype. While nutritional genomics continues to develop, the groundwork was established over 50 years ago by pioneers such as Linus Pauling and Roger Williams. Dr. Pauling, Nobel Prize winner for Chemistry in 1954, and Peace in 1962, was already teaching about the importance of nutrients in modulating physiological processes at the biomolecular level (Pauling, Th e Roots of Molecular Medicine ). Roger Williams is credited with developing the concept of biochemical individuality, and has been described as having “contributed to the evolution of the understanding of the molecular origin of disease” and advanced the concept of genotrophic disease (Williams, 1998). Th e catalyst for the development of present-day nutritional genomics has been the Human Genome Project, a multinational undertaking that began in 1990. While there were a number of goals, the primary goal was to identify the nucleotide sequence of the human DNA. However, the specifi c goals have changed over time, since the Human Genome Project was completed in 2003, earlier than expected. Current research is focused on identifying the total number of genes, their chromosomal location, and their function (Human Genome Project Information, 2007 ). Why is this important to the healthcare team? One reason may be because the impact of the Human Genome Project has created new information that is expected to alter the approach to risk assessment of nutritional issues. However, in order for the digestive healthcare practitioner’s evolving role in the application of nutritional genomics to clinical practice to occur eff ectively, it will require a deepened understanding of genomics and gene–diet interactions. (Kozma, 2003 ).

Individual gene variants called SNPs (single nucleotide polymorphisms) result in differential response to environmental factors including diet.

Fogg-Johnson and Kaput ( 2003 ) explain that some of the new information of the Human Genome Project is surfacing in areas that are not totally predictable. Th rough the Human Genome Project, it has been discovered that 270 INTEGRATIVE GASTROENTEROLOGY individual gene variations exist, and are referred to as single nucleotide polymorphisms (SNPs, pronounced “snips”). Th ese SNPs result in diff erential response to environmental factors, such as diet. Th e science of how naturally occurring chemicals in foods alter expression of genetic information at the molecular level, and how this aff ects the individual phenotype, is the essence of what nutritional genomics scientists seek to uncover (Fogg-Johnson & Kaput, 2003 ).

An understanding of genomics and gene–diet interactions will impact the delivery of personalized clinical nutrition practices.

Diet, lifestyle, and environment have signifi cant infl uence on the way an individual can metabolize specifi c substances based upon his or her genetic uniqueness. Th ese discoveries have opened the door for the future of molecular medicine, and the development of a personalized medicine that recognizes aspects of gene–diet–environment interactions and their roles in individual disease causation, and the design of specifi c intervention programs. Th e takeaway from these concepts is that one size does not fi t all. Diet and nutritional intervention must be personalized to the genetic characteristics of the individual. Gastrointestinal health is particularly important to achieving optimal nutrition and aff ords several examples of how diet and genes interface and how the fi eld of nutritional genomics can assist the healthcare team in maximizing nutrition care interventions for the individual.

The GI tract functions as a selective barrier between the internal and external environment and the intestinal microﬂ ora plays an active role in maintaining gut integrity.

The Healthy Gut

Gastrointestinal health affords several examples of how nutritional genomics can maximize nutrition care intervention.

Th e gastrointestinal (GI) tract is the second-largest body surface area. Th e condition of this organ’s microfl ora is essential to optimal health. Th e healthy intestinal wall is coated with hundreds of diff erent species of microorganisms, The Role of Nutritional Genomics and Functional Medicine 271 both benefi cial and pathogenic bacteria, numbering in the trillions (Whitney, Cataldo, & Rolfes, 1998 ). Th is rich protective coating of microorganisms acts in concert with the physical barrier provided by the cells lining the intestinal tract, and other factors, to provide the body with important fi lter-like protection. So, in addition to digesting, absorbing, and eliminating food substances and nutrients, the normal GI tract functions as a critical semipermeable (selective) barrier between the internal and external environment. Th is prevents toxic, antigenic, or pathogenic molecules or microorganisms from entering the bloodstream. Ultimately, the importance of the intestinal microfl ora and, more specifi cally, its composition, in physiological and pathophysiological processes in the human GI tract, is becoming more evident (Jones, 2005 ).

I n ﬂ ammatory Bowel Disease

Infl ammatory bowel disease (IBD) is a critical and chronic disorder of the intestines. Generally, its complications can be severe, widespread, and very painful. Crohn’s disease and ulcerative colitis (UC) are two forms of IBD. As researchers try to understand its long-unknown etiology, there does not appear to be one precise cause of Crohn’s disease. However, it is clear that Crohn’s disease is relapsing in nature, and it aff ects all layers of the intestines from mouth to anus. In comparison, UC is generally limited to the large bowel and does not necessarily aff ect all layers of the intestine.

Risk Factors

Crohn’s disease and ulcerative colitis are two forms of inﬂ ammatory bowel disease (IBD) with multiple etiologies including genetic susceptibility.

Th ere are several risk factors (see Table 30.1 ) for Crohn’s disease, which range from adult appendectomy to the use of various substances, including nicotine (Somerville, Logan, Edmond, & Langman, 1984 ; Cottone, Rosselli, Orlando, Oliva & Puleo1994 ; Lindberg, Jarnerot, & Huitfeldt, 1992 ), oral contraceptives, antibiotics, and nonsteroidal anti-infl ammatory agents (NSAIDs). Even second-hand smoke exposure has been shown to increase risk for developing CD (Lashner, Shaheen, Hanauer, & Kirschner, 1993 ; Persson et al., 1990 ). Other demographic factors, such as economic, educational, geographic, and occupational status, can increase the risk of developing CD (Sonnenberg et al., 1991 ). Despite these risk factors, Ferguson (Ferguson, L., Shelling, A. N., 272 INTEGRATIVE GASTROENTEROLOGY

Table 30.1. Risk Factors for Crohn’s Disease

• G e n e t i c s • Medications: oral contraceptive agents, antibiotics, nonsteroidal anti-infl ammatory agents (NSAIDs) • Diet • S t r e s s • Socioeconomics • H i s t o r y o f e c z e m a

Browning, B. L., Huebner, C., & Petermann, I 2007 ) explains that “IBD is considered a genetic disease,” as approximately 20% of people with one form of IBD have a blood relative also with IBD, and 58% of monozygotic twins share the disease as compared to 4% of dizygotic twins (Jess et al., 2005 ; Halfvarson et al., 2005 ). Other factors that appeared to increase disease risk were history of eczema and consumption of a low-fi ber diet (Bartel et al., 2008 ) Research has demonstrated that stress can be a contributing factor in Crohn’s disease. Crohn’s disease is characterized by increased intestinal permeability, and extensive animal research has shown stress signifi cantly infl uences intestinal permeability (Hollander, 1999 ). Furthermore, psychological stress, anxiety, depression, and altered quality of life are likely to infl uence further Crohn’s disease activity following a relapse (Mittermaier et al., 2004 ).

The Immune–Inﬂ ammatory Connection

Th e gastrointestinal tract contains trillions of bacteria that are, ideally, in homeostasis with the host immune system (MacDonald, 2005 ). Th e gut contains most of the immune cells in the body, and engages in attacking harmful pathogens while leaving symbiotic bacteria largely unscathed (Rescigno & Chieppa, 2005 ).

Th1 & Th2 cells are important regulators of the gastrointestinal immune system and Th1/Th2 balance plays an important role in gut mucosal integrity.

One theory of immune regulation involves homeostasis between T-helper 1 (Th 1) proinfl ammatory and T-helper 2 (Th 2) anti-infl ammatory activity (Kidd, 2 0 0 3 ) . “ Th 1” and “Th 2” cells are “important regulators of the class of immune response.” (Kidd, 2003 ) Alterations in the host gastrointestinal fl ora can have a signifi cant infl uence on the Th 1/Th 2 balance of the gastrointestinal immune The Role of Nutritional Genomics and Functional Medicine 273 system (gut-associated lymphoid tissue, or GALT; see Mazmanian et al., 2005 ). Sometimes referred to as systemic versus organ-specifi c immune responses, respectively, balance of Th 1/Th 2 cytokines produced by the mucosa-associated lymphoreticular system (MALT) and the GALT plays a role in the stabilization of mucosal surfaces in the gut (Neurath et al., 2002 ). Mullin et al. ( 1996 ) were the fi rst to elucidate the predominance of Th 1 responses in the intestinal mucosa of Crohn’s disease patients. Th ese mucosal surfaces have multiple tasks that include absorption, macromolecule transfer, and intestinal barrier and secretory functions. Large mucosal surfaces, such as the 300 square meters found in the human intestinal tract, are continuously exposed to millions of potentially harmful antigens from the environment, food, and intestinal microbes. Th e mucosal surfaces possess a unique immune system that tightly controls the balance between responsiveness and nonresponsiveness. Loss of this immunological recognition of “friend versus foe” in the gut can result in activation of the infl ammatory process (Rescigno & Chieppa, 2005 ). Th ere is growing evidence that chronic infl ammatory disorders in the mucosa, such as IBD, are due to the dysregulation of the mucosal immune system, leading to a Th 1-dominant infl ammatory reaction and impairment of the barrier function of the gut (Neurath et al., 2002 ). Th e Th 1–Th 2 immune response paradigm hypothesizes hypotheses that, under the infl uence of a variety of factors including the cytokines, interleukin 4 (IL-4) and IL-12, naive T-cells can mature into one of two phenotypes, Th 1 or Th 2, that counter-regulate each other. Th is model illustrates that, in most circumstances, interaction between Th 1 and Th 2 cells is more complex than originally thought. Th ese cell types probably represent extreme examples of a spectrum of phenotypes, and it is possible that a cell is not committed irrevo- cably to one phenotype (see Figure 30.1 ).

Genes/Gene Variants Associated With IBD — What Do We Know?

Knowing the genes and gene variants associated with IBD can be useful for the practitioner, once it is understood what genes are involved and how their variations are related to underlying mechanisms of IBD pathogenesis. Furthermore, evidence-based nutrition intervention can be used to modulate genetic expression, which can ultimately aff ect phenotypic outcome of the individual. While IBD appears to be of polygenic etiology, research strongly supports the assumption that susceptibility to IBD, especially Crohn’s disease, is inherited. It also indicates that IBD is not inherited as a Mendelian trait, but rather 274 INTEGRATIVE GASTROENTEROLOGY

Table 30.2. Susceptibility Genes Associated with IBD

Name of the gene Gene abbreviation Gene variants Areas genes affect (discussed in this review)

Caspase-activated CARD15/NOD2 • A r g 702Trp Aff ects bacterial recruitment domain • G l y 908Arg recognition of the 15/nucleotide • 1007 fi nsC or intestinal wall oligomerization c.3020insC domain 2

Autophagy-related ATG16L1 Aff ects bacterial 16-like 1 recognition of the intestinal wall

Human beta defensins HBD-2, HBD-3 Aff ects bacterial B2, B3 and B4 and HBD-4 recognition of the intestinal wall

Major histocompatibility MHC Aff ects immune complex response

Interleukin-23 receptor IL23R Aff ects immune response

Toll-like receptors TLRs Aff ects immune response

Sodium dependent SLC22A4/ • S L C 22A4 1672 C> T Aff ects mucosal organic cation SLC22A5 • S L C 22A5 -207 G > C transport or transporters (also called polarity of the OCTN1/ intestinal wall OCTN2)

ATP-binding cassette ABCB1 Aff ects mucosal subfamily B member 1 transport or polarity of the intestinal wall

Drosophila discs large DLG5 • D L G 5 113G> A Aff ects mucosal homologue 5 • P. P 1371Q transport or • P. G 1066G polarity of the • R s 2289308 intestinal wall • D L G _ e 26 • P. D 1507D The Role of Nutritional Genomics and Functional Medicine 275 has a complex genetic basis, with many contributing genes and at least nine susceptibility loci identifi ed (Neurath et al., 2002 ; Chamaillard et al., 2006 ). Table 30.2 is a classifi cation of the susceptibility genes, their variants, and aff ected areas (Hampe et al., 2001 ; Hugot et al., 2001 ; Chamaillard et al., 2006 ; Schreiber et al., 2005 ; Ogura et al., 2001 ; Peltekova et al., 2004 ; Stoll et al., 2004 ; Cho, 2006 ; Buning et al., 2006 ).

IBD has a complex genetic basis with many contributing susceptibility genes and gene variants.

Th is chapter is focused specifi cally on three IBD-associated genes that appear to identify major susceptibility loci for Crohn’s disease: (1) CARD15/ NOD2; (2) DLG5; and (3) SLC22A4/A5 (OCTN1/OCTN2).

Gene Variants and Their Potential Impact on IBD Pathogenesis

CARD 15/NOD2. Alterations in this gene have been associated with a defective bacterial signal that leads to NF-κ B overexpression and subsequent excessive immune response, which can lead to chronic gut infl ammation in susceptible individuals. DLG5. Variations in this gene seem to predispose individuals to what has been coined “leaky gut syndrome,” thus allowing for intestinal permeability and integrity dysfunction. SLC22A4/SCL22A5 (OCTN1/OCTN2). Functional polymorphisms decreasing OCTN activity and/or expression have been associated with chronic infl ammation, and contribute to CD/IBD pathogenesis. Specifi cally, this may be due to reduced carnitine transport function, resulting in impaired fatty acid metabolism in the gut, and toxic bacterial metabolites generated due to reduced ability for proper clearance of bacterial byproducts.

CARD15/NOD2 : associated with exaggerated immune response DLG 5: associated with increased intestinal permeability SLC22A4/SCL22A5 (OCTN1/OCTN2 ): associated with impaired fatty acid metabolism and reduced clearance of toxic bacterial byproducts 276 INTEGRATIVE GASTROENTEROLOGY

Current Medical Management

Conventional pharmacological treatment has been directed toward suppressing infl ammation, and antibiotics for lowering bacterial antigenic drive to the overactive mucosal immune system. Typical drugs (see Table 30.3 ) used to treat Crohn’s include aminosalicylates (such as sulfasalazine and mesalamine), corticosteroids (such as prednisone and budesonide), immunosuppressive agents (such as azathioprine, 6-mercaptopurine, methotrexate), and antibiotics (Baumgart & Sandborn, 2007 ). More recently, anti-TNF-alpha monoclonal antibodies, such as infl iximab and related drugs (Remicade® , Enbrel® , Humira ®), are being prescribed, since tumor necrosis factor appears to play a signifi cant role in the pathogenesis of Crohn’s disease (Bamias et al., 2003 ; Braegger et al., 1992 ). Antidepressants are typically off ered for assisting with stress management, as stress can also aggravate Crohn’s disease symptoms (Lerebours et al., 2007 ). Unfortunately, medications used in the therapy of IBD oft en contribute to the development of many nutrient defi ciencies (see Table 30.4 ). For example, sulfasalazine produces folate malabsorption, by competitive inhibition of the jejunal folate conjugate enzyme (Hoffb rand et al., 1968 ). Corticosteroids suppress small intestinal calcium absorption and increase urinary calcium excretion. Cholestyramine (which is sometimes used in patients who have undergone

Table 30.3. Pharmaceuticals Used in the Management of Crohn’s Disease

Aminosalicylates Sulfasalazine

Corticosteroids mesalamine

prednisone

budesonide

Immunosuppressants azathioprine

6-mercaptopurine

methotrexate

Anti-TNF-alpha monoclonal antibodies Remicade®

Enbrel ®

Humira ® The Role of Nutritional Genomics and Functional Medicine 277

Table 30.4. Drug-Induced Nutrient Deﬁ ciency and Potential Mechanisms

Drug Nutrient depleted Potential mechanism

Sulfasalazine Folic acid competitive inhibition of the jejunal folate conjugate enzyme

Corticosteroids Calcium suppresses small intestinal absorption and increase urinary excretion

Cholestyramine Fat, calcium, and used in those who have undergone fat-soluble vitamin post-ileal resection in Crohn’s disease to defi ciencies prevent diarrhea

Sulfasalazine Water and fat-soluble may cause nausea, vomiting, and vitamins dyspepsia

5-aminosalicylic Water and fat-soluble acid vitamins

metronidazole Water and fat-soluble vitamins

post-ileal resection in Crohn’s disease to prevent diarrhea) produces fat, calcium, and fat-soluble vitamin defi ciencies. Sulfasalazine, 5-aminosalicylic acid, and metronidazole may cause nausea, vomiting, and dyspepsia, which frequently lead to decreased nutrient intake (Riley et al., 1988 ; Singleton et al., 1 9 7 0 ) .

Nutritional Management

Drug-induced nutrient depletion is a common side effect of commonly prescribed medications for IBD.

Elemental diets, elimination diets, omega-3 fi sh oils, high-fi ber, low-fi ber, high-protein, low-residue diets, and bland diets have all been used in one form or another as part of the nutritional management of IBD, and are reviewed in Chapter 44 (Ferguson, L., Shelling, A. N., Browning, B. L. et al., 2007 ; Ferguson, L. R., Shelling, A. N., Lauren, D. et al., 2007 ; Han et al., 1999 ; O’Sullivan & O’Morain, 2006 ; Hodges, 2005 ). However, nutritional protocols have been inconsistent, despite growing research on IBD. Until recently, theories on nutritional management of IBD have been somewhat disunifi e d . 278 INTEGRATIVE GASTROENTEROLOGY

Functional Clinical Tests

Genetic testing, along with functional assays, such as intestinal permeability, can be useful in identiﬁ cation and treatment of IBD.

A major task of the intestine is to form a defensive barrier to prevent absorption of damaging substances from the external environment. Th is protective function of the intestinal mucosa is called permeability . Ample evidence indicates that permeability is increased in most patients with Crohn’s disease, and in 10% to 20% of their clinically healthy relatives (Secondulfo, M. de Magistris, L., Fiandra, R., Caserta L & Belletta M 2001 ). Th e major determinant of the rate of intestinal permeability is the opening or closure of the tight junctions between enterocytes in the paracellular space. A combination of functional clinical testing that includes an intestinal permeability assessment, combined with genetic testing (e.g., screening for CARD15/NOD2, DLG5, etc.), could prove to be a prudent way to identify those at risk of IBD.

Increased intestinal permeability is common Crohn’s disease patients and 10 % –20% of their healthy relatives.

Because the increase in intestinal permeability in Crohn’s disease could be caused by the infl ammation itself, or by some predisposing genetic abnormality, permeability in patients and their healthy relatives have also been studied (Hollander, 1988 ) Approximately 10 % to 20% of healthy relatives of patients with Crohn’s disease also have an abnormal increase in intestinal permeability (Hollander et al., 1986 ; Katz et al., 1989 ; May et al., 1993 ). Th ese observations link genetic abnormalities and a leaky gut, which predisposes an individual to the development of Crohn’s disease (Hollander, 1988 ; Hollander, 1993 ). Clearly, a genetic predisposition could not be the only abnormality; rather, the presence of specifi c, as yet unknown, antigens in luminal contents or infectious agents, as well as possible abnormalities in the intestinal immune responses, are presumed to be additional factors in the genesis of the disease. Th e “leaky gut” explanation ties together the infl uence of luminal antigens and an abnormal immune reactivity, and off ers a unifying concept that explains the interaction between luminal factors and the immune system (Hollander, 1994 ). Conducting a fecal calprotectin evaluation is one type of test for measuring intestinal infl ammation (Teahon, Roseth, Foster, & Bjarnason, 1997 ; Tibble, Sigthorsson, & Bjarnason, 1999 ). Calprotectin is a calcium-binding protein The Role of Nutritional Genomics and Functional Medicine 279 found in the following types of white blood cells: neutrophilic granulocytes, monocytes, and macrophages (Teahon et al., 1997 ). Calprotectin resists metabolic degradation and can be measured in the feces. Th e fecal calprotectin test makes use of the fact that the release of calprotectin in the stool is associated with damage to the GI mucosa, and increased infl ammatory processes (Tibble et al., 1999 ).

Nutritional Inﬂ uences in IBD

Buddington and Weiher ( 1999 ) proposed that, in managing functional gastrointestinal disorders, the GI system should be viewed as a fl ow system or “river.” Th e GI tract is a complex ecological system that fl ows from top to bottom and requires an optimum environment, which is infl uenced by nourishment to create the appropriate “ecology” within the small and large intestines.

Fecal calprotectin is a functional measure of damage to the GI mucosa, and resultant inﬂ ammatory processes.

A variety of nutrients have been found to be defi cient in Crohn’s disease patients (See Table 30.5 ).

Table 30.5. Malnutrition in Individuals with Crohn’s Disease (adapted from Mullin, 2009)

Deﬁ ciency Percentage of individuals Treatment with Crohn’s disease with nutrient deﬁ ciency

Negative Nitrogen 69% Adequate energy and protein Balance

Vitamin B12 48% 1000 mcg/d x 7 then Q mo

Folate 67% 1 mg/d

Vitamin A 11% 5,000–25,000 IU/d

Vitamin D3 75% 5,000–25,000 IU/d

Calcium 13% 1,000–1,200 mg/d

Potassium 5–20% Variable

Iron 39% Fe Gluconate 300 mg TID

Zinc 50% Zn Sulfate 200 mg daily or BID 280 INTEGRATIVE GASTROENTEROLOGY

The GI system can be viewed as a complex ecological system that ﬂ ows like a river and is inﬂ uenced by its environment.

Causes include:

• Malabsorption in the small intestine • Increased nutrient need because of disease activity • Low nutrient intake • Nutrient loss due to chronic diarrhea or increased transit time or eff ect of medications

Nutrient deﬁ ciencies are common in Crohn’s disease, due to: • Malabsorption • Compromised dietary intake • Disease activity • Chronic diarrhea • Increased nutrient losses • Medications

One study examining multiple nutrient defi ciencies found 85% of 279 Crohn’s disease patients had defi ciencies. Nutrients most frequently found defi cient were iron, calcium, zinc, protein, vitamin B12, and folate (Rath et al., 1998 ). It has recently been suggested that certain protective nutrients and functional foods can provide protection of the gut mucosa from the CARD15/ NOD2-related Th 1-dominant infl ammatory reactions (Duggan et al., 2002 ). Th e amino acids glutamine and arginine, and the essential micronutrients vitamin A, zinc, vitamin E, and the B vitamin, pantothenic acid, are among these protective nutrients. Evidence indicates that chronic IBD is associated with elevated oxidative stress in the intestinal mucosa, with increased levels of reactive oxygen species and protein carbonyls in tissues, along with other markers of free radical injury (Lih-Brody, 1996; Ding et al., 2007 ). Th erefore, supplementation with antioxidants, including ascorbic acid, tocopherol, and food fl avonoids like quercetin (found in apples) and epicatechin gallate (from green tea) may be benefi cial. Shapiro et al. (2007 ) discuss the addition of polyphenols to nutritional formulas to improve the outcome of patients with IBD. Five polyphenols in particular have shown, in animal and human studies, (Shapiro et al., 2007 ; Gupta et al., 1997 ; Gupta et al., 2001 ; Gerhardt et al., 2001 ; Gautam et al., 2007 ; Camacho-Barquero et al., 2007 ; Kurup et al., 2007 ; Sharma et al., 2007 ; Holt et al., 2005 ; Hanai et al., 2006 ) to have benefi t in IBD The Role of Nutritional Genomics and Functional Medicine 281 by reducing infl ammation associated with variations of the CARD15/NOD2 and SLC22A4/A5 genes:

• B o s w e l l i a • C u r c u m i n • E p i g a l l o c a t e c h i n • Q u e r c e t i n • R e s v e r a t r o l

Prebiotics and probiotics are also important substances that support proper function of the GALT and lead to the repair phase of gastrointestinal restoration (Duggan et al., 2002 ).

Free radical injury, and increased oxidative stress in the intestinal mucosa, warrants a diet rich in antioxidants, along with concomitant nutrient supplementation.

Functional medicine seeks to understand the antecedents, triggers, and mediators underlying dysfunction.

Putting it all Together with the Functional Medicine “4RTM ” GI Restoration Program

Th ere is a growing awareness that understanding the etiology at the genetic– molecular–environmental level may be just as important, if not more important, than disease classifi cation. “Functional Medicine” — an evidence-based systems biology approach— addresses this concept of underlying etiology and root cause solutions, and is now being encouraged by the National Institutes of Health under the new program NIH Roadmap, a route to accelerate medical discoveries that will improve health (OPASI, 2007 ). In essence, functional medicine assessment is concerned with understanding the antecedents, triggers, and mediators of dysfunction that give rise to molecular imbalances underlying the signs and symptoms of disease (Jones, 2005 ). Th e following is a brief adaptation of the “4R TM GI Restoration Program” pioneered by the Institute for Functional Medicine for the management of gut dysfunction and chronic disease. (Jones, 2005 ; Liska & Lukaczar, 2001 ). It is a conceptual framework within which to target therapies aimed at improving GI function. 282 INTEGRATIVE GASTROENTEROLOGY

The 4R GI Restoration Program is a functional medicine GPS to assist the practitioner in targeting therapies to improve GI function, and includes: • Remove (offending foods, toxins, infections, stress) • Replace (enzymes and other digestive factors) • Reinoculate (probiotics) • Regenerate or Repair (healing nutrients)

1. REMOVE What does this patient need to have removed for healthy GI f u n c t i o n ?

Remove focuses on eliminating pathogenic bacteria, viruses, fungi, parasites, and other environmentally derived toxic substances from the GI tract. Dietary modifi cation is important, since foods to which a patient is intolerant or allergic can exacerbate GI dysfunction, and stimulate immune and infl ammatory responses systemically. Because Crohn’s disease is characterized by elevations in anti-Saccharomyces cerevisiae (brewer’s yeast) antibodies in up to 60 % of cases (Vermeire & Rutgeerts, 2004 ), eliminating foods with yeast may prove to be therapeutic. Β-glucuronidase is a marker for fecal putrefaction associated with increased risk of the adverse eff ects of colonic fermentation by bacteria. Interestingly, reduction of β -glucuronidase in the stool was a favorable outcome observed with rice bran supplementation, but not with wheat bran (Gestel et al., 1994 ).

2. REPLACE What does this patient need to have replaced to support normal GI f u n c t i o n ?

Replace refers to the replenishment of enzymes and other digestive factors lacking, or in limited supply, in an individual’s GI environment. GI enzymes that may need to be replaced include proteases, lipases, and saccharidases normally secreted by cells of the GI tract or by the pancreas. Other digestive factors that may require replenishment include betaine hydrochloride and intrinsic factor, normally produced by parietal cells in the stomach wall (Griffi n et al., 1989 ).

Regenerate (Repair) nutrients may include: • L-Glutamine • Fish Oils (EPA/DHA) • Zinc carnosine The Role of Nutritional Genomics and Functional Medicine 283

3. REINOCULATE What does this patient need to support or reestablish a healthy balance of microfl ora?

Reinoculate refers to the reintroduction of desirable bacteria, or probiotics, into the intestine to reestablish microfl ora balance and to limit proliferation of pathogenic bacteria, candida, and microbes associated with variation in the CARD15/NOD2 gene. Probiotics serve a variety of functions in the GI tract: they synthesize various vitamins, produce short-chain fatty acids necessary for colonic cell growth and function, degrade toxins, prevent colonization by pathogens, improve epithelial and mucosal barrier function, and alter immune regulation via stimulation of secretory IgA or reduction in TNF-alpha (Faber, 2001 ; Johnston, 2001 ; Malin, Suomalainen, Saxelin, Isolauri. 1996 ; Borreul Carol & Casellas 2002 , Plain & Hotz, 1993 ).

4. REGENERATE (also referred to as the REPAIR phase) What does this patient need to support the healing of the gastric and mucosal layer?

Regenerate refers to providing support for the healing and regeneration of the GI mucosa. Part of the support for healing comes from removing insults that continually reinjure or irritate the mucosa, and promoting healthy microfl ora. Zinc carnosine is a chelate compound consisting of a zinc ion and L-carnosine, a dipeptide of beta-alanine and L-histidine. Studies have demonstrated that zinc carnosine promotes wound-healing action, has an anti oxidant eff ect in the GI system, and seems to have anti-Helicobacter pylori activity (Lee et al., 2000 , Mahmood et al., 2007 ). Supplementation with omega-3 fatty acid-rich oil (3.24 gm of EPA and 2.16 gm of DHA daily) lowered the infl ammatory response associated with variation of the CARD15/NOD2 and SLC22A4/A5 genes (decreased rectal levels of leukotriene B4), and improved remission in patients with IBD (Belluzi et al., 1996 ). L-glutamine supplementation has also been found useful as part of a repair and regenerate program to restore GI mucosal integrity associated with the variation in the DLG5 gene (Souba, 1990 ). A fi ft h “R” has recently been added (Functional Medicine Clinical Series, 2006):

5. RELIEVE

Relieve addresses acute discomfort in patients while treating the underlying conditions. Lavender oil has been used as an upper GI antispasmodic 284 INTEGRATIVE GASTROENTEROLOGY

(Blumenthal, 2003 ), while chamomile fl ower extract and peppermint leaf oil have been studied as lower GI antispasmodics (O’Hara et al., 1998 ). Additionally, Chinese licorice root, tienchi ginseng root, and astragalus root may have a role in addressing heartburn and mild indigestion (Blumenthal, 2003 . Promoting gastrointestinal health through this type of program may have signifi cant eff ects, not only on localized intestinal infl ammatory risk, but also on systemic infl ammatory processes associated with the loss of intestinal m u c o s a l i n t e g r i t y .

A ﬁ fth R for Relieve addresses easing the discomfort with herbs, such as lavender oil, chamomile ﬂ ower extract, peppermint leaf oil, and Chinese herbs.

Future Strategies

Th e application of nutritional genomics can create a better understanding of IBD pathology, and has focused attention on the interaction between genetic factors and bacteria within the gut. Increasing scientifi c evidence supports the notion that IBD results from a genetic predisposition to abnormal interaction with an environmental stimulant— most probably, part of the normal luminal bacterial fl ora— which, in turn, leads to excessive immune activation and chronic infl ammation. Th ere are many putative bioactive molecules being identifi ed that can help modulate genetic expression of infl ammation; however, many of these components still need to be tested further with in vivo animal models of human disease. In the past decade, nutrition research has undergone a shift in focus from epidemiology and physiology to molecular biology and genetics. Th is shift has resulted in a growing realization that we cannot understand the eff ects of nutrition on health and disease without determining how nutrients act at the molecular level. Muller and Kersten (2003 ) pointed out that “there has been a growing recognition that both macronutrients and micronutrients can be potent dietary signals that infl uence the metabolic programming of cells and have an important role in the control of homeostasis.” As a result, adequately trained health professionals who possess an authentic and experienced understanding of the interconnectedness of the biological systems in the human body, as well as the common underlying mechanisms that cut across many diseases, syndromes, conditions, and organ systems, will be required to interpret and communicate this information both to the public and with regulatory offi cials, to responsibly develop, apply, and progress this new fi eld. The Role of Nutritional Genomics and Functional Medicine 285

Additionally, this solid background and training will allow for far more personalized preventative care that incorporates a client-centered approach, tailored to the patients’ unique needs. Nutrition-focused practitioners are at a pivotal point in the history of their practice. Kauwell ( 2003 ) recently stated, “Armed with the fi ndings of the Human Genome Project and related research, dietetics practitioners will have the potential to implement more effi cient and eff ective nutrition intervention strategies aimed at preventing and delaying the progression of common chronic diseases.” Vay Liang W. Go explains in a 2005 article that “with the advent of the postgenomic era, biological and medical research and clinical practice [have] witnessed an explosion in strategies and goals. Th is eventually will revolutionize the classical practice of nutrition from the current evidence-based medicine towards genomic-based medicine” (Go et al., 2005 ). But this very explosion can be part of the barrier to realizing the vision for healthcare professionals. Clinicians today must contend, as never before, with a massive amount of information emerging from the scientifi c literature. One thing that can be done now, to move this vision ahead, will be the unbi- ased utilization of the already created and available organizational architecture of information that moves beyond the well-established “silos” of organ system medicine. For example, the eff ects of chronic infl ammation on one organ system do not necessarily stop there. Th e infl ammatory process can operate throughout the patient entirely, aff ecting multiple systems including the brain, the immune system, and the endocrine system. Utilizing this type of “functional medicine” approach will allow for a more precise and clear evaluation, formulation, and integration of all the information at our disposal, to create a systematic and eff ective nutrition care plan for our patients that can potentially alter the trajectory of their health status f o r e v e r .

Conclusion

Th e emerging fi eld of nutritional genomics, defi ned as the interface between genes and nutrition, is credited with debunking the concept that “one size fi ts all” as it relates to nutritional management of chronic disease, including infl ammatory bowel disease (IBD). Crohn’s disease, a subcategory of IBD, contributes to signifi cant morbidity, particularly in industrialized nations. It is characterized by chronic infl ammation and ulceration that can occur in any portion of the intestinal tract. A number of factors contribute to its etiopatho- genesis, including genetic, microbial, infl ammatory, immune, and permeability abnormalities. Several susceptibility genes have been associated with IBD; 286 INTEGRATIVE GASTROENTEROLOGY however, this review focused specifi cally on three IBD-associated genes that appear to identify major susceptibility loci for Crohn’s disease: (1) CARD15/ NOD2, (2) DLG5, and (3) SLC22A4/A5 (OCTN1/OCTN2). Variations of these genes and their potential impact on IBD pathogenesis are discussed. Nutritional management, including the use of various functional clinical tests, nutritional infl uences in IBD and a functional medicine systems biology approach referred to as the 4R ™ Gastrointestinal (GI) Restoration Program weredescribed. Th e 4R ™ approach, “Remove, Replace, Reinoculate, Regenerate” provides a framework in which to focus clinical assessment and intervention. Future strategies including a discussion of the evolving role of the registered dietitian as a vital clinician in the integrated healthcare team were off e r e d . 3 1 Functional Foods for Digestive Health and Disease

ELIZABETH LIPSKI

key concepts

■ D i e t a ff ects GI health: Food can be infl ammatory; food can be healing. ■ Th e Standard American Diet (SAD) accelerates chronic disease. ■ Probiotics, prebiotics and fi ber help restore balance in the GI tract. ■ Th e Elimination Diet can become a useful tool to reduce gut infl ammation in digestive conditions. ■ Functional foods can facilitate and restore digestive health and w e l l - b e i n g . ■

Introduction

ood is our most intimate contact with our external environment. Each day we put several pounds of food into our mouth. (Amber Waves F 2005). Th e body must read and react to the food as friend or foe, which is why fully two-thirds of our immune system is located in the digestive system. Increased intestinal absorption and dysbiosis can lead to systemic illness and symptomatology and have been well-covered previously in this text. As discussed in Chapter 30), food is information that elicits a genetic and cellular response.

287 288 INTEGRATIVE GASTROENTEROLOGY

Food can be infl ammatory and anti-infl ammatory. In our Western culture, much of the food that is commonly eaten is infl ammatory. In a recent issue of the Journal of the American College of Cardiology , Guiliano et al state:

“Dietary patterns high in refi ned starches, sugar, and saturated and trans- fatty acids, poor in natural antioxidants and fi ber from fruits, vegetables, and whole grains, and poor in omega-3 fatty acids may cause an activation of the innate immune system, most likely by an excessive production of proinfl ammatory cytokines associated with a reduced production of anti-infl ammatory cytokines.”(Giugliano, Ceriello et al., 2006 )

For example, processed foods contain denatured fatty acids, which lead to a build-up of arachidonic acid and omega-6 fatty acids and a defi cit of omega-3 fatty acids. A high omega-6-to-3 ratio commonly increases production of arachidonic acid and the resulting infl ammatory PGE2 prostaglandins. For further details, see Th e Omnivore’s Dilemma by Michael Pollan ( 2007 ). Th is chapter will discuss the infl ammatory nature of the standard American diet, use of elimination diets to reduce digestive and systemic infl ammation, and use of specifi c foods to protect the gastrointestinal system.

NUTRITION AND DIGESTIVE WELL-BEING

Appropriate nutrition is critical for digestive well-being. In the Surgeon General’s Report on Nutrition and Health (Koop, 1988 ), diet was reported to play an important role in 5 out of the 10 leading causes of death. Although no digestive illness is listed in the top 10, the digestive system serves to transport nutrients to each cell of the body. If cells cannot assimilate adequate nutrients, virtually any illness or condition can occur. Th is makes the process of digestion critical for overall health and well-being. Although there is a growing public interest in nutrition, whole foods, and food quality, nutrition is a topic rarely discussed except peripherally in the physician’s offi ce. Food diaries are seldom used as part of an initial medical history, even though they are an essential part of understanding a patient’s overall health.

THE STANDARD AMERICAN DIET IS INFLAMMATORY AND LOW IN NUTRIENTS

Dietary patterns have changed dramatically during the last decade. Th e current standard American dietary pattern is high in refi ned starches, sugar, and Functional Foods for Digestive Health and Disease 289 saturated and trans fats, poor in natural antioxidants and fi ber from fruits, vegetables, and whole grains, and poor in omega-3 fatty acids. Th is may lead to (Figure 31.1 ):

• activation of the innate immune system • excessive production of proinfl ammatory cytokines • reduced production of anti-infl ammatory cytokines

Disappearance data indicates that Americans are eating 523 calories more each day than in 1970 (Amber Waves 2005). It’s no wonder that we are increasingly obese. Our foods are mainly processed, and each time a food is processed it loses essential nutrients. Th e defi nition of a nutrient is that it is essential for life; chronic defi ciencies lead to changes in all body systems. Americans eat 20.4  of their calories as refi ned grains, yet only 3.5  as whole grains. When grains are refi ned, they lose 58.1  of 19 vitamins and minerals they contain (see Appendix C). Refi ned sugars, such as high-fructose corn syrup and white sugar, comprise an additional 18.6 of our caloric intake, at an average of 141 pounds per year, or 6.2 oz. per day (United States Economic Research Service Food Consumption, 2007). Refi ned vegetable oils make up another 17.6 , and alcohol 1.4 . Th e damaged and nutritionally depleted omega-6 fatty acids and oils used in processed foods increase levels of arachidonic acid and infl ammatory cytokines, which help promote infl ammatory gut conditions such as Crohn’s disease. Worse, potatoes as French fries are the vegetable most commonly eaten by toddlers over 15 months of age. In 2004, soft drinks were the third most commonly consumed food among American children ages 2 to 5, with cookies and French fries ranking sixth and seventh, respectively (Demory-Luce, 2004 ) No wonder rates of childhood obesity and other diseases are rapidly increasing. All told, the typical American eats 58  of his or her total calories as high- sugar, highly processed, nutritionally depleted, infl ammatory foods (Cordain et al., 2005 ). Th e fi lm “Supersize Me” increased public awareness about the infl ammatory nature of processed fast food and its overconsumption. A Swedish study (Kechagias et al., 2008 ) replicated the movie’s results. An intervention group of 18 people with an average age of 26.6 were asked to eat at least two fast food meals per day for 28 days. Th e goal was to double their regular caloric intake, increase total body weight by 5  to 15  , and follow a sedentary lifestyle of not more than 5,000 steps per day. Th irteen of the subjects (72.2 ) had pathological increased levels of the liver enzyme alanine aminotransferase ALT; 23 had steatohepatitis; and 13  had fatty liver. In most subjects, these elevations occurred during the fi rst week. One man was dismissed in the third week due to increased ALT of 447 (normal is 0 to 40). 290 INTEGRATIVE GASTROENTEROLOGY

Th is study is relevant to the eating habits of many Americans, including children. An estimated 26.5  of Americans eat at fast food restaurants, which contributes one-third of their total caloric intake. Fast foods have lower levels of vitamin A, carotenoids, vitamin C, magnesium, fruits, and vegetables (Bowman & Vinyard, 2004 ). Fift een percent of adults in the United States have nonalcoholic fatty liver disease, and 50  of adults with diabetes or hyperlipidemia have hepatic steatosis (Pitt, 2007 ). A 2006 study at the University of San Diego School of Medicine looked at autopsies of 742 children and teens who had died due to accidents, homicide, or suicide. Based on their results, the researchers estimate that 10 of children in San Diego County have steatohepatitis. High-fructose corn syrup and end-stage glycation products have been implicated in steatohepatitis (Th uy et al., 2008 ).

Use of the Elimination Diet

Approximately 3  of children and 1  of adults have IgE mediated food allergies. Peanut allergies alone doubled from 1997 to 2002 (Sicherer, Muñoz- Furlong & Sampson, 2003 ). One person in three changes their diet to adapt for what they consider to be food allergies, although the true incidence of such allergies is estimated to be around 5 (Cordain et al., 2005 ). Th e majority of the people who believe that they have food allergies likely have food hypersensitivities or food intolerances instead. Seventy percent of the world’s population is considered to be lactose intolerant, for example; others have fructose intolerance. In addition people can have other negative reations to substances in food such as: Food hypersensitivity reactions (IgG, IgG4, IgM, IgA), lectins, tyramines (found in cheese, caff eine, coff ee, chocolate), complement reactions, sulfate reactions (due to impaired sulfation pathways), inability to handle phenols, oxalates, food dyes, food additives, or other possible food substances. In my clinical experience as a nutritionist, it is common for symptomatic patients who test negative for celiac disease to respond positively to a gluten- free diet. Although research on gluten intolerance is nearly nonexistent, one can hypothesize that damage from gluten-containing grains is on a continuum, with celiac disease at the far end of the spectrum. When working with someone with gastrointestinal (or rheumatological, autoimmune, or respiratory) illness, it can be useful to begin with a low- antigen, low-infl ammation diet (Sköldstam. 1986 ; Sköldstam & Magnusson, 1991 ; Kjeldsen-Kragh, Haugen et al., 1994 ; Kjeldsen-Kragh, Hvatum et al., 1995 ). Working with a “clean slate” can clear myriad symptoms by reducing total load, enhancing detoxifi cation pathways, and reducing infl ammatory cytokines. It’s simple and cost-eff ective. Functional Foods for Digestive Health and Disease 291

Research on elimination diets has been promising, One meta-analysis reports that the only eff ective dietary strategy for ulcerative colitis is the elimination diet, but this observation was based upon one study (Galandi & Allgaier, 2002 ) Fasting has been well-researched in rheumatoid arthritis (Muller, de Toledo, & Resch, 2001 ) Th ere is an increasing number of controlled studies on elevations in IgG antibodies and the use of elimination diets for a variety of GI issues. Research substantiates use of IgG and IgE testing in irritable bowel, atopy, and other digestive and systemic conditions. In a study by Atkinson, 150 patients who had IgG food antibody testing were randomized to receive either an appropriate elimination diet or a sham diet. Aft er 3 months, there was a 24 reduction in symptoms in the study group (Atkinson, Sheldon, Shaath, & Whorwell, 2004 ). A similar study was done in China: IgG antibodies for 14 common foods were tested in 55 people with diarrhea-dominant IBS, 32 people with constipation-dominant IBS, and 18 normal controls. Sixty-three percent of subjects with diarrhea-dominant IBS and 43.8  of subjects with constipation- dominant IBS had positive IgG food antibodies. Both groups had more positive food antibodies than controls. Aft er adhering to individualized eliminated diets for 2 months, a total of 65.7  of people reported either complete improvement (31.4 ) or remarkable improvement (34.3 ; see Yang & Li, 2007 ). Zar, Kumar, and Benson (2001 ) report that elevations of IgG antibodies in subjects with IBS. Drisko et al. (2006 ) investigated food intolerance using Rome II criteria, in 20 patients with IBS who had failed standard care. IgG and IgE food and mold panels, comprehensive stool analysis, and small bowel bacterial overgrowth were assessed. Subjects fi lled out quality of life questionnaires and complied with elimination diets based on IgE and IgG testing results. Th ey were also given probiotics. Testing was repeated at 6 months, with follow up at 12 months. In subjects who had signifi cant responses to the diet, 100 had baseline abnormalities in IgG and IgE antibody levels. Th ere were signifi cant improvements in stool frequency and quality of life. At baseline, 100  of subjects had imbalances in benefi cial and dysbiotic fl ora. At 6 months, there was a trend toward normalization of benefi cial bacteria, with no change in dysbiosis. At one year, there was continued adherence to the food rotation diet and minimal issues with IBS. Th ere is much anecdotal evidence for use of the Specifi c Carbohydrate Diet, which was popularized by Elaine Gottschall Ph.D. in Breaking the Vicious Cycle, in GI disorders, especially in Crohn’s disease. Unfortunately no controlled studies have been done on the Specifi c Carbohydrate diet. Th is diet is entirely grain-free and limits disaccharides from starchy vegetables as well. ( w w w . s c d i e t . c o m ) 292 INTEGRATIVE GASTROENTEROLOGY

Table 31. Case1 Sidebar.

Case History:

• 48-year-old male, Caucasian

• Weight: 245 lbs. Height: 6’1”

• Current Medical Diagnoses

• IBS

• O s t e o a r t h r i t i s

• D e p r e s s i o n

• H y p e r t e n s i o n

• H i g h c h o l e s t e r o l

• E c z e m a

• Obesity (BMI of 32)

• A l l e r g i e s

• C u r r e n t M e d i c a t i o n s

• W e l l b u t r i n X L

• B e n i c a r H C T

• To p i c a l s t e r o i d o i n t m e n t

• A s p i r i n

• Previously had been on Lipitor

• Primary Complaints:

• Constant GI cramps for 2 to 3 days; sharp pains are relieved with diarrhea, which lasts 2 to 3 days

• Occurs several times a month

• A b d o m i n a l b l o a t i n g

• BM: At least three times daily

• Secondary Complaints:

• Lower back: fairly consistent low-grade pain, with fl are-ups sending pain to hips and legs

• M u s c l e i n fl ammation, diffi cult to grip without pain.

• Constant pain in hands and feet. Functional Foods for Digestive Health and Disease 293

Table 31. (Continued)

Case History:

• E c z e m a

• A l l e r g i e s / s t u ff y nose: cats, dust, pollen, molds

• D e p r e s s i o n

• L o w e n e r g y l e v e l

• C a ff eine necessary to jump start

• Legs swollen by the end of the day

• H i s t o r y / F a m i l y H i s t o r y

• Life-long GI issues— remembers several times a year as a child recurrent abdominal pain (RAP) and diarrhea.

• Asthma as a child at age 10

• B r o t h e r s a l s o h a d a s t h m a

• Had stomach ulcer as a child

• N o s i g n i fi cant family history noted

• P r i o r Te s t i n g

• Upper GI: negative

• E n d o s c o p y : n e g a t i v e e x c e p t f o r h i a t a l h e r n i a

• C o l o n o s c o p y : n e g a t i v e

• F o o d D i a r y

• Breakfast: fruit, cereal (oat, rice or corn), soy or rice milk, coff ee, sometimes fruit juice

• Lunch: fruit, beans & rice, or Garden burger with veggie slices and bread, mustard.

• Dinner: beans and rice, vegetable (yams, broccoli, kale, green beans), fi sh, pasta, bread, and margarine

• Removed meat and dairy from diet a few weeks ago. Th is was a drastic change

• I n i t i a l T r e a t m e n t P l a n :

• IgG and IgE food sensitivity/allergy testing

• Ask physician to run Celiac Panel (IgG, trans-glutaminase, endomysial, anti-gliaden)

• In the meantime, begin Elimination Diet plan for 2 weeks

• Replace potassium (99 mg), calcium (400 mg), and magnesium (200 mg) lost to hydrochlorothiazide.

(continued) 294 INTEGRATIVE GASTROENTEROLOGY

Table 31. (Continued)

Case History:

• T w o - W e e k R e c h e c k

• C e l i a c t e s t i n g : n e g a t i v e

• Carefully followed elimination diet, which consisted of fruits, vegetables, poultry, fi sh, rice, olive oil, salt, pepper, herbs, spices

• L o s t 8 p o u n d s

• No gut pain, cramping, or diarrhea

• No hand, foot, leg or hip pain

• P l a y e d fi ddle at a concert for 3 hours

• D e p r e s s i o n h a s l i ft e d

• Has not started calcium, magnesium, or potassium.

• N a s a l c o n g e s t i o n h a s c l e a r e d .

• Continue with diet. Just sent blood to lab IgG/IgE.

• Four-Week Recheck

• IgG and IgE results indicate gluten, dairy, and egg intolerance. Eliminated eggs from diet.

• Experiencing continued well-being.

• Six-Week Recheck

• More improvement without eggs in diet

• Has lost 18 pounds

• N o a r t h r i t i s

• No IBS symptoms

• O ff Wellbutrin

• Has good energy, not relying on caff e i n e

• N o i m p r o v e m e n t w i t h e c z e m a

• H y p e r - s e n s i t i v e t o g l u t e n

• Resistant to further testing or taking any supplements

• Th ree-Month Recheck

• Continues to feel great. “I never realized I’d actually feel younger.” Functional Foods for Digestive Health and Disease 295

Table 31. (Continued)

Case History:

• Found Belgian beers without gluten

• L o s t 3 0 p o u n d s

• E n e r g y l e v e l i s h i g h

• No IBS/No arthritis/No depression

• Stopped ALL Medications

• E c z e m a c h a n g i n g s l o w l y

• E x t r e m e s e n s i t i v i t y t o g l u t e n

• Resistant to further testing or taking any supplements

• O n e - y e a r R e c h e c k

• Still on the diet

• Feeling great!

• O ff of all medications

• C h o l e s t e r o l a n d b l o o d p r e s s u r e i m p r o v e d

• E c z e m a n o t c l e a r e d

• G u m s a r e h e a l t h i e r t h a n e v e r

• Still sensitive to gluten

• Seems more sensitive to dairy than before

• Hay fever and allergies are diminished

• Resistant to further testing, nutritional supplements, or any other intervention

The Functional Foods

Simply stated, a functional food is a food that confers one or more specifi c physiological benefi ts that reduce risk of disease. A food or spice may be considered to be a functional food in its natural state. Functional foods are oft en manufactured foods that contain specifi c nutraceutical ingredients. Th ese are oft en also called “medical foods.” 296 INTEGRATIVE GASTROENTEROLOGY

MEDICAL FOODS

• Th ere are two types of medical foods that can be eff ective for many people, when working with gastrointestinal issues: those designed to upregulate liver detoxifi cation, and those designed to support GI function. • Currently one nutraceutical manufacturer produces a product that is specifi cally designed to support gastrointestinal function. Th is product is based on a low-allergy, high-amylase rice fl our, plus amino acids, vitamins and minerals, and gut supportive nutrients, such as zinc, L-glutamine, panthothenic acid, and fructooligosaccharides (FOS). Th ere are no specifi c case studies or published clinical research on this product. • Most nutraceutical companies have a medical food product designed to upregulate phase I and phase II liver detoxifi cation pathways (see Figure 31.3 ). • Phase I nutrients include ribofl avin, niacin, pyridoxine, folic acid, vitamin B12, glutathione, branched-chain amino acids, fl avonoids, and phospholipids. Nutrients included to assist with the reactive oxygen intermediates include carotenes, vitamins C and E, selenium, copper, zinc, manganese, coenzyme Q10, thiols, biofl avonoids, silymarin and pycnogenol. • Phase II nutrients include the amino acids: glycine, taurine, glutamine, ornithine and arginine. Cysteine and N-acetylcysteine are also used as methylation cofactors.

PROBIOTICS AND PREBIOTICS IN FOOD

Probiotics and prebiotics are increasingly being added to foods, primarily cultured dairy products. For an extensive review of probiotics, see Chapter 29, by Gerald Friedman. Th ere is a simultaneous resurgence in the popularity of probiotic-laden fermented and cultured foods that have been used in traditional diets.

Health Beneﬁ ts of Prebiotics and Probiotics: • have a positive inﬂ uence on immune development • improve colonic integrity Functional Foods for Digestive Health and Disease 297

• regulate local and systemic immune function • decrease incidence and duration of infections in the intestinal tract, urinary tract, vagina, and respiratory system • downregulate allergic response • improve digestion • regulate gut transit and stool regularity • increase lactose tolerance • improve elimination • prevention or regulation of diarrhea induced by antibiotics, rotovirus, and lactose intolerance • reduce concentration of cancer-promoting enzymes and/or putrefactive (bacterial) metabolites in the gut • have benefi cial effects on infl ammation in diseases of the gastrointestinal system • prevent or alleviate atopic disease and allergies in infants • benefi cial effects on cholesterol, ischemic heart disease, autoimmune disease, and oral health are less well documented • regulate appetite through leptin and ghrelin • manufacture vitamins B1, B2, B3, B5, B6, B12, and K • metabolic control of nutrients: glycemic control, cholesterol, amino acids

(Hanaway 2010 , Lipski 2004 , Liska, 2006 ; de Vrese & Schrezenmeir, 2008 ; de Vrese, 2008 )

Prebiotics are insoluble fi bers that selectively stimulate the growth and/or activity of probiotics in the intestines. Th ey are nondigestible food carbohydrates, and are oft en called resistant starch, soluble fi ber, nonstarch polysaccharides, and soluble oligosaccharides that promote the growth or activity of a limited number of bacterial species for the benefi t of host health and help optimize microbiotica health and function (Douglas & Sanders, 2008 ). Th ey include fructans, inulin and fructooligosaccharides, arabinogalactans (larch), and soy oligosaccharides (Plummer, Quilt, & Crockett, 2003 ; Liska & Bland, 2006 ). Prebiotics pass undigested through the stomach and small intestine and are subsequently completely fermented in the colon by microfl ora, primarily Bifi dobacteria species, producing short-chain fatty acids (acetic acid, butyric acid, and propionic acid).

Characteristics of Prebiotics: • change in composition of short-chain fatty acids • differential stimulation of probiotic bacteria in the colon 298 INTEGRATIVE GASTROENTEROLOGY

• promote growth of Biﬁ dobacteria and lactobacilli • increased fecal weight • mild reduction in luminal colon pH • decrease in nitrogenous end-products • increased expression of binding proteins or active carriers associated with mineral absorption • discourage growth of clostridial species • normalize bowel function

(Hanaway, 2010 , Douglas & Sanders, 2008 ) For a list of best food sources of prebiotics, see Appendix X.

Traditional populations have all had fermented foods and/or cultured dairy products in their native diet. Koreans ate a variety of pickled vegetables. Europeans made sauerkraut and pickles. Eskimos fermented fi sh by burying it for months. Worldwide, dairy products were fermented into cheese and cultured milks such as yogurt and kefi r. In many cultures, grains were fermented to create sourdough breads. Fermenting and culturing foods enhances their digestibility, can improve nutritional content (increased B complex, decreased mineral-binding phytates), and decrease toxicity (as in cassava or poi). Di Cagno and colleagues (2003, 2004 , 2005 ) have reported that traditionally fermented sourdough bread and pasta have been well-tolerated by people with celiac disease. Probiotics (as discussed in Chapter 4) are defi ned as living microorganisms that, when consumed in adequate amounts, confer a health symbiotic benefi t to the host (Douglas & Sanders, 2008 ). Th e most well researched bacterial species are Lactobacilli and Bifi dobacteria , and a yeast called Saccharomyces boulardii .

Probiotic rich foods: • cultured dairy products (yogurt, keﬁ r) • sauerkraut • kim chee • miso • natto • tempeh • poi • natural soda beverages (kvoss, ginger beer) • fermented grains (gruel, sourdough bread) Functional Foods for Digestive Health and Disease 299

FIBER TO REGULATE GI FUNCTION

Prebiotics, discussed above, are one type of benefi cial dietary fi ber that specifi cally enhances digestive function. Dietary fi ber refers to a group of plant polysaccharides that are not digested or absorbed. Examples of dietary fi ber include prebiotics, cellulose, hemicelluloses, pectins, beta-glucans and gums. Soluble fi ber dissolves and/or swells when it is added to water; some soluble fi bers can hold up to 20 times their weight in fl uid. Insoluble fi bers do not dissolve or absorb fl uids. For example, oatmeal that sits in water overnight will swell and partially dissolve; a carrot will not change. Foods generally are composed of a blend of soluble and insoluble fi bers. Most grains and vegetables contain mainly insoluble fi bers. Soluble fi bers have been shown to lower serum cholesterol levels, and add bulk to and soft en stools. Insoluble fi bers are bulking agents, and help with peristalsis and bowel transit time. Further categories of fi bers include those that hold water and form a gel-like consistency, and those that are fermentable fi bers. Gel-like fi bers aid in peristalsis and increase bulk of the stools. Fibers that are fermented by Bifi dobacteria in the large intestine become short-chained fatty acids that are the essential energy and maintenance source for colonic mucosal cells (Liska et al., 2004 ; Jones, 2006; McGuire & Beerman, 2007 ). Dennis Burkitt, father of the fi ber theory, believed that people in Africa who ate traditional diets had few modern chronic diseases yet the same people living in cities developed them. He reported that the average weight of a Western daily bowel movement was about 3.5 oz (100 grams); people who ate traditional diets had stools that weighed at least 1 pound daily. It is recommended that we consume 20 to 35 grams of fi ber daily, yet the average American gets only about 14 to 15 grams daily. Th e average worldwide fi ber intake is in the 50 to 75 grams per day range. Fiber plays an important role in both phase I and phase II liver detoxifi cation pathways.(Liska et al., 2004 ; Jones, 2006; McGuire & Beerman, 2007 ) Studies in mice show upregulation of cytochrome P450 and glucuronidation pathways. Foods high in dietary fi ber include legumes, fruits, vegetables, nuts, seeds and whole grains. People should increase dietary fi ber gradually to prevent fl atulence and bloating.

Polyphenols in Digestive Health

Polyphenols are phytochemicals that are found in food substances produced from plants. Th ey are diff erent from essential micronutrients in that a 300 INTEGRATIVE GASTROENTEROLOGY

Table 31.1. Fiber Chart

Soluble Fiber Insoluble Fiber

Benefi ts Benefi ts • Lowers cholesterol levels • Promotes peristalsis and bowel regularity • Regulates glucose • Provides substrate for Bifi dobacteria to • Regulates pH balance in produce butyrate and other short- chain the intestines fatty acids in colon • Binds bile acids • Improves IBS • Regulates phase 1 and 2 liver • Increases satiety detoxifi c a t i o n • C a n c e r p r o t e c t i v e • May reduce risk of diverticulosis

Food Sources Food Sources • A p p l e p u l p • Apple skin • B a r l e y • Beets • Beans • Bran (wheat, corn) • Bran (oat and rice) • Brussels sprouts • Carrots • Carrots • Citrus fruits • Caulifl ower • Flaxseed • Fruit skin • P e a s • Green beans • P o t a t o e s • Green leafy vegetables • Psyllium seeds • Nuts • Oats • R o o t v e g e t a b l e s • Oranges • Seeds • R i c e • Turnips • Soy • Whole grains such as wheat and rye • S t r a w b e r r i e s

defi ciency state has not been identifi ed for them; nevertheless, these chemicals are believed to play a biologically active role and have been shown to act as potential immunomodulators (Clarke, Mullin et al., 2008 ). Polyphenols are found in colorful foods, such as fruits, tea, coff ee, and to a lesser extent, vegetables, grains and legumes. Common polyphenols include isofl avones, gallic acid, catechins, fl avanones, fl avonols, fl avonoids, stilbenes, tannins and quercetin (Manach, Williamson, Morand, Scalbert, & Rémésy 2005 ; alsosee Appendix C for Polyphenols in Food chart.) On average, Americans consume about one gram of polylphenols, phenols, and tannins daily, in ranges from 100 mg to more than 2 grams. More than 95 of these substances reach the colon and are fermented by colonic bacteria (Parkar, Stevenson, & Skinner, 2008 ). Polyphenols have established antioxidant, anti-cancer, and anti-infl ammatory eff ects on the digestive system and throughout the body. A growing Functional Foods for Digestive Health and Disease 301 body of research indicates that they also have regulatory eff ects on cell signaling pathways, and help to regulate energy metabolism and GI health. (Stevenson & Hurst, 2007 )

Demulcent Foods

Herbalists use the word “demulcent” to describe any substance that soothes infl amed mucous membranes. A wide variety of foods have demulcent eff ects on the digestive system, including fenugreek, fl ax, ghee, and oat gruel. Th e following foods appear to enhance digestive function and improve overall well-being:

GREEN BANANAS/PLANTAINS

It has been observed that specifi c varieties of “green bananas” (just barely ripe) and plantains (bananas of the Musa species) have anti-ulcer eff ects. Several studies in rats have attempted to elucidate the physiological benefi ts of bananas. Green bananas have been reported to increase mucosal tolerance to stomach acids (Rao, 1991 ; Best, 1984 ), and plantains have been reported to stimulate the growth of gastric mucosa (Rao, 1991 ). Unripe bananas also contain protease inhibitors, which may play a role in curing stomach ulcers (Rao, 1991 ). Other researchers have isolated a substance called leucocyanidin, which prevents aspirin-induced ulcers in rats.

BONE BROTHS

It is instinctive to bring chicken soup or beef consume to someone who is ailing. Bone broths are alkaline and mineral rich. Th ey have been found to contain gelatin, free amino acids, calcium, glycinate, proline, phosphorus, hyaluronic acid, chondroitin sulfate, magnesium, potassium, sulfate and fl uoride. In 1985, Dr. Erich Cohn, of the Medical Polyclinic of the University of Bonn, recommended bone broths for catarrh, which is now known as irritable bowel syndrome. He also recommended a concentrated calf’s foot broth for more serious digestive disorders. Gelatin was reported to balance both defi ciencies and excesses of hydrochloric acid. Traditionally, gelatin was believed to act as a demulcent, soothing the gastrointestinal tract. In 1908, a researcher named C. A. Herter suggested that the 302 INTEGRATIVE GASTROENTEROLOGY gelatin in bone broths helped reduce carbohydrate fermentation due to gastrointestinal bacterial infections, now called fermentation dysbiosis . He stated that:

“Th e use of gelatin as a foodstuff in bacterial infections of the intestinal tract has never received the attention it deserves. Th e physician is not infrequently confronted with a dietetic problem which consists in endeavoring to maintain nutrition under conditions where no combination of the ordinary proteins with fats and carbohydrates suffi ces to maintain a fair state of nutrition. Th e diffi culty which most frequently arises is that every attempt to use carbohydrate food is followed by fermentative disturbances of an acute or subacute nature which delay recovery or even favor an existing infection to the point of threatening life. A great desideratum, therefore, is a food which, while readily undergoing absorption, shall furnish a supply of caloric energy and which at the same time shall be exempt from ordinary fermentative decomposition. Such a food exists in gelatin.” (Daniel, 2003 )

Bone broths are simple to prepare. Th e key is to use a few tablespoons of either lemon juice or vinegar to help pull more nutrients from the alkaline bones.

Bone Broth Recipe • Take the bones from poultry, beef, lamb, shellﬁ sh, or whole chicken or whole ﬁ sh (remove meat after it has cooked for about 1 hour) • Cover with water and add: • 1 to 2 tbsp. of lemon juice or vinegar • 1 to 2 tsp. salt • ½ tsp. pepper • Carrots, onions, and celery • Parsley, sage, rosemary, thyme, and bay leaf • Cook between 4 and 24 hours on the stove, or in a crockpot on low • Remove bones and skim off fat

CABBAGE JUICE

Th ere is a strong evidence-based tradition for the use of cabbage juice in people with peptic ulcers, diabetes, cirrhosis, cancer, and arthritis (Miron, Hancianu, Aprotosoaie, Gacea, & Stanescu, 2006 ). Its effi cacy may be due to immuno- modulary polysaccharide compounds found in cabbage. Cabbage juice contains glutamine, methionine and sulforaphanes. Functional Foods for Digestive Health and Disease 303

Th e original research was conducted by Garnett Cheney at Stanford University Medical School from 1949 to 1952 (Cheyney, 1949 ) In a study of 181 patients, Cheney reports that cabbage juice helped decrease pain and led to improvement on X-rays. More than 80 of patients were symptom-free in 1 week, and two-thirds reported improvement within 4 days. Other studies followed, with researchers typically recommending 1 quart of cabbage juice daily for 7 to 10 days. Most subjects experienced relief within the fi rst few days (Doll & Pygot, 1954 ; Strehler & Hunziker, 1954 , Klimov, 1961 ; Trusov, Belosludtsev, Pevchikh, & Shinkareva, 1964 ; Dunaevskiĭ, Migunova, Rozka, & Chibisova, 1970; Zhgun & Aloiants, 1971 ). More recently, sulforaphanes have demonstrated eff ects against H. pylori and gastric cancers. Th is particular study used sulforaphanes from broccoli and broccoli sprouts, but cabbage also has high levels of sulforaphanes (Fahey et al., 2002 ). Dosage: 1 quart fresh, green cabbage juice daily for 7 to 10 days in divided doses. Th e taste can be intense, so people will probably be more compliant if it is diluted with other fresh vegetable juices.

GINGER

Ginger is one of the most widely used culinary spices. Its best-studied active ingredient, gingerol, has the following characteristics:

• A n t i e m e t i c • A n t i t u s s i v e • Bile stimulating • C a n c e r p r o t e c t i v e • C a r d i o t o n i c • H e p a t o p r o t e c t i v e • H y p e r t e n s i v e • Prostaglandin suppressive • S e d a t i v e

(al Somall, Coley, Molan, & Hancock, 1994 ; Schulick, 1994 ) Ginger itself:

• i n h i b i t s p r o i n fl ammatory cytokines: IL-12,TNF-alpha; IL-1-beta, MCP-1, and RANTES • suppresses inducible NOS and COX-2 synthesis • inhibits platelet aggregation and thromboxane synthesis in vitro (Alt. Med.Review, 2003; Tripathi, Maier, Bruch, & Kittur, 2007 ) 304 INTEGRATIVE GASTROENTEROLOGY

For the digestive system, research focus has focused mainly on ginger’s use in reducing morning sickness of pregnancy and post-surgical nausea and vomiting (Chaiyakunapruk, Kitikannakorn, Nathisuwan, Leeprakobboon, & Leelasettagool, 2006 ). While the exact mechanism of action is unclear, ginger seems to inhibit serotonin receptors and to have anti-emetic eff ects on the GI and neurological systems, anti-spasmodic eff ects and carminative eff ects ( Alt. Med. Review, 2003; White, 2007 ). Ginger can be used fresh, dried, or as an extract. It can be added in cooking or used as a tea, in ginger ale or ginger beer, or as crystallized ginger.

HONEY

Honey has long been used worldwide for its medicinal eff ects on wound healing, infection, and digestive issues. Researchers in New Zealand studied 345 honey sources and found that antibacterial activity varied greatly, depending on plant sources. Honey from manuka fl owers ( Leptospermum scoparium ) had the highest level of antibiotic activity. In an in vitro study, it was determined that manuka honey had a strong inhibitory eff ect on H. pylori . Th e researchers found that the minimum inhibitory dosage of manuka honey could be achieved with 2.5 ml (½ tsp.) taken prior to a meal. Th is would be tolerable and perhaps enjoyable for the average person, and is a low-cost, low-side-eff ect option to standard therapy (al Somall et al., 1994 ). Another group looked at chemically induced ulcerative colitis in rats. Th ey compared honey, glucose, fructose, sucrose and maltose mixtures that were administered orally and rectally once daily for 4 days. On the third day, a 3 acetic acid solution was used to induce colitis. Biopsies were taken on day 4. Honey protected against acetic-acid-induced colonic damage. At dosages of 5 gram/kg there was almost 100  protection. Th ere was no protection with any of the other sugars used (Mahgoub, el-Medany, Hagar, & Sabah, 2002 ). Dosage: 1 tsp. daily

PEPPER

Black pepper is one of the most commonly used spices. Several benefi ts to the GI system are attributed to piperine, one of the active ingredients in pepper. Piperine has been reported to stimulate pancreatic enzymes, reduce bowel transit time, and enhance digestion (Srinivasan, 2007 ). It has an inhibitory infl uence on drug biotransformation reactions in the liver, strongly Functional Foods for Digestive Health and Disease 305 inhibiting hepatic and intestinal aryl hydrocarbon hydrolase and UDP- glucoronyltransferase. It has also been shown in vitro to have antioxidant eff ects.

PEPPERMINT

Peppermint oil has long been used as a fl avoring and relaxes smooth muscle in the digestive tract. Although no studies have been conducted on peppermint-leaf tea, there is much research on the use of peppermint oil. Enteric-coated peppermint oil has been well-researched in children and adults for its benefi cial eff ect on irritable bowel syndrome, non-ulcer dyspepsia, and colonic spasm. Two studies have found it to be of benefi t in reducing spasm during barium enema and possibly colonoscopy (Kligler & Chaudhary, 2 0 0 7 ) .

INDIAN SPICES

Use of spices not only makes food taste better, but simultaneously enhances digestion. Fennel, fenugreek, cumin, cardamom, and coriander seeds are provided by Indian restaurants for this purpose. Fennel tea has been a standard of care in Europe for colicky and fussy babies. A review article by Platel and Srinivasin ( 2004 ) discusses the digestive actions of spices and herbs used in Indian cooking. Th ey report that spices stimulate digestive function primarily through increased bile production and secretion. Various spices also increase production and secretion of pancreatic lipases and amylases, and aff e c t a l k a l i n e p h o s p h a t a s e . Th e same researchers report rat studies that show bowel transit time was shortened by the ingestion of most herbs and spices. Th is shortening did not aff ect growth rates or produce diarrhea. Shortened bowel transit time has been associated with a decreased risk of colon cancer.

TURMERIC (CURCUMA LONGATA )

Turmeric, a member of the ginger family, is one of the primary anti- infl ammatory substances used in traditional Indian and Hawaiian medicine. Much research has been done on the anti-infl ammatory eff ects of turmeric, and especially on one active component, curcumin. 306 INTEGRATIVE GASTROENTEROLOGY

Table 31.2. Digestive Stimulation from Spices

Pancreatic Lipase activity Signiﬁ cantly > activity Stimulated > of at Alkaline amylases > > up to 80 % of disaccharides: least one disaccharase phosphatase sucrase, lactase, and enzyme maltase. Effects most pronounced when consumed on a regular basis

• G i n g e r • C u r c u m i n • C o r i a n d e r • G i n g e r • Increased: • Curcumin > nearly 300  • A j o w a n • Onion • O n i o n • F e n n e l • W h i t e • Cumin Asafetida coriander • Curcumin • Decreased: • Capsaicin (from • C o r i a n d e r cayenne) • Fenugreek • Piperine (from • M i n t black pepper) • Mustard • A s a f e t i d a

Adapted from Platel & Srinivasan,  ; Indian J Med Res,  , –. Review Article: Digestive stimulant action of spices: A myth or reality?

Turmeric has the following reported eff ects:

• inhibits infl ammation • a n t i o x i d a n t e ff ects • a n t i - m i c r o b i a l e ff ect • h e p a t o p r o t e c t i v e • c a n c e r p r o t e c t i v e

Th e studied mechanisms of action of curcumin include:

• inhibits TNF-alpha • inhibits arachidonic acid production • cortisone-like inhibitory action on phospholipases • a potent inhibitor of transcription factor NF-kappa B • antioxidant activity (Alternative Medicine Review, 2001).

Dosage: Take either 1 fi nger-sized piece of fresh turmeric twice daily or 1 tbsp. dried turmeric daily. If using fresh turmeric, place in blender with juice or water. If using dried turmeric, mix into foods such as salad dressings, Functional Foods for Digestive Health and Disease 307 grains, juice or tea. Some people enjoy simply mixing it with honey and adding it to tea.

UMEBOSHI PLUMS

Umeboshi plums are a traditional condiment used throughout Japan, Korea and China for their health benefi ts. Th e ume plum is picked unripe, dried in the sun, then pickled in a brine of sea salt and shiso leaves. Th e net result is a highly alkaline, naturally fermented pickle that is rich in enzymes and probiotics. Researchers have found it to have antioxidant and antibiotic properties. It has been used traditionally for hangovers, liver support, detoxifi cation, nausea, as an appetite stimulant, for skin diseases such as eczema, and for bad breath, dysentery, typhoid, and paratyphoid (Kuleshnyk, 2008 ). Umeboshi plums can be eaten in many ways. Th ey are used as a condiment on vegetables or rice. Th e plums are very salty, but can be eaten whole from the jar. Umeboshi vinegars are also available for use in salad dressings or on rice or other grains. Whole plums or umeboshi paste can also be drunk as a tea. Just let them steep in boiled water for 5 minutes, then drink. Th is is a very r e s t o r a t i v e t o n i c .

WHEATGRASS JUICE

Wheatgrass has been claimed to benefi t many conditions, but there has been only one good study on the use of wheatgrass juice for digestive diseases. Scandinavian researchers (Ben-Arye E 2002 ) studied 23 people with active distal ulcerative colitis who consumed either wheatgrass juice (two-thirds of an ounce to begin with, and increasing to 3.5 oz. daily) or placebo for one month. Th ere was signifi cant improvement in overall disease activity; sigmoi- doscopy showed improvement in 78  of people drinking wheatgrass juice, compared to 30 of people on placebo; 33 experienced nausea, while 41 reported an increase in vitality. Other researchers have linked wheatgrass juice to reduced need for blood transfusions in thalassemia (Marawaha, Bansal, Kaur, & Trehan, 2004 ), and a pilot study reports reduced myelotoxicity in women receiving chemotherapy for breast cancer. Wheatgrass juice can induce nausea, perhaps by acting as a powerful cholagogue and activator of liver detoxifi cation, a side eff ect that is oft en too strong for many people. Wheatgrass can be grown in a tray in the kitchen and then juiced with a special wheatgrass juicer. Wheatgrass juice can also be purchased at most 308 INTEGRATIVE GASTROENTEROLOGY natural food stores. Begin with small amounts and titrate up to prevent possible nausea.

Conclusion

Eating whole foods rather than packaged foods can signifi cantly enhance GI function. Th ere is a growing body of research on the use of customized diets to optimize function. When GI dysfunction occurs, it may be useful to clear the board and begin with a modifi ed fast or elimination diet. In clinical practice, use of a 2- to 3-day food diary on an initial visit can be one of your most useful diagnostic tools. Probiotics, prebiotics, fi ber, and polyphenols contribute to a well-balanced microbiota. It is the life in foods that gives us life: Th ink colors. Th ink fresh. Th ink about how your ancestors ate and move toward a more traditional diet, which will in turn move you toward optimal health.

32 The Role of Herbal Medicine in Integrative Gastroenterology

TIERAONA LOW DOG

Of the history of medicine the average person is likely to know only the tall tales of supposedly nonsensical treatments such as phlebotomy, poultices and purges… Such fl ippant rejection of many millennia of accumulated knowledge has its price, as does the rejection of traditional medicines from foreign cultures. Ignorance of the past has never been a fi rm foundation for the present. —Robert and Michele Root-Bernstein, Honey, Mud, Maggots and Other Medical Marvels

key concepts

■ Many functional gastrointestinal disorders are not eff ectively managed with conventional medications. ■ A number of botanicals show promise in the fi eld of gastroenterology, particularly when used within an integrative approach. ■ Ginger rhizome is an eff ective antiemetic and prokinetic. ■ Enteric-coated peppermint oil eff ectively treats irritable bowel syndrome. ■ Artichoke leaf is a reliable choleretic. ■ Berberine-rich plants have broad antimicrobial activity against numerous gut pathogens. ■ Turmeric is a potent anti-infl ammatory in infl ammatory bowel disease and potential chemopreventive agent in colorectal cancer. ■ S i l y m a r i n i s a n e ff ective hepatic protectant against drug- induced damage. ■ Clinicians should inquire about patient use of all dietary supplements, including botanicals, and document in the medical chart.

309 ■ Report adverse events from dietary supplements to FDA Medwatch and/or your local poison control center. ■

Herbal Medicine and Gastrointestinal Disorders

ince specifi c disorders are covered in depth throughout this text, this chapter will explore in broad terms the physiological action of plants S that are utilized in the treatment of gastrointestinal disorders. Gastrointestinal complaints rank among the most frequent reasons for primary care visits in the United States. Direct costs are in excess of $85 billion annually (Sandler et al., 2002), with an additional $20 billion in indirect costs due to days off work (Mullin et al., 2008 ). Many of these complaints fall into the category of functional gastrointestinal disorders, a group of conditions— such as irritable bowel syndrome (IBS), GERD, chronic constipation or diarrhea— for which no structural or biochemical cause can be found. A meta- analysis of 53 studies published in 1996 concluded that, due to methodological fl aws, there are no proven eff ective therapies for the treatment of non-ulcer dyspepsia (Veldhuyzen van Zanten et al., 1996 ), making many of these conditions of maldigestion amenable to the use of herbal medicine. In addition, herbal therapies are being explored for their benefi cial eff ects in infl ammatory bowel disease (IBD), as hepatoprotectants and for their potential to reduce gastric and colorectal cancer. While this chapter will focus on the use of botanicals, it should be implicitly understood that the use of these remedies must exist within a framework that includes appropriate diagnosis and holistic treatment; e.g., dietary recommendations, mind–body therapies, manual medicine, or other approaches that may promote wellness and healing in the patient. For the specifi c integrative management of irritable bowel syndrome, GERD, infl ammatory bowel disease, etc., please see the appropriate chapters within the text.

Introduction to Herbal Medicine

Herbal medicine, also referred to as phytotherapy or botanical medicine, is the use of plants, plant parts, and preparations made from them for therapeutic and/or preventive purposes. Herbal medicine gave rise to the modern sciences of botany, pharmacy, perfumery, and chemistry. Some of our most useful and benefi cial The Role of Herbal Medicine in Integrative Gastroenterology 311 drugs originate from plants, including aspirin (salicylic acid derivates derived from willow bark and meadowsweet), quinine (from cinchona bark), digoxin (from foxglove) and morphine (from opium poppy). Th rough isolating the potent actives in these plants, pharmaceutical products can be produced with a consistent and uniform composition. Indeed, one primary drug discovery model has been the identifi cation, isolation, and production of single active compounds. Th ese active compounds can then be researched, patented, and sold as drugs. While there are drugs that are made directly from plant material, these isolated compounds are not considered herbal medicines in the classic sense. In the traditional practice of herbal medicine, the plants and plant parts are themselves considered medicinally functioning wholes. Th ey are chemically complex mixtures, and the entire plant, or part, is considered the “active.” Refi nement of knowledge, tradition, and the preparations themselves are not stagnant, however, and the fi eld continues to evolve alongside our scientifi c studies. Milk thistle ( Silybum marianum ) has been used to treat a variety of conditions over the centuries. Its common name, “milk” thistle, is a reminder that the seeds have been valued as a lactagogue, or an agent that can help stimulate the production of breast milk. References to its use for liver and other digestive disorders can be found over the past several hundred years. In 1830, silymarin, a group of fl avones, were isolated and extracted from the seeds. An antidote for Amanita phalloides (deathcap mushroom) poisoning was later developed from these compounds. From the broad to the narrow, from crude plant to highly refi ned extract, the fi eld of herbal medicine continues to grow and fl ourish. Unfortunately, there has been little fi nancial incentive to study herbal medicines that can be easily grown in the garden or harvested in the wild, or to study products for which there is no type of protection for manufacturers. Nor has there been a way for consumers to distinguish clinically tested products from the myriad “me-too” products in the marketplace that piggyback off other companies’ research. And, all too oft en, the research that is undertaken is focused on the use of one particular herb for one specifi c condition, even though most experienced herbal practitioners individualize their prescriptions based upon the unique characteristics of the patient. Herbal mixtures are oft en preferred over single herbs, as they are thought to off er greater effi cacy and, to some degree, greater safety. Multi-herb formulations may have addi- tive, or synergistic, eff ects and secondary herbs can be included to modify potential side eff ects from the primary herb. For example, an anthraquinone- based herbal laxative (e.g., senna, cascara sagrada) oft en causes intestinal griping, which can be reduced or eliminated by adding gut antispasmodics (e.g., fennel, ginger). Given the number of traditional medical systems that utilize herbal formulations, the focus on single herb preparations may be a critical shortcoming in botanical research, though monotherapy is probably 312 INTEGRATIVE GASTROENTEROLOGY the best approach for the clinician who is just starting to use herbs in his or her practice. Getting to know each herb in this way allows the practitioner to gain greater familiarity and expertise with its use.

Quality of Botanical Products

Given the dizzying array of herbal products, it is understandable that both consumers and healthcare professionals have diffi culty navigating the supplement marketplace. Consumers look down the aisle and ask, “Which product should I take? What dose? Will it interact with my medications? Does it work? Is it safe?” In addition to questions of effi cacy and safety inherent to the plant, there are also concerns about the quality of dietary supplements in general, and botanical products in particular, as the media and professional literature are fi lled with reports of product adulteration and contamination, as well as variation between what is printed on the label and what is actually in the bottle. Th ough not a signifi cant problem with products manufactured in the United States, cases of heavy metal poisoning (e.g., mercury, lead, and arsenic) from Chinese, Indian, Arabic, and African traditional remedies have been reported, and testing has demonstrated that a number of these products contain unacceptable levels of arsenic, lead, mercury, and cadmium (Cooper et al., 2007 ; Obi et al., 2006 ; Saper et al., 2004 ). While many manufacturers produce high-quality botanical products, the unscrupulous and/or incompetent have, unfortunately, tarnished the industry, making it relatively diffi cult for consumers or practitioners to distinguish the good companies from the bad. With the passage of the new good manufacturing guidelines (GMP) by the Food and Drug Administration (FDA) in June of 2007, concerns of contamination, adulteration, and poor quality will hopefully become less of an issue in the future. Th e inspection of dietary supplement manufacturers by the FDA will increase in 2009, when companies will be required to come into compliance with the new guidelines. A number of companies will in all likelihood not be able to meet the stringent requirements for supply chain management and traceability. Th e burden on manufacturers, however, should actually help the industry in the long run, as consumers will become more confi dent in the products they purchase, and healthcare providers will be more comfortable making supplement recommendations.

Safety

Overall, most of the herbs in general commerce in the United States have a relatively good safety profi le when used appropriately and manufactured to The Role of Herbal Medicine in Integrative Gastroenterology 313 high-quality standards. As more concentrated herbal products are introduced into the marketplace, many of which will be taken for extended periods of time, new questions of safety will undoubtedly arise. Th e chronic use of certain herbs (e.g., comfrey, chaparral, licorice) can cause hepatic, renal, or electrolyte abnormalities. Like any chemically active substance, whether an herb is safe or toxic depends upon the dose, type of product, and the underlying constitution o f t h e p a t i e n t .

The concomitant use of botanical remedies with prescription or over-the- counter medications may lead to adverse interactions, especially in elders and those with diminished renal or hepatic function.

A national survey noted that 16  of prescription drug users also reported taking one or more herbals/supplements within the prior week (Kaufman et al., 2002 ). It is imperative that clinicians dialogue with patients about their use of botanical medicines and other dietary supplements, to help prevent potentially dangerous herb–drug interactions. Th ere are a wide variety of herbal practices and products available in the United States, which makes gen- eralizations diffi cult; however, by asking a few open-ended questions, clinicians should be able to assess the patient’s beliefs, cultural practices, and use of botanical remedies:

• When you were growing up did you, or your family, ever use any medicinal plants or herbal remedies to improve your health or treat an illness? • How do you use herbs or herbal remedies in your home? • Are you taking any herbs or herbal medicines now? If so, what are you trying to treat, and do you think the herbs are working?

Document all patient responses in the medical chart and be alert for potential adverse eff ects and herb–drug interactions, as well as therapeutic benefi t .

If you suspect a possible adverse effect, report it to FDA Medwatch at www. fda.gov/medwatch. Another excellent resource is to contact your local poison control centers; the new nationwide toll-free number in the U.S. for poison control is 800-222-1222. 314 INTEGRATIVE GASTROENTEROLOGY

Herbal Actions

When examining botanicals it is useful to start with a basic understanding of how they work. In some cases, scientifi c research has identifi ed key compounds within the plant that account for its physiological eff ects; in other cases, there are multiple compounds working in harmony that account for the overall therapeutic eff ect, making the hunt for an “active compound” futile at best. More than 2,000 years ago, anticholinergic plants such as Atropa belladonna were used to treat painful gastrointestinal spasm, even though the tropane alkaloids atropine, hyoscyamine, and scopolamine would not be isolated for many centuries. Practitioners observed the physiologic action of these plants and were able to use them eff ectively in their patients, even in the absence of isolating specifi c compounds or having a detailed understanding of cellular physiology. Th us, this section is a blending of traditional wisdom and modern science, observation and reductionism. It is beyond the scope of this chapter to address all herbal actions; it will focus only on those commonly considered when addressing GI disorders.

ANTIEMETIC

Th e most potent antiemetic plants are those containing the anticholinergic tropane alkaloids hyoscamine, scopolamine and/or atropine. Th e dominant plants in this category include belladonna ( Atropa belladonna), jimson weed ( Datura stramonium) and henbane (Hyoscyamus niger). Scopolamine patches have been widely used to reduce postoperative nausea and vomiting, as well as motion sickness; however, these plants and their isolated alkaloids are associated with considerable side eff ects and are not generally used by practicing herbalists today. A mild, yet eff ective, antiemetic is ginger (Zingiber offi cinale). While commonly referred to as “ginger root” it is actually a rhizome, or underground stem. Ginger is a popular home remedy for dyspepsia and has been clinically studied for hyperemesis gravidarum, motion sickness, and chemotherapy- induced nausea and vomiting. A meta-analysis of randomized controlled trials favored ginger over placebo for relief of nausea and vomiting in general (Ernst & Pittler, 2000 ), while a review of six randomized controlled trials specifi cally addressing nausea and vomiting of pregnancy found 1.0–1.5 grams/day of dried ginger more eff ective than placebo (Borrelli et al., 2005a ). Th e way in which ginger acts as an anti-emetic is not completely understood. One class of antiemetics used in conventional medicine is the 5-hydroxytryptamine (5-HT) antagonists, such as ondansetron, that work The Role of Herbal Medicine in Integrative Gastroenterology 315

specifi cally on 5-HT3. Several components of ginger; 6-gingerol, 6-shogaol and galanolactone, have shown anti-5-HT activity with galanolactone acting as a competitive antagonist at ileal 5-HT3 receptors (Huang et al., 1991 ). Cisplatin, one of our most emetogenic chemotherapeutic agents, inhibits gastric-emptying, which is thought to be the primary reason it causes nausea. Both the acetone extract of ginger and ginger juice eff ectively reverse cisplatin- induced delay in gastric emptying. Th e reversal produced by ginger acetone extract was similar to the eff ect seen with ondansetron, while ginger juice at oral doses of 2 and 4 ml/kg, was superior to the drug (Sharma & Gupta, 1998 ). A study in 24 healthy human volunteers found that 1,200 mg of dried ginger accelerated gastric emptying and stimulated antral contractions greater than placebo (Wu et al., 2008). Note: dried rhizome is a more potent antiemetic t h a n f r e s h .

Because of ginger’s prokinetic and antiemetic activity, it is often included in formulations for gastroparesis, which can present with signs and symptoms such as heartburn, gastroesophageal reﬂ ux, early satiety, abdominal bloating, and nausea and/or vomiting several hours after eating a meal. The dose is typically one gram dried rhizome, taken 15 to 20 minutes after meals. Another excellent prokinetic herb is corydalis (Corydalis ambigua ), a plant related to the opium poppy. It has been used in traditional Chinese medicine for centuries as a sedative and to relieve abdominal pain. The combination of corydalis root and pharbitis seed (Pharbitis nil. or P. purpurea ) signiﬁ cantly accelerated gastric emptying, and restored delayed gastric emptying caused by apomorphine and cisplatin, up to almost normal levels in animal models (Lee, 2008).

ANTI-INFLAMMATORY

Th ere are numerous botanicals with anti-infl ammatory activity, and since all orally ingested herbs pass directly through the gut, many are useful for relieving gastrointestinal irritation and infl ammation. Research demonstrates that botanicals reduce infl ammation through a variety of mechanisms including mediation of cytokine secretion, histamine release, immunoglobulin secretion, lymphocyte proliferation, and cytotoxic activity (Plaeger, 2003 ). Compounds with potent anti-infl ammatory activity particularly relevant to the GI tract include curcumin (turmeric), gingerols and shogaols (ginger), glycyrrhizin (licorice), alpha-bisabolol and azulenes (chamomile), resveratrol (red grapes), tea polyphenols (tea), silymarin (milk thistle), boswellic acids (boswellia) and 316 INTEGRATIVE GASTROENTEROLOGY withanolides (ashwagandha; see Khanna et al., 2007 ). Green tea polyphenol extracts (Abboud, 2008 ; Mazzon, Muià, & Paola, 2005 ) and resveratrol (Martín, 2006, 2004 ) attenuate intestinal injury in animal models of experimental colitis. Animal data and small pilot studies in humans indicate that Boswellia serrata extracts may be of some benefi t in collagenous colitis, ulcerative colitis and Crohn’s disease (Madisch, Miehlke, & Eichele, 2007 , Ammon, 2006 ). Ashwagandha (Withania somnifera) reduces gastric acidity and ulceration in animal models of stress induced ulcer (Bhatnagar, Sisodia, & Bhatnagar, 2005 ). Th e gastro-protectant eff ects of licorice root (Glycrrhiza glabra, G. uralensis ) have been known for centuries. Research has shown licorice to be a useful anti-ulcer agent as eff ective as H2 blockers (Aly, 2005). Compounds in licorice increase local prostaglandin levels that promote mucus secretion and cell proliferation in the stomach (Baker, 1994).

Prolonged use of licorice at doses higher than 1 gram per day can lead to pseudoaldosteronism. A special preparation, deglycyrrhizinated licorice (DGL), has had the glycyrrhizin removed and may be taken without concern. I ﬁ nd DGL to be very effective for managing GERD and for helping patients wean slowly off proton-pump inhibitors. The usual dosage is 760 mg, chewed, taken 20 minutes before meals for 4 to 6 weeks and then as needed.

It is turmeric (Curcuma longa), or more oft en the isolated polyphenoic compounds collectively referred to as curcumin, that is being heavily researched these days. Th ere are numerous Phase I and II studies evaluating the eff ectiveness of curcumin alone, or in combination with other compounds, for a wide range of conditions including colorectal cancer, pancreatic cancer, multiple myeloma, Alzheimer’s disease, psoriasis, IBD, IBS, familial adenomatous polyposis (FAP), oral lichen planus, and rheumatoid arthritis (clinicaltrials.gov). Curcumin has a range of molecular targets that contribute to its overall pharmacological eff ects, such as modulating the activation of various transcription factors and regulating the expression of infl ammatory enzymes, cytokines, adhesion molecules and cell survival proteins. As curcumin is poorly absorbed from the gut, much of its therapeutic benefi t is concentrated in the GI tract. Studies show that doses of 760 mg to 2.0 grams per day of curcumin are benefi cial for improving symptoms or preventing relapse in patients with ulcerative colitis and Crohn’s disease (Holt, Katz, & Kirshoff , 2005 ; Hanai et al., 2006 ). Curcumin is also a highly promising chemopreventive agent. Th e combination of 480 mg of curcumin and 20 mg of quercetin taken orally three The Role of Herbal Medicine in Integrative Gastroenterology 317 times a day reduced the number and size of ileal and rectal adenomas in patients with FAP (Cruz-Correa et al., 2006 ). Th e average daily intake of turmeric in India is approximately 2 to 2.5 grams/ day, which corresponds to an intake of 60 to 100 mg of daily dietary curcumin (Goel, Jhurani, & Aggarwal, 2008 ). Phase I clinical trials demonstrate that curcumin is safe at doses as high as 12 grams/day (Anand, 2007 ). While many practitioners recommend turmeric over the isolated or concentrated curcuminoids, it is important to note that the medicinal doses used in many clinical trials would require the consumption of more than 25 grams per day of turmeric!

When two grams of curcumin was given orally to healthy humans, serum curcumin levels were either very low or undetectable. Concomitant administration of piperine, a primary alkaloid in black pepper, increased bioavailability by 2000 % (Shoba et al., 1998 ). Interestingly, black pepper has been traditionally added to many herbal preparations to enhance absorption and increase the effectiveness of the formulation. To concentrate curcumin in the gut, it is best to take a non-lipid preparation without piperine on an empty stomach or 1 to 2 hours after eating.

ANTIMICROBIAL

Plants contain multiple constituents: phenols, quinones, fl avones, tannins, ter- penoids and alkaloids, with antibacterial, antiprotozoal and antiviral activity (Cowan, 1999 ). Botanical antimicrobials that are safe, eff ective, and inexpensive may have signifi cant global health implications in areas endemic with infectious diarrhea, and may expand our arsenal against Helicobacter pylori . Many common spices have antimicrobial activity. Turmeric, ginger, chili, and cumin are bactericidal to Helicobacter pylori, and turmeric reduces adhesion of the bacterium to the stomach mucosa (O’Mahony et al., 2005 ). Berberine- containing plants, such as goldenseal (Hydrastis canadensis ), barberry (Berberis vulgaris), Oregon grape root ( Mahonia aquifolium) and goldthread ( Coptis sinensis), have been traditionally used to treat gastritis and infectious diarrhea. Crude methanol extracts of goldenseal root and rhizomes are highly active against multiple strains of H. pylori (Mahady et al., 2003 ). Berberine inhibits the growth of Giardia lamblia, Entamoeba histolytica, Trichomonas vaginalis , and Leishmania donovani (Kaneda, Tanaka, & Saw, 1990 ). Berberine reduces intestinal secretion of water and electrolytes induced by cholera toxin, and directly inhibits some V. cholera and E. coli enterotoxins, signifi cantly reducing smooth muscle contraction and intestinal motility (Akhter, 1979 ). 318 INTEGRATIVE GASTROENTEROLOGY

I have successfully treated a number of patients with Entamoeba histolytica who failed multiple rounds of metronidazole with both goldenseal and Oregon grape root. All berberine-rich plants taste bad; better compliance will be achieved with encapsulated products. I generally recommend 1,000 mg of Oregon grape root three times daily for 14-30 days.

Allium vegetables, particularly garlic ( Allium sativum), exhibit broad antimicrobial activity against many organisms. Louis Pasteur documented the antibacterial activity of garlic in 1858, while Albert Schweitzer reportedly relied upon it to treat amoebic dysentery. Modern research confi rms that garlic is active against a number of diarrhea-causing bacterium, including Salmonella and Escherichia coli O15 (Adler, 2002 ). It is also active against Entamoeba histolytica and Giardia lamblia, major sources of gastrointestinal infection worldwide (Ankri, 1999 ; Harris et al., 2000 ). When the garlic clove is crushed, the odorless amino acid alliin is metabolized by the enzyme alliinase, to yield allicin and other thiosulfi nates that are the source of garlic’s characteristic odor. Th e thiosulfi nates and other secondary metabolites are thought to be responsible for garlic’s antimicrobial activity (Yoshida et al., 1999 ). Th ough low heat does not appear to destroy the antimicrobial eff ects of garlic — one study found the antibacterial activity of garlic stable at 100° C, or 212° F (Sasaki et al., 1999 ) — raw garlic preparations are probably the best choice. In addition to its antimicrobial eff ects, there is a body of evidence suggesting that garlic is protective to the GI mucosa. Multiple studies confi rm that aged garlic extracts prevent or reduce the gastrointestinal toxicity that can result from administration of methotrexate (Li et al., 2008 , Horie et al., 2006 , Yüncü, Eralp, & Celik, 2006 ), while a systematic review found an inverse relationship between raw and cooked garlic consumption and colorectal cancer risk (Ngo, 2007 ).

ANTISPASMODIC

Antispasmodic plants with specifi c affi nity for the GI tract include hops ( Humulus lupulus ), valerian ( Valeriana offi cinalis; V. wallachii ), wild yam (Dioscorea villosa), bogbean ( Menyanthes trifoliata), chamomile (Matricaria recutita), and lemon balm (Melissa offi cinalis). Chamomile is commonly used to alleviate minor abdominal pain in children and elders, as it is mild in action and low in adverse eff ects. Animal data confi rm the antispasmodic activity of both aqueous and ethanolic extracts of chamomile, with fractions being similar or superior to papervine, a known smooth muscle relaxant (McKay & The Role of Herbal Medicine in Integrative Gastroenterology 319

Blumberg, 2006 ). Valerian, though primarily known as a mild sedative or calmative, has been shown to reduce small bowel contractions in animal studies (Gilani et al., 2005 ), and is oft en included in IBS formulations for those with anxiety or nervousness. Wild yam was traditionally referred to as “colic” root, a nod to its historical use in crampy intestinal pain. One of the most popular gut remedies for alleviating intestinal gas and abdominal cramps is peppermint ( Mentha x piperita ). Peppermint oil signifi cantly prolongs orocecal transit time (Goerg, 2003) and directly inhibits smooth muscle contractions by interacting with calcium channels (Hills & Aaronson 1991 ). Th e active compounds in peppermint oil, menthol and men- thone, are highly fat-soluble and rapidly absorbed from the proximal gut. Th us, enteric-coated sustained release peppermint oil capsules are the ideal formulation for IBS, particularly diarrhea dominant. Peppermint oil is oft en found in combination with caraway seed oil. Caraway seed oil inhibits smooth muscle contraction (Al-Essa 2010 ) and both peppermint and caraway oils inhibit gallbladder emptying (Goerg, 2003). A review of four randomized clinical trials found the fi xed combination of peppermint and caraway oil to have eff ects of similar or greater magnitude when compared with conventional therapies used in dyspepsia, as well as a very good safety profi le (Th ompson Coon & Ernst, 2002 ). Interestingly, caraway may be protective against colon carcinogenesis (Deeptha et al., 2006 ), as well as having lipid- and triglyceride-lowering eff ects (Lemhadri et al., 2006 ).

There are a number of high-quality peppermint oil capsules in the marketplace. The dose is 0.2 ml enteric-coated softgel capsule taken 3 times per day, 30 minutes before meals. If this causes heartburn or anal burning, instruct the patient to take with food. Iberogast ® is a proprietary blend of nine herbs (chamomile, lemon balm, caraway, peppermint, clown’s mustard (Iberis amara), and others) that has demonstrated beneﬁ cial effects in cases of functional dyspepsia and irritable bowel syndrome (Rosch 2006 ). It has a pleasant taste and is suitable for both children and adults, though it contains 31% alcohol. It should be noted that the mixture contains small amounts of greater celandine ( Chelidonium majus), which may induce hepatotoxicity at high doses. However, this blend has been used for more than 40 years in Europe with good postmarketing surveillance safety data, even in pediatrics.

BITTERS

Bitter-tasting herbs have been used for millennia as digestive aids. Th e bitter taste stimulates a sensory response in the tongue, which in turn increases the 320 INTEGRATIVE GASTROENTEROLOGY production of gastric acid and primes the exocrine pancreas. Bitters are generally taken 20 minutes before the main meal for those who experience symptoms such as bloating, gas, sluggish stools, and a sense of fullness aft er eating. Some of the most commonly used bitter herbs include artichoke (Cynara scolymus ), dandelion root (Taraxacum offi cinale ), gentian ( Gentiana lutea ), hops, and bitter orange peel (Citrus aurantium ). Dandelion is a well-known bitter digestant with anti-infl ammatory and prebiotic activity (Schütz, 2006 ). While the leaves are predominantly employed as a diuretic, the roots are used in cases of habitual constipation, sluggish digestion, bloating aft er meals, and poor appetite. Bitter orange peel is oft en included in small amounts in herbal formulations as a fl avoring agent, and also a mild bitter and carminative.

Angostura bitters, a proprietary product available in the liquor section of most grocery stores, is a classic bitter aperitif, taken before meals to aid digestion. There are numerous other proprietary bitters for sale. I often recommend Gallexier Herbal Bitters by Floradix, as it does not contain any alcohol or the laxative herbs found in some blends. The small amount of bitter orange peel in digestive formulations is quite safe— but be aware that many weight-loss products contain very concentrated forms of the herb, standardized for high synephrine content.

CARMINATIVES

Carminatives are herbs that relieve bloating and intestinal gas. Th ese plants are oft en rich in volatile oils that relax the GI smooth muscle; thus, they are also referred to as gut antispasmodics. Carminatives are usually included in herbal laxative formulations to reduce the abdominal cramping that can occur with both bulk-forming and stimulant laxatives. Th e vast majority of carminatives fall into the spice/culinary herb category. Aniseed, cinnamon, fennel, dill, caraway, and peppermint are classic examples. Fennel is used to relieve digestive complaints in young children, as it is mild tasting and well tolerated. Two small studies have shown that fennel emulsion (Alexandrovich, 2003 ) and fennel tea, in combination with chamomile and lemon balm (Savino et al., 2005 ), improves infantile colic. Peppermint, fennel, or anise can be made into a pleasant aft er- dinner tea (tisane), or the East Indian tradition of chewing fennel seeds aft er the meal is also eff ective for relieving bloating and gas. Herbal digestifs have a longstanding tradition of use in Europe for improving digestion. Classic examples include Anisette and Crème de Menthe. Generally, one tablespoon is taken alone or diluted in water aft er the meal. The Role of Herbal Medicine in Integrative Gastroenterology 321

CHOLERETICS/CHOLAGOGUES/DIGESTANTS

Choleretics increase the production of bile by the liver, cholagogues stimulate the contraction and release of bile from the gallbladder, and digestant is a general term used to describe those remedies that act on the gallbladder and exocrine pancreas. All three of these terms are used somewhat interchangeably in herbal medicine. Many spices and culinary herbs fall under this category, as gastric secretions are stimulated by their aroma and pungent taste. Ginger, coriander, cumin, turmeric, chili, and peppercorn increase pancreatic lipase and amylase activity (Platel & Srinivasan, 1996 ), as well as bile volume and bile acid secretion, improving the digestion of dietary fats and carbohydrates (Platel et al., 2002 ). Ginger, chili, and peppercorn dramatically enhance pancreatic trypsin, enhancing the digestion of protein. A premiere choleretic/cholagogue is globe artichoke leaf ( Cynara scolymus ), considered a specifi c for digestive disorders in traditional herbal medicine, especially those accompanied by fl atulence, abdominal pain, bloating, and poor digestion of fats. Artichoke leaf is a potent choleretic and cholagogue (Speroni, 2003) and the enhanced biliary cholesterol excretion (Saenz Rodriguez 2002 ) likely contributes to its clinically documented lipid-lowering eff ects. Interestingly, globe artichoke is a member of the milk thistle family and also a source of the hepatoprotectant compound silymarin, the cold-pressed seed oil yielding up to 85  . Artichoke and yarrow are also potent choleretics.

DEMULCENTS

Demulcents soothe and protect irritated tissues. Th ese herbs are typically rich in mucopolysaccharides that become “slimy” when they come in contact with water. Th ese compounds are destroyed by high alcohol content, so are best prepared as teas. Demulcents are used to alleviate irritation of the mouth, throat, esophagus, stomach, and bowels. Marshmallow (Althaea offi cinalis ) and slippery elm bark (Ulmus rubra ) are classic demulcents. Th e British Herbal Compendium recognizes the use of marshmallow root or leaf in cases of duodenal ulceration, ulcerative colitis, and enteritis. Th e inner bark of slippery elm (Ulmus fulva, U. rubra) has been used as a food and medicine for centuries, and was an offi cial drug in the United States Pharmacopeia from 1820 to 1936. Native Americans and early settlers made a nutritious gruel from the inner bark, in a fashion similar to oatmeal. Th e polysaccharide-rich mucilage found within the bark is an eff ective cough 322 INTEGRATIVE GASTROENTEROLOGY suppressant, soothes a sore throat, and helps to heal the mucosa of the gastrointestinal tract. Indications listed in the British Herbal Compendium for slippery elm bark include “infl ammations and ulcerations of the gastrointestinal tract, such as oesophagitis, gastritis, colitis, gastric or duodenal ulcers; diar- rhoea” (Bradley 1992). Th ough there are virtually no modern studies on slippery elm, the FDA has approved slippery elm as a safe nonprescription product for demulcent use. Demulcents are usually taken at least one hour aft er prescription medications to prevent interference with absorption.

There are slippery elm lozenges, ﬂ avored and unﬂ avored, as well as medicinal teas readily available at most natural grocery stores. You can make your own by taking 1 tsp. of the powdered bark, adding 1 to 2 tbsp. water and making into a paste. Then add 2 cups boiling water. Let steep for 10 minutes. Pour off the liquid and add a pinch of cinnamon, nutmeg, or pumpkin pie spice. It’s great for soothing a sore throat, easing a cough, or relieving occasional heartburn.

HEPATICS

Hepatics generally refer to herbs that have a benefi cial eff ect upon the liver. Th e prime examples include milk thistle ( Silybum marianum), katuka (Picrorrhiza kurroa ), artichoke ( Cynara scolymus ) and phyllanthus ( Phyllanthus amarus ). Th e most rigorous research has focused on the benefi cial eff ects of milk thistle. Th e seeds of milk thistle have been used for more than 2,000 years as a treatment for liver and biliary disorders. Modern studies on the fl avono- lignans collectively referred to as silymarin have demonstrated hepatoprotection from various substances including alcohol, acetaminophen, and the toxins from Amanita phalloides, or deathcap mushroom. Th e main eff ects of silymarin are the membrane stabilizing and antioxidant eff ects, which can assist in liver cell regeneration, decrease infl ammation and inhibit fi brogenesis in the liver. Th ese results have been established by experimental and clinical trials. A systematic review and meta-analysis concluded that the use of silymarin is reasonable in Amanita phalloides poisoning, alcoholic liver disease (as an addition to abstinence) and Child’s A cirrhosis (Saller, 2008). A recent study using intravenous silymarin in combination with ribivarin demonstrated rapid suppression of hepatitis C viremia (Biermer, 2009 ). Together, these and other data suggest that silymarin may be used for its antiviral eff ects in future clinical trials for hepatitis C. Th e fl avonolignan silibinin competitively antagonizes toxins from binding to liver cell membrane receptors in mushroom poisoning and other hepatotoxic The Role of Herbal Medicine in Integrative Gastroenterology 323 exposures. Administration of silibinin up to 48 hours aft er mushroom ingestion appears to be eff ective for preventing severe liver damage. Th e dose of silibinin: IV 20 to 50 mg/kg/d. Interestingly, while widely available in other countries, this IV form of milk thistle is not presently available in the United States. In addition to hepatic protection, animal studies suggest that silymarin may protect against chemotherapy-induced renal toxicity from cisplatin (Bokemeyer et al., 1996 ) and adriamycin (El-Shitany 2008 ) and that silymarin administered prior to radiation acts as a renal protectant (Ramadan et al., 2002 ).

Milk thistle is a fantastic example of an herb that may offer a real beneﬁ t in today’s modern world as it can offer hepatoprotection from environmental, toxin- and drug-induced damage. Silymarin appears to offer both liver and renal protection in patients undergoing chemotherapy or radiation. It is reassuring that in vivo studies demonstrate that oral administration of silymarin does not inhibit CYP3A4 (Fuhr 2007), however in vivo pharmacokinetic studies are lacking at this time for other CYP enzyme systems and intravenous administration likely has a different proﬁ le. Typical dose for silymarin is 420-760 mg silymarin per day, taken in three divided doses. Higher doses may be necessary based upon emerging evidence.

LAXATIVES

Laxatives stimulate the intestines, causing the body to eliminate waste. Th e primary types of plant laxatives include fi ber or bulk, stimulants or cathartics, and stool soft eners. Bulk-forming laxatives are indigestible, hydrophilic substances that absorb water, forming a bulky, emollient gel that distends the colon and promotes peristalsis. Psyllium seed and husks are prototypical of the category, though they oft en take up to four weeks for patients to notice a signifi cant improvement in bowel function. Encouraging patients to drink herbal teas of ginger, fennel, or caraway can help ease the abdominal distension and gas that oft en accompanies initial increases in fi ber intake. Flaxseed (Linum usitatissimum ) is another bulk-forming laxative, containing both soluble and insoluble fi ber, which can be used to ease constipation and may also help reduce the risk of colon cancer when consumed regularly in the diet (Bommareddy et al., 2006 ). Th is nutty fl avored seed is also rich in alpha linolenic acid, an omega 3-fatty acid, and is a good source of magnesium. Grind fl ax seeds in a coff ee grinder to enhance their digestibility and nutritional value. Take 1 to 2 tbsp. two times per day to improve regularity. Each tablespoon contains 2.2 grams of fi ber, 1.6 grams of protein, and 1,800 mg of omega-3 fat. 324 INTEGRATIVE GASTROENTEROLOGY

While little known in the United States, a common Ayurvedic remedy for constipation is Triphala, made from the dried fruits of three medicinal plants: Terminalia chebula, Terminalia belerica and Phyllanthus embelica . I have had tremendous success using it for those with constipation dominant irritable bowel syndrome, as well as elders and children with hard, dry stools. Take 1 to 2 grams per day for 5 to 7 days, and increase to 3 to 4 grams per day if needed. Triphala is not habit forming and is available in capsules or powders that can easily be mixed with food or in beverages.

Many stimulant laxatives and cathartics are derived from plants rich in bitter anthraquinone glycosides, such as cascara sagrada ( Rhamnus purshiana), senna (Cassia angustifolia), aloe latex ( Aloe spp) and turkey rhubarb (Rheum palmatum ). Th e anthraquinone glycosides are metabolized slowly by gut microfl ora, resulting in a period of 8 to 10 hours between ingestion and evacuation of stool. Concerns regarding the relationship of anthraquinone laxative use and colon cancer, or the belief that chronic use causes structural or functional impairment of enteric nerves or intestinal smooth muscle, are inconclusive at best (Borrelli et al., 2005b ; Wald, 2003 ; Nusko et al., 1997 ). For patients who fail to respond to bulk or osmotic laxatives, these plants represent a reasonable alternative. Many herbalists contraindicate the use of stimulant laxatives during pregnancy, but when bulk-forming laxatives are ineff ective, senna is considered safe (Prather, 2004 ).

Conclusion

Herbalists consider a well-functioning GI system to be the foundation of health. Proton pump inhibitors, antacids, and NSAIDs, while of great benefi t, are used far too oft en and can have devastating eff ects on the gut long term. In herbal medicine, the mantra is remove, repair and restore. Remove foods and other substances that are disruptive to the integrity of the gut (e.g., food allergens, drugs, tobacco, etc.). Repair the gut through a wholesome diet rich in plant fi ber, appropriate use of botanicals that have anti-infl ammatory and demulcent activity, and supplements such as glutamine that nourish the colonic tissue. Restore both motility and healthy microfl ora by adding fermented foods, prebiotics, probiotics, dietary fi ber, and by using prokinetic agents as needed. When reviewing the history and contemporary research, it is clear that herbal medicines have played, and continue to play, a signifi cant role in treating The Role of Herbal Medicine in Integrative Gastroenterology 325 disease and improving health. Given the vast number of botanicals that have yet to be explored for their medicinal eff ects, it is likely that plants will continue to contribute to our understanding and management of gastrointestinal disease. However, there remains much work to be done from “bench to bedside” to determine which botanicals are most effi cacious and how they are best used in clinical practice. While this text cites the clinical trials that are being conducted on herbal medicines for various GI disorders, the research literature refl ects only a very small percentage of plants that have potential benefi t, and there is defi nitely a need for more rigorous and creative research in this area. 33 Brief Review of Mind–Body Medicine in Gastroenterology Practice

MIRANDA A.L. VAN TILBURG , STEPHAN R. WEINLAND , AND OLAFUR S. PALSSON

key concepts

■ Mind–body medicine recognizes that illness symptoms and behaviors cannot be completely explained by biological processes alone, but only from the interaction between biological and psychosocial processes. ■ Both psychosocial and biological aspects are important targets for therapy. ■ Practicing mind–body medicine means, fi rst and foremost, that physicians elicit information from the patient about his/her illness beliefs and expectations for treatment. ■ Behavioral and cognitive interventions for functional gastrointestinal disorders comprise a range of therapeutic modalities (cognitive-behavioral therapy, hypnotherapy, biofeedback, guided imagery, relaxation training) that have at their core a therapeutic relationship and an understanding of the mind– body connection. ■ Behavioral and cognitive treatments aimed at reducing gastrointestinal symptoms have proven eff ectiveness for the treatment of highly prevalent conditions like IBS and functional dyspepsia. ■

he dualistic model, common in medical practice, characterizes patient symptoms as either of organic or functional origin, with little under- T standing of relational aspects between the two. Th is view has been propagated through medical education and persists in clinical practice and

326 Brief Review of Mind–Body Medicine in Gastroenterology Practice 327 research. Patients are oft en categorized as either having “biomedical” or “psychosocial” diffi culties and are treated accordingly (Drossman, 1998 ) However, it is increasingly recognized that this type of medicine is insuffi cient in treating many bodily ailments. Mind–body medicine, on the other hand, recognizes that illness symptoms and behaviors cannot be completely explained by biological processes alone, but only by understanding the interaction between biological and psychosocial processes. Th erefore, both biological and psychosocial processes are addressed in medical care. Th e application of the mind– body approach to medicine and gastroenterological illness has gained increased prominence since George Engel fi rst introduced the biopsychosocial model of illness (Engel, 1977 ). Nowadays, the U. S. National Institutes of Health describes mind–body medicine as a fi eld that views health care providers as “catalysts and guides” in the process of health promotion, and diseases as “opportunity for personal growth and transformation” (NCCAM, 2008 ). Th is change in view of medicine away from having biological focus to a more experiential one that feels awkward to many practitioners. However, a change in name or direction does not mean that the scientifi c method is not applicable to studies of mind–body relationships and treatments. Indeed, empirical validation is critically important when considering newer treatments. In this chapter, we will briefl y review mind–body medicine in gastroenterology practice. Few areas of medicine demonstrate clearer connections between mind and body as those seen in gastroenterology. Lay terms of experiencing “butterfl ies in the stomach” in the presence of anxiety or “not having the stomach” to face a situation are just some of the ways that an understanding of a brain–gut connection is communicated (Read, 1993 ). Although mind–body medicine can be and is practiced across all areas of gastroenterology, it has gained the most acceptance for the treatment of functional gastrointestinal disorders because of the large literature supporting its use.

Physician–Patient Relationship

Mind–body medicine starts in the physician’s offi ce. Working with patients experiencing GI diffi culties in practice can be diffi cult when the disorders have a “functional” presentation. Standard care for functional GI disorders by physicians and other medical professionals is aimed primarily at psychosocial aspects, such as reassurance and advice on diet/exercise/stress, and only secondarily at pharmacological and other biomedical approaches (Whitehead et al., 2004 ). Since most patients believe in a biomedical approach to illness, this type of treatment may not be easily accepted. Many physicians experience diffi culty in working with patients who present with increasingly complex 328 INTEGRATIVE GASTROENTEROLOGY disorders as one moves up the care hierarchy. Mitchell and Drossman (1987 ) have found that patients with irritable bowel syndrome, a typical “functional” GI illness, make up 12 of primary care issues and up to 28 of gastroenterology practice. Patient–physician interactions can play a signifi cant role in the benefi t/detriment experienced by GI patients in working with clinicians. Drossman and colleagues have extensively written on the use of eff ective physician-patient communications in functional gastrointestinal disorders (for example see (Drossman, 1997 )) (Drossman, 2009 ) Here, we will briefl y describe some important aspects.

Practicing mind–body medicine means, ﬁ rst and foremost, that physicians elicit information from the patient about his/her illness beliefs and expectations for treatment. This involves understanding not only the symptoms, but the life context within which the symptoms developed. The patient’s worries and concerns must also be identiﬁ ed and addressed.

A common fear oft en elicited from the patient is that of having an underlying cancer. Quickly dismissing the concern by stating that “nothing is seriously wrong” may not be reassuring to the patient, particularly if the concerns have not been properly addressed through proper diagnostic testing. A quick dismissal may lead the patient to believe that the physician is incompetent, or that “it must be in my head.” When a diagnosis is made, it is helpful to explain to the patient that the symptoms are occurring within a biopsychosocial construct; i.e., with the integration of biological and psychosocial processes in their illness and disease. Also, many patients have never been told what they suff er from, and providing a positive diagnosis (e.g., of IBS) and then explaining the physiological basis for the symptoms can be very empowering. A physician needs to communicate that (s)he is rather confi dent, based on the current fi ndings, that the patient suff ers from a functional disorder, but will stay vigilant for changes that require future testing. Th is approach emphasizes continuation of care, and understanding of the patient’s concern while limiting ordering unnecessary tests. Furthermore, many patients feel unable to deal with their symptoms, and therefore relinquish control of their symptoms to the physician. With any chronic illness, no matter what the cause, self-management is a crucial aspect of medical care. Th erefore, patients and physicians should negotiate shared responsibility of care. Ideally, patients should accept a primary role in their care, while physicians need to be available for support a n d a d v i c e . Brief Review of Mind–Body Medicine in Gastroenterology Practice 329

The presence of a physical or sexual abuse history in patients is often dismissed or not adequately assessed in GI practice; however, an appropriate understanding of such a history and its effects on mind–body connections is critically important in patient care.

In a study published in 1990, Drossman and colleagues reported that up to 50 of patients in a tertiary care setting have a history of physical or sexual abuse, though only 11.4 of the physicians were aware of this history (Drossman et al., 1990 ). Th e association between abuse and gastrointestinal symptoms has also been found in children (Van Tilburg et al., 2010 ). Later work showed that an abuse history has profound eff ects on health status in patients with functional or structural diagnoses in terms of quality of life, health care utilization, symptom severity, or even risk of having surgery (Drossman et al., Lesserman, Toomey, Hu 1996 ) Recent literature has shown a relationship between a history of physical or sexual abuse and central upregulation of pain-reporting centers in the brain (Drossman, 2005 ). For a comprehensive examination of ways this issue can be identifi ed and addressed during the course of the biopsychosocial interview, readers are directed to a more comprehensive review (Chang & Drossman, 2002 ). Standard medical care may not be suffi cient for most patients. We have found, for example, in a study of 1,665 patients with functional bowel disorders seen in a U.S. health maintenance organization (Whitehead et al., 2004 ), that only 22  of patients had a larger than 50  reduction on a global bowel symptom index six months aft er a doctor visit for their bowel symptoms, and only 51 of patients judged their symptoms to be at least somewhat better at that time. Similarly, Th ompson et al. ( 1997 ) reported that less than half of IBS patients in primary care are satisfi ed with the care they have received. Th is fi nding is echoed by a recent study of almost 2,000 patients in an Internet survey (Drossman. Morris, Schnek, Hu, Norton, Weinland, Dalton, Leserman., 2008 ). About a third of patients pursue alternatives to regular medical care, such as herbal medicine, massage therapy, and yoga (van Tilburg et al., 2008 ).

Patients who do not respond to medical therapy and/or have comorbid psychiatric disorders may beneﬁ t from behavioral therapy such as cognitive- behavioral treatment, hypnosis, or biofeedback. 330 INTEGRATIVE GASTROENTEROLOGY

Both clinical care and behavioral interventions should be integrated. In medical communities, it is advisable to at least identify a psychologist who is familiar with treating patients who have functional GI disorders, and who can be closely connected with the ongoing medical care. Ideally psychologists are part of the clinical program and are seeing patients in the same clinical setting. Th is helps to bridge the gap between medical and psychological care, and allows for a more unifi ed biopsychosocial approach. Th ere is a wealth of evidence to show that behavioral treatments are eff ective in treating functional gastrointestinal disorders. It must be kept in mind that these treatments typically involve specifi c behavioral intervention modalities applied on top of the behavioral and cognitive interventions (e.g., soliciting and challenging erroneous beliefs, such as a fear of cancer) routinely provided in standard medical care.

Behavioral and Cognitive Therapies for Functional Gastrointestinal Disorders

Behavioral and cognitive interventions for functional gastrointestinal disorders comprise a range of therapeutic modalities that have at their core a therapeutic relationship and understanding of the mind–body connection. Psychologists and other licensed practitioners working in behavioral medicine or clinical health psychology have a range of therapeutic modalities and options that have been shown to be eff ective in managing GI illness (Lackner et al., 2004 ). From these options, a mounting level of evidence for effi cacy has been found in utilizing cognitive-behavioral therapy (CBT), biofeedback, hypnosis/guided imagery, and relaxation training.

COGNITIVE-BEHAVIOR THERAPY

CBT is a form of semi-structured psychotherapy that is usually conducted individually as a course of 8–12 weekly treatment sessions. Th e therapist aims to help patients to overcome distorted and negative thinking patterns that amplify physical symptoms or adversely aff ect life functioning as well as psychological well-being. Th erapy tasks commonly include: increasing awareness of the association between stressors, thoughts, and symptoms; examining and correcting irrational beliefs; countering automatic negative thoughts; and identifying and adopting alternative, more adaptive coping strategies to handle challenging life situations and deal with bowel symptoms. Brief Review of Mind–Body Medicine in Gastroenterology Practice 331

CBT has been most extensively used in IBS. Th ere are several controlled and uncontrolled trials studying its eff ectiveness for treating IBS. In a review of the literature Toner ( 2005 ) concluded that there is some support for CBT in improving symptoms associated with irritable bowel syndrome (IBS), but many studies have important shortcomings, making it hard to draw fi rm conclusions. Drossman and colleagues (2003 ) have completed the largest and methodologically most rigorous trial in the history of behavioral treatments for GI conditions— treating 431 women with functional bowel disorders, most of whom met Rome criteria for IBS— in a randomized, placebo-controlled, multicenter study. Th ese investigators compared a 12-week cognitive-behavior therapy to the same amount of education intervention. Th ey found that cognitive-behavior therapy resulted in treatment response rate that was almost twice as high (70 versus 37 ) compared to the education control intervention. In order to increase access to CBT, low-cost self-administered treatments are being developed as a fi rst-line psychological intervention for IBS. Initial results are promising. In two studies, GI symptoms were decreased as compared to waitlist control, while self-administered CBT was comparable to standard CBT (Lackner et al., 2008 ; Sanders, Blanchard, & Sykes, 2007 ).

BIOFEEDBACK

Biofeedback is a treatment method that uses recordings of specifi c physiological parameters, such as muscle tension or intraluminal gut pressure, to provide patients with moment-to-moment feedback of their physiological activity, which can help them to learn to regulate physiological activity that is related to the targeted symptoms. Patients are asked to repeatedly make attempts at deliberate control over the targeted physiological processes while observing the response in their body, and in that way to gradually gain control through successive approximation. Biofeedback has been successfully used for chronic constipation due to pelvic fl oor dyssynergia (PFD) and fecal incontinence (Heymen et al. 2007 , 2009 ). Biofeedback for PFD is directed at teaching patients to relax their pelvic fl oor muscles while simultaneously applying downward intra-abdominal pressure to generate propulsive force (Valsalva maneuver). Th is is done with the aid of visual or auditory feedback to the patients from either electromyography sensors measuring electric activity in the external anal sphincter, an anal canal pressure sensor device, or both of these in combination. Th is training is sometimes combined with practice in defecating a water-fi lled balloon. 332 INTEGRATIVE GASTROENTEROLOGY

Biofeedback for fecal incontinence is aimed at enhancing or restoring the key functions that maintain stool continence. Continence depends on adequate rectal sensation to detect distention of the rectum, as well as on the capability to synchronously contract the external anal sphincter in response to the refl exive inhibition of the internal anal sphincter that occurs when the rectum fi lls. Th ree types of biofeedback to ameliorate fecal incontinence problems are: (1) coordination training, where patients are taught to coordinate or synchro- nize contractions of the pelvic fl oor muscles; (2) strength training, which trains patients to contract the external anal sphincter to prevent leakage from the bowel; and (3) sensory training to diminishing rectal distensions without muscle contractions. A large research literature has accumulated over decades on the outcomes of these two gastrointestinal biofeedback applications. (Palsson et al., 2004 , Chiarioni et al., 2008 , Heymen et al., 2003 , Heymen et al., 2 0 0 1 ) .

A 2004 systematic review of the world literature (Palsson, Heymen, & Whitehead, 2004 ) found 74 published prospective studies of biofeedback treatment for functional anorectal disorders, making biofeedback the most investigated of all behavioral treatment modalities for gastrointestinal disorders. A recent systematic review concludes that biofeedback helps about 75% of fecal incontinence and 70% of patients with PFD constipation (Chiarioni & Whitehead, 2008 ).

HYPNOSIS AND GUIDED IMAGERY

Hypnosis is a form of therapy that makes use of a special mental state of narrowed focus of attention and heightened mental receptivity to suggestion (hypnotic state), and achieves its therapeutic eff ects through therapeutic suggestions and imagery given by the therapist to patients in this facilitative state. Most of the work on hypnosis for gastrointestinal disorders has, until recently, focused on irritable bowel syndrome. More than 20 published studies have assessed the therapeutic utility of this mode of treatment for IBS, including six controlled studies. Although most of the trials of hypnosis for IBS have been small, and they have been variable in quality, recent systematic reviews examining this entire body of literature (Gholamrezaei, Ardestani, & Emami, 2006 ; Whitehead, 2006 ; Wilson et al., 2006 ) have generally concluded that hypnosis is an eff ective treatment for IBS, as evidenced in nearly universally positive outcomes and high success rate. An analysis provided in the review by Whitehead ( 2006 ) found that the median success rate of this treatment Brief Review of Mind–Body Medicine in Gastroenterology Practice 333 modality for IBS across all formal trials was 86 , that bowel symptoms were generally reduced by more than half aft er treatment, and that the therapeutic eff ects commonly lasted one or more years. Recent randomized controlled trials have shown hypnotherapy to be equally eff ective for the treatment of dyspepsia (Calvert et al., 2002 ), noncardiac chest pain (Jones et al., 2006 ) and for functional abdominal pain in children (Vlieger et al., 2007 ; Weydert et al., 2006 ; Van Tilburg et al). Hypnosis is a highly specialized form of therapy, and one of the limitations to wide availability has been the dearth of therapists in many locations that provide this form of treatment, as well as unfamiliarity of most therapists who use such methods with how to apply them for treating gastrointestinal disorders. However, a couple of innovations led by our research group are brighten- ing the prospects for wide application of this treatment modality. One of these is the development and distribution of a fully scripted hypnosis protocol for IBS that therapists can easily follow verbatim, making it much easier to use (Palsson, 2006 ). A second innovation is to develop home treatment programs to make this treatment entirely self-administered. A pilot study (Palsson, Whitehead, & Turner, 2003 ) of a home therapy version of the scripted North Carolina Protocol, delivered via audio CDs, found that overall IBS severity was twice as likely to show reduction of at least 50 aft er six months than a comparison group receiving standard medical care (53  versus 26  of patients). Similarly, a controlled study by van Tilburg et al. (2009 ) of 30 children ages 7–15, testing a two-month home treatment of self-hypnosis, delivered on CDs, found that children’s abdominal pain symptoms improved substantially more aft er guided imagery compared to children receiving standard medical care.

RELAXATION TRAINING

Because functional GI symptoms are widely recognized to be associated with heightened stress, relaxation training and meditation are sometimes applied in their treatment to combat the physical aspects of stress. Such training can take a variety of forms. Common techniques include progressive muscle relaxation, autogenic training, or meditation. However, they all have in common that the goal is to reduce sympathetic arousal (stress response) and create physiological changes associated with physical relaxation that can have benefi cial eff ects on gastrointestinal symptoms. Relaxation training has oft en been applied as a component of multimodal treatments, in published studies of treatment of gastrointestinal disorders. For example, it is a common complement to cognitive therapy or hypnosis treatment. However, it has been studied as the main or sole therapeutic ingredient in four controlled studies, and found eff ective in 334 INTEGRATIVE GASTROENTEROLOGY most of these trials (Shaw et al., 1991 ; Voirol & Hipolito, 1987 ; Keefer & Blanchard, 2001 ) except for one, which is likely underpowered (Boyce et al., 2 0 0 3 ) .

LIMITATIONS

In spite of the numerous impressive studies discussed above, demonstrating the advantage of cognitive and behavioral treatments over standard medical care or other comparison groups, use of these treatments is still an exception rather than the rule— even when patients are unresponsive to standard management. Although standard medical care fails to give adequate relief to 4 out of every 5 patients, behavioral treatment is only off ered or suggested to 10  of patients (Whitehead et al., 2004 ). Th is disconnect can be explained by several factors. First, in a healthcare climate highly concerned with containing skyrocket- ing costs, physicians and third-party gatekeepers may consider behavioral treatments to be a luxury for functional GI problems. Physicians who take time to develop a supportive relationship with their patients aren’t being reimbursed for the extra time they spend with the patient, and mental health programs are severely underfunded. In view of long-term data in functional dyspepsia (Calvert et al., 2002 ) and irritable bowel syndrome (Gonsalkorale et al., 2003 ), it is almost certainly an erroneous view that behavioral treatments are a luxury. When the cumulative benefi ts associated with years of reduced medication and healthcare needs, and lessened disability following behavioral treatments, become further documented in multiple studies, off ering such treatments to patients who are unresponsive to conventional medical care might become a required standard of care to contain costs and maximize positive outcomes. Secondly, there is an art to referral. Patients may perceive the referral as a sign that their physician thinks they are “crazy.” Only about 30 of IBS patients have confi dence in the referral by their physician to a mental health provider (van Tilburg et al., 2008 ). Lack of confi dence may lead to failure to follow up on the referral, and/or discontinuing the treatment early. An important aspect in referral is to present these treatments in a way that is acceptable to patients. For example, CBT can be off ered as a way to learn management strategies to better anticipate and respond eff ectively to episodes when they occur. In addition referral to CBT should be accompanied by reassurance that referral complements the medical treatment, and does not mean the physician believes the symptoms are “all in your head.” It is important to stress that CBT has been found to eff ect IBS symptoms, independent of changes in patient’s psychological distress (Lackner et al., 2007 ). Brief Review of Mind–Body Medicine in Gastroenterology Practice 335

Only those patients who are open to behavioral treatments should be referred to a mental health provider. Otherwise, it is unlikely that the patient will follow up on their physician’s advice (and even if they do. it is unlikely to be successful), while uniformly pushing a treatment may damage the very important physician–patient relationship.

Th irdly, there is an enormous shortage of qualifi ed therapists. In a system that prepares most mental health providers for the treatment of mental disorders, very few will know how to approach behavioral treatment of medical disorders. It is important to make sure that the patient is referred to a therapist who understands functional gastrointestinal disorders. In many areas, no such therapist may be around. Some centers, such as ours, have recruited and trained our own psychologists who operate as part of a treatment team that includes medical doctors, physician assistants, and nurses. Others have developed close relationships with therapists in the catchment area. Th e lack of availability of suitably specialized therapists, and the cost of therapy, hinder widespread use of these treatments. Creative methods to minimize these hurdles could greatly increase the use of behavioral treatments. With that aim in mind, our group at UNC-Chapel Hill has begun testing of a home-treatment hypnosis program delivered via audio CDs and facilitated by Internet-mediated symptom monitoring. Th e fi rst pilot results have been promising (Palsson, Whitehead, & Turner, 2003 ; Van Tilburg et al 2009 ), although response rate is lower than in our face-to-face therapy studies. Similarly, Lackner and colleagues in New York have reported encouraging results from a self-administered CBT program for IBS (Lackner et al., 2008 ). New treatment modalities like these off er promise for the widespread use of behavioral treatments in FGIDs.

Conclusions

Adopting a mind–body medicine approach to the care of functional gastrointestinal disorders is important. As no organic cause can be found to treat with medical therapy, psychosocial aspects become an important target for therapy. Physicians can deliver eff ective care when developing a good relationship with their patients. But for many patients, additional treatment is required. Behavioral and cognitive treatments aimed at reducing gastrointestinal symptoms have proven eff ectiveness for the treatment of highly prevalent conditions like IBS, chronic constipation and functional dyspepsia. Adding behavioral 336 INTEGRATIVE GASTROENTEROLOGY treatments to standard medical care can potentially reduce overall GI symptom severity by more than half, provide long-lasting therapeutic benefi t, benefi t treatment refractory patients, and reduce healthcare utilization substantially, while having no serious side eff ects. Th e current level of evidence suggests it is time to start regarding behavioral treatments as serious and responsible options in routine care for functional GI patients with moderate or severe symptoms. 34 Mind-Body Medicine in Digestive Disease

DOUGLAS A. DROSSMAN AND WILLIAM E. WHITEHEAD

key concepts

■ Th e UNC Center for Functional GI and Motility Disorders has a 15-year history in the biopsychosocial knowledge and care of patients with functional gastrointestinal and motility disorders, with initiatives in the area of research, patient care, training, and patient education: ■ Th e clinical program provides multidisciplinary, patient- centered care involving gastroenterologists, physiologists, psychologists, and physician assistants. ■ Emphasis in clinical training is placed on advanced interview methods and relationship building to maximize an eff ective provider–patient interaction, and on the use of newer gut- directed and psychopharmaceutical agents. ■ Th e research program is internationally recognized in the areas of psychosocial and psychophysiological investigation, epidemiology, and treatment of functional gastrointestinal and motility disorders. ■ On-site training is provided to students, trainees, and established clinicians and investigators to help them gain advanced skills in research and patient care. ■

337 Introduction

he practice of gastroenterology has changed from a patient-based quality-of-care model to a business model with emphasis on income T generation. Th is has occurred with the use of endoscopy and related procedures, along with brief, disease-focused clinic visits. (Drossman, 2004 ) Furthermore, training in the care of patients with functional gastrointestinal disorders (FGIDs) is limited and at times deemphasized, because FGIDs are considered “second class” (Drossman, 2005b ), thus reducing motivation for clinical practice. (Drossman, 2001 ) Nevertheless, people with FGIDs comprise the largest segment of patients seen in gastroenterology practice (Russo et al., 1999 ). Th ese patients tend to believe that their care is unsatisfactory and their needs are unmet (Drossman et al., 2008a ). With regard to research, the greatest interest and support for federal funding is in basic and translational research; the goal is to understand the basic mechanisms of disease, with the intent to cure and ultimately benefi t the patient. However, this research emphasis does not help patients with chronic functional GI disorders. Furthermore, with the decreasing availability of NIH funds, success in obtaining and sustaining research related to pathophysiological mechanisms of the FGIDs, and the proper care of patients, has been challenging and discouraging at best. In the face of these realities, the UNC Center for Functional GI and Motility Disorders has continued to promote and successfully sustain a quality-based model of patient care, a biopsychosocial model of research, and state- of-the- art training in the FGIDs. Th e center has maintained its supremacy in providing new scientifi c knowledge to the fi eld, innovative training opportunities for physicians and investigators, and optimal service to our patients. Th is chapter will review the history and philosophy of the center, and the ways in which its goals have been accomplished.

Brief Overview of the Center

Th e UNC Center for Functional GI and Motility Disorders (www.med.unc. edu/ibs) was established in 1994, when Dr. William Whitehead moved from Johns Hopkins University and joined Dr. Douglas Drossman at the University of North Carolina Division of Digestive Diseases. Prior to that, Dr. Drossman had an active clinical practice in irritable bowel syndrome (IBS) and the Mind-Body Medicine in Digestive Disease 339

functional GI and motility disorders, as well as a biopsychosocial research program related to clinical and psychosocial outcomes in the FGIDs. (Drossman, 1998a ) Dr. Whitehead, who had established a research and biofeedback treatment program for motility disorders at Johns Hopkins with Dr. Marvin Schuster, was recruited to set up what has become a world-class motility program at UNC. Drossman and Whitehead combined their skills and expertise in an eff ort to establish a research and clinical program that was committed to the fi eld of functional GI and motility disorders. Th e Center’s mission (to advance the biopsychosocial understanding and treatment of functional gastrointestinal and motility disorders through an integrated approach to patient care, research, training and education) was imple- mented through four areas of activity: (1) Patient Care – to off er state-of-the-art evaluation and treatment for the full range of functional GI and motility disorders; (2) Research – to conduct studies on the physiological and psychosocial mechanisms underlying functional GI and motility disorders, their impact on quality of life and health outcomes, and their treatment; (3) Training – to provide multidisciplinary training and education in clinical and research skills with an emphasis on patient-centered care and advanced research methods; and (4) Patient Education – to provide helpful and up-to-date information through seminars and workshops, as well as printed materials, videos, and the Internet.

Structure of the Center

One of the most unique features of the new center was Drs. Drossman and Whitehead’s shared responsibility as co-directors. Th is collaboration between two senior academicians has sustained the program for more than 15 years. Dr. Drossman coordinates the clinical activities, Dr. Whitehead established the motility program, and both have active research programs with independent and shared federal, foundation, and pharmaceutical support. In addition, several new faculty and investigators have joined the center and established their own research careers and clinical programs. Th e center also has developed collaborations with dozens of investigators worldwide; established a clinical program to implement multidisciplinary care; recruited an administrative staff to coordinate day-to-day activities including visiting scholars, media development, website maintenance, and the production of teaching tools; and established data management and biometry cores to provide advanced clinical and website-based research and data a n a l y s i s . 340 INTEGRATIVE GASTROENTEROLOGY

Clinical Program

Th e Functional GI and Motility Disorders Clinic is a tertiary care referral site for patients with diffi cult-to-diagnose functional GI and motility disorders, who present with challenging management issues. A team of gastroenterologists, psychologists, physician assistants, gastroenterology fellows, and visitors in training or on sabbatical, work together to provide a unique multidisciplinary approach that integrates medical, physiological, and psychological factors in the evaluation and treatment of patients. Emphasis is placed on a patient-centered diagnostic interview, with the goal of establishing an eff ective physician–patient relationship; state-of-the-art physiological and clinical investigations including endoscopy, breath H2, and motility testing; and psychological assessment and pharmacological treatments using the most advanced agents. Th e clinical program provides several therapeutic initiatives:

1. Establishment of an Eff ective Physician-Patient Relationship. Th e basis for optimal treatment rests in establishing an eff ective physician– patient relationship (Drossman, 2007a ). Borrowing from the work of George Engel (Morgan & Engel, 1969 ) and Karl Rogers (Rogers, 1980 ), we view the presenting symptoms in the context of the patient’s illness beliefs. From that point, the clinician applies his or her medical knowledge to develop an optimal negotiated treatment plan, along with provision for continuity of care. An example of the ways in which an eff ective therapeutic relationship can be established is shown in Table 34.1. 2 . State of the Art Pharmacological Treatments. At UNC, the FGID clinicians are thoroughly familiar with the full range of pharmacological treatments for the FGIDs, including the newer psychopharmacological agents used to treat visceral hypersensitivity and comorbid conditions. Th e use of advanced treatment approaches requires proper preparation; the method at the UNC Center is shown in Table 34.2. In addition, the UNC Center is continually involved with providing new investigative agents as part of Phase II and III studies, and then off e r i n g t h e m t o p a t i e n t s . 3 . Biofeedback. Certain FGIDs— including pelvic fl oor dyssynergia, fecal incontinence, and levator syndrome— are amenable to biofeedback treatment. In fact, our clinicians and researchers have in many cases published the seminal literature in this area of investigation. Th e center also has a dedicated Pelvic Floor Biofeedback Clinic. 4. Psychological Treatments. Our psychologists are skilled in the full range of psychological interventions, including cognitive-behavioral therapy, stress management, relaxation therapy, and hypnosis. Mind-Body Medicine in Digestive Disease 341

Table 34.1. Behaviors that Affect Physician-Patient Relationship

Behavior Facilitates Inhibits

Nonverbal

Clinical Private, comfortable Noisy, physical barriers environment

Eye contact Frequent Infrequent or constant

Body posture Direct, open, relaxed Body turned, arms folded

Head nodding Helpful if well timed Infrequent, excessive

Body proximity Close enough to touch Too close or too distant

Facial expression Interest, empathy, Preoccupation, boredom understanding disapproval

Touching Helpful when used to Insincere if not appropriate or communicate empathy properly timed

Verbal

Question forms Open-ended to generate Rigid or stereotyped style hypotheses

Closed-ended to test Multiple-choice or leading hypotheses questions (“You didn’t . . . ?”)

Use of patient’s words Use of unfamiliar words

Fewer questions and More interruptions

Question style Nonjudgmental Judgmental

Follows lead of patient’s Follows preset agenda or style earlier responses

Use a narrative thread HPI - > PMH - > ROS - > Psych

Appropriate silence Frequent interruptions

Appropriate reassurance Premature or unwarranted reassurance

Elicits psychosocial data in a Ignores psychosocial data or uses sensitive and skillful manner “probes”

(Adapted from Drossman and Chang,  ) 342 INTEGRATIVE GASTROENTEROLOGY

Table 34.2. Management of FGIDs with Psychopharmacological Agents

1. Choice of the agent based on :

• Th e specifi c symptom treated

• Th e side-eff ect profi le

• Th e cost of the drug

• Previous experiences and preferences with psychotropic agents

• Coexisting psychiatric conditions targeted

2. Initiating treatment

• N e g o t i a t e t r e a t m e n t p l a n.

• Consider previous drugs that worked.

• Start with a low dose (e.g. 25 mg/day of TCA).

3. Continuing treatment:

• Escalate dose by 25% –50 % every 1–2 weeks to receive therapeutic eff ect with least possible dose.

• Wa t c h f o r s i d e e ff ects – Counsel that most of them disappear in 1–2 weeks. If not, try to continue same or lower dose from same class before switching to a diff erent class.

• Follow up within 1st week and then within 2–3 weeks to ensure adherence.

• Gauge treatment benefi t with improvement in coping, daily function, QOL, and emotional state.

• If a poor initial response:

• Re-address patient concerns

• Switch to a diff erent class

• Consider combination therapies (eg. SSRI+ TCA, pharmacological and psychological treatment).

• If needed, obtain psychiatry consultation for pharmacotherapy.

• Increase doses up to full psychiatric doses if patient can tolerate before discontinuing.

• I f t h e r e i s n o b e n e fi t in 6–8 weeks on higher doses, alternate strategies (e.g., adding psychological treatment or referral) should be sought.

• Depending upon the response and side eff ects, another agent with diff erent mechanism of action can be added to augment treatment effi cacy and minimize side eff ects.

4. Stopping treatment: Continue treatment at minimum eff ective doses for 6–12 months. Long term therapy may be warranted for some patients. Gradual taper to prevent withdrawal symptoms.

(Adapted from Grover & Drossman,  ) Mind-Body Medicine in Digestive Disease 343

Research Program

Th e UNC Center has been a leader in research on the functional GI and motility disorders since its inception. Our seminal contributions to the fi eld include the following. (See Appendix D for details).

• Diagnostic criteria: Th e center’s co-directors have made major contributions to the development and validation of reliable diagnostic criteria for the functional GI and motility disorders through their research, including factor analysis studies (Whitehead et al., 1990a ; Whitehead et al., 1998a ; Whitehead et al., 2003a ), epidemiological surveys (Drossman et al., 1993 ), validation studies (Whitehead, 2006 ) and their leadership of the Rome Foundation. Th e Rome Criteria have been a major impetus to scientifi c discovery by enabling investigators to select more homogenous groups of patients and communicate replicable fi ndings. Dr. Drossman has served as the President of the Rome Foundation from its inception, and Dr. Whitehead has served on the Board of Directors. • Pathophysiological mechanisms of IBS: Research by Center investigators has established the key role of visceral hypersensitivity and motility in the symptoms of IBS (Whitehead et al., 1990c; Dorn et al., 2007 ; Kanazawa et al., 2008b ), and the CNS mechanisms that mediate visceral pain sensitivity. (Ringel et al., 2003a ; Ringel et al., 2008 ) • Psychosocial contribution to the development of IBS: With NIH support, UNC Center faculty and investigators have identifi ed and documented the key role played by sexual and physical abuse in the development of IBS. (Drossman et al., 1990 ; Leserman et al., 1996b ) Th ey have also articulated a model for understanding the ways in which psychosocial and biological factors interact to produce the symptoms of IBS and other functional GI disorders. (Drossman, 1998b ) • Psychological treatment of IBS: Th e Center has carried out the largest NIH-funded randomized, controlled trial of the treatment of painful functional bowel disorders with cognitive-behavior therapy and antidepressants. (Drossman et al., 2003b ) We also developed a scripted protocol for hypnotherapy (the “North Carolina model”) that is used throughout the world. In addition, we are pioneers in the investigation of psychotropic drug treatment for IBS and the FGIDs. 344 INTEGRATIVE GASTROENTEROLOGY

• Biofeedback treatment of pelvic fl oor disorders: We described pathophysiological mechanisms for fecal incontinence (Chiarioni et al., 2002a ) and dyssynergic defecation (Chiarioni et al., 2005b ), and carried out randomized, controlled trials (Chiarioni et al., 2006b ; Heymen et al., 2007a ) to show that biofeedback is the treatment of choice for these disorders. • Outcome assessment : We have developed widely used questionnaires for assessing symptom severity (Drossman et al., 1995 ; Drossman et al., 2000c), sexual abuse (Leserman et al., 1997a ), impact on quality of life (Drossman et al., 2000b ; Drossman et al., 2007a ), and comorbidity (Palsson et al., 2002 ). • Brain imaging : Center investigators have published studies, initially with PET and later fMRI imaging, from a hypothesis-driven perspective, looking to understand the role of psychosocial factors and, in particular, sexual and physical abuse on anterior cingulate activation. (Ringel et al., 2008 ; Ringel et al., 2004 ; Ringel et al., 2003b; Drossman et al., 2003a ; Drossman, 2005a ) Th is provides a possible mechanism for understanding the role of stress factors on pain threshold via cingulate activation. • Pharmaceutical trials : Th rough our research (Whitehead et al., 2006b ), leadership positions in the Rome Foundation (Irvine et al., 2006 ), and consultations to industry, we have shaped the guidelines for conducting pharmaceutical trials. In addition, our broad involvement with current and emerging pharmaceutical agents permits the availability of several Phase II and III treatment trials in which our patients may p a r t i c i p a t e .

RESEARCH TEAM

Th e center’s research program currently includes 14 faculty investigators within the UNC Division of Gastroenterology and Hepatology (including 6 who are principal investigators for NIH grants), plus four fellows or visiting scientists on site. Th ese investigators are supported by four research coordinators, three physician assistants who participate in research, two research nurses, and 12 research assistants. We also have a large number of collaborators in other departments and schools within UNC, and an extensive network of investigators at other institutions (see Figure 34.1). Mind-Body Medicine in Digestive Disease 345

Center investigators have received a number of national and international honors and awards, including: two Janssen Clinical Investigator Awards, the AGA Fiterman Award in Clinical Research, the AGA Education Award, the AGA Mentor Scholars Award, two FBGRG Senior Investigator Awards, an FBGRG junior investigator award, and two senior IFFGD Awards for Research Excellence. Th e center’s co-directors also serve on national review panels. Dr. Drossman was on the Council of the National Center for Complementary and Alternative Medicine, the NIDDK Digestive Diseases Commission, and the Institute of Medicine Committee on Gulf War and Health: Physiologic, Psychologic, and Psychosocial Eff ects of Deployment- Related Stress. He chairs the program committee and the research awards committee for the IFFGD. Dr. Whitehead serves on the Data Safety and Monitoring Board for the NIDDK Gastroparesis Research Network, and is a co-investigator on the NICHD Pelvic Floor Disorders Network. He is a member of the NIH BMIO Review Panel, and chairs the Rome Foundation Research Committee. Research support for the center has come chiefl y from the NIH (approximately 60  ). Center investigators currently hold an R24 Mind–Body Infrastructure grant, two RO1s, two R23s and an R21, in addition to support they receive as co-investigators on grants by their collaborators outside the center. Th is support from the NIH is supplemented by several investigator- initiated research contracts with pharmaceutical companies for outcomes research unrelated to drug approval (for example, estimating the impact of FGIDs on quality of life and health economics).

RESEARCH INFRASTRUCTURE

Currently, the center is supported by an R24 Mind–Body Medicine infrastructure grant, which funds a number of cores that support the research of our investigators. Th ese cores are as follows:

• Research Administration Core, which provides a registry of research participants and staff support for recruiting research subjects, assistance with the recruitment of Hispanic and other minority subjects, and a team of research coordinators. • Biometry Core, which provides consultation on experimental design and statistical analysis, questionnaire and data entry forms, and data management schemes. For selected studies, this core provides actual data management and data analysis. • Data Acquisition and Technology Applications Core, which provides technical support for automated data entry (scan-able questionnaires, 346 INTEGRATIVE GASTROENTEROLOGY

Internet-based questionnaires and surveys), creation of websites for study management, and maintenance of a secure server, which serves as a reservoir for databases. • Education and Dissemination Core, which maintains a website to educate patients and healthcare providers and disseminate research fi ndings, prepares posters, slides, and brochures for center investigators, and publishes a quarterly newsletter. • Seed Grant Core, which provides one-year grants of $37,500 to new investigators to collect pilot data for grant submissions. Th is program has been highly successful, in that six of the fi rst nine seed grant recip- ients have obtained independent NIH funding related to their seed grants (two RO1s, two R21s, one R23s, and a supplement to an R24).

International Activities

Th e center is represented nationally and internationally through a network not only of research activities (see above) but also in leadership positions. As noted, Dr. Drossman is President and Dr. Whitehead on the Board of Directors of the Rome Foundation, the organizational responsible for standardization in diagnosis in the FGIDs. Center investigators are actively involved on the advisory boards of pharmaceutical companies, NIH, FDA, and the International Foundation for Functional GI Disorders, have held leadership positions in the Functional Brain-Gut Research Group, have served as associate editors for Gastroenterology, and are editors or on editorial boards for Gastroenterology , Internal Medicine, and Psychosomatic Medicine . Th e center is frequently highlighted by the media in newspapers and magazines, and several videos, radio, and TV shows have been produced on site.

Academic Training and Public Education

A major commitment of the center is to provide onsite training not only for our GI fellows but for visitors from around the world. Th e Visiting Scholars Program provides an opportunity for faculty, investigators, and clinicians from other institutions to visit the center for a few days to several weeks. Th e Visiting Scientists Program hosts faculty and investigators for sabbaticals and extended stays for one to two years. In this capacity, the visitors spend enough time to return to their home institution and establish independent research careers, or set up their own clinical programs in the FGIDs. Th ere are several components to the training program: Mind-Body Medicine in Digestive Disease 347

1. Mentored Learning. Trainees work in an individually structured relationship with one or more faculty mentors, who provide ongoing support and feedback to their work. Guidelines developed by the center for providing this mentored learning are available (Drossman, 2007b ). Th e senior investigators at the center have independently established research careers with NIH funding, and are able supervise trainees in all aspects of research, including project development, grant writing, ongoing project administrative support, abstract and manuscript preparation, and presentation skills. Clinicians are off ered the opportunity to observe our clinical staff in the care of patients seen in the clinic (with patient permission). With proper credentialing, they are able to independently work with patients in a preceptorship arrangement. 2. Training Seminars. We hold a weekly clinical case conference, where patients seen by the clinicians are presented and discussed among the entire clinical staff to provide new insights into diagnostic and therapeutic approaches. In addition, the center hosts a monthly psychosocial skills seminar, with GI fellows and clinicians outside the division, to facilitate learning about patient care. Th is includes live patient interviews and discussions, videotaped learning sessions on the medical interview, role plays, and small group learning. Th ere is also a monthly interdisciplinary Anorectal Motility Case Conference, in which gastroenterology, radiology, surgery and urogynecology staff discuss the diagnosis of patients with complex pelvic fl oor disorders and plan optimal treatment approaches. 3. Public Education. Th e center’s education programs target patients and their families and friends, healthcare professionals at all levels, and the public at large. Th e center promotes increased awareness and understanding of the FGIDs through a biennial all-day patient sym- posium, printed materials, videos, and its website (www.med.unc. edu/ibs). Many of these programs have won national recognition, including the Freddy Award and the Communicator Award, and have been shown on TV and webcasts on major networks.

Concluding Comments

In the current healthcare environment that emphasizes procedures over time spent with patients, the UNC Center has been able to sustain a patient- centered biopsychosocial model of care that is quality based and eff ective. Furthermore, with federal research emphasis on biomedical research, and 348 INTEGRATIVE GASTROENTEROLOGY shrinking research funding, we have successfully maintained a broad and comprehensive NIH-funded research portfolio that has helped to move the fi eld forward. We have also been successful in communicating our clinical and research agenda to other healthcare providers and investigators around the world. Hopefully this eff ort will ultimately help our patients with functional GI and motility disorders.

35 Yoga and Digestive Health

SAJIDA CHAUDRY AND BETH NOLAN

key points

■ Yoga is a means to experience consciousness and harmony with the world. ■ Yoga and ayurveda are sister sciences— both believe in the inseparable nature of the mind, body and spirit. ■ Patanjali’s eight limbs of yoga include yama, niyama, asana, pranayama, pratyahara, dharana, dhyana and Samadhi. ■ Yoga poses and breathwork for digestive health enhance relaxation and reduce sympathetic nervous system stimulation. ■

Introduction

Evenness of the mind is called yoga. —Bhagavad Gita

Yoga is believed to have two meanings, union and discipline. Yoga comes from the Sanskrit work “yuj” which means to join together. Th e root is similar to the work yoke, which also means to bond together. At its very core, yoga brings together the individual self (jiva — our physical body) and the cosmic or universal self (atman— the entire universe) to form a single unity. Yoga is the vehicle to achieve consciousness, to transcend the ego–personality and to experience Unity. In this state of Unity, there is no inner confl ict and complete harmony with the world.

349 350 INTEGRATIVE GASTROENTEROLOGY

Th e practice of yoga can be dated back to the third millennium BCE. Patanjali, the Indian sage, wrote the Yoga Sutras around 200 CE in the form of 195 organized and codifi ed terse aphorisms. Th us, classical yoga emerged. Yoga and ayurveda are considered to be sister sciences— both believe in the inseparable nature of the mind, body and spirit and both view the body as channels of energy (nadis) that can result in disease if blocked. Kapha, pitta and vata imbalances aff ect the entire body including the gastrointestinal system. Balancing doshas (see ayurvedic section) is fundamental to both yoga and ayurveda. Yoga is divided into eight stages, know as Patanjali’s eight limbs of yoga:

1. Yama - universal moral commandments 2. Niyama - self-purifi cation by discipline 3. Asana - posture 4. Pranayama - rhythmic control of the breath 5. Pratyahara - withdrawal and freedom of the mind from the senses and the exterior world 6. Dharana - concentration 7. Dhyana - meditation 8. Samadhi - state of bliss or super-consciousness where the individual merges with the universal spirit

Yoga as practiced in the West focuses mainly on asana, poses named aft er animals, but really yoga intends for integration of the mind, body and spirit through all of the above stages. Th e yogic path involves body and mind purifi - cation, asana preparing the body for meditation and samadhi.

Yoga and Digestive Health

In terms of gastrointestinal health, yoga allows relaxation, balancing the physiological eff ects of stress. Reduction in skeletal muscle tension decreases sympathetic system stimulation and subjective tension and may improve gut motility (Drossman, 2003 ). Relaxation training includes imagery, breathwork, meditation and biofeedback — all components of yoga. Gastrointestinal disorders such as irritable bowel syndrome involve enhanced motility and visceral hypersensitivity associated with brain–gut dysfunction. With its meditative approach, yoga helps with changing the relationship to stress, and the actual postures bring awareness of the body with gentle physical activity. Yoga has been compared in a small randomized, controlled trial to standard drugs (loperamide) in diarrhea-predominant IBS. Both have Yoga and Digestive Health 351 been shown to work at 2-month follow-up, with yoga having the additional benefi t of increased parasympathetic activity (Taneja et al., 2004 ). Th e yoga intervention group consisted of a set of 12 asanas (e.g., Vajrasana, Shashankasana, Ushtrasana, Marjariasana, Padhastasana, Dhanurasana, Trikonasana in two variations, Pawanmuktasana and Paschimottanasana), along with Surya Nadi pranayama (right-nostril breathing) two times a day for 2 months. Other studies have looked at pranayama (yogic breathing), asanas (yoga postures) and meditation and have concluded that yoga may be a benefi cial, low-risk, economical addition to the treatment of illnesses that can worsen gastrointestinal health such as stress, anxiety and depression (Brown & Gerbarg, 2005 ). Yoga teaches us how to breathe deeply and fully. Breathing this way brings the natural functions of the organs into balance, especially the eliminatory organs. Th e diaphragm and the lungs expand and contract, thus massaging the internal organs. In the case of weak abdominals, the digestive and eliminatory functions are weakened as well. Th e diaphragm is connected to some of the abdominal muscles via connective tissue. If the muscles are weak, a full, deep breath is limited. Yoga postures using the complete three-part breath can strengthen the abdominal wall and the digestive organs, supporting good h e a l t h a n d v i t a l i t y .

Yoga Postures for Patients with Digestive Illness

A compassionate approach to one’s body is essential. There is no beneﬁ t if there is pain. The goal is to ﬁ nd relaxation in the body and mind through breathing deeply and fully in the postures.

Th ere are numerous yoga postures that address digestive health. Five will be covered here. Th ese fi ve are easy and simple enough for any patient to practice. All postures can be modifi ed to accommodate any physical limitations by using pillows, bolsters, and even chairs. Good advice to health practitioners is to consider experimenting with the poses themselves, to understand them experientially. To achieve the greatest benefi t from each of these postures, patients will need at least 10 to 15 complete yogic breaths per pose. If at any 352 INTEGRATIVE GASTROENTEROLOGY time your patient is uncomfortable, recommend readjusting the body, or ask your patient to take himself or herself completely out of the posture to rest. Th en ask your patient to consider returning to the posture and attempting to challenge themselves again. Usually, anyone with digestive problems feels discomfort and agitation. Starting with Viparta Karani (legs up the wall) calms the nervous system and the mind, bringing focus to the breath deep in the lower abdomen. Th e height of the bolster supporting the hips will vary according to the severity of the discomfort. In the case of irritable bowel syndrome (IBS), it is best to use a folded blanket — about an inch high — so as not to over-stretch the abdominal walls and intestines, which would cause more irritation. Th e idea is to bring calmness to the intestines and to one’s breathing. Due to its supportive nature, this posture can be recommended with a hold for 10 to 15 minutes. Once your patient has been in Viparta Karani, and his or her body, mind, and breath are calmer, a forward bend series will help massage and encourage the elimination process. Patients can assume the Dandasana (staff pose) by engaging their muscles and breathing the full three-part breath. Th is posture can tone the abdominal organs, lift sagging abdominal walls, improve digestion, and reduce heartburn and gas. Th e Janu Sirasana (head to knee pose) has the ability to massage the ascending colon when the right leg is extended out fi rst, and the descending colon when the left leg is extended. Th is posture can be recommended with a strap to create a more vigorous massage, or with a chair or bolster. Th is supports the head and arms for a more restorative eff ect. Aft er your patient has completed this pose on both sides, ask them to return to Dandasana and to prepare for Paschimottanasana (full forward bend). As in the last posture, this position can be very active and engaging for patients by using their hands or strap to fully work the posture, and by bolster- ing their head and upper body with pillows and or a chair. Th e key to any of these variations is to ask patients to keep the full three-part breath, expanding and contracting to massage the organs from the inside out. Aft er this pose, ask patients to return to Dandasana with 3–5 breaths, and roll down to their backs, resting in Savasana (relaxation or corpse pose). If there is any lower back pain or discomfort, ask patients to bend their knees and bring them toward the chest. Patients can gently roll around to relieve any discomfort, and then return to Savasana. If there is still discomfort, then patients may rest with a pillow under their knees, or keep their knees bent and feet fl at on the fl oor. Encourage focus on the three-part breath. Resting between postures or a series of postures allows your patient’s body to integrate and feel the benefi ts as they rest. Marichyasana (spinal twist) is a great benefi t to the body as a whole. By twisting the spine, they are aff ecting Yoga and Digestive Health 353 the nervous system, which increases energy levels and massages the organs under the rib cage. Th is improves the functions of the liver, spleen, pancreas, kidneys, and intestines. Spinal twist also has the ability to realign the spine, allowing the nerve impulses to fl ow and respond more effi ciently. Spinal twists should be done with caution. Avoid recommending them if the patient has diarrhea, dysentery, insomnia, or migraines. Variations of spinal twist can be recommended; these are done while lying down, practicing knee-down twist or the traditional twist with one leg bent and the other extended, or by twisting with crossed legs.

Advasana (Reversed Corpse or Relaxation Pose)

Th e next series of postures start in Advasana— the opposite of Savasana— lying fl at on the stomach. Ask your patient to turn his or her head to one side or the other to get an even stretch in the neck while breathing the three-part breath. Th is allows the stomach and/or diaphragm to expand and press into the fl oor with each breath. Allow the exhalation to relax the patient into the fl oor. To deepen the massage of the digestive tract, place hands or fi sts under the stomach and continue breathing. Recommend that the patient always be gentle, never causing pain or discomfort. A compassionate approach to one’s body is essential. Th ere is no benefi t if there is pain. Th e goal is to fi nd relaxation in the body and mind through breathing deeply and fully. 36 Integrative Approaches to Abdominal Pain

ROBERT A. BONAKDAR AND EMILY G. SINGH

key concepts

■ Patients with chronic abdominal pain deserve a biopsychosocial approach (Figure 36.1 ) to their condition, including a thorough evaluation of organic causes as well as focus on psychological state, family dynamics, and coping strategies. ■ Use of standardized tools (Irritable Bowel Syndrome Symptom Severity Score, Brief Pain Inventory) is encouraged to enhance global understanding and monitoring. ■ Th e most common cause of abdominal pain, especially recurrent pain in children, is irritable bowel syndrome (IBS). ■ In addition to currently approved medications, an evidence- guided approach should be utilized to recommend or consider the following treatments on an individual basis: ■ Mind–Body Th erapies ■ Reassurance and education ■ Cognitive-behavioral therapy (CBT) for IBS, number needed to treat (NNT) of 2 1 ■ Biofeedback, especially for pain associated with pelvic fl oor dyssynergia (PFD)/functional constipation ■ Hypnosis, especially gut-directed hypnotherapy, trial in patients who fail standard medical therapy, ■ Biologically Based Th erapies ■ Dietary counseling by a qualifi ed practitioner for optimizing dietary intake ■ Peppermint oil for IBS, NNT of 2.5 ■ Probiotics for IBS, NNT of 8.9

1 Number Needed to Treat (NNT): Defi nes the number of subjects needed to be treated to have a successful outcome versus control treatment.

354 ■ Fiber for IBS, NNT of 11 ■ Alternate Medical Systems/Energy-Based Treatments ■ Acupuncture for IBS, trial in patients who fail standard medical therapy ■ Herbal medicine and dietary interventions from a traditional Chinese medicine, Tibetan Ayurvedic, or naturopathic perspective for IBS ■ Transcutaneous electrical nerve stimulation (TENS) used on acupoints for IBS or pain related for functional dyspepsia ■ In some cases, a formally structured multidisciplinary program may need to be initiated for optimal management. ■

INTRODUCTION

bdominal pain, especially of a chronic, functional nature, can be a complex, diffi cult-to-treat condition requiring global assessment and A individualized care options. As described below, the most common cause of abdominal pain, especially in children, is irritable bowel syndrome (IBS). Unfortunately, as noted in most the recent meta-analysis of available drug treatments in the setting of IBS currently, options are not optimal, with global assessment and treatment required:

“Th e evidence for effi cacy of drug therapies for IBS is weak. Although there is evidence of benefi t for antispasmodic drugs for abdominal pain and global assessment of symptoms, it is unclear whether anti-spasmodic subgroups are individually eff ective. Th ere is no clear evidence of benefi t for antidepressants or bulking agents. Th e physician should be aware that global assessment is a construct containing various dimensions. For each individual, these will have a diff erent weighting and treatment should be aimed at the most debilitating symptom.” (Quartero et al., 2005 )

In this setting, it is not surprising that many patients consider the use of non-pharmacological (NP) and complementary and alternative medicine (CAM) for pain and symptom management. Chapter 37 will provide an overview of these treatment options including prevalence, patient rationale for utilization, and clinical effi cacy. Most importantly, as many of these choices are 356 INTEGRATIVE GASTROENTEROLOGY accessed without the input of a clinician, the chapter aims to provide guidance regarding the discussion and coordination of care for these treatments.

OVERVIEW AND IMPACT

Chronic abdominal pain is defi ned as pain that has been symptomatic for three months or more. In addition, pain may be categorized as organic or functional (absence of anatomic abnormality, infl ammation, or tissue damage). Various diagnoses fi t into the category of functional gastrointestinal disorders, as noted Table 36.1 (Guthrie & Th ompson, 2002 ). In some cases, a diagnosis may fi t into more than one category. For example, IBS, which will be the main discussion point in this chapter, is typically defi ned as a functional bowel disorder. However, more recent evidence demonstrates potential infl ammatory and infectious etiologies that may explain at least a portion of IBS cases (Alonso & Santos, 2009 ). IBS appears to be one of the most common causes of chronic or recurrent abdominal pain. Irritable bowel syndrome aff ects 10 to 15 of the North American population, and thus is comparable in incidence to other chronic conditions such as asthma, coronary heart disease, diabetes, hypertension, and migraine (Cash, Sullivan, & Barghout, 2005 ; American College of Gastroenterology, 2002 ). Even though IBS accounts for nearly 3  of general practitioner consultations, only a quarter of those with IBS actually seek medical treatment for their symptoms (Th ompson et al., 2000 ; Drossman & Th ompson, 1992 ). Th us, on average, an IBS suff erer has symptoms for 10 years before diagnosis (International Foundation for Functional Gastrointestinal Disorders, 2002 ). For many reasons, IBS has the ability to create a substantial fi nancial and quality-of-life burden on the patient and society (American

Table 36.1. Categories for Functional Gastrointestinal Disorders

• F u n c t i o n a l d y s p e p s i a • Ulcer-like dyspepsia • Dysmotility-like dyspepsia • U n s p e c i fi ed dyspepsia • Functional diarrhea • Functional constipation • I r r i t a b l e b o w e l s y n d r o m e • Functional abdominal bloating • U n s p e c i fi ed functional bowel disorder • Functional abdominal pain syndrome • U n s p e c i fi ed functional abdominal pain

(Reprinted with permission from Guthrie &Th ompson ( 2002 ) BMJ, 325 (7366), 701–703). Integrative Approaches to Abdominal Pain 357

Gastroenterological Association, 2004 ; Frank et al., 2002 ). Estimates place combined direct and indirect costs of IBS at nearly $30 billion a year (Cash, Sullivan, & Barghout, 2005 ). Because of the signifi cant use of healthcare resources, and indirect costs including absenteeism and loss of productivity, the estimated cost of IBS appears to be greater than that of conditions including asthma or migraine, and comparable with hypertension and congestive heart failure. Additionally, chronic abdominal pain is well recognized to have detrimental eff ects on quality of life, which may be more diffi cult to delineate (Cash, Sullivan, & Barghout, 2005 ; Hahn et al., 1999 ).

OVERVIEW OF INTEGRATIVE OPTIONS *

Non-pharmacological and CAM treatments include a vast array of choices for the abdominal pain patient. Th e defi nitions of these treatments vary and are constantly being updated. Non-pharmacological treatments are typically defi ned as options that are not prescription medications. However, several options that have been nonprescription options in the past, such as omega-3 oils and B vitamins, are now available in formulations requiring a prescription. In addition, several options, such as S-adenosyl methionine (SAMe), which are nonprescription in the United States, may require prescriptions outside the United States. Similarly, CAM was previously defi ned as treatments not included in medical school training. Currently, more than 60 of the nation’s allopathic medical schools are providing some level of instruction on CAM (Wetzel, Eisenberg, & Kaptchuk, 1998 ). More recently, CAM has been defi ned by the National Institutes of Health Center for Complementary and Alternative Medicine (NCCAM) as treatments or medical systems that are not typically incorporated in conventional treatment recommendations. Th is defi nition has evolved to include integrative medicine, which is the practice of incorporating selected evidence-based CAM options into mainstream practice. Th e NCCAM system classifi es CAM into categories that are helpful for discussion. Currently, there is no consensus and large overlap in the use of these terms. For this chapter, the non-pharmacological and CAM treatments reviewed will be referred to collectively as NP/CAM options. An overview of NP/CAM options categorized under NCCAM headings is noted in Table 36.2.

PREVALENCE OF NP/CAM USE *

NP/CAM use is quite common, especially in those suff ering from pain. CAM usage was reported in approximately one-third of the United States population 358 INTEGRATIVE GASTROENTEROLOGY

Table 36.2. Overview of Non-pharmacological and Complementary and Alternative Medicine (CAM) Treatments

Category Overview Examples

1. Alternative Medical Traditional Chinese Medicine Systems Ayurveda Systems of care based on Naturopathy unifying health paradigms, Homeopathy which may incorporate individual treatments including those noted in the categories below.

2. Mind–Body Biofeedback Hypnosis Interventions Meditation Visualization Diverse techniques that Yoga Guided imagery utilized cognitive, Exercise, various Cognitive- behavioral, and movement Tai chi/qi gong behavioral therapies in order to modify Creative therapies therapies and increase awareness (art, music or dance) Group support between mental and Relaxation Autogenic training physiological functioning Spirituality

3. Biologically Based Dietary modifi cation (dietary elimination, fasting, or Th erapies specifi c dietary regimen) Th erapies that modify Dietary Supplements: Herbal supplements (white willow nutrient intake, either bark) through dietary intervention Non-herbal supplements (glucosamine), vitamins or supplementation (vitamin D), minerals (selenium)

4. Manipulative and Chiropractic manipulation Body-Based Methods Osteopathic manipulation Techniques that utilize Manual and massage therapy manipulation, movement, and/or stretching of one or more parts of the body

5. Energy Th erapies Acupuncture ( biofi eld therapies) Qi gong Techniques that involve the Healing Touch application of human or Th erapeutic touch nonhuman energy fi elds

Adapted from What Is CAM? http://nccam.nih.gov/health/whatiscam/ Integrative Approaches to Abdominal Pain 359 in 1990, and increased to 42 by 1997. At that point, this represented 628 million offi ce visits and $27 million spent on CAM services, which far exceeded total out-of-pocket expenditure and offi ce visits (328 million) for conventional primary care providers in the same year. A follow-up analysis demonstrated that approximately one-third of the visits to CAM providers were for the treatment of pain (Wolsko et al., 2003 ).

A more recent analysis of CAM use by the NIH found that a majority of the top 10 reasons for CAM use were related to pain complaints, with abdominal pain in the top 10 in 2002 and top 15 in 2007. (Barnes et al., 2002; Barnes, Bloom, & Nahin, 2007).

PREDICTORS AND PATTERNS OF USE *

Several surveys have demonstrated that approximately half or more of IBS suff erers use CAM. In one survey of 413 GI clinic patients (61 IBS, 22 functional dyspepsia [FD], 17 gastroesophageal refl ux disorder [GERD]), a total of 181 users of CAM were identifi ed, or 44 of the group. Th e use of CAM was most frequent for IBS (51  IBS, 36  FD, 27  GERD). Th e most frequently utilized treatments were herbal medicines.

Predictors of CAM use were diagnosis with IBS, history of abdominal surgery, emergency room visits, disabilities and prescription of benzodiazepines and 3 or more medical visits for gastrointestinal tract disorders within the previous year. (Carmona-Sánchez & Tostado-Fernández, 2005 ).

In another survey examining the acceptability of various — mostly NP/ CAM — treatments for IBS, Harris and Roberts ( 2008 ) found a number of reasons for non-use, including dislike or disbelief in the treatment modality, as well as insuffi cient knowledge. Th e proportion of patients fi nding various treatments for IBS acceptable is noted in Table 36.3. In a multicenter pediatric survey, Vlieger et al. ( 2008 ) compared CAM use in patients with functional and organic gastrointestinal diseases. Th e overall prevalence of CAM use was 37.6 and, as expected, use was higher in patients with functional disorders than organic disorders (25.3  versus 17.2  ). Predictors of CAM use included less than satisfactory or adverse eff ects of conventionally prescribed medications, school absenteeism, and age 11 years 360 INTEGRATIVE GASTROENTEROLOGY

Table 36.3. Proportion of Patients Finding Various Treatments for IBS Acceptable

Tablets 83.9 %

Diet change 81.6 %

Yoga 76.6 %

Stomach cream 67.6 %

Homeopathy 64.8 %

Heat pad 63.7%

Hypnotherapy 63.7%

Acupuncture 59.0%

Suppository 57.4%

(adapted from Harris and Roberts, 2008 )

or below. Interestingly, 93 of the parents considered it important for pediatri- cians to be involved in CAM research, and 51 of were willing to participate in CAM research trials. Th ose who utilize CAM for IBS may share characteristics with the general CAM user, which may be important for the clinician to keep in mind. Namely, CAM users are more likely to be women with higher levels of education and income. Th ose using CAM have health values, beliefs, and coping systems that are also quite important to keep in mind. Th ose who are involved in “active coping behaviors,” which includes physical activity and particular diets, tend to view CAM use in a similar manner (Astin, 1998 ). Additionally, patients with a more “holistic outlook” wish to utilize complementary methods that take their viewpoint into consideration (Furnham & Bhagrath, 1993 ). Th ere has been speculation that CAM use signals dissatisfaction with conventional care. One survey found that rheumatology patients with more medical skepticism had a higher likelihood of utilizing a CAM provider. Th is fi nding was especially true for abdominal pain patients (Callahan et al., 2008 ). However, the more likely scenario is that of CAM as an adjunct to conventional care. In fact, dissatisfaction with conventional care did not predict use of CAM in a previous survey, and less than 5 of CAM users did so in isolation from conventional care. Most CAM users state that their motivation for CAM use is that it provides them more control over their health care, and up to 80  report benefi t from its use a previous survey (Astin, 1998 ). Integrative Approaches to Abdominal Pain 361

CAM users have been noted to have more frequent relationships with a primary care physician, have regular physician follow-up, and good compliance with recommended preventative health behaviors such as regular mam- mography. Thus, what may be termed “medical skepticism” may in fact be an active coping behavior attempting to identify and incorporate potentially helpful treatments. As discussed below, the coordination of these efforts by a medical provider is quite important to help maximize treatment utility. (Astin et al., 2000 ).

Approach to the Patient *

Regardless of their experience or particular beliefs about CAM, clinicians have an ethical obligation to discuss treatment alternatives with their abdominal pain patients. Th is is quite pertinent in the abdominal pain population that has an especially high use of NP/CAM. In this setting, it is especially important to have an open, nonjudgmental discussion about all treatments being considered or utilized, in order to provide full and optimal coordination of care. Unfortunately, the interaction between patients and clinicians regarding CAM use is oft en suboptimal. Th is situation is linked to several factors noted below, including the patient’s and clinician’s CAM knowledge base, level of discussion, and management strategies such as charting and follow-up. Several strategies and pertinent resources are reviewed to help optimize the approach to the abdominal pain patient.

KNOWLEDGE BASE *

Th e knowledge base of the average clinician and consumer regarding NP/ CAM, including popular areas such as dietary supplements, is suboptimal. Physician surveys have found that physicians may have an insuffi cient general understanding of commonly utilized supplements, as well as their safety, regulation, and interaction profi les (Ashar, Rice, & Sisson, 2007 ; Kemper, Gardiner, Gobble, & Woods, 2006 ). Similarly, consumers and patients tend to have misconceptions regarding product claims and effi cacy. As pointed out by a previous Harris Poll, the majority of consumers believe that the government ensures a higher level of safety and regulation than actually exists (Harris Interactive, 2002). Th ese misconceptions, as well as biased or anecdotal information found on some health websites and advertising, may create a scenario of decreased 362 INTEGRATIVE GASTROENTEROLOGY perceived need for clinician guidance regarding CAM (Washington, Fanciullo, Sorensen, & Baird, 2008 ).

Discussion *

Th e level of discussion regarding NP/CAM that occurs in the average pain consultation can be quite minimal. Th is is exemplifi ed by the example of an editorial from the journal Pain, entitled “Food and Pain: Should we be more interested in what our patients eat?” Th e average pain clinician does not spend signifi cant time discussing diet in general, or as an intervention. Th e reasons for this may include lack of training and resources and more comfort prescribing other interventions, including medication (Bell, 2007 ; Smith, 2004 ). Th e level of discussion regarding CAM, specifi cally, may be even more defi c i e n t .

Surveys have found that in approximately 70 % of encounters there was no discussion of CAM use, and that neither the patient nor clinician introduced the topic. More concerning is the fact that if a patient is hospitalized by a specialist, CAM use is not identiﬁ ed up to 88% of the time. It is important to understand why patients may not discuss CAM use. (Wold et al., 2007 ; Azaz-Livshits et al., 2002 ).

Surveys indicate that factors including anticipation of a negative clinician response, as well as belief that the clinician will not provide useful information, motivated non-discussion (Adler et al., 1999 ). However, most important may be clinician inquiry, because patients demonstrate a willingness to disclose supplement use, but only if asked by a clinician (Hansrud et al., 1999 ). Unfortunately, a recent survey of physicians found that few felt comfortable discussing CAM with their patients. One of the major reasons for this lack of comfort was related to a need for improved knowledge base regarding CAM (84 of responders). It is theorized that with improved education and knowledge base about CAM, physicians may be more willing to discuss and counsel patients (Corbin-Winslow et al., 2002 ).

INVOLVING THE FAMILY

To most successfully understand and treat abdominal pain, it is imperative to view the condition and coping strategies as linked to a complex matrix of Integrative Approaches to Abdominal Pain 363 potentially medical, as well as personal, family and community factors. Th us, when evaluating a patient with abdominal pain, a thorough biopsychosocial history of the patient and family is essential. Family pain histories are also quite important, as the frequency, severity, and level of catastrophizing of children with pain has been associated with degree of pain in the family (Schanberg et al., 2001 ).

PATIENT AND CLINICIAN EDUCATION

A number of resources are available to clinicians interested in better understanding NP/CAM as a means of improving patient communication and treatment options. Th ese resources include print and online information on evidence-based use of NP/CAM, as well as continuing medical education courses available to clinicians. Th e H.E.R.B.A.L. Mnemonic is off ered in Table 36.4 as a clinical tool for aiding clinicians when discussing and managing CAM use, especially dietary supplements.

Regulation *

Th e regulation of NP/CAM varies widely based on the therapy described, the training of practitioners, and state laws. For example, acupuncture provided by a licensed acupuncturist (LAc) or physician acupuncturist may have vastly diff ering regulation as set forth by the state board, traditional Chinese medicine, medical board, or department of consumer aff airs. In addition, the level of training, oversight, and continuing education for acupuncture varies widely by state, and the referring clinician should help guide patients in fi nding qualifi ed and experienced CAM practitioners whenever possible. Verifi cation of

Table 36.4. The H.E.R.B.A.L. Mnemonic ©

H ear the patient out with respect

E ducate the patient

R ecord

B e aware of potential interaction and side eff ects

A gree to discuss and follow-up

L earn 364 INTEGRATIVE GASTROENTEROLOGY licensure can be obtained by contacting the state’s medical board, department of consumer aff airs, or therapy-specifi c national certifi cation organizations, as listed in Table 36.5. Dietary supplements are regulated according to the Dietary Supplement Health and Education Act (DSHEA) of 1994. Regulation diff ers from prescription medication, which must proceed through multiphase trials to gain approval from the FDA. Supplements (with established ingredients) are not strictly required to have safety, effi cacy, or bioavailability data prior to market- ing. Th e FDA must utilize adverse drug reports and product analysis to monitor products in the marketplace (FDA, 2002, 2003). Two more recent regulatory measures, Th e Dietary Supplement and Non-Prescription Drug Consumer Protection Act (S. 3546), which mandates the reporting of serious adverse events to the FDA, and Good Manufacturing Practices (GMPs) for dietary

Table 36.5. Regulatory and Practitioner Resources for Behavioral and Complementary and Alternative Medicine

Organization / Agency Website

Federation of State Medical Boards http://www.fsmb.org/m_ pub.html

American Academy of Medical Acupuncture http://www. medicalacupuncture.org

Th e National Certifi cation Commission for Acupuncture http://www.nccaom.org/ and Oriental Medicine

American Psychological Association http://www.apa.org/

American Society of Clinical Hypnosis http://www.asch.net

Th e Center for Mind–Body Medicine http://www.cmbm.org

Th e Biofeedback Certifi cation Institute of America www.bcia.org/

American Dietetic Association www.eatright.org

American Chiropractic Association’s http://www.acatoday.org

Th e National Certifi cation Board for Th erapeutic Massage http://www.ncbtmb.com and Bodywork

Association for Applied Psychophysiology and Biofeedback. www.aapb.org

American Association of Naturopathic Medicine www.naturopathic.org

Association of Accredited Naturopathic Colleges www.aanmc.org Integrative Approaches to Abdominal Pain 365 supplements, which began incorporation in August 2007, should be helpful in ensuring better-regulated supplements (FDA, 2007). In addition to the above governmental measures, several agencies off er testing and monitoring services that allow manufacturers to demonstrate their adherence to regulatory standards. Th ose that pass inspection may carry an independent “Seal of Approval” on their label and advertising. Several of the government and independent agencies currently involved in oversight are listed in Table 36.6. Clinicians should become familiar with well-regulated and well-researched brands for the supplements that are most likely to be discussed with patients.

Interventions—Evidence-Guided Care

Abdominal pain patients encounter, consider, and incorporate a large number of interventions for their condition and comorbidities. Understanding the motivation for, benefi t from, and integrative potential for these treatments on

Table 36.6. Governmental and Independent Regulatory Agencies

Agency Website

GOVERNMENTAL

Food and Drug Administration (FDA) Medwatch www.fda.gov/medwatch Program for collecting adverse reactions to prescription and OTC medications, as well as dietary supplements

Federal Trade Commission (FTC) site for submitting www.ft c.gov/ft c/complaint. complaints on false or misleading advertising htm

American Association of Poison Control Centers for www.poison.org or reporting and management of adverse eff ects (800)222-1222

INDEPENDENT LABS PROVIDING SUPPLEMENT TESTING

Th e Consumerlab Product Review www.Consumerlab.com

Dietary Supplement Verifi cation Program (DSVP) through www.uspverifi ed.org the United States Pharmacopeia (USP)

National Sanitation Foundation(NSF) www.NSF.ORG/consumer/ dietary_supplements 366 INTEGRATIVE GASTROENTEROLOGY an individual basis is essential in helping to frame an eff ective multidisciplinary treatment plan. Unfortunately, the research base in this area is quite heterogeneous and at times diffi cult to interpret. As an example, several meta-analyses of integrative options in the setting of abdominal pain, especially IBS, have been inconclusive. Th is includes meta-analyses of acupuncture and hypnosis, and all dietary interventions for treatment of IBS (Webb, Kukuruzovic, Catto- Smith, & Sawyer, 2007 ; Lim et al., 2006 ; Huertas-Ceballos, Logan, Bennett, & Macarthur, 2009 ). Additionally, studies appear to be confounded by the high rate of placebo eff ect in CAM trials of IBS (Dorn et al., 2007 ). While awaiting more defi nitive evidence-based guidelines in this area, the clinician needs to provide evidence-guided care. In the setting of abdominal pain, because of the varied number of interventions and methodologies, the provider must oft en strive for evidence-guided care to fi nd a successful compromise between available clinical evidence, patient preference, and clinical experience. In this paradigm, the clinician must review the available evidence to determine the safety and effi cacy of various interventions. Th is is especially true of interventions that may be provided and initiated with varied methodologies, dosages, and directives. A prime example of this is hypnosis for IBS/ abdominal pain, which is covered in more detail below. If a clinician were to follow the conclusion of a recent meta-analysis in this area when encountering a pain patient interested in trying this intervention, his or her response might be to avoid this intervention. However, when more closely examined in the setting of hypnosis, or any NP/CAM, if there are no positive trials and/or the treatment demonstrated signifi cant potential for harm, then the directive should be one of avoidance. However, if the treatment is of minimal harm and has the potential of benefi t (such as hypnosis), or has positive evidence that demands a more focused detail of the intervention, the treatment may be recommended. Th is recommendation requires attention to specifi c protocols for modalities, and specifi c dosage and brand for supplements, along with appropriate monitoring and follow-up reassessment aft er a trial period. An example of this in the setting of hypnosis would be a specifi c gut-directed hypnotherapy in patients with IBS whose predominant symptom was abdominal pain. Th is specifi c, cost-eff ective modality was able to signifi cantly decrease physical symptoms and in six of the eight health-related quality-of-life domains measured (emotional, mental health, sleep, physical function, energy, and social role). Th ese gains were most signifi cant in female patients with abdominal pain as their predominant symptom (Smith, 2006 ). In this example, through sift ing of available trials, a positive protocol can be found that may be worth discussing and incorporating by a trained professional. Integrative Approaches to Abdominal Pain 367

TREATMENT OVERVIEW

Acupuncture

Acupuncture typically involves the therapeutic insertion of fi ne needles at selected body points based on a traditional or neuroanatomical basis.

Acupuncture is often utilized in the setting of abdominal pain because it is believed to be helpful for pain management, based on speciﬁ c and nonspe- ciﬁ c local, neurochemical, and cortical modulation. (Pariente et al., 2005 ; Sprott, Franke, Kluge, & Hein, 1998).

From a mechanistic standpoint, acupuncture appears to increase solid gastric emptying and improve dyspeptic symptoms in patients with functional dyspepsia (Xu et al., 2006 ). Th ere also appears to be improvement in heart rate response, consistent with an increased parasympathetic tone, with acupuncture that is not seen with placebo acupuncture. Th e increase in parasympathetic tone also correlates with positively with improvement in abdominal pain (Schneider, Weiland, & Enck, 2007 ). Th e potential for benefi t in the setting of abdominal pain is diffi cult to answer from a research perspective largely based on the poor methodology and varied application of acupuncture in trials (Berman, Swyers, & Ezzo, 2000 ). Th e most recent Cochrane review of trials meeting inclusion criteria found that the evidence was inconclusive (Lim et al., 2006 ). A more recent trial found that quality of life related to IBS improved signifi cantly whether real or sham acupuncture was utilized. Th is led the authors to conclude that the benefi t in quality of life with acupuncture may be related to unspecifi c eff ects (Schneider, Streitberger, & Joos, 2007 ). Th is demonstrates the diffi culty in studying acupuncture in the setting of IBS, as far as the placebo response. In one estimate, based on diff erences between real and placebo acupuncture, a study would need 566 patients to potentially prove benefi t beyond placebo. Th is number is far beyond what is typically seen in trials of IBS (Schneider, Enck, Streitberger et al., 2006 ). Th e dichotomy between mechanistic/observation trials and clinic trials may be related to inappropriate study design. A more appropriate design may be similar to that seen in headache trials. Th is condition has also been demonstrated to have a nonspecifi c needle eff ect that is similar to sham acupuncture and superior to usual care (Vickers et al., 2004 ). Several trials have 368 INTEGRATIVE GASTROENTEROLOGY demonstrated this phenomenon, and proceeded to not focus on the diff erence between real/sham but instead on any acupuncture and usual care in pragmatic design. Th ese trials have shown benefi t in severity of headache and related measures, which has correlated to a positive economic impact (Wonderling, Vickers, Grieve, & McCarney, 2004 ). Considering the economic impact of IBS ($30 billion/year), which exceeds that of common conditions such as migraine, future trials of acupuncture should focus on a pragmatic design approach. Th is design looks not only at diff erences between needle interventions, but whether acupuncture can have a meaningful impact compared to usual care on IBS symptoms, quality of life, and related costs (absenteeism, offi ce visits, and medication). One such trial has explored this potential design (Reynolds, Bland, & MacPherson, 2008 ) and found that a pragmatic, randomized, intention-to-treat controlled trial compared 10 sessions of acupuncture plus usual primary care, with usual primary care alone. At three months, the patients receiving acupuncture in this trial had a signifi cant 138-point improvement on the IBS Symptom Severity Score (scored 0–500). Th e authors estimate that a sample size of 108 patients per arm would be required for a fully powered study. Th e authors conclude, “A pragmatic trial design will not be able to distinguish between acupuncture specifi c eff ects and placebo eff ects; however, it is the design of choice to determine cost eff ectiveness.” In summary, as a recent systematic review noted, “. . . it must be discussed on what terms patients benefi t when this harmless and obviously powerful therapy with regard to [quality of life] is demystifi ed by further placebo- controlled trials” (Schneider, Streitberger, & Joos 2007 ). For clinicians advising patients regarding acupuncture while awaiting more defi nite evidence from pragmatic or placebo-controlled trials, it is wise to assess the global impact of the conditions and benefi t from usual care. For those patients with refractory symptomology and reduced quality of life, it appears prudent to utilize a short trial of 8 to 10 treatments by a qualifi ed practitioner to assess benefi t. It is also advised that a standardized questionnaire, such as the IBS Symptom Severity Score, be utilized in conjunction with monitoring of medication use, productivity, and other lifestyle measures to pragmatically view the potential benefi t of acupuncture in this setting.

PHYSICAL THERAPIES

Modalities and physical therapies include a wide range of therapies that are practitioner based and/or patient guided. Th e most common of these therapies utilized in abdominal pain/IBS are various electrostimulation or transcutaneous Integrative Approaches to Abdominal Pain 369 electrical nerve stimulation (TENS) techniques. Th ese therapies are based on several potential areas of benefi t, which may correct areas of abnormality seen in abdominal pain/IBS, including muscular tension, autonomic hypersensitivity, altered skin temperature, and dysfunctional motility (McAllister, McGrath, & Fielding, 1990 ).

Electrical Stimulation

Various types of transcutaneous electrical nerve stimulation (TENS) devices have been utilized in the setting of abdominal pain. One trial found that TENS at acupuncture points appears to improve dyspeptic symptoms and increases high-frequency heart rate variability in patients with functional dyspepsia (Liu et al., 2008 ). A pilot study also evaluated acupoint TENS in patients with diarrhea-predominant irritable bowel syndrome (IBS-D), constipation-predominant irritable bowel syndrome (IBS-C), functional constipation (FC) and healthy controls. IBS-D patients had signifi cantly lower rectal sensory thresholds of the fi rst sensation of stool, urgency of defecation, and pain than IBS-C or FC patients or healthy controls (P < 0.05). Aft er 2 months of acupoint TENS treatment in IBS-D patients, there was signifi cant improvement in rectal sensory thresholds, stool times, and the intensity of abdominal pain (Xiao & Liu, 2004 ). Electrostimulation may be considered based on preliminary data in the setting of refractory symptoms, especially diarrhea-predominant irritable bowel syndrome (IBS-D).

Mind–Body Therapies (MBT)

Mind–body Th erapies (MBTs) are diverse techniques that utilize cognitive, behavioral, and movement therapies to modify and increase awareness between mental and physiological functioning. Th ese therapies can be as simple as one- time directed educational eff orts, and as elaborate as long-term behavioral and psychological interventions. Several MBTs utilized in the setting of abdominal pain/IBS are reviewed below. Overall, the recent Cochrane review concluded that “psychological interventions may be slightly superior to usual care or waiting list control conditions at the end of treatment,” although few long- term follow-up results were available for review (Zijdenbos et al., 2009 ). Specifi cally, for improvement in abdominal pain, the standardized mean difference (SMD) at 2 and 3 months were 0.54 and 0.26 compared to usual care, and the SMD versus placebo at 3 months was 0.31. 370 INTEGRATIVE GASTROENTEROLOGY

reassurance Several articles have noted poor patient understanding of their condition, as well as catastrophizing, as factors related to increased symptom severity in IBS (Lackner, Quigley, & Blanchard, 2004 ). One trial attempted to determine the benefi t of a single session of reassurance in self-perception of impairment in patients with IBS. In 55 patients seen for initial consultation, a questionnaire was provided to assess factors related to healthcare seeking. Th ese included pain/discomfort, 78 ; cancer fear, 11 ; daily function impairment, 33  ; symptom related to stressfulness, 60  ; and none, 2  . Aft erwards, patients were provided with an explanation of the disease and reassurance, with readministration of the questionnaire. Th e authors found that one-time reassurance acutely decreased self-perception of daily function impairment (P=.003) and was independent of the subjects’ educational level (Schmulson, Ortiz-Garrido, Hinojosa, & Arcila, 2006 ).

cognitive-behavioral therapies (cbt) Cognitive-behavioral therapies enable patients to better understand how various beliefs, thoughts, and perceptions can aff ect their condition. Techniques such as restructuring, prioritization, and goal-setting are utilized to repattern behavior. Mechanistically, PET scanning in conjunction with CBT training has demonstrated reduction in limbic activity (Lackner et al., 2006 ). In the setting of CBT clinical trials, meta-analysis of 17 trials found an odds ratio of 12.0 in creating a > 50  reduction in GI symptoms. Overall, the NNT to provide benefi t versus controls was 2 (Lackner et al., 2004 ). Th is intervention should be freely recommended, especially in patients who exhibit psychological sequelae as a means of better approaching their condition or other therapies.

hypnosis Hypnosis has been defi ned in various ways, but typically involves, “the use of aroused, attentive, focused concentration and relative suspension of peripheral awareness to create opportunities for suggestion” (Astin, Shapiro, Eisenberg, & Forys, 2003 ). Th e overall evidence for hypnosis in the setting of IBS is inconclusive, as noted by a recent Cochrane meta-analysis (Webb, Kukuruzovic, Catto-Smith, & Sawyer, 2007 ). However, for short-term benefi t in the setting of abdominal pain and IBS symptoms, the authors noted that hypnotherapy was superior to waiting list control or usual medical management in patients who fail standard medical therapy. As mentioned above, the most-studied regimen is known as gut-directed hypnotherapy, which has demonstrated signifi cant benefi t in the majority of clinical trials (Wald & Rakel, 2008 ). Unfortunately, incorporation has not been universal because trials have suff ered from methodological weaknesses and treatment requires a 6 to 12 week commitment. Alternatives to the treatment have been investigated, including a self-hypnosis audio recording, which provided similar (52  ) Integrative Approaches to Abdominal Pain 371 improvement to gut-directed hypnotherapy (Forbes, MacAuley, & Chiotakakou- Faliakou, 2000 ). At this point, hypnosis may be considered as a likely eff ective mind–body therapy in the motivated or refractory pain/IBS patient.

biofeedback Biofeedback utilizes various techniques or sensors to increase mind-body awareness and identify areas of potential modifi cation such as muscle tension (sEMG) or autonomic tone (peripheral temperature, heart rate variability [HRV], galvanic skin response). Because of the autonomic dysfunction described in IBS, biofeedback training aff ords a potential treatment for active nervous system retraining. Trials in this area have used various biofeedback techniques in a number of GI conditions including IBS, fecal incontinence, and pelvic fl oor dyssynergia (PFD)/functional constipation, which is oft en associated with anorectal pain. Th e most robust evidence for pain management appears to be in the area of PFD, in which a review of 38 trials found that the overall average probability of successful treatment outcome for patients treated with biofeedback was 62.4 (Palsson, Heymen, & W h i t e h e a d , 2 0 0 4 ) .

guided imagery Guided imagery encompasses various techniques, which combine “the use of inner images and symbols (self-guided or interactive) with therapies to induce a specifi c psychobiologic state (e.g., immune enhancement, relaxation, confl ict resolution)” (Astin, Shapiro, Eisenberg, & Forys, 2003 ). In a preliminary trial of 22 children (aged 5 to 18 years), guided imagery with progressive muscle relaxation (GI + PMR) was compared to breathing exercises, as provided in 4 weekly sessions with a therapist. At baseline, the children who received guided imagery had more days of pain during the preceding month (23 versus 14 days). Children who learned guided imagery with progressive muscle relaxation had signifi cantly greater decrease in the number of days with pain and days with missed activities, at one and two months. At 2-month follow-up, more children who had learned guided imagery had 4 or fewer days of pain each month, with no missed activities. Although a small trial, the ability to reduce days of pain from greater than 20 to fewer than 5, with a relatively short-term, benign intervention, deserves consideration while awaiting additional trials (Weydert et al., 2006 ).

Biologically Based Therapies

A number of trials have attempted to investigate the use of dietary intervention for IBS-related symptoms including pain. Th ese are subdivided in the following sections. 372 INTEGRATIVE GASTROENTEROLOGY

fiber Fiber supplementation studies for IBS symptoms vary based on types (soluble vs. insoluble), formulation (food based, dietary supplement) and amount recommended. Overall, fi ber has been compared with placebo or a low-fi ber diet in 6 studies with a total of 591 subjects (Quigley et al., 2008). Fiber improved symptoms in 48  of subjects versus 43  in the placebo or low fi ber groups. Th e NNT with fi ber for clinical success is 11, although the range was large a large range (5 to 100) based on varied methodology. Bran fi ber has specifi cally been compared with placebo or a low-fi ber diet in 5 studies with a total of 221 subjects. A summary of all trials demonstrates no statistically signifi cant improvement in IBS symptoms with use of bran fi ber. Psyllium (ispaghula husk) has specifi cally been compared with placebo in 6 studies with a total of 321 patients. Psyllium improved symptoms in 48 of subjects versus 36 in the placebo group. Overall, the number needed to treat with ispaghula to prevent one patient having persistent symptoms was 6, although the range was large (3–50) based on varied methodology. Lastly, guar gum (5 g/day) has been compared to wheat bran (30g/day) in one IBS. Although both treatments improved symptoms related to abdominal pain and bowel habits, guar gum was better tolerated and preferred by patients (Parisi et al., 2 0 0 2 ) .

probiotics Probiotics are broadly defi ned as benefi cial microbes taken to improve health. Because IBS has been linked to microfl ora alteration, the use of probiotics has been discussed as a helpful treatment. Th e mechanism of benefi t, in addition to reducing the population of symptom-causing microfl ora, may also include the anti-infl ammatory and opioid-releasing ability of some strains. In a study of bifi dobacteria, 8 diff erent strains were analyzed for their eff ects on in vitro models of non-infl amed and infl amed intestinal epithelium. Th e results demonstrated that although none of the bifi dobacteria induced nuclear factor κ B (NF- κ B) activation, six of the eight bifi dobacteria tested inhibited lipopolysaccharide- (LPS-) induced NF- κ B activation in a dose- and strain-dependent manner. Th is response was accompanied in specifi c strains by a dose-dependent reduction of interleukin 8 (IL-8) secretion and by decreased mRNA levels for infl ammatory markers including IL-8, TNF-α , cyclooxygenase 2 (Cox-2) and intercellular adhesion molecule 1 (ICAM-1). Th e authors stated that certain bifi dobacteria may be of benefi t in the setting of chronic intestinal infl ammation (Riedel et al., 2006 ). A number of clinical trials have attempted to test various probiotic strains in the setting of IBS pain and symptom management. In a meta-analysis of 20 such trials, McFarland and Dublin ( 2008 ) compared 23 probiotic treatment arms in 1,404 subjects. In this analysis, probiotic use was associated with improvement in global IBS symptoms compared to placebo (relative risk Integrative Approaches to Abdominal Pain 373

RR=0.77, 95  confi dence interval [95 CI; 0.62–0.94]). Specifi cally, probiotics were associated with decreased abdominal pain compared to placebo (RR = 0.78 [0.69–0.88]). Th e number needed to treat (NNT) for reducing abdominal pain was 8.9. Considering that this is a relatively benign intervention, a trial should be considered in the appropriate setting. Several limitations are present, however, in the use of probiotics for abdominal pain associated with IBS. Namely, numerous strains at various doses have been studied, as noted in Table 36.7. In the setting, the clinician should be aware of various formulations, as noted below, and may need to attempt various brands before fi nding one p o t e n t i a l l y h e l p f u l .

peppermint Th e use of peppermint extract for IBS-related symptoms has been studied in four placebo-controlled trials. Th ese trials, which enrolled 392 patients, were reviewed by Ford et al ( 2008 ). While 65  of patients receiving placebo had persistent symptoms, this dropped to 26  of patients randomized to peppermint oil. Th e NNT with peppermint oil to prevent one patient having persistent symptoms was 2.5 (2.0 to 3.0). A review of these trials is noted in Table 36.8.

other dietary interventions A number of herbal medicines have demonstrated benefi t versus placebo in IBS trials, including Chinese herbal formulas, STW 5, STW 5-II and Tongxie Yaofang, Tibetan herbal formula Padma Lax, and certain Ayurvedic formulas (Liu, Yang, Liu, Wei, & Grimsgaard, 2006 ). Other dietary interventions, including incorporating food antibody testing and dietary supplements such as l-glutamine, zinc, and cromolyn sodium, have been mentioned in the setting of IBS (Wald & Rakel, 2008 ). Although individualized cases may benefi t from the incorporation of various interventions, the evidence for generalized benefi t is either lacking or confl icting. Clinicians should openly discuss these options to ascertain the potential benefi t of a particular intervention.

Conclusion and Coordination of Care

Abdominal pain is a complex disorder that involves both central and peripheral sensitization, causing pain amplifi cation and multisystem dysfunction, creating signifi cant autonomic, functional, and psychological sequelae. It is quite important to take a biopsychosocial approach to this condition, as single modality approaches are rarely curative or of long-term benefi t. A model of a biopsychosocial approach is noted in Figure 36.1 . Because of the sometimes disparate presentation of patients with abdominal pain/IBS it is imperative to Table 36.7. Relief of Abdominal Pain in 11 Probiotic/Placebo Treatment Arms

Reference Probiotic Improvement in abdominal pain Deﬁ nition of secondary outcome 1

Probiotic n/n ( % ) Placebo n/n ( % )

Gade (46) Strept faccalis 25/32 (78) 10/22(45) Absence or presence of symptom

Nobaek (48) L. plantarum 9/25 (36) 5/27 (18) Decrease ≥ 1.5 on VAS symptom scale

O’Sullivan (49) L . rhamnosus GG 9/19 (47) 12/19 (63) Symptom improved

Niedzielin(50) Lacto plantarum 20/20 (100) 11/20 (55) Absence or symptoms

Bausserman (52) Liicto rhamnosus GG 11/25 (44) 10/25 (40) Decrease of ≥ 1 point symptom score

Kajander(54) L. rhamnosus GG + L. rham. LC705 + 27/41 (66) 17/40 (43) Symptoms alleviated Bifi d. brene Bb99 + Prop. freudenreichii

Whorwell(35) Bifi do. infantis (10 6 dose) 32/74 (43) 39/76 (52) Adequate relief of symptoms

Whorwell(35) Bifi do. infantis (10 8 dose) 42/72 (59) 39/76 (52) Adequate relief of symptoms

Whorwell(35) Bifi do. infantis (10 10 dose) 28/71(39) 39/76 (52) Adequate relief of symptoms

Enck(59) E. coli + Strept faccalis 108/149 (72) 66/148 (45) ≥ 50 % decrease in symptom score

Gawronska (60) Lacto rhamnosus GG 6/18 (33) 1/19 (5) Absence of pain

1 All secondary outcomes are defi ned based on patient report. Reprinted with permission from Lynne V. McFarland. Table 36.8. Peppermint for IBS: Characteristics of randomized controlled trials of peppermint oil versus placebo in irritable bowel syndrome

Study Country Setting Diagnostic Criteria to deﬁ ne symptom Sample Dose of peppermint Duration of Jadad criteria for improvement after therapy size oil therapy score irritable bowel syndrome

Lech 1988w29 Denmark Secondary Clinical Patient reported improvement in 47 200 mg three times 4 weeks 3 care diagnosis and global symptoms daily investigations

Liu 1997 w30 Taiwan Secondary Clinical Patient reported improvement in 110 187 mg three or 1 month 4 care diagnosis and abdominal pain four times daily investigations

Capanni Italy Secondary Rome II Improvement in global 178 2 capsules three 3 months 5 2005 w32 care symptoms assessed by validated times daily questionnaire

Cappello Italy Secondary Rome II and ≥ 50 % improvement from 57 225 mg twice daily 4 weeks 5 2007 w31 care investigations baseline in overall irritable bowel syndrome symptom score using questionnaire data

Reprinted with permission from Ford AC et al. BMJ. 2008 Nov 13;337:a2313. doi: 10.1136/bmj.a2313. 376 INTEGRATIVE GASTROENTEROLOGY individualize care. In addition, because of several factors, including high levels of treatment failure, potential sensitivity to pharmacological interventions, and preference for specifi c treatment options, it is imperative for clinicians to be aware of NP/CAM options and to actively engage patients in discussion and coordination of these therapies when appropriate. Several resource tables and fi gures are provided to enable initial and ongoing discussion and management of NP/CAM options in abdominal pain. Several of the therapies reviewed in this chapter can provide safe, eff ective avenues of treatment for abdominal pain and its comorbidities. In many cases, the clinician is essential in helping abdominal pain patients to practically incorporate the various NP/CAM options available, to come up with a successful integrative management plan. If properly coordinated, there is evidence that an integrative/multidisciplinary approach, which typically involves both biological and MBT, may be more eff ective than monotherapy in creating a more satisfi ed abdominal pain patient with self-management skills. In the future, we look forward to additional research that helps to understand the synergy of NP/CAM therapies with conventional pharmacological care.

* Portions of this chapter are excerpted with permission from Non-pharmacological, Complementary & Alternative (CAM) Treatments for Fibromyalgia, McCarberg W and Clauw D, eds., Fibromyalgia , Informa Healthcare USA, Inc., New York, 2009.

37 Over-the-Counter Remedies for Digestive Health: Potion or Poison?

JERRY HICKEY AND GERARD E. MULLIN

key concepts

■ More than 50 million American adults experience frequent heartburn. ■ Proton-pump inhibitors (PPIs) are the third-bestselling class of medications in the United States. ■ Omeprazole is the only PPI that inhibits CYP2C19 while increasing the expression of CYP1A2. ■ Proven complications of PPI therapy include: ■ Bacterial colonization ■ C. diffi cle infection ■ Interstitial nephritis ■ Small bowel bacterial overgrowth ■ Community-acquired pneumonia ■ H i p f r a c t u r e ■ Nutrient malabsorption (calcium [O’Connell et al., 2005 ],

magnesium, iron, vitamin B12 ) ■ H2 receptor antagonists (H 2RAs) are weaker than PPIs but can suppress 24-hour gastric acid secretion by about 70  . ■ Cimetidine: ■ interacts with various Phase 1 detoxifi cation enzymes including CYP1A2, CYP2C9, and CYP2D6 ■ can cause a broad array of CNS symptoms ■ can include galactorrhea in women, and gynecomastia, reduced sperm count, and impotence in men (Hoogerwerf WA, Pasricha PJ, 2006 1) For all H2 Receptor Antagonists

(H2 RAs), thrombocytopenia and other blood dyscrasias have also been reported.Nutrient depletions are similar to the PPIs.

377 ■ Stimulant Laxatives: ■ induce low-grade infl ammation and enhance gastrointestinal motility ■ long-term use of irritant laxatives may lead to colonic pathology, “cathartic colon” ■ mineral oil side eff ects include leakage of oil, greasy stools; rarely, if aspirated, it can cause lipid pneumonitis. ■ Mineral Oil: ■ side eff ects include leakage of oil, greasy stools ■ rarely, if aspirated, it can cause lipid pneumonitis ■ can interfere with the absorption of minerals and all fatty soluble nutrients. ■

Outline

● Proton Pump Inhibitors • Issues concerning OTC drugs for gastrointestinal indications: • Side eff ects • Toxicity • Complications of PPIs • Drug interactions • N u t r i e n t d e p l e t i o n s ● H 2 Receptor Antagonists (H 2 R A s ) • Issues concerning OTC drugs for gastrointestinal indications: • Side eff ects • Toxicity • Drug interactions • N u t r i e n t d e p l e t i o n s ● A n t a c i d s • Issues concerning OTC drugs for gastrointestinal indications: • Side eff ects • Toxicity • Drug interactions • N u t r i e n t d e p l e t i o n s Over-the-Counter Remedies for Digestive Health: Potion or Poison? 379

● L a x a t i v e s • Issues concerning OTC drugs for gastrointestinal indications: • Side eff ects • Toxicity • Drug interactions • N u t r i e n t d e p l e t i o n s

Proton Pump Inhibitors for GERD

TREATING FREQUENT HEARTBURN

Frequent heartburn is defi ned as symptoms occurring two or more days per week. More than 50 million American adults experience frequent heartburn. In the United States, 25 million adults experience heartburn daily. Heartburn aff ects quality of life, disrupting sleep and interfering with work and social activities (National Heartburn Alliance, 2003 ; Oliveria et al., 1999 ; Revicki et al., 1998 ). Heartburn is slightly more common in women; the mean age of reporting symptoms is 45 to 50 years of age. In rare cases it can lead to esophageal adenocarcinoma (Cappell, 2005 ). Access to OTC medications has been reported to improve patient adherence to a treatment regimen.

PROTON PUMP INHIBITORS FOR FREQUENT HEARTBURN

Increasingly, the more powerful proton pump inhibitors are replacing Histamine-2 (H2) antagonists in clinical practice. Omeprazole is the fi rst proton pump inhibitor available without a prescription. Omeprazole is available as Prilosec OTC Delayed-Release Tablets 20 mg.

• P r i l o s e c O T C i s t h e fi rst proton pump inhibitor (PPI) to be available over-the-counter for frequent heartburn treatment. • Prilosec OTC is for people with frequent heartburn (two or more days per week). • One pill a day of Prilosec OTC works to relieve heartburn for up to 24 hours as part of a 14-day course of therapy. * • Directly shuts down many active proton pumps over time that make acid, but purported to leave enough acid for digestion, with one pill a d a y . 380 INTEGRATIVE GASTROENTEROLOGY

Side Effects

Th e most common side eff ects are:

• N a u s e a • A b d o m i n a l p a i n • C o n s t i p a t i o n • F l a t u l e n c e • D i a r r h e a

However, mild myopathy, arthralgias, headaches and skin rashes have also been reported. Chronic use of omeprazole may lead to hypergastrinemia in 5  to 10  of chronic users. Discontinuation of omeprazole aft er chronic use in patients with hypergastrinemia may cause a rebound hypersecretion of gastric acid (Freston, 1994 ).

Complications of PPIs

the top ten list 1) PPIs can lead to twofold increased rates of Clostridium diffi cile colitis Gastric acid provides a natural protective barrier to orally ingested pathogens. Th e signifi cance of this association is accentuated by the emergence of a hyper- virulent strain of C. diffi cile that is highly transmissible, causes severe colitis that sometimes requires colectomy, and has a fatality rate as high as 20  . Th is disease is more commonly a complication of outpatient antibiotic usage, which is being overprescribed at record levels (Dial et al., 2005b ). Development of drug resistance and alteration of the intestinal fl ora are felt to predispose to digestive disease. PPIs are a major contributor to nosocomial Clostridium diffi cile infection (Howell MD et al., 2010).

2) Bacterial colonization with resistant microbes in the intensive care unit (ICU) setting. Many investigations have reported the overuse and misuse of PPIs by physicians hospital-wide and in the intensive care unit (ICU) setting (Eid SM et al, 2010 ). Our own surveys demonstrate misperceptions, misuse, and overuse of PPIs by resident and attending physicians. Our fi ndings led to restricted usage, Over-the-Counter Remedies for Digestive Health: Potion or Poison? 381 to reduce inappropriate use and to diminish the risk from nosocomial infection in the intensive care setting (White, Storch & Mullin, 2003 ; Mian et al., 2003 ).

3) PPIs are associated with an increased risk of community-acquired pneumonia. PPIs increase the risk of bacterial infections by reducing the bactericidal activity of immune cells (Zedtwitz-Liebenstein et al., 2002 ). A study using a database of 500,000 records reported in JAMA found that current use of PPIs was associated with an increased risk of community-acquired pneumonia (CAP).

4) Drug-induced acute interstitial nephritis. PPIs are one of the most frequent causes of drug-induced acute interstitial nephritis (in some cases leading to renal failure), which is a trade secret, since most gastroenterologists are unaware of this potential toxic eff ect (Geevasinga et al., 2006 ).

5) Possible cardiovascular events. In 2007, Astra Zeneca provided the FDA data from two small ongoing studies showing that individuals taking the “purple pill” were at an increased risk for cardiovascular events, such as myocardial infarction and congestive heart failure. Th e agency did not issue a safety warning at that time. On August 7, 2007, the FDA made an unprecedented “early communication” to dismiss the adverse events as age-related and preexisting conditions. ii In early 2009, some proton pump inhibitors were reported by Canadian researchers to reduce or eliminate the antiplatelet benefi ts of clopidogrel (Plavix) and increase the risk of a second heart attack (Juurlink et al., 2009 ). In a six-year population-based study of heart attack patients published in the Canadian Medical Association Journal, current use of three proton pump inhibitors was associated with a 27 increase in the risk of another heart a t t a c k .

Explain to interested patients that clopidogrel (Plavix) is prescribed after a heart attack for secondary prevention. Note that this study found that taking the drug along with some proton pump inhibitors increases the risk of recurrence. 382 INTEGRATIVE GASTROENTEROLOGY

Th e fi nding came as the FDA began a review of the so-called “clopidogrel resistance phenomenon,” in which between 5 and 15 of patients do not respond to the drug at all. Sanchez-Munoz-Torrerro et al ( 2010 ) subsequently reported that in patients with established arterial disease, concomitant use of PPIs and clopidogrel was associated with a nearly doubling of the incidence of subsequent myocardial infarction or ischemic stroke. Th e story of the interaction between clopidogrel and PPIs and their potential increase risk to patients with underlying coronary artery disease is unfolding.

6) Bacterial overgrowth of the stomach and proximal small intestine. A concern for physicians and their patients about PPI usage is that chronic acid inhibition may lead to bacterial overgrowth of the stomach and proximal small intestine. In GERD patients who are being treated with PPIs, there is an increased load of intragastric bacteria compared with those in whom PPI therapy has been discontinued (Gregor, 2004 ). Furthermore, a study that used a well-defi ned database consisting of about 500,000 patient medical records showed that acid-suppressive drugs such as PPIs are associated with an increased risk of community acquired pneumonia (CAP) (Laheij et al., 2004 ). Bacterial overgrowth may not only become a source of pneumonia from colonization, but it appears to become a susceptibility factor for a subtype of IBS that requires antibiotics to improve symptoms (Pimentel & Lezcano, 2007 , Lombardo et al., 2010 ).

7) Pneumonia in the elderly: increased risk and worse prognosis. PPIs may be particularly risky for the elderly. Pneumonia is a major source of mortality in the elderly, immunocompromised patients, individuals with asthma or chronic obstructive lung disease, and children. Due to the age- related reduction of gastric acid aft er 60 years, and partially due to a decreased immune response, elderly patients are likely to experience severe infection (Dial et al., 2005a ). Th is study demonstrated a dose-response eff ect, as the relative risk of pneumonia was greatest for those taking more than one daily dose of a PPI. To avoid excessive pneumonia in the elderly, the study’s authors recommended that the elderly, “immunocompromised patients, those with asthma or chronic obstructive lung disease, and children should be treated with acid-suppressive drugs only when needed and with the lowest possible dose.”

8) Hip fracture. Most recently, and of particular concern, long-term PPI use appears to predispose to the development of hip fracture (adjusted odds ratio 2.6; see Yang et al., 2006 ). Millions of individuals have been using these medications Over-the-Counter Remedies for Digestive Health: Potion or Poison? 383 on a continuous or long-term basis. Given that the elderly have reduced omeprazole clearance, caution should be exercised toward this complication, and bone density scanning may become necessary for early detection of osteoporosis from PPIs.

9) PPIs cause malabsorption of calcium, iron, and vitamin B12 from lowering gastric acidity Signifi cant defi ciency in gastric acid, called “hypochlorhydria,” is already prevalent among the elderly population without adding PPIs to the mix (Malfertheiner et al., 2007 ) . Th e elderly appear to have decreased PPI clearance from their bloodstream, and may be more likely to have more profound hypochlorhydria at baseline (without any PPI usage), due to a higher prevalence of Helicobacter pylori infection, which itself causes hypochlorhydria (Lai & Sung, 2007 ). PPIs result in calcium malabsorption, since gastric acid is required for solubilization prior to absorption (Recker, 1985 ). In fact, limited animal and human studies have shown that PPI therapy may decrease insoluble calcium absorption or bone density (O’Connell et al., 2005 ; Camilleri et al., 2 0 0 7 ) .

10) Bacterial gastroenteritis. Gastric acid is a defense mechanism against gastrointestinal infections caused by ingested bacteria. Studies have suggested that the use of acid- suppressing drugs may increase the risk of gastroenteritis (GE). Current use of PPIs was found by scientists in Madrid, Spain, to be associated with an increased risk of bacterial GE compared with nonuse, regardless of the treatment duration (Garcia Rodriguez, Ruigomez, & Panes, 2007 ). In contrast, no association with gastroenteritis was observed with histamine receptor-2 antagonists (H2 RA), which are weak stomach acid blockers. Doubling the PPI dose further increased the risk of developing bacterial GE. Th e eff ect of PPI use did not vary signifi cantly with regard to treatment indication. Th e increased risk associated with PPI use was similar for both omeprazole and lansoprazole, whereas neither of the H2 RAs, cimetidine nor ranitidine, showed any increased risk. Campylobacter (n = 4124) and Salmonella (n = 1885) were the two species most frequently responsible for GE episodes in the case group (n = 6414). Th e case-control group consisted of 50,000 non-PPI users. When analyzed separately, both species reproduced the increased risk associated with PPI use and not H2 RA therapy. Conclusions: Th is study strongly suggests that gastric acid suppression induced by PPIs, but not H 2 RA, is associated with an increased risk of Campylobacter and Salmonella G E . 384 INTEGRATIVE GASTROENTEROLOGY

Fact

Omeprazole therapy signiﬁ cantly decreased calcium absorption in elderly women. (O’Connell et al., 2005 ).

Proton-pump inhibitors (PPIs) are among the most commonly prescribed drugs, and a large number of patients use these on a daily basis as maintenance therapy for gastroesophageal refl u x d i s e a s e .

Fact about PPIs

Despite the widespread use of PPIs in GERD, the prevalence of pre-neoplastic complications of GERD (Barrett’s esophagus) and esophageal adenocarcinoma are on the rise in the United States.

Although they are considered safe by the FDA and approved for long-term use, a number of concerns continue to be raised. Because of their strong acid-suppressive eff ect, PPIs lead to increased secretion and plasma levels of the hormone gastrin, which may support the development of neoplasia at high sustained levels. Two studies (Yang et al., 2007; Robertson et al., 2007) published in the journal Gastroenterology (United Kingdom, Denmark) found that long-term PPI therapy ( > 5 years) at regular doses was not associated with a signifi cantly increased risk of colorectal cancer (CRC). However, the study by Yang et al., found a strong association between recent (<1 year) PPI therapy and the risk of CRC (OR, 2.6; 95  CI, 2.3–2.9; P < .001). Th e increased risk in Yang’s study was observed exclusively with recent short-term use (within the preceding 12 months). Jan Tack and John M. Carethers wrote a commentary about these articles in the September 2007 issue of Gastroenterology . Th eir closing comment on the articles stated:

“Both studies found that long-term PPI therapy was not associated with a signifi cantly increased risk of CRC. Th ese reassuring fi ndings are important from a public health point of view for patients taking PPIs as well as for Over-the-Counter Remedies for Digestive Health: Potion or Poison? 385

gastroenterologists prescribing PPIs. However, as PPI use increases over time, continued monitoring of the eff ect of PPI therapy on the risk of CRC over longer follow-up times seems warranted.”

Drug Interactions

Omeprazole has a number of drug interactions because it is metabolized by various cytochrome-p 450 enzymes. Omeprazole is the only PPI that inhibits CYP2C19, therefore decreasing the rate of excretion of disulfi ram, phenytoin, and other drugs. Omeprazole increases the expression of CYP1A2, thereby increasing the rate of excretion of imipramine, some antipsychotic drugs, tacrine, and theophylline. Additionally, omeprazole interacts with warfarin, diazepam, and cyclosporine (Relling MV & Giacomini KM, 2006 ). Nutrient Depletion Calcium. Researchers at the University of Pennsylvania School of Medicine report that chronic use of proton pump inhibitors, especially at higher doses, increases the risk of hip fracture. Hypochlorhydria interfered with the absorption of calcium (Yang, Lewis, Epstein, & Metz, 2006 ). Magnesium . Th ere have been reports of severe magnesium depletion in users of omeprazole. Researchers from the University of Auckland found that omeprazole inhibited the absorption of magnesium, and this eff ect could be partially corrected by supplementing with high-dose oral magnesium (Cundy & Dissanayake, 2008 ). Other nutrients: omeprazole inhibits the absorption of zinc (Ozutemiz et al., 2002 ), vitamin B12 , vitamin B1 , folic acid, and iron, sodium, and beta-carotene (Vagnini & Fox, 2005 ). Although PPIs are considered by many to be devoid of adverse eff ects, nutrient depletions can be severe. Recently, there was a case of omeprazole-induced hyponatremic delirium accompanied with rhabdomyolysis in an emergency department patient. Aft er cessation of omeprazole and emergency treatment, the patient recovered completely (Bebarta & King, 2008 ).

nutrients depleted by ppis: • C a l c i u m • M a g n e s i u m • Z i n c

• V i t a m i n B12

• V i t a m i n B1 • F o l i c a c i d • I r o n 386 INTEGRATIVE GASTROENTEROLOGY

• S o d i u m • B e t a - c a r o t e n e

H2 RECEPTOR ANTAGONISTS (H RAS) 2

H2-receptor antagonists competitively inhibit the binding of histamine at receptor sites on parietal cells, decreasing the production of acid. Although weaker than PPIs, H 2RAs can suppress 24-hour gastric acid secretion by about 70 (PPIs; 80-95 ) (Hoogerwerf WA, Pasricha PJ, 2006 -1). Th ese drugs are approved for treating uncomplicated GERD, but are increasingly being replaced by PPIs in clinical practice. H2-receptor antagonists available without a prescription include:

• Cimetidine (Tagamet HB) • Famotidine (Pepcid AC) • Nizatidine (Axid AR) • Ranitidine (Zantac 75)

Side Effects

Th e side eff ects of H2-receptor antagonists are considered to be minor, but include:

• D i a r r h e a • H e a d a c h e s • D r o w s i n e s s • F a t i g u e • M u s c u l a r p a i n • C o n s t i p a t i o n

Th ere are less common but more serious side eff ects that aff ect the CNS, including delirium, confusion, hallucinations, and slurred speech, which can occur in elderly subjects. Cimetidine, in particular, aff ects sex steroid hormones if used long term and, typically, at higher dosages. Th e drug infl uences estrogen metabolism in women and testosterone binding in men. Th e result can include galactorrhea in women, and gynecomastia, reduced sperm count, and impotence in men (Hoogerwerf WA, Pasricha PJ, 2006 -2). Th rombocytopenia and other blood dyscrasias have also been reported (Freston, 1982 ). Increased incidence of community-acquired pneumonia has been linked to the use of famotidine (Hauben, Horn. Reich, & Younus, 2007 ). Over-the-Counter Remedies for Digestive Health: Potion or Poison? 387

Drug Interactions

Cimetidine interacts with various phase 1 detoxifi cation enzymes, including CYP1A2, CYP2C9 and CYP2D6. Ranitidine also interacts with hepatic CYPs but with only 10 of the affi nity seen with cimetidine. Famotidine and nizatidine have very little infl uence on these enzymes (Pharmacotherapy, 2006 ). Th erefore, any drug metabolized by these CYPs will have an interaction with cimetidine and a possible interaction with ranitidine.

Nutrient Depletions

Calcium is reportedly depleted at least to some extent by H2-receptor antagonists (Vagnini & Fox, 2005 ). Iron: Gastric acid secretion is required to facilitate iron absorption. Malabsorption of dietary iron may result from inhibition of acid secretion by the H2-receptor antagonists. H2-receptor antagonists are considered to be effi - cient chelators of Fe2+ . Th is probably lacks clinical importance during the short term; however, long-term use of these drugs could contribute to the occurrence of iron-defi ciency anemia. Such impairment of nonheme iron absorption could be amplifi ed for individuals concurrently using antacids on a regular basis in conjunction with H2-receptor antagonists (Aymard et al., 1988 ). Zinc: Reduced gastric acid secretion can exert both direct and indirect eff ects on the absorption of zinc that parallel its impairment of iron absorption. In a study involving healthy adults, 300 mg/day of ranitidine for 3 days signifi cantly reduced gastric acid and zinc absorption (Sturniolo et al., 1991 ).

Vitamin B12 : H2-receptor antagonists decrease acid secretion by the gastric parietal cells. Gastric acid and pepsin produced by these cells are required for the cleavage of vitamin B12 from dietary sources. H2-receptor antagonists prevent dietary B12 from being freed from its protein binder during digestion.

Studies have demonstrated a signifi cant reduction in food-bound vitamin B12 absorption secondary to decreased acid secretion in patients taking H2-receptor antagonists. Th is probably lacks clinical importance during the short term; however, long-term use could contribute to the occurrence of vitamin B 12 - defi ciency anemia. Such impairment of vitamin B12 absorption could be amplifi ed for individuals taking antacids on a regular basis along with ranitidine (;Aymard et al., 1988 ; Force & Nahata, 1992 ). Other nutrients: H2-receptor antagonists have also been reported to interfere with the absorption of copper, folic acid, and vitamins B1 and D (Vagnini & Fox, 2005 ; Gaby et al., 1999 ). 388 INTEGRATIVE GASTROENTEROLOGY

Pharmacist’s Corner

I have been recommending deglycyrrhizinated licorice (DGL) to clients with GERD for more than a decade with little or no untoward effects, although I have had a few complaints regarding taste. Licorice contains a chemical known as glycyrrhizic acid, which is responsible for many of its reported side effects, including those associated with electrolyte disturbances. The DGL form of licorice has the glycyrrhizic acid component removed, and therefore is considered safer to use (Medline Plus; Petry & Hadley, 2001). DGL is used for heartburn (PDR Health) and has a number of beneﬁ cial effects in patients with GERD. It enhances mucus secretion and accelerates healing of digestive tissue (van Marle, Aarsen, Lind, & van Weeren-Kramer, 1981 ; Das, Das, Gulati, & Singh, 1989 ).

ANTACIDS

Antacids have largely been replaced by more eff ective and convenient drugs. Nevertheless, they continue to be used by patients for a variety of indications (Hoogerwerf WA, Pasricha PJ, 2006 -3). Antacids are used to relieve heartburn, acid indigestion, and stomach upset. Th ey may be used to treat these symptoms in patients with peptic ulcer, gastritis, esophagitis, hiatal hernia, or too much acid in the stomach (gastric hyperacidity). Th ey combine with stomach acid and neutralize it. Aluminum hydroxide, magnesium hydroxide, and calcium carbonate are common ingredients in antacids.Simethicone is added to a number of antacids. Simethicone is a surfactant that breaks up gas bubbles. It also may reduce foaming, and may hence aid esophageal refl ux (Hoogerwerf WA, Pasricha PJ, 2006 -3). Side eff ects from aluminum hydroxide and magnesium hydroxide are not common, but may include:

• D i a r r h e a • C o n s t i p a t i o n • L o s s o f a p p e t i t e • Unusual tiredness • M u s c l e w e a k n e s s

Side eff ects of calcium carbonate are rare and mild:

• B e l c h i n g • A b d o m i n a l d i s t e n t i o n Over-the-Counter Remedies for Digestive Health: Potion or Poison? 389

• F l a t u l e n c e • R e b o u n d a c i d s e c r e t i o n

Drug Interactions

Because they alter gastric acidity and urine pH, antacids can inhibit the absorption of some drugs including thyroid hormones, allopurinol, and imidazole antifungal agents. Aluminum and magnesium, antacids are notorious for their ability to chelate other drugs present in the GI tract, forming insoluble complexes that are not absorbed (Hoogerwerf WA, Pasricha PJ, 2006 -3).

Nutrient Depletions

Because they alter gastric acidity and have an affi nity to chelate, antacids can inhibit the absorption of many nutrients. Th ere is evidence that antacids decrease the levels of vitamins A and D and folic acid, as well as binding with calcium, chromium, iron, magnesium, phosphorus, and zinc (Vagnini & Fox, 2005 ; Gaby et al., 1999 ).

LAXATIVES

Johns Hopkins Medicine Health Alerts defi nes constipation as a common but typically benign condition characterized by infrequent bowel movements and diffi culty passing stool. Th e eleventh edition of Goodman & Gilman cites a few interesting studies: by questionnaire, 25 of the U.S. population, more commonly women and the elderly, complain of constipation. A survey of bowel habits in the United States showed that 18  of respondents used laxatives at least once a month but nearly one-third of these users did not have constipation (Pashricha PJ, 2006 ). In the bowel, water accounts for at least 70 of stool weight, and fl uid largely determines its volume and consistency. Th e digestive tract has to extract fl uid, minerals, and nutrients from food to supply the body for its needs, and leave behind suffi cient fl uid for regular expulsion of waste matter via defecation. Normally, 8 or 9 liters of water enter the small intestine daily from exogenous and endogenous sources. Pressure diff erentials due to the fl ow of ions cause absorption of water from the small intestines, leaving only about 1 to 1.5 liters of water to cross into the large intestine. Th e colon extracts most of the remaining fl uid, leaving about 100 ml daily for the feces (Pashricha PJ 2006 ). 390 INTEGRATIVE GASTROENTEROLOGY

So, fl uid intake is important for avoiding constipation. Fiber intake is also important. Unfortunately, many Americans do not respond well to their physicians’ advice for consuming more fruits and vegetables, but many do respond to using fi ber supplements A variety of fi ber products are available on the market, including psyllium, wheat, and methylcellulose. Fiber also protects against colon diverticulosis, carcinoma of the large bowel and stomach, Type 2 diabetes, metabolic syndrome, and cardiovascular disease (Trepel, 2004 ).

Medication for Constipation

NONSPECIFIC STIMULANT OR IRRITANT LAXATIVES

Stimulant laxatives have direct eff ects on enterocytes, neurons, and GI smooth muscle. Th ese agents trigger low-grade infl ammation in the bowels, inducing the accumulation of fl uid and electrolytes and increasing intestinal motility. Stimulant laxatives include bisacodyl, and the herbs senna and castor oil. Bisacodyl is a common ingredient in OTC laxative products. Th e gastrointestinal tract is in a constant state of contraction, absorption and secretion. Bisacodyl works to inhibit net fl uid absorption and secretion by augmenting intestinal permeability (Farack & Nell, 1984 ). It also increases motility. Food can decrease the absorption of bisacodyl. Laxatives with bisacodyl include Carter’s Little Pills, Correctol, Dulcolax, Feen-a-Mint and PMS-Bisacodyl. Castor oil is an age-old remedy. It is derived from the bean of the castor plant. Castor oil is a brisk cathartic, and as little as 4 ml if taken on an empty stomach can produce a laxative eff ect within just 1 to 3 hours. Th e cathartic dosage for an adult ranges from 15 to 60 ml. Th e products Neoloid and Purge contain castor oil (Pashricha PJ, 2006 ). Senna is obtained from the dried leafl ets of pods of Cassia acutifolia or Cassia angustifolia . Senna is found in Senokot and Ex-Lax. Side eff ects of stimulant laxatives include:

• U p s e t s t o m a c h • Stomach cramps • D i a r r h e a • P o s s i b l e d e h y d r a t i o n • Stomach and intestinal irritation • F a i n t n e s s • Irritation or burning in the rectum (from suppositories) • Senna commonly causes yellow-brown urine; this is harmless • Long-term use of irritant laxatives may lead to colonic pathology Over-the-Counter Remedies for Digestive Health: Potion or Poison? 391

Drug Interactions

Irritant laxatives can deplete potassium possibly increasing the toxicity of digoxin. Bisacodyl can decrease the eff ectiveness of warfarin.

Nutrient Depletions

Irritant laxatives deplete calcium, potassium and sodium (Gaby et al., 1999 ; Vagnini & Fox, 2005 ).

STOOL-WETTING AGENTS

Stool-wetting agents include docusate and mineral oil. Docusate is a surfactant. It lowers the surface tension of the stool, allowing fatty soluble and water soluble components to mix and making the stool soft er, permitting easier defecation. Dioctyl sodium sulfosuccinate is found in Colace, DSS, and Doxinate, and dioctyl calcium sulfosuccinate is in Surfak. Docusate is only marginally helpful in many cases of constipation. Mineral oil is a mixture of hydrocarbons obtained from petrolatum, which in turn is obtained from petroleum. Th ese fatty hydrocarbons penetrate and soft en the stool, easing passage. Mineral oil side eff ects include leakage of oil and greasy stools. Rarely, if aspirated, it can cause lipid pneumonitis. Depletions: Mineral oil can interfere with the absorption of minerals and all fatty soluble nutrients. Th ese include beta-carotene, vitamins A, D, E, and K, calcium, phosphorus, and potassium (Vagnini & Fox, 2005 ; Gaby et al., 1999 ). Osmotic laxatives include magnesium citrate, magnesium sulfate, magnesium hydroxide, and sodium phosphate. Th ey create an osmotic eff ect, bringing water to the stool stimulating peristalsis and evacuation. Th ese drugs are fairly well tolerated. 38 Systemic Interactions Between Dental and Gastroenterological Diseases

PHILIP E. MEMOLI

key concepts

■ GI conditions producing soft tissue oral lesions: ■ Crohn’s Disease ■ Behcet’s Disease ■ C e l i a c D i s e a s e ■ Th e dental-systemic management of generalized immunodysfunction: ■ Infections and Antigens from Marginal Periodontitis ■ Infections and Antigens from Apical Periodontitis ■ Antigenic Potential of Dental Biomaterials ■ Clinical Nutritional Considerations ■ GI disturbances producing hard tissue oral lesions: ■ G a s t r o e s o p h a g e a l R e fl ux ■ I Conditions Producing Halitosis ■ Bulimia Nervosa ■ Th e dental-systemic management of GI-induced hard tissue lesions: ■ Prevention, Treatment and Monitor Model ■ M a n a g e m e n t o f t h e A g g r e s s i v e , P a t h o l o g i c a l C o m p l e x L e s i o n ■

392 GI Diseases Producing Soft Tissue Oral Lesions

CROHN’S DISEASE

nfl ammatory bowel disease (IBD) consists primarily of Crohn’s disease and ulcerative colitis. Crohn’s disease is characterized as a panenteric I infl ammatory condition, while ulcerative colitis is, by defi nition, generally limited to the colon. Th e etiology is unknown although the mechanism of acute episodes is believed to be of an unknown antigenic origin that stimulates the immune cells of the intestinal mucosa to produce the pro-infl ammatory cytokines TNF-α , IL-1b and IL-6, resulting in enteric infl ammation (Griffi ths, 1999). Th e oral lesions may precede GI lesions in up to 30 of cases where both oral and gastroenterological pathology are evident (Lisciandrano et al., 1996 ). A wide range of nonspecifi c oral lesions has been reported, ranging from a “cobblestone” appearance of the mucosa, to aphthous-like ulcerative lesions, to deep granulomatous ulcers. Perioral symptoms may occur, and include angular cheilosis and lip fi ssures. Other symptoms may include gingival bleeding, gingival hyperplasia and metallic dysgeusia. Pyostomatitis vegetans, an oral fi nding, appears to be a marker for IBD and precedes GI symptoms (Ficarra et al., 1993 ). Th e lesions appear as yellow-white pustules with a characteristic “snail-track” appearance, speckled over an erythematous palatal and vestibular mucosa. Oral management is rarely required except in the event pustules rupture and ulcerate (Neville et al., 2002 ). Th e lesions of pyostomatitis vegetans will, as stated, precede GI symptoms, and generally follow the pattern of appearing with GI exacerbations and regressing with GI remissions. One study found that healing of pyostomatitis vegetan lesions occurred when oral zinc was supplemented, a mineral frequently lost when chronic diarrhea is present. Th e conclusion was that oral lesions may, in specifi ed cases, be a result of malnutrition caused by nutrient excretion (Ficarra et al., 1993 ).

BEHCET’S DISEASE

Th e syndrome, fi rst described by Hulusi Behcet in 1937, compromised a combination chronic ocular infl ammation with oral, genital, and anal ulcerations. Th e mechanism appears also to be immunodysregulatory and either primary or secondary to specifi c triggers, which may include streptococci, viruses, heavy metals, and pesticides. 394 INTEGRATIVE GASTROENTEROLOGY

Th e oral lesions appear similar to aphthous ulcers; that is, a diff use erythematous mucosa with an irregular bordered ulceration, but diff er in number and location. Whereas aphthae may number from one to fi ve, Behcet’s patients will frequently have six or more lesions. Further, lesions diff er in location; Behcet’s syndrome lesions usually appear on the soft palate and oropharynx, whereas aphthae are most commonly found on the ventral surface of the tongue, followed by the mucobuccal fold and fl oor of the mouth. Th e soft palate and keratinized gingiva are rarely involved, but may form as extensions from adja- cent areas. Oral involvement is present at least once in 99 of patients, and is the fi rst manifestation in 25 to 75 of those cases (Krause et al., 1999 ).

CELIAC DISEASE

Primary immunodysfunction, it is hypothesized, may be associated with specifi c histocompatibility antigen (HLA) types in the subgroups of patients with aphthous and aphthous-type ulcerative lesions in the oral cavity. Crohn’s disease and Behcet’s disease have been associated with HLA subgroups, which demonstrate aphthous-like lesions. Celiac disease has been associated with similar HLA subgroups and hence, has the potential to also demonstrate aphthous-like lesions.

Systemic Dental Management of Immunodysfunction

Th e oral cavity, structurally, functionally, and immunologically, represents the “gateway” to the gastrointestinal system. As such, there are factors of immunological importance such as nutrition, fl ora, pathogens, and antigens of either bacterial or dental biomaterial origin, which must be considered in the interdisciplinary management of immunodysfunction. Dentate status can also aff ect nutritional status, and may indirectly compromise immune function. Further, the oral tissues possess the unique tendency to serve as a marker for nutrient defi ciency which, in turn, is conducive when monitoring nutrient status, immunologic status, and malabsorption. Dentate status refers to the number of natural teeth and the ability of patients to properly chew or masticate their food. Poor dentate status, by contrast, refers to a condition in which there are insuffi cient teeth for mastication, resulting in the delivery of unchewed food into the stomach with the potential for maldigestion and malabsorption. Studies have found the chewing effi ciency of people with full dentures to be 20 of those with a full dentition (Kapur & Soman, 1964). Various studies have consistently demonstrated that Systemic Interactions Between Dental and Gastroenterological Diseases 395 poor dentate status results in food choices higher in carbohydrates, cholesterol, and saturated fats, with fewer vegetables and nutrient-dense foods (Joshipura. Willet, & Douglass, 1996 ). In cases of weight loss associated with protein-calorie malnutrition among the elderly, poor dentate status is oft en a causative factor (Sullivan et al., 1993 ). Poor oral health, and edentulousness in particular, has been found to be associated with various gastrointestinal disorders (Brodeur et al., 1993 ). Certain GI diseases, such as Crohn’s, Behcet’s, and celiac disease, appear, as previously indicated, to exhibit an etiopathological basis in immunodysfunction and, if one is susceptible, to produce aphthous-like lesions in the oral cavity. Th e immunodysfunction may be primary, which may involve one of several specifi c histocompatibility antigens (HLA) types, such as HLA-B12, B51 and CW7. Secondary immunodysfunction, at least for the oral aphthae, has a highly variable etiology, which contains numerous population subsets including nutritional defi ciencies, infectious agents, allergies, stress, trauma, genetic predisposition, and hematologic and hormonal infl uences. Infectious agents may range from streptococci to viruses such as herpes simplex, cytomegalovirus, adenovirus, and varicella zoster virus (Neville et al., 2002 ). Antigens and infections, with the potential to elicit an immune dysfunction response in susceptible individuals, are present in the oral cavity. Th ese include pathogens and their antigens from marginal and apical periodontal infections, as well as antigens from implanted dental biomaterials. In those gastroenterological cases mediated by immunodysfunction and exhibiting moderate– severe and severe–fulminant exacerbation, the treating physician must consider ruling out dental contribution as a predisposing secondary factor.

Infections and Antigens from Marginal Periodontitis

Systemic implantation from periodontal disease is perhaps one of the most researched subjects in current dental studies. Mattila and colleagues discovered an epidemiological relationship between gum infections, myocardial infarction, ischemia and atherosclerosis (Mattila et al., 1989 ). Th e DeStefano study, the result of a 14-year follow-up of 9,760 individuals, further demonstrated the relationship of oral focal infections, strokes, and coronary artery disease (DeStefano et al., 1993 ). Relationships have thus far been demonstrated in the following areas, with other areas still under study:

• Myocardial infarction (Genco, 1998 ; Mattila et al., 1989 ) • Coronary artery disease (Xu et al., 1991, 1993; Mattila et al., 1993 , 1995 ; Syrjänen, 1990 ) 396 INTEGRATIVE GASTROENTEROLOGY

• Diabetes (Genco et al., 1998 ; Grossi et al., 1997, 1998; Loe, 1993 ) • Respiratory infections and complications (Scannapicco et al., 1996 , 1998 ; Donowitz & Manell, 1990 ; Fiddian-Green & Baker, 1991 ) • Obstetric complications such as preterm birth and low birth weights (Dasanayake, 1998 ; Loe & Silness, 1963 ; Off enbacher et al., 1996 , 1998 , 1998 )

Th e periodontal fl ora comprise as many as 300 to 500 species, serotypes, and ribotypes of bacteria, all of which are considered nonpathogenic (Loesche, 1994 , 1997 ; Kilian, 1982 ; Paige, 1998 ). When a patient has decreased immune function, virulence factors present in the oral fl ora may now initiate chronic infl ammatory periodontal disease (CIPD). CIPD represents an opportunistic or endogenous infection, and eff orts to control the systemic focal activity of such infections must be based in proper immune system nutrition, function, and regulation. Once the pathogens predominate, a complex biofi lm can evade the immune system and function to gain access to systemic circulation (Socransy & Haff ajee, 2002 ). Th ere are three metastatic mechanisms by which microorganisms, bacterial antigens, and local cytokines from the oral tissue gain access to circulation to produce systemic and secondary site eff ects, such as in the gastrointestinal system (Van Velzen et al., 1984). Metastatic infection is the result of bactere- mia, which, although transient, may fi nd susceptible tissue. Th ose bacteria that have evolved or acquired mechanisms for cellular adherence and colonization have been demonstrated to cause such conditions as infective endo- carditis, acute bacterial myocarditis, brain abscess, prosthetic joint infections, and others (Rams & Slots, 1992 ). Metastatic injury, another mechanism, may occur from microbial toxins such as exotoxins and endotoxins (Van Velzen et al., 1984). Gram-negative bacteria are constantly shedding endotoxins or lipopolysaccharides (LPS) which, in circulation, produce systemic eff ects. Even when Gram-negative bacteria are killed by antimicrobials, large amounts of LPS are released that continue to exert immunological reactions, such as pyrexia and malaise. Finally, metastatic infl ammation is another mechanism whereby soluble antigen may react with a specifi c antibody, giving rise to immune complex formation (Van Velzen et al., 1984; Van Dyke et al., 1986 ; Rams & Slots, 1992 ). Th e risk of metastasis from the oral cavity must be considered in those conditions possibly involving an immunodysfunction mechanism. Regarding metastatic infl ammation, it is believed this mechanism can cause immunological injury and promote secondary infl ammation in infl ammatory bowel disease (IBD; see Walker, 1975 ). Although circulating immune complexes have been found in IBD, their etiology is still unknown (Jewell & Machennan, 1973 ). Systemic Interactions Between Dental and Gastroenterological Diseases 397

Among the various systemic manifestations of IBD are its oral symptoms, particularly ulcerations, and moderate to advanced involvement of periodontal disease. Th e oral fl ora of those with IBD was studied and was found to be remarkably diff erent from those without IBS; see Van Dyke, 1986 ). Whereas typical oral fl orae consist of aerobic, Gram-positive cocci and rods, the IBD patients demonstrated motile, anaerobic, Gram-negative rods found to be consistent with the Wolinella species. Further, the altered fl orae were similar in all IBD patients with and without periodontal disease, although those subjects with CIPD simply showed higher gingival sulcus bacterial levels. Regarding host resistance, the patients affl icted with IBD and CIPD were found to possess a serum-mediated neutrophil chemotaxis defect (Van Dyke, 1986 ). A similar defect is found in localized juvenile periodontitis, although this form of CIPD is not particular to IBD patients. Th e goal of an interdisciplinary and integrated periodontal treatment plan for those with immunodysfunction follows the traditional prevention–monitor– treatment paradigm. CIPD patients with immune dysfunction do not respond well to conventional therapy such as root planing and periodontal surgery. Nonetheless, proper oral hygiene and a proper maintenance period to monitor signs of exacerbations are necessary to minimize disease activity. Further, infl ammatory gingivitis and periodontitis must be closely controlled to minimize the risk of metastasis and the potential for secondary complications. Also, nutritional therapy should be instituted to determine whether the patient presents with nutrient defi ciencies, has conditional nutrient requirements, or has any off ending food sensitivities or allergies.

Infections and Antigens from Apical Periodontitis

Another potential source of bacterial infection and antigens may reside in apical periodontitis (AP) or endodontal (root canal) lesions; that is, infections of tooth origin at the tip or “apex” of the root. AP is a condition characterized as an acute or chronic condition, existing in the untreated or pre-root-canal-treated tooth. Some researchers are questioning the persistence of AP in apparently healed and asymptomatic root-canal-treated teeth, and the potential for bacterial pathogens and antigens to gain access to systemic circulation. AP was studied in epidemiological studies in which those with chronic dental infections demonstrated associations between acute myocardial infarction (Mattila et al., 1989 ) and coronary atherosclerosis (Mattila et al., 1993 ). AP infections may possess 200 species of predominately anaerobic, Gram-negative rods, of which proximity to circulation can facilitate metastasis and systemic dissemination (Tronstad, 1992 ). A study isolated Gram-positive anaerobic bacteria from 398 INTEGRATIVE GASTROENTEROLOGY patients undergoing treatment of AP and concluded, based on biochemical and antibiotic sensitivity testing, that recovered microorganisms from the bloodstream originated from the teeth undergoing endodontic therapy (Debilian, 1995 ). Th e primary cause of AP is untreated dental caries, which infect the pulpal cavity of the tooth resulting in apical extension into the surrounding bone to produce a lesion. Treatment options include tooth extraction or endodontic therapy, the former being the current treatment of choice. Th e goal of endodontic or root canal therapy is to sterilize the tooth and, by the use of bacterial sampling, to verify sterility before completion of the root canal. However, due to the inability to reach secondary canals and the dentinal microtubules, the assumption these teeth are sterile and not capable of focal infections is currently being questioned (Wu et al., 2006 ). Post-treatment AP, a condition characterized as an asymptomatic tooth with radiographic healing aft er root canal therapy, may, in fact, still present as a chronic infection capable of activating immune cells. (Wu et al., 2006 ) Further, post-treatment AP may be associated with 50 to 90 of root-canal-treated teeth (De Moor et al., 2000 ; Kirevang et al., 2001 ; Dugas et al., 2003) and may serve as a physiological attempt to prevent metastasis of bacteria and toxic metabolic byproducts into systemic circulation. (Wu et al., 2006 ) Th e standard of care in the determination of healing of the AP lesion is the absence of a radiographic translucency, as an indication that no osseous lesion is present. However, several researchers have repeatedly documented the presence of post-treatment AP despite radiographic evidence to the contrary. (Bender & Selzer, 1961 ; Bender, 1982 ; van der Stelt, 1985 ; Huumonen & Orstavik, 2002 ) Some have found that a lesion up to 8 mm may be present without any trace of radiographic evidence (Ricucci & Bergenholtz, 2003 ). Th e treatment of AP has recently been redefi ned as the elimination of post-treatment AP at both the radiographic and the histologic level. (Orstavik & Pitt Ford, 1998 ; Friedman, 2002 ; Trope, 2003 ) Th e causes of post-treatment AP are well documented and are, for the most part, not treatable with current endodontics. Apical microsurgery, recently perfected by microscopy (Rubenstein & Kim, 1999 ; Nari et al., 2005), removes the causative infected apical portion of the root and surrounding bone, resulting in clinical removal of the post-treatment AP lesion. Th e early reported successes of apical microsurgery are promising; 97  of lesions greater than 10 mm were completely healed within one year aft er surgery. (Rubenstein & Kim, 1999 ) It is a concern, particularly in patients presenting with immunodysfunction, to rule out apical periodontitis and chronic infl ammatory periodontal disease as sources of longstanding, low-grade infections capable of activating immune cells, which may then cause secondary immunologic injury to other normal cells and infi ltrate the gut. (Ridker et al., 1997 , 2001 ) Systemic Interactions Between Dental and Gastroenterological Diseases 399

Antigenic Potential of Dental Biomaterials

Another area of metastatic concern may involve dental restorative and implant materials, or biomaterials proper. All materials are reactive, and all biological interfaces are receptive; hence, there is no such phenomenon as a nonreactive or universal biocompatible material. When biomaterials are placed in the oral cavity, they undergo corrosion, degradation, separation and absorption (Cliff ord, 1990 ; Wataha, 2003 ). Once absorbed, each individual’s immune system will independently react or not react to determine if the test material is compatible for the person. Sensitized biomaterial antigens, unlike environmental antigens, when placed into the mouth present the possibility of chronic (24 hours a day, 365 days a year) exposure. Th ere are very few government or industry standards for biocompatibility testing and, until recently, such testing was not performed routinely (Wataha, 2003 ). Recently, toxicological research in Europe has generated intense interest in dental biomaterial compatibility (Ahlqwist et al., 1998; Richardson, 1999 ; Berlin et al., 1999 ; Lindh et al., 2001 ; Siblerud, 1990 ; Lindqvist et al., 1996 ; Lichtenberg, 1993; 1997; Halbach, 1998 ) and protocols are currently being developed to ensure a new level of safety can be achieved (Wahaha, 2003). Adverse reactions from sensitized dental materials include toxicity, infl ammation, allergenicity, and mutagenicity (Wataha, 2003 ). Allergenicity in the oral cavity may occur by nickel, palladium or acrylic, which may result in contact dermatitis (Wataha, 2003 ). Th irty-eight percent of women demonstrate nickel allergies, whereas up to 3  of men may be aff ected (Hindsen et al., 1999 ). Nickel is utilized in adult crowns, pediatric stainless steel crowns, partial denture frameworks, and orthodontic brackets and wires (Wataha, 2003 ). Metal ions such as mercury (Hg2 +) and palladium (Pd 2 +), components of restorative materials and crowns, both deplete glutathione levels in monocytes at subtoxic concentrations. Hydroxyethylmethacrylate (HEMA), a component of dental bonding systems, has also been demonstrated to reduce TNF- α secretion by monocytes at subtoxic levels (Wataha, 2003 ). Bonded composites and sealants contain bisphenol-A (BPA), an estrogenic substance, although the physiological impact is unknown (Wataha, 2003 ). Titanium, a component of implants, can negatively impact the immune system by causing hypersensitivity (Stejskal et al., 1999 ; Ahlgren et al., 2002 ; Ahnlinde et al., 2000 ). Further, titanium has been found to corrode in the body, particularly when exposed to fl uoride. (Strietzel et al., 1998 ; Reclaro et al., 1998 ) IL-1 and complement were also found to be upregulated by titanium implants. (Perala et al., 1991 ) Nickel, copper, beryllium, some components of root canal sealers, and dental resins have demonstrated mutagenic potential (Wataha, 2003 ). Th e carcinogenicity 400 INTEGRATIVE GASTROENTEROLOGY of arsenic, hexavalent chromium (Cr 6 +) and nickel (Ni2 +) has been established, whereas antimony and cobalt may be human carcinogens (Hayes, 2005 ). Clinical biomaterials can corrode to produce systemic and remote site concentrations suffi cient to predict that an adverse reaction could occur, particularly with immune responses, metal overload, and accumulation conditions (Black, 1984 ). Epidemiological studies on a large scale are necessary to assess the systemic eff ects of biomaterials, whether oral, knee, or hip (Black, 1984 ). Further, the release of metals in the mouth is of suffi cient quantity to elicit an immunological reaction in sensitive individuals (Lindh et al., 2002 ). Th e management of a biomaterial-sensitized individual must focus on prevention and monitoring. Th e mechanism of toxicity, both individual and quantal, must be considered in relation to what these biomaterials can exert on the whole individual in terms of exposure, toxicokinetics, toxicodynamics, and toxic interactions. Treatment, if necessary, must consider the immunological record of the patient. All known allergens and mutagens, regardless of amount, concentration, or bioavailability, should not be implanted or placed in the oral cavity. If a sensitive or allergic material must be placed for lack of a biocompatible equivalent, steps should be taken, if possible, to desensitize the individual. A dental and orthopedic material reactivity screening test is now available to screen individuals for potential sensitization (Cliff ord Consulting and Research). Th ere are at least 89 known reactive groups in more than 6,000 dental materials, and these can be analyzed to determine IgG or IgM sensitivity (Cliff ord, 1990 ). A positive or adverse immunological reaction would preclude the use of any material containing a proven reactant to that patient. Such precautions would prevent the corrosion of dental reactive products and the consequent release of chemical compoundsand haptens, and diminishsys- temic and gastroenterological adverse events.

Clinical Nutritional Considerations

Th e oral tissues, by virtue of a high mucosal cellular turnover rate, high salivary production, and high alveolar bone growth rate, are an excellent indicator of nutritional health due to a high nutrient demand, and may be the fi rst visible body tissue to refl ect nutritional status (DePaola et al., 1999 ). Th e relationship between nutrition and disease is illustrated in Figure 38.1 , which exemplifi es the multifactorial causative interactions that, if homeostatic mechanisms break down, will give rise to tissue disturbances (Memoli., 2007 ). It is interesting to note the role of the gastrointestinal system in this algorithm as being the centerpiece of the interactions between nutrients, metabolism, immune system, and exposure. Systemic Interactions Between Dental and Gastroenterological Diseases 401

Diseases of malabsorption, ranging from maldigestion, to mucosal dysfunction, to luminal dysfunction may, as a result of nutrient defi ciency, produce a sign or symptom in the oral cavity. Malabsorption most commonly presents with GI symptoms such as a watery diarrhea to a steatorrhea. Non- gastrointestinal symptoms, however, are not uncommon and may produce other malabsorption-related conditions such as (Kelly, 1999 ):

• F a t i g u e , m a l a i s e • Muscle weakness, tetany, cramps • Bone pain, pathologic fractures • Poor wound healing • P a r e s t h e s i a , n u m b n e s s

Further, it is not uncommon for non-gastrointestinal diseases to have an underlying malabsorption syndrome resulting in systemic manifestation (Kelly, 1999 ):

• Rheumatological (Raynaud’s) and arthralgias may suggest infl ammatory bowel disease, scleroderma, or Whipple’s disease. • Vascular disease of an extensive nature may indicate mesenteric ischemia. • Endocrinopathies such as hyperthyroidism, hyperparathyroidism, and diabetes mellitus can result in malabsorption.

Th e treating gastroenterologist who suspects malabsorption in a particular patient can survey the oral cavity, where systemic nutrient defi ciency may fi rst appear. Likewise, the treating dentist can apprise his or her colleague of any changes in the oral tissues that indicate malabsorption or a change in gastroenterological status. Th e following list highlights such oral manifestations (adapted from DePaola et al., 1999 ).

Oral Signs and Symptoms of Nutrient Deﬁ ciency

MINERALS

Iron: burning tongue, angular cheilosis, dysphagia; non-oral: pale blue sclera, pagophagia (ice eating) Calcium : tooth mobility, osteomalacia, osteoporosis, excessive bone resorption and bone fragility Magnesium: alveolar bone fragility, gingival hypertrophy 402 INTEGRATIVE GASTROENTEROLOGY

Zinc: increased susceptibility to caries during tooth formation, increased susceptibility to infections and candidiasis, loss of taste and smell acuity Copper: decreased alveolar bone trabeculation, decreased tissue vascularity

Vitamins

Vitamin A: impaired healing, mucosal desquamation, xerostomia (dry mouth), leukoplakia, gingival infl ammation B-Complex: angular cheilosis, leukoplakia, burning tongue Folic Acid: angular cheilosis, stomatitis, mucositis, aphthous-like ulcers, sore or burning mouth Cobalamin: angular cheilosis, sore burning mouth, xerostomia, epithelial dysplasia, paresthesia, delayed wound healing, halitosis, tooth mobility; non-oral: yellow sclera (note: compare to iron defi ciency) Vitamin C : susceptibility to infection, blood vessel fragility, increased risk of gingivitis and periodontitis, delayed healing Vitamin D: incomplete tooth and alveolar bone calcifi cation, osteomalacia, osteoporosis Vitamin K: risk of hemorrhage, candidiasis

GI Disturbances Producing Hard Tissue Lesions

GASTROESOPHAGEAL REFLUX (GERD)

GERD can be considered a major health concern for two overriding reasons. First, it is a common condition that aff ects up to an estimated 20 to 25 of the American population. Second, it may predispose one to esophageal cancer, which, over the last 25 years, has outdistanced all other malignancies by a 350 increase in incidence (Glenn, 2001 ). Regarding the symptomatic population reporting the condition, one-half of those report weekly dysfunction whereas one-quarter suff er daily symptomology. Recent studies (Vial M et al., 2010 ) have revealed male gender, obesity and GERD (in the form of heartburn) as high risk factors for the development of esophageal adenocarcinoma. Refl ux of stomach acids in the oral cavity generally results in erosion of tooth structure. Loss of enamel aft er tooth formation can occur from dental caries, trauma, attrition, abrasion, amelogenesis imperfecta and dentinogene- sis imperfecta, and erosion (Neville et al., 2002 ). Erosive-type lesions are characterized by a chemical or electrochemical breakdown of tooth structure. Systemic Interactions Between Dental and Gastroenterological Diseases 403

Th e treating dentist, with proper history and examination, can rule out all other etiology and further determine whether the lesions are of an exogenous or endogenous nature (Dawson, 2007 ). Exogenous factors include prolonged oral exposure to many foods or drinks below the critical pH 5.5 necessary to induce tooth demineralization (Grippo et al., 2004 ). Acidic substances causing erosive-type lesions include chronic use of chewable vitamin C tablets, cola “swishers,” fruit “mullers” and exposure to industrial acids (Abrahamsen, 1992 ). Further, alcoholics undergoing disulfi ram (Antabuse) therapy may suff er erosion as a result. Endogenous factors occur primarily from GERD or bulimia nervosa, and are primarily diagnosed by the treating gastroenterologist. Th e clinical lesion associated with GERD occurs at the lingual (inside) surface of the posterior molars (Dawson, 2007 ). Severity is dependent upon the degree of the condition and the oral health care measures taken by the patient. Dentists detecting such lesions should refer the patient to a gastroenterologist, and follow preventive dental management protocols.

GI Conditions Producing Halitosis

Halitosis, that is, oral malodor, may aff ect up to 30 of the population and is most commonly associated with poor oral hygiene in combination with food debris accumulation (Porter & Scully, 2006 ). Oral microorganisms produce odiferous toxins such as volatile sulfi des, diamines, and short-chain fatty acids, which have been determined to cause the disorder. Ten percent of halitosis cases have been determined to be systemic in origin, of which certain gastroenterological disorders may be etiologic (Hughes & McNab, 2008 ). Th e differential diagnosis between oral and systemic halitosis is based upon exhalation; a systemic condition is suspected when nasal exhalation produces the same malodor as oral exhalation. Another common etiology is respiratory, in the form of a sinus infection or nasal obstruction; however, this form is usually transient and occurs in the morning upon wakening as morning halitosis. GI disorders that may produce systemic halitosis include (Porter & Scully, 2006 ):

• G a s t r o e s o p h a g e a l r e fl ux • Pharyngoesophageal diverticulum • P y l o r i c s t e n o s i s • D u o d e n a l o b s t r u c t i o n • Hepatic failure (fetor hepaticus)

Helicobacter pylori infection has also been implicated in subjective changes in oral odor. (Hoshi et al., 2002 ) A fi nding of chronic, nontransient halitosis 404 INTEGRATIVE GASTROENTEROLOGY with no apparent oral etiology would therefore warrant a gastroenterological assessment. GERD-associated halitosis, as with GERD proper, possesses oral lesions and likewise requires interdisciplinary management.

Bulimia Nervosa

Eating disorders, such as anorexia nervosa and bulimia nervosa, represent deviations in behavior that can result in esophageal irritation and dental erosion lesions. Bulimia is common in young adult women concerned with body shape and weight. Th e condition features binge eating followed by self-induced vomiting, the frequency of which determines the severity of the disorder. No symptoms may be present until frequency produces dental erosive lesions and calluses of the knuckles (Huse & Lucas, 1999 ). Th e bulimia-associated dental lesion is caused by the acidic purge, which consists of stomach acids in the pH 1 range, well below the critical pH 5.5 levels to induce enamel demineralization. Th e lesion proper is characterized as erosive on site-specifi c tooth surfaces; the palatal (inside) surface of the maxillary (upper) anterior teeth and the occlusal (biting) surfaces of the posterior teeth. Th e symptoms attending the lesions range from an asymptomatic dentition to tooth hypersensitivity, which may involve thermal or contact sensitivity and, in some cases, involve sensitivity to normal mastication. Hypersensitivity may further be indicative of chronicity and serve as a marker for cessation of purging and, hence, for recovery of the disorder. Further, parotid gland enlargement and sensitivity to palpation is another indication, as the parotids become symptomatic between two and six days aft er vomiting (DePaola et al., 1999 ). In the case of severe bulimia, an oral lesion characterized as a “complex” lesion may be seen primarily as an erosive lesion from the bulimia, and secondarily as a result of toothbrush attrition. Once erosion penetrates the enamel and exposes the underlying dentin, demineralization now proceeds sevenfold. Many of these patients, being concerned with their appearance, are equally obsessed with their dental cosmetic image and oral hygiene. In an eff ort to cleanse their mouth of vomitus and its taste, copious amounts of abrasive- containing toothpastes are employed in aggressive brushing patterns, which together produce an attrition lesion on a previously compromised erosive lesion. Th e result is severe pathological loss of tooth structure and gum tissue which, in some cases, cannot be corrected with restorative dentistry. I have seen cases where complex lesions have so debilitated the dentition as to require prosthetic rehabilitation with full dentures in young women. Systemic Interactions Between Dental and Gastroenterological Diseases 405

Dental Systemic Management of GI-Induced Hard Tissue Lesion

When hard tissue lesions are present, the role of the dentist becomes one of interdisciplinary intervention with the treating gastroenterologist. Th e process of dental management for GERD and bulimia follows a prescribed prevention, monitoring, and treatment paradigm. Preventive measures are employed to minimize tooth loss during exposure. Monitoring occurs in the form of dental prophylaxis and communication of the dentist with the treating gastroenterologist. Treatment results when irreversible tooth loss occurs, which must be restored before the general dentition becomes compromised. In regard to GERD, preventive procedures must be tailored to the type of secretions that enter the oral cavity. While acid refl ux from gastric acids is the dominant form of heartburn, an alkaline refl ux from pancreatic secretions in the duodenum may also occur. Further, patients on antacids, proton-pump inhibitors (e.g., Prilosec) and histamine 2 receptor antagonists (Tagamet) may, in theory, produce a neutral refl ux. Th erefore, it is important for the treating dentist to measure pH to determine whether the refl ux is acidic, alkaline, or neutral, and thereupon determine treatment. If the refl ux is acidic in nature and enters the oral cavity, I will recommend an alkaline rinse for one minute. Th e patient will be instructed to mix one teaspoon of baking soda with four ounces of water and rinse for a full minute. If the refl ux continues, the rinse should be repeated every hour. In severe cases, with nocturnal refl ux associated with lower esophageal sphincter incompetence, a mouth guard can be employed with a slight alkaline solution to maintain a buff ered environment around the teeth, particularly in those cases in which xerostomia (dry mouth) is a secondary factor. For those patients exhibiting an alkaline refl ux, I instruct them to squeeze 10 to 20 drops from a fresh organic lemon in a four-ounce glass of water and to rinse for a full minute. Again, if the refl ux continues, rinse continuously. Further, if there is a nocturnal component, employ a mouth guard. Th e monitoring component should fi rst determine whether oral lesions are of a GERD-associated endogenous component or exogenous in nature. For those diagnosed with a history of GERD, monitoring protocols are meant to ensure that preventive measures are stabilizing the oral component. For undiagnosed cases, a history and inquiry into the patient’s dietary habits, and the result of the oral examination of the lesions, should determine the nature of the lesions. For cases of an exogenous nature, preventive behavioral changes 406 INTEGRATIVE GASTROENTEROLOGY can easily retard the progress of such lesions. Progressive endogenous lesions likewise indicate further treatment measures. Th e treatment of GERD-associated oral lesions would primarily involve composite bonding to restore lost tooth structure. Monitoring of these restorations on a regular basis is essential to guard against microleakage of the bonding interface and decalcifi cation around the margins. Either of those defects would result in the destruction of more tooth structure and the need to perform more extensive dental restorations. Th e dental preventive management of bulimia nervosa must also be tailored to the frequency of the refl ux and the compliancy of the patient. General oral hygiene measures should include brushing only once per day, particularly in the morning. Aft er a refl ux episode, the patient should be instructed to avoid brushing altogether, especially with abrasive toothpastes. A mouth guard should be constructed, preferably for the patient to insert before vomiting. If the patient is not compliant with this procedure, the alkaline rinse previously described should be performed to cleanse the teeth, periodontium, and mucosa of acid residues. Aft er rinsing, an alkaline paste of simply water and baking soda should be placed inside the mouth guard and worn for a minimum of thirty minutes.

PREVENTIVE MEASURES WITH BULIMIA

• Brush only once per day with nonabrasive toothpaste (do not use baking soda or whitening formulations). Note: one may rinse but not brush with baking soda. • Insert mouth guard before vomiting (if possible). • A ft er vomiting, do not brush ; instead, rinse or apply alkaline paste (baking soda and water) inside the mouth guard and wear for a minimum of 30 minutes.

It is of particular importance to guard against the creation of the aggressive, pathological complex lesion; therefore, a monitoring system at a frequency suitable to prevent tooth destruction must be instituted. During the periodic dental examination, an acid exposure and lesion assessment must accompany the dental prophylaxis. Acid exposure must still be analyzed in terms of exogenous and endogenous exposure. Exogenous acids must be ruled out, and if the patient presents with such lesions she must be counseled to reduce such habits. Severe endogenous exposure must be communicated to the treating gastroenterologist in order for an interdisciplinary approach to treat recurrences. Lesion analysis should include charting, Systemic Interactions Between Dental and Gastroenterological Diseases 407

measurement, and symptomology, in order to further determine frequency and recurrences. Th e treatment of the complex lesion must consider potential dental implications, such as the loss of lower facial skeletal height and pathological tooth destruction. A bonded hybrid composite restoration is primarily utilized to treat the early erosive lesions. Again, these restorations must be monitored for caries, microleakage, and decalcifi cation. If the patient is noncompliant with preventative and monitoring measures, there is an increased risk of developing severe complex lesions. In general, as the teeth erode, there is a compensatory eruption of tooth and bone in order to maintain facial height. However, if the erosive lesions occur more rapidly than biological compensation, lower face height may be lost, resulting in cosmetic disfi gurement. Prosthetic eff orts such as restoring posterior teeth and maintaining proper anterior guidance can prevent edge-to-edge attrition, which can further result in accelerated tooth destruction. If such eff orts cannot be performed, prosthetic rehabilitation in the form of implant-retained dentures may be necessary to reestablish function, comfort, and esthetics. (Neville et al., 2002). With the knowledge of the possibility of a bulimic or anorexic patient developing a pathological complex erosive lesion that could potentially destroy a patient’s dentition, it behooves both gastroenterologist and dentist to coordinate a preventive interdisciplinary treatment plan. 3 9 Upper Gastrointestinal Disorders: Dyspepsia, Heartburn, Peptic Ulcer Disease, and Helicobacter pylori

ANIL MINOCHA

key concepts

■ Most complementary therapies are based on clinical-symptom complexes. Th ere is a paucity of studies employing precise, modern day diagnostic criteria. ■ Th erapies based on Chinese medicine (e.g., multi-herbal formulation Iberogast also known as STW 5 and acupuncture) are eff ective in functional dyspepsia. ■ Th e addition of probiotics to standard antibiotic treatment increases Helicobacter pylori eradication while reducing the therapy- associated side eff ects. On the other hand, vitamin C and E supplements may reduce the effi cacy of H. pylori eradication therapy. ■ Use of psychological interventions can improve outcome in functional GI disorders. ■ L i f e s t y l e m o d i fi cations like cessation of smoking and drinking may help ameliorate dyspeptic symptoms. Th e role of diet in management of upper gastrointestinal disorders is patient- specifi c . ■

408 Introduction

pper gastrointestinal illness, whether induced by ulcers, gastritis, dysmotility, or H. pylori, is a common problem that aff ects hundreds U of millions of people worldwide. However, patients are more interested in relief and less interested in what may be causing the problem. Whether the diagnosis is ulcer or gastritis based on modern medicine, or a disharmony of the body systems of Vata, Pita, or Kapha as in Ayurveda, the patient’s goal remains the same. Many patients just use over-the-counter medications, but complementary and alternative treatments are gaining in popularity. A smaller number of people actually see a doctor.

Historical Perspective

Until the late eighteenth and early nineteenth centuries, most symptoms of possible gastroesophageal refl ux disease (GERD) and peptic ulcer disease (PUD) were lumped into the category of dyspepsia or indigestion. Treatments varied depending upon the culture or civilization. Some of these treatments have stood the test of time and are still preferred over modern medicine by millions of people. Th e ancient descriptions of the use of powdered coral, chalk, and seashells for relief of dyspepsia provide clues to the occurrence of this problem long before the modern descriptions of GERD and PUD. Hunter in 1784 advocated the use of milk as a natural antacid. Illogical approaches, such as the use of antimony, arsenic, and mercury, as well as application of leeches to the abdomen, were in vogue in the eighteenth century. In 1876, Leube advocated the use of bowel rest on top of implausible interventions like alcohol and glucose rectal enemas. Other treatments used in the past include synthetic resins, cabbage, pectin, pituitary extract, insulin, and histamine. Surgeons like Billroth made the fi rst advance in modern treatment by performing surgery for PUD in the 1880s. H. pylori was rediscovered by Warren and Marshall in the 1980s, which earned them the Nobel prize.

CAM Treatments

Most diagnoses made by practitioners of complementary and alternative medicine (CAM) are based on symptoms and follow the holistic treatment pattern. 410 INTEGRATIVE GASTROENTEROLOGY

Th e diagnosis is mostly clinical, and centers on dyspepsia or some equivalent. Similar patients may receive diff erent treatment plans, however, based on variety of other factors (e.g., based on body constitution in Ayurveda). In this chapter, we will review the human data wherever available; in addition, we will discuss the laboratory investigations supporting or refuting the biological plausibility of treatment eff ect. Since there is overlap in herbal therapies, we will review them as one category regardless of the system of medicine from which they are derived. Th e depth and breadth of discussion of any particular therapy in this chapter are related more to the extent of peer-reviewed literature on the subject than to the popularity of the treatment.

Herbal Therapies

An herbal medicinal product is defi ned as any medicinal product containing as active ingredients only plants, parts of plants or plant materials, or combinations thereof, whether in the crude or processed state. Herbal therapies may be administered individually or as combinations of herbs.

PEPPERMINT OIL (MENTHA PIPERITA L )

Peppermint oil has been used for dyspepsia and spasms/colic in various cultures for centuries. It may be used singly or in combination with other herbs. Th e clinical effi cacy of the combinations (except for caraway) will be discussed in the subsection about herbal combinations.

The Science Behind It

In addition to relaxing pylorus, peppermint oil enhances the early phase of gastric emptying (Inamori et al., 2007 ), thus aff ecting gastroduodenal motility. Others have shown that the eff ect of peppermint oil and caraway on gastric emptying is similar to that of the drug, cisapride; however, there were no differences as compared to placebo (Goerg & Spilker, 2003 ). Caraway ( Carum carvi) is frequently added to peppermint, and is also known to cause inhibition of smooth muscle relaxation. Peppermint oil and caraway act locally in the stomach and duodenum to produce smooth-muscle relaxation (Micklefi eld, Jung, Greving, & May, 2 0 0 3 ) . Th e principal eff ect of intraluminal peppermint oil on the gastrointestinal tract (Bell, 2004 ) is a dose-related antispasmodic action on the smooth musculature Upper Gastrointestinal Disorders 411 due to the interference of menthol with the movement of calcium across the cell membrane (Grigoleit, 2005). A randomized, double-blind, double-dummy, controlled trial showed that peppermint oil reduces gastric spasm during upper endoscopy (Hiki Kurosaka, & Tatsutomi, 2003 ). An instillation of 20 ml of 1.6% peppermint oil solution in the duodenum during ERCP results in duodenal relaxation (Yamamoto et al., 2006 ). Peppermint has choleretic and anti- foaming eff ects and attenuates postinfl ammatory visceral hyperalgesia in rats (Adam et al., 2006 ). Peppermint inhibits the in vitro proliferation of various bacteria, including H. pylori, in a dose-dependent manner (Imai et al., 2001 ). Interestingly, these antibacterial activities were almost the same against antibiotic-resistant and antibiotic-sensitive strains of H. pylori . Peppermint aromatherapy has major eff ects on decreasing pain and depression levels, suggesting another possible mechanism for peppermint in dyspepsia i.e., analgesia (Kim, Nam & Paik 2005 ) Peppermint oil inhibits daytime sleepiness, and this invigorating eff ect may favorably aff ect psychological disturbances associated with various upper gastrointestinal disorders (Norrish & Dwyer, 2005 ).

Clinical Data

Peppermint oil improves abdominal symptoms in patients with abdominal pain and irritable bowel syndrome. May and colleagues conducted studies of the effi cacy and tolerability of a combination of peppermint oil and caraway oil versus placebo in patients with functional dyspepsia. Th ey found the active treatment was superior with respect to pain intensity, sensation of pressure and heaviness plus fullness, as well as the investigators’ rating of global improvement (May, Köhler, & Schneider, 2000 ; May, Kuntz, Kieser, & Köhler, 1996 ). A multicenter, reference-controlled, double-blind equivalence study using a peppermint/caraway oil preparation or cisapride found them to be equivalent for treatment of functional dyspepsia (Madisch et al., 1999 ). Th e effi cacy of peppermint oil and caraway oil in patients with functional dyspepsia is unaff ected by H. pylori (May, Funk, & Schneider, 2003 ). Th e benefi cial eff ects of a peppermint/caraway oil combination in functional dyspepsia are similar whether the drug is taken in an enteric-coated capsule or as an enteric soluble formula (Freise & Kohler, 1999 ). Patients with GERD have long been warned to avoid peppermint oil. However, this recommendation appears to be based predominantly on theoretical grounds and lacks good scientifi c data to support it. Th is recommendation also fl ies in the face of centuries-old use of peppermint aft er meals, with 412 INTEGRATIVE GASTROENTEROLOGY perceived benefi cial eff ects against indigestion. Th e administration of peppermint oil eliminates chest pain, as well as simultaneous esophageal contractions, in patients with diff use esophageal spasm (Pimentel et al., 2001 ). Aromatherapy eff ectively reduces the perceived severity of postoperative nausea. However, aromatherapy with peppermint is no better than saline placebo in relieving postoperative nausea, suggesting that benefi cial eff ects may be related more to controlled breathing patterns than to the actual aroma inhaled (Anderson & Gross, 2004 ). Side eff ects of peppermint oil include allergic contact dermatitis.

LICORICE

Licorice is widely used in the medicinal and the confectionery sectors. However, the ingestion of licorice, and/or its active metabolites, can lead to an acquired form of apparent mineralocorticoid excess syndrome manifested by sodium retention, potassium loss and suppression of the renin-angiotensin- aldosterone system, leading to increased blood pressure and edema. Compared to licorice, deglycyrrhizinated licorice (DGL) does not signifi cantly aff ect blood pressure and salt retention, and some practitioners have advocated its use.

The Science Behind It

Numerous studies have documented the gastroprotective eff ects of licorice. Cimetidine and DGL combined provide greater protection than either drug alone against aspirin-induced gastric mucosal damage in rats (Bennet et al., 1980 ). Most studies that show benefi cial eff ects have used licorice as part of an herbal combination product.

Clinical Trials

Clinical trials using DGL in peptic ulcer disease have yielded confl icting results. Turpie et al. (1969 ) conducted a randomized, placebo-controlled clinical trial of DGL in gastric ulcers. Th ey found a reduction in ulcer size in patients on DGL versus the placebo (78% vs. 34 %). In addition, the ulcer completely resolved in 44% of patients in the treatment group, compared to 6 % in the placebo group. Other researchers have reported similar results (Doll & Hill, 1962 ; Doll, Hill, & Hutton, 1965 ; Engqvist, von Feilitzen, Pyk, & Reichard, 1973 ). Some studies, Upper Gastrointestinal Disorders 413 however, have failed to confi rm these gastroprotective fi ndings (Bardhan, Cumberland, Dixon, & Holdsworth, 1978 ; Feldman & Gilat, 1971 ). DGL does not appear to have prophylactic eff ects against recurrence of healed gastric ulcer (Hollanders et al., 1978 ).

TURMERIC (CURCUMA )

The Science Behind It

Turmeric increases bile formation and secretion and promotes gallbladder contraction in addition to having antispasmodic activity. It protects against gastric ulcers by blocking H2 type histamine receptors (Kim, 2005 ).It also increases the gastric wall mucus and restores the nonprotein sulfh ydryl content in glandular stomachs (Rafatullah, Tariq, & Al-Yahya, 1990 ). Phenolic fractions of Curcuma amada are potent inhibitors of proton potassium ATPase activity, as well as H. pylori growth (Siddaraju & Dharmesh, 2 0 0 7 ) .

Clinical Trials

One study found that turmeric ( Curcuma longa Linn 600 mg x 5/d x 4 weeks) resulted in healing of 48 % of cases of peptic ulcer. Seventy-six percent of patients did not have ulcers at the end of 12 weeks (Prucksunand et al., 2001 ). A controlled clinical trial found liquid antacid and Curcuma longa Linn to be equivalent in the treatment of gastric ulcers (Kositchaiwat, Kositchaiwat, & Havanondha, 1993 ). Another randomized, placebo-controlled study comparing curcuma with an herbal formulation is described in the section on herbal combinations (Th amlikitkul et al., 1989 ).

CHILI POWDER

The Science Behind It

A chili-rich diet decreases capsaicin-stimulated gastrin secretion from human antral glands (Ericson, Nur, Petersson, & Kechagias, 2008). Intragastric perfu- sion of aqueous spice extracts of red pepper increases acid secretion in anes- thetized albino rats (Vasudevan, Vembar, Veeraraghavan, & Haranath, 2000 ). Both black and red pepper may induce epigastric pain by removing the 414 INTEGRATIVE GASTROENTEROLOGY

stomach’s hydrophobic lining and activating intramucosal pain receptors (Lichtenberger et al., 1998 ).

Human Studies

Capsaicin administered as 20g of chili orally protects against aspirin-induced gastroduodenal injury in healthy human subjects (Yeoh et al., 1995 ). Endoscopy showed that the median gastric injury score aft er chili was 1.5 compared to 4 in the control group (P < 0.05). On the other hand, capsaicin enhances noxious postprandial heartburn, presumably by direct eff ects on sensory neurons (Rodriguez-Stanley et al., 2000 ).

While chili pepper may cause symptoms in susceptible subjects in the short term, over the long term it relieves functional dyspepsia by capsaicin- induced desensitization of the selective nociceptive C ﬁ bers.

Epidemiologic surveys in Singapore have shown that gastric ulcers are three times more common in people of Chinese descent than in those of Malaysian and Indian descent, who tend to consume more chili peppers (Satyanarayana , 2006 ). Among Chinese patients, the median amount of chili use per month was much lower in those with ulcers than in the controls (Kang et al., 1995 ). Bortolotti et al. (2000) examined the eff ect of red pepper (2.5g/d) on the treatment of functional dyspepsia (n=30) in a double-blind, placebo-controlled trial. Th e overall symptom score, as well as the epigastric pain, fullness, and nausea scores, improved signifi cantly in the red pepper group compared to the p l a c e b o .

AMALAKI

Amalaki is an Ayurvedic herbal remedy derived from pericarp of the dried fruit of Emblica offi cinalis . Chawla et al. (1982 ) compared the treatment of dyspepsia using Amalaki or gel antacids for 4 weeks. Patients (n=38) included those with peptic ulcer (n=10) and non-ulcer dyspepsia (n=28). Compared to the baseline, symptoms improved in both treatment groups. Side eff ects during Amalaki treatment included diarrhea and vomiting in some patients. Upper Gastrointestinal Disorders 415

BANANA POWDER (PLANTAIN BANANA)

The Science Behind It

Th e natural fl avonoid present in unripe plantain banana pulp protects the gastric mucosa from aspirin-induced erosions (Lewis, Fields, & Shaw, 1999 ). Plantain banana powder strengthens mucosal resistance and promotes the healing of ulcers via its action on gastric mucosal shedding (Mukhopadhyaya et al., 1987 ).

Clinical Studies

Treatment with banana powder (8 capsules per day for 8 weeks) results in marked improvement (partial or complete relief) of patients with non-ulcer dyspepsia compared to controls (Arora & Sharma, 1990 ).

MASTIC

Mastic is a concrete resinous exudate obtained from the stem of the tree Pistacia lentiscus .

The Science Behind It

It reduces the intensity of experimentally induced gastric mucosal damage associated with decrease of free acidity (Al-Said, Ageel, Parmar, & Tariq, 1986 ). Mastic gum kills H. pylori (Huwez, Th irlwell, & Cockayne, 1998 ), although the eff ect is modest (Al-Said et al., 1986 ). Monotherapy with mastic does not eradicate H. pylori infection in mice (Loughlin, Ala’Aldeen, & Jenks, 2003 ).

Clinical Studies

A double-blind, placebo-controlled trial of mastic (1g/d for two weeks) for the treatment of duodenal ulcer demonstrated endoscopically proven healing in 70 % patients on mastic compared to 22 % patients on placebo (Al-Habbal, Al-Habbal, & Huwez, 1984 ). 416 INTEGRATIVE GASTROENTEROLOGY

BRAHMI

Fresh juice from the whole plant of Bocapa monniera Wettst, commonly known as Brahmi, is used in Ayurveda for dyspepsia. Brahmi promotes mucosal defenses via enhanced mucin secretion and mucosal glycoprotein, and decreased cell shedding in experimental models of ulcer (Rao, Sairam, & Goel, 2000 ).

ASPARAGUS RACEMOSUS (SHATAVARI)

Asparagus racemosus (Shatavari) is used in Ayurveda for dyspepsia and as a galactogogue. It reduces gastric emptying time in normal healthy volunteers. Asparagus racemosus has an inhibitory eff ect on the release of gastric hydrochloric acid, and its protection against indomethacin-induced gastric mucosal damage in animals is comparable to that of ranitidine (Bhatnagar, Sisodia, & B h a t n a g a r , 2 0 0 5 ) .

ASHWAGANDHA (WITHANIA SOMNIFERA DUNAL )

W. somnifera shows potent inhibitory activity towards the complement system, mitogen induced lymphocyte proliferation, and delayed-type hypersensitivity reaction. Th is Ayurvedic remedy, also known as ashwagandha, is eff ective in the treatment of stress-induced ulceration in animals and its effi cacy is comparable to that of ranitidine (Bhatnagar et al., 2005 ).

GREATER CELANDINE (CHELIDONIUM MAJUS )

Greater celandine or tetterwort is derived from the celandine plant, which is a member of the poppy family. Its roots, herb, and juice are used for medicinal purposes. It is reputed to have calming eff ects and is widely used for intestinal spasms.

The Science Behind It

Celandine contains about 20 biologically active alkaloids, which have anti- spasmolytic action on smooth muscles and also stimulate bile fl o w . Upper Gastrointestinal Disorders 417

Clinical Studies

Ritter and colleagues studied the eff ect of a standardized celandine extract in a placebo-controlled, double-blind trial of 60 patients with functional dyspepsia over a 6-week period (Ritter et al., 1993 ). Patients in the treatment group reported fewer gastrointestinal symptoms compared to those on placebo (27 % vs. 60% ) .

ARTICHOKE LEAF EXTRACT

Holtmann et al. ( 2003 ) studied the effi cacy of artichoke leaf extract (2 x 320 mg plant extract 3 times a day for 6 weeks) in the treatment of patients with functional dyspepsia in a double-blind, randomized placebo-controlled trial. Th e artichoke leaf extract demonstrated superior effi cacy in alleviating symptoms and improved the disease-specifi c quality of life in patients with functional dyspepsia.

GINGER ROOT

Ginger root has been studied for postoperative nausea and morning sickness, as well as chemotherapy-induced nausea. Th e results are promising (Ernst & Pittler, 2000 ).

The Science Behind It

Ginger accelerates gastric emptying and stimulates antral contractions in healthy volunteers (Wu et al., 2008 ). Th ese eff ects could potentially be benefi - cial in symptomatic patient groups.

TERMINALIA

Terminalia arjuna is a deciduous tree, the bark of which is used in herbal medicine. Terminalia is widely used in Ayurveda to regulate blood pressure and promote cardiovascular health. It suppresses the release of nitric oxide and superoxide from macrophages, and also inhibits aggregation of platelets. Terminalia has antioxidant actions and may reduce oxidative stress and inhibit anaerobic metabolism. It ameliorates severe cellular damage and pathological 418 INTEGRATIVE GASTROENTEROLOGY changes caused by H. pylori lipopolysaccharide (Devi, Kist, Vani, & Devi, 2008 ). Terminalia arjuna has protective eff ects on diclofenac sodium-induced gastric ulcer in experimental rats. Terminalia chebula is commonly advocated in Ayurveda to improve gastrointestinal motility. It has been shown to reduce gastric emptying time in rats (Tamhane, Th orat, Rege, & Dahanukar, 1 9 9 7 ) .

TANGWEIKANG

Tangweikang is a Chinese herbal preparation used in diabetes. It improves glucose and lipid metabolism and regulates microcirculation. It hastens gastric emptying in diabetic gastroparesis (Jiang, Zhang, & Bai, 2007 ).

Herbal Combinations

Both functional and organic disorders have multiple underlying pathogenic mechanisms. Th e use of herbal combinations has the potential to aff ect a disease process at multiple levels in its pathogenesis.

STW 5

STW 5 is a fi xed combination of nine herbs: bitter candytuft plant (aka clown’s mustard), German chamomile fl ower, peppermint leaves, caraway fruit, licorice, lemon balm leaves, celandine, angelica root and rhizome, and milk thistle.

The Science Behind It

STW 5 modulates the amplitude and frequency of slow waves in circular smooth muscle of the mouse small intestine (Storr et al., 2004 ). It also lowers gastric acidity and inhibits secondary hyperacidity (Khayyal et al., 2006 ). In addition, STW 5 lowers serum gastrin levels in rats, an eff ect that runs parallel to its ability to lower gastric acid production (Khayyal et al., 2006 ). STW 5-induced stimulation of gastric relaxation and antral motility may contribute to its eff ects on functional dyspepsia (Pilichiewicz et al., 2007 ). Upper Gastrointestinal Disorders 419

Clinical Studies of STW 5

Multiple studies have documented the effi cacy of STW 5 and STW 5-II in the treatment of functional dyspepsia (Madisch et al., 2004 ). A multicenter, double-blind, placebo-controlled study on the eff ects of STW 5 in 315 patients with functional dyspepsia for 8 weeks reported a signifi cant improvement in the Gastrointestinal Symptom Score of patients taking STW 5 compared to placebo, irrespective of H. pylori status (von Arnim, Peitz, Vinson, Gundermann, & Malfertheiner, 2007 ). A double-blind, double-dummy study demonstrated that the eff ects of STW 5 and STW 5-II administered for 4 weeks are equivalent to those of cisapride for the treatment of patients with functional dyspepsia of dysmotility type (Rösch et al., 2002 ). A retrolective multicenter epidemiological cohort study with parallel groups found STW 5 to be superior to metoclopramide in patients with functional dyspepsia (Raedsch et al., 2007 ). Signifi cantly more patients were symptom- free aft er STW 5 treatment (71.6% vs. 62.8% p = 0.012). Th e median duration of inability to work (1 vs. 3 days) was signifi cantly diff erent in favor of STW 5, and more physicians assessed STW 5 as eff ective (71.6 % vs. 63.1% p<0.01) and very well tolerated (90 % vs. 70.6% p<0.001). Meta-analysis of double-blind, randomized, clinical trials on the effi cacy of STW 5 in patients with functional dyspepsia has demonstrated a clear, highly signifi cant overall therapeutic eff ect (Gundermann, Godehardt, & Ulbrich, 2003 ; Melzer et al., 2004 ). Tolerability of the drug was excellent (Gundermann et al., 2003 ). A recent review came to similar conclusions (Rösch et al., 2006 ). Adverse events are rare and, with respect to frequency and spectrum, essen- t i a l l y s i m i l a r t o t h o s e f o u n d w i t h p l a c e b o .

Based on efﬁ cacy and safety, STW 5 is a valid therapeutic option for patients seeking phytotherapy for symptoms of functional dyspepsia.

LIU-JUN-TANG

Liu-Jun-Zi-Tang, also known as Rikkunshi-to and TJ-43, is a Chinese herbal medicine that contains spray-dried aqueous extracts of Atractylodis laneae 420 INTEGRATIVE GASTROENTEROLOGY

rhizoma , Ginseng radix , Pinelliae tuber , Hoelen , Zizyphi fructus , Aurantii nobilis pericarpium , Glycyrrhizae radix and Zingiberis rhizoma . It increases gastric emptying and plasma somatostatin and gastrin levels, and promotes gastric adaptive relaxation. It prevents intracellular signaling disorders in gastric smooth muscle of diabetic rats (Sakai et al., 2004 ). Compared to placebo, TJ-43 (2.5g three times a day) improves gastric emptying as well as gastrointestinal symptoms of epigastric fullness, heartburn, belching, and nausea (Tatsuta & Iishi, 1993 ). Liu-Jun-Zi-Tang can rarely cause interstitial pneumonia (Maruyama et al., 1 9 9 4 ) .

SHENXIAHEWINING

Shenxiahewining is a Chinese herbal medicine that contains Ginseng radix , Pinelliae tuber , Coptidis rhizoma , Zingiberis rhizoma exsiccatum and Glycyrrhizae radix . Chen (1994 ) studied 100 subjects with non-ulcer dyspepsia. Patients received either Shenxiahewining (15 capsules/d; 0.42g/capsule) or a control drug in similar capsules for 20 days. Improvement was seen in 92% of the treatment group compared to only 20 % in the control group.

GOREI-SAN (TJ-17)

Gorei-san (TJ-17) is a Japanese herbal medicine composed of fi ve herbs (Alismatis rhizoma , Atractylodis lanceae rhizoma , Polyporus , Hoelen , and Cinnamomi cortex). It is used for treatment of nausea, dry mouth, headache, and dizziness. Yamada et al. (2003 ) examined the effi cacy of TJ-17 for treatment of SSRI-induced nausea or dyspepsia. TJ-17 was added to the previous regimen in 20 such patients. Symptoms disappeared completely in 9 patients and were decreased in 4 patients. No adverse events related to TJ-17 were reported.

HANGE-KOBOKU-TO (BANXIA-HOUPO-TANG, HKT)

Hange-koboku-to accelerates gastric emptying in patients with dyspepsia, as well as in healthy controls (Table 39.1 ). Th is improvement in gastric emptying is accompanied by improvement in dyspeptic symptoms in patients with functional dyspepsia (Oikawa et al., 2005 ). Upper Gastrointestinal Disorders 421

Table 39.1 Treatments to Enhance Gastric Emptying

Asparagus racemosus (Shatavari)

Ginger

Tangweikang

Liu-Jun-Tang (TJ-43)

Hange-koboku-to

Terminalia chebula

Peppermint oil

Probiotics

Acupuncture

H y p n o s i s

Music therapy

PEPPERMINT PLUS GINGER

A randomized, double-blind, placebo-controlled trial of peppermint oil plus ginger extract (180 mg/day and 25 mg/day x 4 weeks) in patients with functional dyspepsia found that the drug improved symptoms in 74 % of the patients compared to only 30% in the placebo group (Stadelmann et al., 1999 ).

The therapeutic efﬁ cacy of herbal combinations challenges the current trend of highly targeted drug molecules that usually focus on one single target or mechanism for disorders with redundancies in the pathogenic pathways, wherein no single receptor group may play a critical role for the control of symptoms.

Miscellaneous Herbal Combinations

Borgia et al. ( 1985 ) conducted a double-blind, double-controlled multicenter trial on the therapeutic activity of a combination of medicinal herbs, including boldo ( Peumus boldus), cascara ( Rhamnus purshianus), gentian ( Gentiana lutea), and rhubarb ( Rheum sp.). Th is combination produced signifi cant improvements in appetite, dyspepsia, and constipation. Mechanisms include 422 INTEGRATIVE GASTROENTEROLOGY boldine-induced smooth muscle relaxation and gallbladder contraction, increasing bile secretion, as well as gentian-induced stimulation of salivary and gastric secretions. Pepticare® is an Ayurvedic herbomineral formulation that includes Glycyrrhiza glabra , Emblica offi cinalis and Tinospora cordifolia . In an experimental rat model, it results in reduction in gastric ulcer index along with the reduction in total gastric acid and an increase in the pH of gastric fl uid (Bafna & Balaraman, 2005 ). Rats treated with a mixture of an Ayurvedic medicine mixture of Glycyrrhiza glabra , Terminalia chebula , Piper longum and Shanka Bhasma recover faster with concomitant increase in beta-glucuronidase activity in the Brunner’s glands (Nadar & Pillai, 1989 ).Th is suggests that this Ayurvedic formulation does not act as an antacid, but rather by improving the secretory status of Brunner’s glands involved in protection against duodenal ulcer. Th amlikitkul et al. (1989 ) conducted randomized, double-blind, placebo- controlled study of Curcuma domestica Val for dyspepsia in a multicenter study (n=116). Patients received turmeric (2 g/day), placebo or a combination treatment known as Flatulence® , which includes cascara dry extract, nux vomica extract, asofoetida tincture, capsicum powder, ginger powder, and diastase. Eighty-three percent of people in the Flatulence ® formula group and 87 % of patients receiving Curcuma responded to the treatment, compared to only 53 % in the placebo group (p<0.05). Niederau and Gopfert (1999 ) studied the eff ect of chelidonium and turmeric root extract on upper abdominal pain due to functional disorders of the biliary system in a placebo-controlled double-blind trial. Th e reduction of dumpy and colicky pain was faster in the treatment group, suggesting that the benefi cial eff ect on pain may be due to its actions on biliary dyskinesia.

Acupuncture and Other Electromagnetic Treatments

Electroacupuncture (EA) has been used to treat gastrointestinal diseases (Diehl, 1999 ). Evidence suggests that in addition to dyspepsia, acupuncture may help prevent postoperative nausea, and treat postoperative nausea and vomiting of pregnancy (Linde et al., 2001 ).

THE SCIENCE BEHIND IT

EA has variable eff ects on gastrointestinal physiology depending upon the site of application. EA at ST-36 increases gastric contractions in rats, and the eff ect Upper Gastrointestinal Disorders 423 is mediated via the vagal pathway (Tatewaki et al., 2003 ). It also stimulates the parasympathetic pathway and accelerates colonic transit in rats (Iwa et al., 2006 ). EA at acupoints of the Foot-Yangming meridian causes enhanced gastric motility, improves gastric mucosal blood fl ow, and regulates the motilin and somatostatin levels in sinus ventriculi and bulbus in an experimental rat model, suggesting that the eff ects of acupuncture may be related to the content of brain–gut peptides (Lin, 2007 ). EA in dogs at both ST-36 and PC-6 accelerates gastric emptying of liquids (Ouyang, Yin, Wang, Pasricha & Chen, 2002 ). EA at ST-36 improves gastric emptying in gastroparesis, and restores vagotomy-induced impaired gastric accommodation in dogs (Ouyang, Xing & Chen, 2004 ; Ouyang et al., 2002 ). It also increases the percentage of normal gastric slow waves in healthy volunteers (Lin et al., 1997 ). EA at PC-6 reduces the dominant power of the gastric slow waves in humans, while EA at ST-36 increases it, suggesting that EA at diff erent acupoints may have opposing eff ects on motility (Shiotani et al., 2004 ). Although acupuncture reduces both the mean basal acid output, as well as maximal acid output in duodenal ulcer patients (Sodipo & Falaiye, 1979 ), its benefi cial eff ects in dyspepsia appear to be mediated via modifi cation of gastroduodenal motility patterns. Th e analgesic eff ect of acupuncture appears to be mediated via the opioid pathway (Diehl, 1999 ).

CLINICAL STUDIES

EA not only improves gastric emptying in subjects with gastroparesis but also improves symptoms of functional dyspepsia in patients with normal, as well as delayed, gastric emptying (Xu et al., 2006 ). A randomized, controlled study of acupuncture and cisapride on gastric motility in 90 patients with functional dyspepsia demonstrated a signifi cant symptomatic improvement in both groups, accompanied by an improvement in gastric emptying as well as plasma motilin levels (Chen, Pan, & Xu, 2005 ). A multicenter randomized, controlled trial of acupuncture at Zhongwan (CV 12) in 276 patients with peptic ulcer found that acupuncture group experienced alleviated stomachache and improved appetite faster than the control group, although the total eff ective rate was similar in the two groups (Niu et al., 2 0 0 7 ) .

Acupuncture administered by an expert may be a reasonable option for patients with functional dyspepsia refractory to standard management. 424 INTEGRATIVE GASTROENTEROLOGY

Various kinds of electromagnetic therapies have also been studied. However, the data is sparse at best. Acupuncture with a low-frequency alternating magnetic fi eld has a positive eff ect on “emotional and personality spheres, as well as vegetative regulation” accompanied by faster relief of the basic symptoms and healing of the ulcer (Kravtsovo, Tiu, Golovanova, & Rybolov, 2000 ). A comparison of therapeutic eff ects of low-frequency pulse plus auricular point magnetic therapy and Propulsid in 50 patients with functional dyspepsia documented 93 % effi cacy in the treatment group compared to 75 % in the controls (Wang et al., 2007 ). A controlled study found that the addition of transcutaneous and refl ex magnetolaser impact to anti- H. pylori treatment shortens time to ulcer healing and promotes eradication of H. pylori in patients with duodenal ulcer exacerbation (Minakov, Romanova, & Khimina, 1999 ). EHF-puncture results in signifi cantly better healing of gastric and duodenal ulcers compared to standard medical treatment (Razumov & Voznesenskaia, 1999 ).

COMPLICATIONS OF ACUPUNCTURE

Complications of acupuncture are rare but can be serious. Signifi cant complications include bleeding, viral hepatitis, HIV, bacterial infections including endoscarditis, pneumothorax, cardiac tamponande, and spinal cord injuries (Ernst & White BMJ. 2000 Feb 19;320(7233):513-4., 2000). Acute pancreatitis may occur (Uhm, 2005 ). Acupuncture may also aff ect the functioning of demand pacemakers.

Probiotics

Limited evidence exists regarding the role of probiotics in upper digestive disorders, including their eff ect on H. pylori .

THE SCIENCE BEHIND IT

Infections exert their eff ect through critically altering T-helper (Th 1/Th 2) regulation, which is supported by the examination of the cytokine profi les. Treatment with probiotics helps produce a balanced T-helper cell response and prevent imbalances (Th 1> Th 2 or Th 2> Th 1) that in part contribute to clinical disease (Th 2 imbalance contributes to atopic disease, while Th 1 predominance is found in conditions such as H. pylori gastritis and Crohn’s disease). Upper Gastrointestinal Disorders 425

IL-8 is involved in Hp-induced gastric infl ammation, and live Lactobacillus gasseri (LG21) suppresses H. pylori and reduces H. pylori -induced infl ammation (Sakamoto et al., 2001 ), as well as H. pylori-induced IL-8 production within gastric mucosa (Tamura et al., 2006 ). LG21 inhibits HCl-induced gastric lesions in a dose-dependent manner and is associated with prostaglandin E2 generation (Uchida & Kurakazu, 2004 ). Fungal colonization of gastric ulcers delays ulcer healing of mucosa in rats, and this eff ect can be attenuated by probiotic therapy (Zwolińska-Wcisło et al., 2006). LG21 can enter into the gastric mucus layer, which may in part explain its mechanism of action (Fujimura et al., 2006 ).

CLINICAL STUDIES

Th e gastric emptying rate is signifi cantly faster in the newborns receiving L. reuteri compared with formula with placebo, and the L. reuteri supplemented babies have a motility pattern resembling that of newborns fed with breast milk (Indrio et al., 2008 ). Studies on the use of probiotics for dyspepsia have largely yielded mixed results. An open label trial found that Lactobacillus acidophilus improves symptoms of bloating, abdominal pain and pressure and fl atulence in patients with dysbioisis/maldigestion (Kocián, 1994 ). LGG may be benefi cial for bloating by altering the intestinal gut fl ora and thus the production of intestinal gas (Di Stefano, Miceli, Armellini, Missanelli, & Corazza, 2004 ). In contrast, Kim and colleagues failed to demonstrate any benefi cial eff ect of commonly used probiotics on GI symptoms in patients with functional gastrointestinal disorders (Kim et al., 2006 ). A double-blind, randomized controlled trial of Lactobacillus rhamnosus GG for functional abdominal pain in children found that it improves symptoms in subjects with irritable bowel syndrome, but not in those with functional dyspepsia (Gawrońska, Dziechciarz, Horvath, & Szajewska, 2007). AB-yogurt (made by the President Enterprise Corporation, Tainan, Taiwan) is fermented milk that contains sugar, high-fructose corn syrup, pectin, galac- tooligosaccharide, and an approximately equal mixture of L. acidophilus La5, B. lactis Bb12, L. bulgaricus, and S. thermophilus at a concentration of at least 107 bacteria/ml. Regular intake of AB-yogurt signifi cantly decreases the urease activity of H. pylori aft er 6 weeks of therapy in asymptomatic H. pylori-positive subjects (Wang et al., 2004 ). A recent epidemiologic study documented a protective eff ect of yogurt consumption on prevalence of H. pylori (Ornelas, Galvan-Potrillo, & López-Carrillo, 2007 ). 426 INTEGRATIVE GASTROENTEROLOGY

Adding Lactobacillus- and Bifi dobacterium-containing yogurt to triple therapy for H. pylori eradication results in greater eradication (91% vs. 78 % ) than the triple-only group (Sheu, 2002 ). Similarly, pretreatment with Lactobacillus- and Bifi dobacterium-containing yogurt to quadruple therapy for eradicating H. pylori infection aft er failed triple-therapy regimen results in a higher eradication rate than the quadruple-therapy-only group (85% versus 71 %; see Sheu et al., 2006 ). Regular intake of cranberry juice or probiotic Lactobacillus johnsonii La1 may be useful in the management of asymptomatic children colonized by H. pylori , although there are no synergistic inhibitory eff ects of consumption of both on H. pylori colonization (Gotteland et al., 2008 ). Other studies using diff erent probiotic strains have yielded negative results (Cindoruk Erkan, Karakan, Dursun, & Unal, 2007 ; Goldman et al., 2006 ). Multiple studies have documented that probiotic therapy reduces the side eff ects induced by anti-H. pylori therapy (Cremonini et al., 2002 ; Nista, Candelli, Cremonini, & Cazzato, 2004 ; Armuzzi et al., 2001 ). A recent review of literature regarding H. pylori and probiotics (Lesbros- Pantofl ickova, Corthésy-Th eulaz, & Blum, 2007 ) concluded that probiotics are inhibitory and are eff ective in reducing H. pylori -associated gastric infl ammation. Th e addition of probiotics to standard antibiotic treatment increases H. pylori eradication while reducing the therapy-associated side eff ects.

Long-term intake of probiotics may have a favorable effect on H. pylori infection in humans, thus reducing the risk of gastritis and, potentially, functional dyspepsia, peptic ulcer disease, and gastric malignancy.

Psychological Therapies

THE RATIONALE BEHIND IT

War and stress are risk factors for peptic ulcer disease (Levenstein, 1999 ). PUD is common during wars and among war survivors (Jhun, Ju, Kim, & Kim, 2005 ). Psychological factors are involved in both noncardiac chest pain and functional dyspepsia. Th ese data suggest a potential target for psychological interventions in treatment of functional as well as organic gastrointestinal disorders.

ESOPHAGEAL DISORDERS

Relaxation exercises ameliorate gastroesophageal refl ux symptoms by reducing esophageal acid exposure (McDonald-Haile et al., 1994 ). Anecdotal reports Upper Gastrointestinal Disorders 427 support the use of psychological therapies for esophageal dysmotility. Successful treatment of refractory diff use esophageal spasm by biofeedback and self- regulation, resulting in weight gain and reduction in chest pain, has been described (Latimer, 1981 ). Use of psychological therapies for noncardiac chest pain appears promising. A randomized, controlled trial of cognitive-behavioral therapy for treatment of persistent noncardiac chest pain demonstrated signifi cant reductions in chest pain, limitations on daily life, autonomic symptoms, and psychological morbidity compared to the control group (Klimes, Mayou, Pearce, Coles, & Fagg, 1990 ). Other studies have yielded similar positive results (Mayou et al., 1997 ; van Peski-Oosterbaan et al., 1999 ). One study compared a psychological treatment package (education, relaxation, breathing training, graded exposure to activity and exercise, and challenging automatic thoughts about heart disease) to waiting-list controls for treatment of noncardiac chest pain (Potts, Lewin, Fox, & Johnstone, 1999 ). Treatment signifi cantly reduced chest pain episodes from median 6.5 to 2.5 per week, accompanied by improvements in anxiety and depression scores, disability rating, and exercise tolerance.

GASTRODUODENAL DISORDERS

Gut-oriented hypnosis accelerates gastric emptying in dyspeptic as well as healthy subjects (Chiarioni, Vantini, De Iorio, & Benini 2006 ). Listening to enjoyable music increases the amplitude of gastric myoelectrical activity in healthy humans. Music therapy may improve gastric motility and may be used to stimulate gastric emptying (Lin, 2007 ). Th ere are scant data on the use of psychological therapies for peptic ulcer disease. Colgan, Faragher, and Whorwell (1988 )conducted a controlled trial of hypnotherapy in relapse prevention of duodenal ulcers healed with ranitidine. Aft er discontinuation of ranitidine, randomly selected patients received either hypnotherapy or no hypnotherapy for 10 weeks. Aft er a follow-up of 12 months, 100 % of the control subjects had relapsed, in contrast to only 53% of the hypnotherapy group. A case of hypnotic control of upper gastrointestinal hemorrhage has also been described (Bishay, Stevens, & Lee, 1984 ). Multiple studies have documented the positive eff ects of psychological therapies for functional dyspepsia. A randomized, placebo-controlled trial of hypnotherapy found that both the short-term as well long-term symptom scores improved, accompanied by better quality of life and fewer physician visits in the hypnotherapy group compared to the supportive and medical treatment groups (Calvert et al., 2002 ). Similarly, a randomized, placebo-controlled 428 INTEGRATIVE GASTROENTEROLOGY

comparison of cognitive-behavioral therapy found it to be better than education alone for treatment of functional bowel disorders (Drossman et al., 2 0 0 3 ) . Biofeedback has the potential to allow patients to manipulate the pathogenic gastroduodenal alterations implicated in dyspepsia. Gastric myoelectric activity can be modifi ed using biofeedback and relaxation techniques through imagery, while watching EGG activity on the screen (Stern et al., 2004 ). A simpler alternative may be the use of a nasogastric tube to provide feedback about gastric pressure waves (Whitehead & Drescher, 1980 ). Breathing exercises with vagal biofeedback can increase drinking capacity and improve quality of life in patients with functional dyspepsia without altering the vagal tone (Hjelland, Svebak, Berstad, Flatab ø , & Hausken, 2007 ).

Psychological therapies may be a cost-effective option in patients with noncardiac chest pain, as well as in those with functional dyspepsia.

A systematic review of psychological interventions for non-ulcer dyspepsia concluded that while psychological interventions appear to benefi t dyspepsia symptoms, there is insuffi cient evidence to confi rm their effi cacy in functional dyspepsia (Soo et al., 2005 ). More recently, a prospective randomized, controlled trial comparing the long-term outcome of intensive medical therapy (with or without cognitive-behavioral or muscle relaxation therapy) with standard medical therapy in patients with refractory functional dyspepsia reported that intensifi ed medical management with psychological intervention improves long-term outcomes and helps control concomitant anxiety and depression (Haag et al., 2007 ).

Homeopathy

Homeopathy is based on the principle of dilutions. It defi es biological plausibility and continues to baffl e scientists, and the debate on its eff ectiveness is ongoing. Th ere is paucity of data examining eff ect of homeopathy in upper digestive disorders. Many, but not all, of the independent reviews and placebo- controlled trials of homeopathy have concluded that its benefi ts seem to be more than just placebo eff ect (Jonas, Kaptchuk, & Linde, 2003 ; Shang et al., 2 0 0 5 ) . S p e n c e Th ompson, and Barron ( 2005 ) recently published the results of Upper Gastrointestinal Disorders 429 their 6-year, university hospital outpatient observational study of homeopathic treatment for chronic diseases (n=6544) including gastrointestinal diseases. Th ey found that 71% of the patients reported positive health changes, with 51% recording their improvement as better or much better. Homeopathy is generally believed to be devoid of side eff ects. However, a case of esophageal ulcer due to a homeopathic pill has been described, suggesting that pill esophagitis can be triggered by substances generally thought to be devoid of toxicity (Corleto et al., 2007 ).

Minerals

Most of the data in this category pertain to the use of zinc. Exogenously administered zinc compounds have been shown to possess anti-ulcer activity against a wide variety of ulcerogenic agents in animals as well as humans. Because of their widespread use in mainstream medicine, antacids/alginate will not be discussed here.

THE SCIENCE BEHIND IT

Th e onset, development, and spontaneous healing of experimental gastroduodenal lesions in rats are associated with an alteration in serum, as well as in duodenal tissue, zinc concentrations (Troskot et al., 1996 ). Zinc pretreatment protects against the development of experimental duodenal lesions in a dose- dependent manner (Troskot et al., 1997 ). Zinc levels in serum and gastric mucosa of patients with peptic ulcer disease are altered, possibly due to the migration of the zinc from serum to the gastric mucosa (Bandyopadhyay et al., 1995 ). Zinc sulfate reduces basal gastric acid secretion in duodenal ulcer patients by 60% (Puscas, Sturzu, & Búzás, 1 9 8 5 ) . Th e antisecretory eff ect of zinc may be mediated via inhibition of the carbonic anhydrase.

CLINICAL STUDIES

A multicenter, double-blind comparison of 600 mg/d of zinc acexamate and 40 mg/d of famotidine for 4 weeks showed that zinc acexamate is as eff ective as famotidine for the symptom resolution as well as healing of duodenal ulcer (García-Plaza et al., 1996 ). Another multicenter, double-blind, placebo- controlled trial (n=276) found that 300 mg/d of zinc reduces the incidence of 430 INTEGRATIVE GASTROENTEROLOGY

NSAID-induced gastric and duodenal ulcers by 92 % (Rodríguez de la Serna & Díaz-Rubio, 1994 ). A meta-analysis found zinc acexamate to be superior to placebo, and as eff ective as H2 receptor antagonists for the treatment of peptic ulcer disease (Jiménez, Bosch, Galmés, & Baños, 1992 ).

Vitamins

Limited data support the use of vitamins in upper gastrointestinal disorders. Adding vitamin C to one-week triple therapy for H. pylori can allow reduction of clarithromycin dose, while preserving the eradication of clarithromycin- susceptible H. pylori (Chuang et al., 2007 ). In contrast, vitamin C and E supplementation to lansoprazole-amoxicillin-metronidazole triple therapy may reduce the eradication rate of metronidazole-susceptible H. pylori infection (Chuang et al., 2002 ).

Preventive Strategies

Aside from pharmacotherapeutics for gastroduodenal illness, patients may be advised to follow some lifestyle modifi cations and to take care using medications, including over-the-counter medicines.

1. Patients should avoid NSAIDs as much as possible, including both prescription and over-the-counter varieties. If NSAIDs are needed, use the lowest possible dose and avoid multiple NSAIDs. Talk to your doctor before making any changes. 2. Smoking increases gastric acidity and aff ects gastroprotective mechanisms, which predisposes patients to peptic ulcers as well as GERD. In addition to cancer prevention, smoking cessation may reduce dyspeptic symptoms and potentially prevent ulcers in some patients. 3. Alcohol has direct toxic eff ects on the gastric mucosa and may lead to gastritis and even gastrointestinal bleeding in some cases. Excessive drinking also increases gastroesophageal refl ux. Avoiding excess alcohol may help reduce dyspeptic symptoms and ulcers in otherwise predisposed individuals. 4. Other routine lifestyle measures for GERD include raising the head of the patient’s bed, avoiding large fatty meals, especially at dinner, not eating within 3 hours of bedtime, and losing weight if overweight. Upper Gastrointestinal Disorders 431

5. Th e role of diet is patient-specifi c and may aff ect symptoms in some individuals with dyspepsia. Dietary modifi cations must be individualized based on the patient’s symptom triggers. Patients who suff er from recurrent peptic ulcer disease may benefi t from eating complex carbohydrates, fresh fruit and vegetables, and avoiding red and fried meats. 40 Celiac Disease

S. DEVI RAMPERTAB AND PETER H.R. GREEN

key concepts

■ Celiac disease occurs in nearly 1% of the population in most countries. ■ Ingested wheat gluten and related proteins of rye and barley trigger an immune response in genetically predisposed individuals. ■ Aside from gastrointestinal symptoms, celiac disease has multiple extraintestinal manifestations including anemia, osteoporosis, and neurological defi cits. ■ All patients with celiac disease have either HLA-DQ2 or DQ8 haplotypes. ■ Upper endoscopy with small bowel biopsy remains the gold standard for diagnosis of celiac disease. ■ H i s t o l o g i c a l l y , t h e a ff ected small bowel mucosa displays villous atrophy, crypt hyperplasia, and increased intraepithelial lymphocytes. ■ With the advent of sensitive and specifi c serological testing, more celiac patients with atypical symptoms or no symptoms are being diagnosed. ■ Untreated celiac disease can lead to signifi cant complications, such as increased risk of malignancy. ■ Treatment of celiac disease is a diet devoid of gluten. ■

432 Introduction

eliac disease is a very common autoimmune disorder that involves close interaction of genetic, environmental, and immunologic com- C ponents. Ingested wheat gluten and related proteins of rye and barley trigger an immune response in genetically predisposed individuals that results in infl ammation, villous atrophy, and crypt hyperplasia in the intestine. Approximately 95% of patients with celiac disease will express human leuko- cyte antigen-DQ2, while the vast majority of the remaining patients will have HLA-DQ8 (Green & Jabri, 2003 ). Once thought to be a rare intestinal disorder of childhood, celiac disease is now becoming increasingly recognized as a common condition that has a wide spectrum of clinical manifestations. While a large percentage of patients are asymptomatic, classic gastrointestinal symptoms of abdominal pain, diarrhea, and weight loss can be present. In addition, some of the extraintestinal features associated with celiac disease include anemia, osteoporosis, neurological defi - cits, malignancy, and other autoimmune disorders. Elimination of gluten and related proteins from the diet of patients with this condition results in clinical and histological improvement.

Epidemiology

Serologic screening tests have revealed that the incidence of celiac disease approaches 1% of the population, based on several studies from Europe and the United States (West et al., 2003 ; Mäki et al., 2003 ; Fasano et al., 2003 ; Bingley et al., 2004 ; Tommasini et al., 2004 ). Th e disease has also been noted worldwide: Asia (Sood et al., 2003 ), the Middle East (Shahbazkhani et al., 2003 ; Tatar et al., 2004 ), North Africa (Catassi et al., 1999 ), South America (Gomez et al., 2001 ) and Australia (Hovell et al., 2001 ). In a recent large national survey from the United States, it was determined that there was a female predominance of celiac disease (2.9 to 1). In addition, the majority of respondents were diagnosed in their fourth to sixth decades of life. It is interesting to note that symptoms preceded the diagnosis of celiac disease a mean of 11 years in this study (Green et al., 2001 ). Th e investigators concluded that this delay was due to decreased awareness of celiac disease, and its various atypical presentations, among physicians in the United States. 434 INTEGRATIVE GASTROENTEROLOGY

Physicians often regard adult celiac disease as rare, and fail to consider it in clinical situations other than the classical chronic diarrhea and malabsorption.

Another possible concept is the “Celiac iceberg” theory proposed by Logan, which states that for every case of celiac disease diagnosed on clinical suspicion (tip of the iceberg), there are many more that remain undiagnosed (area below the waterline; see Logan, 1996 , and Figure 40.1 ). Th ese cases may remain undetected, either because patients have latent or asymptomatic disease or have been misdiagnosed by their physicians.

Pathogenesis

I. GENETIC FACTORS

Genetic factors are thought to participate in the pathogenesis of celiac disease. Celiac disease is an HLA-associated illness limited to genetically predisposed individuals who express HLA-DQ2 or HLA-DQ8 haplotypes (Sollid & Lie, 2005 ).

HLA-DQ2 is present in about 95 % of those afﬂ icted with celiac disease, and most of the remainder have HLA-DQ8 (Green & Jabri, 2003 ).

Th ese HLA genes confer up to 40 % of the genetic risk; therefore, the rest is attributable to non-HLA genes (Louka & Sollid, 2003 ). Interestingly, about 30 %–40 % of Caucasians carry DQ2 or DQ8, yet <3% of them will develop celiac disease. Th is suggests that the presence of these alleles is necessary but not suffi cient for the eventual development of the disease. Th e concordance rate for celiac disease is much higher in monozygotic twins (approximately 70 %) as compared to HLA-matched siblings (30 % ; see Greco et al., 2002 ). Th is indicates that there may be non-HLA susceptibility genes involved that are shared by monozygotic twins that may not necessarily be shared by siblings. About 10 % of fi rst-degree relatives of aff ected individuals have celiac disease overall (Green & Jabri, 2006 ).

II. THE ROLE OF GLUTEN

Th e causative agent in celiac disease is gluten, a protein derived from wheat, barley, and rye. It is enriched in glutamine and proline, and poorly absorbed in the human upper digestive tract (Vader et al., 2003 ). Celiac Disease 435

Gliadin is the alcohol-soluble fraction of gluten, and houses the bulk of the toxicity associated with it. Undigested molecules of gliadin are resistant to degradation by gastric, pancreatic, and intestinal brush-border membrane proteases in the human intestine, and therefore will remain in the intestinal lumen long aft er gluten ingestion. Aft er changes in intercellular tight junctions and increased intestinal permeability (i.e., aft er gastrointestinal infection), gliadin enters the lamina propria to interact with antigen-presenting cells.

III. MUCOSAL IMMUNE RESPONSES

Figure 40.2 provides an illustrative review of the immunological mechanisms responsible for potentiating the mucosal damage seen in celiac disease. Th e enzyme tissue transglutaminase (TTG) has an important role in the pathogenesis of celiac disease, in that it is responsible for converting glutamine residues on the gliadin protein into glutamic acid, thereby producing a negative charge which favors binding and presentation by the HLA-DQ2 and DQ8 molecules in the lamina propria. Th is process is critical and is termed deamidation .

Deamidated gliadin, when presented by HLA-DQ2 and/or HLA-DQ8 molecules to CD4 T cells, stimulates the production of cytokines. These cytokines are then responsible for the host of immune responses that occur, ultimately resulting in damage within the intestinal mucosa (as evidenced by villous atrophy and crypt hyperplasia) and activation of plasma cells to produce antibodies to gliadin, tissue transglutaminase (TTG), and endomysium (Green & Cellier, 2007 ).

Two types of immunity are responsible for the propagation of intestinal damage in celiac disease. Innate immunity refers to the antigen-nonspecifi c defense mechanisms that a host uses immediately, or within several hours, aft er exposure to almost any microbe. Th is is the immunity one is born with, and is the initial response by the body to eliminate microbes and prevent infection. Adaptive (acquired) immunity, refers to antigen-specifi c defense mechanisms that take several days to become protective and are designed to react with and remove a specifi c antigen. Th is is the immunity one develops throughout life. Whereas the actions of gliadin in the lamina propria are mediated by the adaptive immune system, the innate immune system is the vector by which gliadin induces damage to the intestinal epithelial lining. In the epithelium, 436 INTEGRATIVE GASTROENTEROLOGY gliadin is directly toxic to epithelial cells, resulting in increased expression of interleukin-15. Th is, in turn, activates intraepithelial lymphocytes. Th ese lymphocytes subsequently become cytotoxic and kill intestinal cells that express MIC-A (a stress protein) on their surface (Green & Cellier, 2007 ).

IV. ENVIRONMENTAL FACTORS

Epidemiologic studies have suggested that there is a protective eff ect of breastfeeding in the development of celiac disease (Persson, Ivarsson, & Hernell, 2002 ). Also, the initial administration of gluten before 4 months of age is associated with an increased risk of disease development, and the introduction of gluten aft er 7 months also denotes a marginal increase in risk (Norris et al., 2 0 0 5 ) .

The best time to introduce gluten to the infant, which would pose the least risk of celiac disease development, would be between 4 to 6 months of age.

Clinical Manifestations

Th e clinical presentation of celiac disease involves a wide spectrum of features including, but not limited to, the intestinal tract. Patients can range from asymptomatic to severe malnutrition. It is key to note that the majority of patients with celiac disease have a silent or atypical presentation and are not diagnosed, therefore substantiating the “iceberg model” theory. Also, since gastrointestinal symptoms may be vague and nonspecifi c, patients are oft en diagnosed with irritable bowel syndrome (Green et al., 2001 ).

Celiac disease should be excluded in all patients who are diagnosed with irritable bowel syndrome.

Celiac disease is sometimes divided into clinical subtypes based on presence/absence of symptoms. Th e terms “symptomatic” or “classic” denote those cases that satisfy the classic features of celiac disease. Th ese include chronic diarrhea, abdominal distension and pain, weakness, and sometimes malabsorption. Malabsorption-related symptoms include steatorrhea, weight loss, failure to thrive, bloating, fl atulence, and a variety of nutrient and mineral defi ciency states. Celiac Disease 437

In contrast, the disease is now evolving and patients are increasingly displaying the more common “atypical” form of the disease, whereby gastrointestinal symptoms may be absent or less pronounced.

Approximately half of the adult-onset celiac disease cases lack any gastrointestinal symptoms (Farrell & Kelly, 2002 ).

Rather, extraintestinal manifestations such as anemia, osteoporosis, short stature, infertility, and neurological defi cits are present (Rampertab et al., 2006 ). Table 40.1 outlines some of the key disorders associated with celiac disease. Lastly, those with “latent” or “silent” celiac disease are asymptomatic. In these patients, there are no classic or atypical symptoms. Th ese individuals are incidentally discovered to have celiac disease, evidenced by villous atrophy, during endoscopy or intestinal biopsy for other reasons (Green et al., 2000 ), or as a result of serological screening.

Extraintestinal Manifestations

I. HEMATOLOGIC

Anemia is one of the most frequent presenting features of celiac disease, and it is most commonly due to iron defi ciency. Th e pathogenesis of iron defi ciency in celiac disease is multifactorial; however, malabsorption of dietary iron from damaged gastrointestinal tract mucosa is the primary etiology. Iron is exclusively absorbed by the proximal duodenum, and this area is almost universally aff ected in celiac disease. In addition, there have been reports of occult bleeding in 40% to 50% of patients with celiac disease (Fine, 1996 ). B12 defi ciency has also been documented in celiac disease (Dahele & Ghosh, 2001 ). Gluten- free diet is usually suffi cient to correct these nutritional defi ciencies and supplementation is usually not required.

II. DERMATOLOGIC

Dermatitis herpetiformis is an extremely pruritic bullous skin lesion with characteristic distribution over the extensor surfaces of the major joints such as the elbows and knees, as well as the buttocks (Karpati, 2004 ). Th e diagnosis of dermatitis herpetiformis is based on pathognomonic granular immunoglobulin A 438 INTEGRATIVE GASTROENTEROLOGY

Table 40.1. Disorders Associated with Celiac Disease

Endocrine

Type I Diabetes

Autoimmune Th yroid Disorders

Addison’s Disease

Reproductive Disorders

Alopecia Areata

Neurologic

Cerebellar Ataxia

Neuropathy

Epilepsy

Migraine

Cardiac

Idiopathic Dilated Cardiomyopathy

Autoimmune Myocarditis

Hepatic

Primary Biliary Cirrhosis

Autoimmune Hepatitis

Autoimmune Cholangitis

Other

Anemia (Iron defi ciency)

Osteoporosis

Selective IgA Defi ciency

Intestinal Lymphoma

Autoimmune Atrophic Gastritis

Sjogren’s Syndrome

Turner Syndrome

Down’s Syndrome

Dental Enamel Defects

Psoriasis

Recurrent Aphthous stomatitis Celiac Disease 439 deposits in the dermal papillae (Reunala, 2001 ). Long-term remissions are maintained only with strict compliance to a gluten-free diet, although dapsone may be used in conjunction with the diet to quickly and eff ectively resolve the itching and the rash.

III. NEUROLOGIC

Neurologic complications have been estimated to occur in 6 % to 10 % of patients with celiac disease (Chin et al., 2003 ). Peripheral neuropathy and cerebellar ataxia are the more common neurologic symptoms; however, epilepsy, myelopathy, myopathy, dementia, and psychiatric illness have also been described (Hadjivassiliou et al., 1996 ). Th e etiology of neurological dysfunction may be related to vitamin defi ciencies (i.e., B6, B12) or autoimmune activity against neural antigens.

IV. HEPATIC

Hepatic manifestations of celiac disease range from asymptomatic elevation of serum aminotransferases to severe liver failure. Mild to moderate elevations in serum aminotransferases may be seen in 15% to 55 % of patients with celiac disease. Conversely, celiac disease is found in approximately 10 % of patients with unexplained transaminasemia (Abdo, Meddings, & Swain, 2004 ). Both the serum transaminases, as well as the celiac disease serology, normalized aft er initiation of a gluten-free diet. Interestingly, celiac disease has been found in 3% to 7% of patients with primary biliary cirrhosis, 4% to 5 % of patients with Type I autoimmune hepatitis, and 7% to 10% of those with Type II autoimmune hepatitis (Kaukinen et al., 2002 ; Sedlack et al., 2002 ; Volta et al., 2002 ). Moreover, in a recent Finnish study, severe liver disease was reported in 4 patients with untreated celiac disease. Marked improvement of their liver disease aft er initiation of a gluten-free diet raised the possibility of causality for celiac disease (Kaukinen et al., 2002 ). In addition, this study has suggested that perhaps all patients with advanced liver disease of unknown etiology, and liver transplant candidates for crypto- genic cirrhosis, ought to be screened for celiac disease.

V. BONE DISEASE

Th e most frequent clinical features of celiac disease-associated bone disease include bone pain, altered gait, retardation of growth, osteopenia/osteoporosis, 440 INTEGRATIVE GASTROENTEROLOGY bone deformities, and fractures (Moreno, 2004). Most studies that have evaluated bone mineral density in celiac patients have noted a low bone mass in both adults and children with celiac disease ((Meyer et al., 2001 ). Specifi cally, osteoporosis (T score < – 2.5) was present in 34% of the patients at the lumbar spine, 27% at the femoral neck, and 36 % at the radius. Low bone mass (T score between – 1.0 and – 2.5) was present in 38 % at the lumbar spine, 44 % at the femoral neck, and 32 % at the radius. In adult patients responsive to the gluten- free diet, the bone density becomes comparable to that of healthy individuals (Valdimarsson et al., 1996 ).

VI. ENDOCRINE DISORDERS

Celiac disease is associated with some immune-mediated endocrine disorders, most commonly Type I diabetes and thyroid disease. Each of these conditions aff ects 5% to 10% of patients with celiac disease (Collin et al., 2002 ). Th e eff ect of adherence to a gluten-free diet on the management of diabetes and thyroid disease is unknown currently.

VII. INFERTILITY

Reduced fertility has been reported in both males and females with celiac disease. In pregnant women, there is an increased risk for miscarriage, stillbirth, perinatal deaths, and intrauterine growth retardation (Ciacci et al., 1996 ; Gasbarrini et al., 2000 ; Tata et al., 2005 ). Ciacci et al. have reported that the relative risk of spontaneous abortion in women aff ected by celiac disease is 8.8 times higher than in healthy subjects, and a gluten-free diet reduced the relative risk of abortion.

Diagnosis

Th e diagnosis of celiac disease requires both a duodenal biopsy that shows the characteristic fi ndings of intraepithelial lymphocytosis, crypt hyperplasia, and villous atrophy while on a gluten-containing diet and clinical improvement in response to a gluten-free diet. Th e diagnostic criteria developed by the European Society for Pediatric Gastroenterology and Nutrition require only clinical improvement with the diet, although histologic improvement on a gluten-free diet is frequently sought and is recommended in adults. However, roughly 10% of cases are diffi cult to diagnose because of a lack of concordance Celiac Disease 441 among serologic, clinical, and histologic fi ndings. A diagnostic schema is presented in Figure 40.3 .

I. SEROLOGICAL TESTING

Typical indications for serologic testing include unexplained bloating or abdominal distress, chronic diarrhea with or without malabsorption, abnormalities on laboratory tests that might be caused by malabsorption (i.e., folate defi ciency and iron defi ciency anemia), fi rst-degree relatives with celiac disease, and autoimmune diseases and other conditions known to be associated with celiac disease. Th e most sensitive antibody tests for the diagnosis of celiac disease are of the IgA class. Th e available tests include those for antigliadin antibodies, connective-tissue antibodies (antireticulin and anti-endomysial antibodies), and antibodies directed against tissue transglutaminase. Th e antigliadin antibodies are no longer considered sensitive or specifi c enough to be used for the detection of celiac disease. Antireticulin antibodies are also rarely measured, having been surpassed in use by endomysial and anti-tissue transglutaminase antibodies. Th e diagnostic standard in celiac serologies remains the endomysial IgA antibodies; they are highly specifi c markers for celiac disease, approaching 100% accuracy. Th e recognition that the enzyme tissue transglutaminase is the autoantigen for the development of endomysial antibodies (Dieterich et al., 1997 ) allowed development of automated enzyme-linked immunoassays that are less expensive and less operator dependent than the endomysial antibody test. Overall, the sensitivity of the tests for both endomysial antibodies and anti-tissue transglutaminase antibodies is greater than 90% , and a test for either marker is considered the best means of screening for celiac disease (Rostom et al., 2005 ). (See Table 40-2 ). Th e titers of endomysial antibodies and anti-tissue transglutaminase antibodies correlate with the degree of mucosal damage (Sategna-Guidetti et al., 1993 ; Tursi et al., 2003 ). Th erefore, serological tests may not detect partial villous atrophy. Selective IgA defi ciency is more common in patients with celiac disease than in the general population, with 1 case in 40 as compared to 1 in 400. Consequently, patients with celiac disease and selective IgA defi ciency lack IgA endomysial antibodies and IgA anti-tissue antibodies against tissue transglutaminase. It is recommended that the test for anti-tissue transglutaminase antibodies be used as a single screening test for celiac disease (Rostom et al., 2005 ; Rostom et al., 2006 ). If the levels of this marker are within the normal range (or if it is absent) and there is a high suspicion of celiac disease, selective 442 INTEGRATIVE GASTROENTEROLOGY

Table 40.2 Serologic Tests for Celiac Disease

Antibody test Sensitivity (% ) Speciﬁ city ( % ) Time course

IgA EMA 85 to 100 96 to 100 Antibody disappears within several months aft er institution of gluten-free diet

IgA 95 90 Limited data; correlated with IgA anti-TTG anti-endomysial antibody in studies

IgA 53 to 100 65 to 100 More persistent than IgA anti- antigliadin endomysial antibody; may persist for 6 months or longer

IgG 57 to 100 42 to 98 Most persistent; may be detectable up to antigliadin 12 months aft er institution of gluten-free diet False positive tests reported in patients with Crohn’s disease, wheat protein allergy, and post-diarrhea states

IgA defi ciency needs to be ruled out by measuring total IgA levels. In such cases, a test for IgG antibodies against tissue transglutaminase should be performed (Lenhardt et al., 2004 ). Th e clinician should be aware that timing of the serological testing is critical, as sensitivities may be aff ected by either a reduced gluten or gluten-free diet.

II. UPPER ENDOSCOPY AND HISTOLOGICAL ASSESSMENT

Biopsy of the small intestine remains the gold standard for diagnosing celiac disease, and it should always be performed when clinical suspicion is high, irrespective of the results of serologic testing. Biopsy confi rmation is crucial, given the lifelong nature of the disease and the resulting need for an expensive and socially inconvenient diet. At least four to six endoscopic-biopsy specimens should be obtained from the duodenum, given the patchy nature of the disease (Bonamico et al., 2004 ; Ravelli et al., 2 0 0 5 ) . In addition to patients whose serologic tests are positive, any patient who has chronic diarrhea, iron defi ciency, or weight loss should undergo duodenal biopsy, irrespective of whether serologic testing for celiac disease has been performed. Th e recognition of endoscopic signs of villous atrophy, such as scalloping of mucosal folds, absent or reduced duodenal folds, mucosal Celiac Disease 443

fi ssures, or a mosaic pattern of the mucosa, should prompt biopsy (Lee & Green, 2005 ). See Fig 40-4 . However, because these abnormalities are not sensitive markers of the presence of celiac disease (Oxentenko et al., 2002 ), biopsy should be performed even if they are absent. It is also important to note that not all scalloping visualized endoscopically is secondary to celiac disease (Shah et al., 2000 ). Some of the characteristic features leading to the diagnosis of celiac disease include villous atrophy (partial or total), crypt hyperplasia, increased intraepithelial lymphocytes, and infi ltration of the lamina propria with infl ammatory cells (Figure 40.5 ). Pitfalls in the pathological diagnosis include over-interpretation of villous atrophy in poorly oriented biopsy specimens, and inadequate biopsy sampling in patients with patchy villous atrophy. Th e histologic fi ndings in celiac disease are characteristic but not specifi c. Indeed, celiac disease is not the only cause of villous atrophy (Table 40.3 ). Th e diagnosis is confi rmed when there is a favorable response to the diet.

Table 40.3 Differential Diagnosis of Villous Atrophy

Celiac Disease

Giardiasis

Collagenous sprue

Common-variable immunodefi ciency

Autoimmune enteropathy

Radiation enteritis

Whipple’s disease

Tuberculosis

Tropical sprue

Eosinophilic gastroenteritis

Human immunodefi ciency virus enteropathy

Intestinal lymphoma

Zollinger-Ellison syndrome

Crohn’s disease

Intolerance of foods other than gluten (e.g., milk, soy, chicken, tuna) 444 INTEGRATIVE GASTROENTEROLOGY

III. HLA-DQ2/HLA-DQ8

Approximately 40 % of the general population in the United States has either HLA-DQ2 or HLA-DQ8. However, virtually all those affl icted with celiac disease have either DQ2 (about 95% of patients with celiac disease) or DQ8 (about 5% of patients with celiac disease; see Green & Jabri, 2003 ). Because virtually all patients with celiac disease have these celiac disease-associated alleles, the absence of these alleles provides a negative predictive value for the disease that approaches 100% .

If the individual lacks one of these alleles (DQ2, DQ8), the disease is virtually excluded. Thus HLA testing may be a useful addition to exclude celiac disease when other diagnostic testing is not clear.

Treatment

Th e only accepted treatment for celiac disease currently involves the lifelong elimination of wheat, rye, and barley from the diet, and is termed “the gluten- free diet.” Clinical studies suggest that oats are tolerated by most patients with celiac disease; however, oats are not uniformly recommended, because most commercially available oats are contaminated with gluten-containing grains during the growing, transportation, and milling processes (Th ompson, 2003 ; Peraaho et al., 2004 ).

Table 40.4 Fundamentals of the Gluten-Free Diet

Grains that should be avoided

Wheat (includes spelt, kamut, semolina, triticale), rye, barley (including malt)

Safe grains (gluten-free)

Rice, amaranth, buckwheat, corn, millet, quinoa, sorghum, teff (an Ethiopian cereal grain), oats

Sources of gluten-free starches that can be used as fl our alternatives

Cereal grains: amaranth, buckwheat, corn (polenta), millet, quinoa, sorghum, teff , rice (white, brown, wild, basmati, jasmine), montina (Indian rice grass)

Tubers: arrowroot, jicama, taro, potato, tapioca (cassava, manioc, yucca)

Legumes: chickpeas, lentils, kidney beans, navy beans, pea beans, peanuts, soybeans

Nuts: almonds, walnuts, chestnuts, hazelnuts, cashews

Seeds: sunfl ower, fl ax, pumpkin Celiac Disease 445

Other grains can serve as substitutes (Table 40.4 ). Because the substitute fl ours are not fortifi ed with B vitamins, however, vitamin defi ciencies may occur. Th erefore, vitamin supplementation is advised. Th e cost of the gluten- free products varies by country, but the diet is usually expensive, making dietary treatment problematic for patients with limited fi nancial resources. Meats, dairy products, fruits and vegetables are naturally gluten-free foods. Patient-support organizations are a valuable source of information about the disease and the diet. Aft er the diagnosis of celiac disease has been established, the patient should be assessed for defi ciencies of vitamins and minerals, including folic acid, B12, fat- soluble vitamins, iron, and calcium, and any such defi c i e n c i e s s h o u l d b e t r e a t e d .

All patients with celiac disease should undergo screening for osteoporosis, which has a high prevalence in this population (Meyer et al., 2001 ). The healthcare team should include a skilled dietician who monitors the patient’s nutritional status and dietary adherence on a regular basis.

Th e elimination of gluten usually induces clinical improvement within days or weeks, though histologic recovery takes months or even years, especially in adults, in whom mucosal recovery may be incomplete (Lee et al., 2003 ). A gluten-free diet fails to induce clinical or histologic improvement in 7 % to 30 % of patients, and such lack of response should prompt a complete evaluation (Figure 40.6 ). Th e fi rst step is to reassess the initial diagnosis, since villous atrophy with associated crypt hyperplasia is not exclusive to celiac disease (Table 40.3 ). In patients with a questionable diagnosis, HLA-DQ2 or HLA-DQ8 typing may be useful, since the negative predictive value of this test is almost 100% . Th e second step is to address the likelihood of dietary nonadherence, the most common cause of unresponsive celiac disease. Th e persistence of endomysial antibodies or anti-tissue transglutaminase antibodies in patients on a gluten-free diet for a year or more is suggestive of poor dietary adherence (Vahedi et al., 2003 ). Other causes of persistent symptoms in patients on a strict gluten- free diet are listed in Table 40.5 .

Complications

I. MALIGNANCY

Th ere are a few noteworthy complications of celiac disease, which include intestinal adenocarcinoma, enteropathy-associated T-cell lymphoma, and refractory sprue (Cellier et al., 2000 ; Rampertab et al., 2003 ). 446 INTEGRATIVE GASTROENTEROLOGY

Table 40.5 Causes of Poor Response to the Gluten-Free Diet

Incorrect diagnosis

Gluten ingestion (intentional or unintentional)

Microscopic colitis

Lactose intolerance

Pancreatic insuffi ciency

Bacterial overgrowth

Intolerance of foods other than gluten (e.g., fructose, milk, soy)

Infl ammatory bowel disease

Irritable bowel syndrome

Anal incontinence

Collagenous sprue

Autoimmune enteropathy

Refractory celiac disease (with or without clonal T-cells)

Enteropathy-associated T-cell lymphoma

Th e rate of malignancy is increased as a whole with celiac disease, although more recent population studies demonstrate that the risk is less than what had previously been quoted (Askling et al., 2002 ). Malignancies that are seen in patients with celiac disease with increased frequency are non-Hodgkin’s lymphomas (both B- and T-cell) that may be intestinal or extraintestinal, oroesophageal and esophageal adenocarcinoma, as well as cancers of the small intestine, colon, hepatobiliary system, and pancreas (Askling et al., 2002 ; Smedby et al., 2005 ). Compared with expected rates, the risks of small bowel adenocarcinoma, esophageal cancer, non-Hodgkin’s lymphoma, and melanoma were increased signifi cantly in a recent study looking at cancer rates in a population of celiac disease patients at a large tertiary care referral center. Specifi cally, the age- adjusted incidence rates for these cancers among the celiac disease group were: non-Hodgkin’s lymphoma, 135 per 100,000 person-years (normal, 14.8 per 100,000 person-years) and small bowel cancer, 40 per 100,000 person-years (normal, 1.2 per 100,000 person-years; see Green, 2003 ). Th ese carcinomas are oft en located in the jejunum, as opposed to sporadic small intestinal adenocarcinomas, which tend to localize to the duodenum. Celiac Disease 447

In addition, small bowel adenocarcinoma in the setting of celiac disease is more likely to follow the adenoma-carcinoma sequence of development, as opposed to dysplasia in fl at mucosa, which is more oft en seen in Crohn’s disease (Green & Rampertab, 2004 ). Although there is currently no data to support the use of video capsule endoscopy to screen for cancers of the small intestine in patients with celiac disease, there is a defi nite role for this modality in investigating symptoms such as occult bleeding, abdominal pain, or recurrence of symptoms in a patient who had initially responded to a gluten-free diet (Culliford, 2005 ). Enteropathy-associated T-cell lymphoma is another diagnosis that must be entertained when a patient develops clinical relapse of symptoms of celiac disease aft er a period of doing well on a gluten-free diet. Unfortunately, due to the fact that it is usually discovered at an advanced stage, prognosis is extremely poor and less than 20% of people survive beyond 30 months (Howdle et al., 2 0 0 3 ) .

II. REFRACTORY CELIAC DISEASE

Refractory sprue is a condition whereby the patient develops persistent symptoms in the setting of villous atrophy, despite strict adherence to a gluten-free diet (Trier, 1991 ). Th e most common symptoms include diarrhea, weight loss, recurrence of malabsorption, abdominal pain, bleeding, and anemia. Ulcerative jejunitis oft en arises as well. Refractory celiac disease may be classifi ed as Type 1, in which there is a normal intraepithelial lymphocyte phenotype, or Type 2, in which there is a clonal expansion of an aberrant intraepithelial lymphocyte population. Type 2 is associated with a high risk of ulcerative jejunitis and frank enteropathy- associated T-cell lymphoma. In active celiac disease, most intraepithelial lymphocytes express CD3 and CD8 (CD3+ , CD8+ ) receptors, whereas in Type 2 (clonal) refractory celiac disease, most of these lymphocytes express CD3 but not CD8 (CD3 + ,CD8− ; Cellier et al., 1998 ; Daum et al., 2001 ). It is interesting to note that patients with Type 1 refractory sprue, as well as celiac patients who are not compliant with the diet, display a normal phenotype (CD3+ , CD8 +) (Patey-Mariaud De Serre et al., 2000 ). Th us, the development of new symptoms (e.g., weight loss, abdominal pain, or fever) or the recurrence of diarrhea in patients who are on a strict gluten-free diet, oft en requires extensive investigation. Treatment of refractory sprue includes nutritional support with repletion of losses, and a strict gluten-free diet coupled with corticosteroids to help induce clinical remission. 448 INTEGRATIVE GASTROENTEROLOGY

Future Directions

Th e development of nondietary therapies that might either supplement or sup- plant the rigorous gluten-free diet are currently being investigated. At present, one possible alternative involves the use of recombinant enzymes that digest the toxic gliadin fractions in the stomach or the upper small intestine (Siegel et al., 2006 ; Stepniak et al., 2006 ). Th erapies that interfere with steps in the immune response (i.e., blocking the action of tissue transglutaminase or blocking the binding of deaminated gliadin to HLA-DQ2 or HLA-DQ8 antigen- presenting cells) can also be considered; however, these may come coupled with unwanted adverse eff ects.

41 Food Reactions and Their Implications in the Irritable Bowel Syndrome

TRENT W. NICHOLS , GERARD E. MULLIN , AND LAURA K. TURNBULL

key concepts

■ Over 3 million children have IgE-mediated food allergies in the United States— representing an 18 % increase over the past 5 years. ■ U p t o 2 5 % of adults report symptoms related to foods; only 3 % are proven to be IgE -mediated food allergies, with the remainder possibly being delayed IgG food sensitivities and intolerances. ■ M o r e t h a n 5 0 m i l l i o n A m e r i c a n s s u ff er from allergies on a yearly basis, with allergy ranking as the sixth leading cause of chronic disease, costing the U.S. healthcare system $18 billion per year in 2001. ■ Recent food allergy tests are more reproducible, reliable and v a l i d . ■

Introduction: History of Food Allergy

he fi rst recorded instance of food sensitivity was by Hippocrates, who observed that milk could cause gastric upset and urticaria. In 200 A.D. T Galen described a case of allergy to goat’s milk, and Willis in 1679 observed that the ingestion of wine could precipitate asthma. Shloss described several cases of atopic dermatitis and food allergy soon aft er the turn of twen- tieth century. In the early 1920s, W.W. Duke published several papers linking

449 450 INTEGRATIVE GASTROENTEROLOGY food ingestion to bladder pain, Meniere’s syndrome, colitis, gastrointestinal upset, and diarrhea. Walzer and his associates performed experiments that demonstrated how ingested food antigens penetrate the GI barrier and are transported through the bloodstream to mast cells in the skin. In the 1930s, Rinkel fi rst described food sensitivities that diff ered from classic immediate anaphylactic reactions. Th e symptoms occurred hours to days subsequent to ingestion, and could be masked or unmasked by the off ending food. Rinkel’s discovery has been borne out by recent research confi rming that delayed-type food allergies (IgG mediated) play a primary role in the immune system’s response to ingestants (Rinkel, 1936 ).

EPIDEMIOLOGY

IgE–mediated food allergies affect between 6% –8% of children in the United States and United Kingdom.

Up to 25 % of adults report symptoms that may be related to foods, although the prevalence of only 3% is proven to be IgE -mediated food allergies with the remainder possibly being delayed IgG food sensitivities and intolerances. More than 50 million Americans suff er from allergies on a yearly basis, with allergy ranking as the sixth leading cause of chronic disease and costing the U.S. healthcare system $18 billion per year in 2001 (American Academy of Allergy, 1996–2001). A recent article was published reporting that food allergies in American children seem to be on the rise, now aff ecting 3 million of them according to the Center for Disease Control and Prevention (Smith, 2007 ). While no one is certain as to what is driving this increase, there are numerous studies validat- ing the trend. For example, earlier studies have demonstrated a doubling in peanut allergies among children. Additionally, children seem to be taking longer to outgrow milk and egg allergies than they did in decades past.

CLINICAL PRESENTATION

Food allergies typically appear between 6 months and 2 years of age. Th e organ systems most commonly involved include the skin (fl ushing, urticaria, angioe- dema, and worsening eczema), the gastrointestinal tract (vomiting, abdominal pain, diarrhea, and cramping) and the respiratory tract (rhinitis, stridor Food Reactions and Their Implications in the Irritable Bowel Syndrome 451

Table 41.1. Most Common IgE-Mediated Food Allergens

Chicken

Corn

Dairy

Egg

Nuts

Soy

Wheat

and asthma). Eczema generally develops in the fi rst 6 months to 12 months of life, is usually the fi rst clinical manifestation of atrophy, and is present in more than 80 % of children with egg allergy. Respiratory allergies like asthma and rhinitis are also common, and are typically diagnosed aft er the appearance of food allergies, usually aft er age 3. Egg allergy or sensitization is the strongest predictor of respiratory allergies in children and adults with asthma. Although eczema and food allergies (IgE mediated) usually resolve in children, they may persist in a substantial number of them, causing illnesses and impaired quality of life through multiple food allergies, eczema, allergic rhinosinusitis, asthma, or combinations of these conditions (Lack, 2008 ). Diff erent foods aff ect diff erent age groups, according to Dr. Gideon Lack. Cow’s milk, hen’s eggs, peanuts, tree nuts, and sesame seeds account for most of the immediate food allergies in young children, and kiwi allergy has been increasing in this group. Wheat and soy allergies are rarely confi rmed, although frequently suspected (Lack, 2008 ). Shellfi sh, fi sh, peanuts, and tree nuts are the most common causes of food allergies in adults (Khakoo, Roberts & Lack, 2000 ). Food sensitivities to tyramine, phenylalanine, phenolic fl avonoids, alcohol, and caff eine have been noted. Food additives such as sodium nitrate, monosodium glutamine, and aspartame are thought to induce migraine head- a c h e s b y m o d i f y i n g v a s c u l a r t o n e ( M e l e t i s , 2 0 0 3 ) .

In general, higher IgE is not greater among people with migraine than the general population. 452 INTEGRATIVE GASTROENTEROLOGY

Table 41.2. Foods that have been Linked as Causative Agents to Migraine Headaches

Chocolate

Citrus fruits

Coff ee

Cola drinks

Milk

Nuts

Pork

Tea

Vegetables

(adapted from Leira & Rodríguez, 1996 )

Classiﬁ cation of Food Reactions

Reactions to foods may be classifi ed as immediate (IgE-mediated) or delayed (non IgE-or IgG-mediated). Th e IgE-mediated food allergies can range from hives to tingling and swelling of the mucous membranes of the mouth, lips, tongue, throat, and airway, with the most serious reaction being anaphylaxis. Th e foods involved in the latter are usually peanuts, shellfi sh, and tree nuts. However, eggs, fi sh, cows milk, citrus fruits, bananas, sesame, chocolate, mango, grains, Chinese foods, seeds, and vegetables have been known to cause anaphylaxis (Frankland, 1987 ).

TYPE I HYPERSENSITIVITY AND IGE TESTING

In Type I reactions, mast cells sensitized with IgE antibody degranulate, releasing mediators when the antibodies are cross-linked by the relevant antigen (Figure 41.1 , Table 41.3 ). When Type I reactions occur aft er food ingestion, the reaction may include, rhinorrhea, asthma, diarrhea, and vomiting, in addition to the more common presentations of anaphylaxis and urticaria. Th ese reactions are oft en associated with a positive skin prick test, and with positive radioallergosorbent test (RAST) to the relative food (Brostoff , 1987 ). Food Reactions and Their Implications in the Irritable Bowel Syndrome 453

Table 41.3. Pharmacologic Mediators of Immediate Hypersensitivity

Mediator

Preformed mediators in granules

histamine bronchoconstriction, mucus secretion, vasodilatation, vascular permeability

tryptase proteolysis

kininogenase kinins and vasodilatation, vascular permeability, edema

ECF-A attract eosinophil and neutrophils (tetrapeptides)

Newly formed mediators

leukotriene B4 basophil attractant

leukotriene C4 , D4 same as histamine but 1000x more potent

prostaglandins D2 edema and pain PAF platelet aggregation and heparin release: microthrombi

TYPE II HYPERSENSITIVITY

Type II or cytotoxic hypersensitivity also involves antibody-mediated reactions. However, the immunoglobulin class (isotype) is generally IgG. In addition, this process involves K-cells rather than mast cells. K-cells are, of course, involved in antibody-dependent cell-mediated cytotoxicity (ADCC). Type II hypersensitivity may also involve complement that binds to cell-bound antibody. Th e diff erence here is that the antibodies are specifi c for (or able to cross-reactivity with) “self” antigens. When these circulating antibodies react with a host cell surface, tissue damage may result. Th ere are many examples of Type II hypersensitivity. Th ese include:

• Pemphigus: IgG antibodies that react with the intracellular substance found between epidermal cells. • Autoimmune hemolytic anemia (AHA): Th is disease is generally inspired by a drug such as penicillin that becomes attached to the surface of red blood cells (RBC) and acts as hapten for the production of antibody, which then binds the RBC surface, leading to lysis of RBCs. 454 INTEGRATIVE GASTROENTEROLOGY

• Goodpasture’s syndrome: Generally manifested as a glomerulone- phritis, IgG antibodies that react against glomerular basement membrane surfaces can lead to kidney destruction.

TYPE III HYPERSENSITIVITY

Type III hypersensitivity is also known as immune complex hypersensitivity (Brostoff , 1987 ). Th e reaction may be general (e.g., serum sickness) or may involve individual organs including skin (e.g., systemic lupus erythematosus, Arthus reaction), kidneys (e.g., lupus nephritis), lungs (e.g., aspergillosis), blood vessels (e.g., polyarteritis), joints (e.g., rheumatoid arthritis), or other organs. Th is reaction may be the pathogenic mechanism of diseases caused by many microorganisms. Th e reaction may take 3–10 hours aft er exposure to the antigen (as in Arthus reaction). It is mediated by soluble immune complexes. Th ey are mostly of the IgG class, although IgM may also be involved. Th e antigen may be exogenous (chronic bacterial, viral, or parasitic infections), or endogenous (non-organ- specifi c autoimmunity; e.g., systemic lupus erythematosus, SLE). Th e antigen is soluble and not attached to the organ involved. Primary components are soluble immune complexes and complement (C3a, 4a and 5a). Th e damage is caused by platelets and neutrophils. Th e lesion contains primarily neutrophils and deposits of immune complexes and complement. Macrophages infi ltrat- ing in later stages may be involved in the healing process (Brostoff et al., 1979 ). Th e affi nity of antibody and size of immune complexes are important in production of disease and determining the tissue involved (André et al., 1975 ). Diagnosis involves examination of tissue biopsies for deposits of immunoglobulin and complement by immunofl uorescence. Th e immunofl uorescent staining in type III hypersensitivity is granular (as opposed to linear in type II such as seen in Goodpasture’s syndrome). Th e presence of immune complexes in serum and depletion in the level of complement are also diagnostic. Polyethylene glycol-mediated turbidity (nephelometry) , binding of C1q and Raji cell test are utilized to detect immune complexes. Treatment includes anti-infl ammatory agents.

TYPE IV HYPERSENSITIVITIES

Type IV hypersensitivity is involved in the pathogenesis of many autoimmune and infectious diseases (tuberculosis, leprosy, blastomycosis, histoplasmosis, Food Reactions and Their Implications in the Irritable Bowel Syndrome 455 toxoplasmosis, leishmaniasis, etc. ), and granulomas due to infections and foreign antigens. Another form of delayed hypersensitivity is contact dermatitis (poison ivy, chemicals, heavy metals, etc . ) in which the lesions are more papu- lar. Type IV hypersensitivity can be classifi ed into three categories depending on the time of onset and clinical and histological presentation (Table 41.4 ). A summary of the types of hypersensitivity responses is presented in Table 41.5 .

1. Mechanisms of damage in delayed hypersensitivity include T lymphocytes and monocytes and/or macrophages. Cytotoxic T-cells (Tc) cause direct damage, whereas helper T-cells (TH1) secrete cytokines that activate cytotoxic T-cells and recruit and activate monocytes and macrophages, which cause the bulk of the damage (Figure 41.2 ). Th e delayed hypersensitivity lesions mainly contain monocytes and a few T - c e l l s . 2. Major lymphokines involved in delayed hypersensitivity reaction include monocyte chemotactic factor, interleukin-2, interferon-gamma, TNF alpha/beta, etc . 3. Diagnostic tests in vivo include delayed cutaneous reaction (e.g., Montoux test) and patch test (for contact dermatitis). In vitro tests for delayed hypersensitivity include mitogenic response, lymphocytotox- icity, and IL-2 production. 4. Corticosteroids and other immunosuppressive agents are used in t r e a t m e n t .

Table 41.4. Delayed Hypersensitivity Reactions

Type Reaction Time Clinical Histology Antigen and Site Appearance

contact 48–72 hr eczema lymphocytes, epidermal followed by (organic macrophages; edema chemicals, poison of epidermis ivy, heavy metals, etc. )

tuberculin 48–72 hr local lymphocytes, intradermal induration monocytes, (tuberculin, macrophages lepromin, etc. )

granuloma 21–28 days hardening macrophages, persistent antigen epitheloid and giant or foreign body cells, fi brosis presence (tuberculosis, leprosy, etc . ) 456 INTEGRATIVE GASTROENTEROLOGY

Table 41.5. Comparison of Different Types of Hypersensitivity

Characteristics Type I Type II Type III Type IV (anaphylactic) (cytotoxic) (immune (delayed type) complex)

Antibody IgE IgG, IgM IgG, IgM None

Antigen exogenous cell surface soluble tissues & organs

Response 15–30 minutes minutes-hours 3–8 hours 48–72 hours Time

Appearance weal & fl are lysis and necrosis erythema and erythema and edema, induration necrosis

Histology basophils and antibody and complement monocytes and eosinophil complement and lymphocytes neutrophils

Transferred antibody antibody antibody T-cells with

Examples allergic asthma, erythroblastosis SLE, farmer’s tuberculin test, hay fever fetalis, lung disease poison ivy, Goodpasture’s granuloma nephritis

SKIN PRICK TESTING

Th e principle behind the skin prick testing method is that sensitized tissue mast cells display IgE antibodies on their cell membranes. When specifi c antigens or nonspecifi c antigens such as lectins cross-link with the Fc receptor for IgE, the mast cell release ohistamine and other infl ammatory mediators. Th is reaction results in a wheal and fl are of the skin, marked by redness and s w e l l i n g .

The results of skin prick testing do not exhibit a strong correlation to food allergy symptoms.

Due to the lack of consistency of correlation of skin prick testing to symptoms, conventional allergists are beginning to abandon this test. Skin prick testing also suff ers the risk of inducing anaphylaxis and false positives in patients with dermatographia and eczema to IgE ELISA (Enzyme-Linked I m m u n o s o r b e n t A s s a y ) t e s t i n g . Food Reactions and Their Implications in the Irritable Bowel Syndrome 457

ELISA is reported to be more sensitive than skin prick testing in the identiﬁ - cation of IgE-mediated food allergies. (Sampson & Albergo, 1984 )

Recently, ImmunoCAP, a specifi c IgE blood test (Phadia, Uppsala Sweden) has been touted as a vast improvement over earlier blood allergy testing (RAST). Th ree hundred twenty-four patients (61 % male: median age 6.1 years) were evaluated. Th e patients were highly atopic (57 % with atopic dermatitis and 58 % with asthma). Sera from the patients were analyzed for specifi c IgE antibodies to peanuts, tree nuts, and seeds, using ImmunoCAP Specifi c IgE. Th e majority of patients with peanut allergy were sensitized to tree nuts (86 % ), and documented clinical allergy was found in 34 % of patients. High correla- tions were found between pistachio, peanut, and cashew (Maloney & Rudengren, 2008 ).

Quantiﬁ cation of food-speciﬁ c IgE is a valuable tool that will aid in the diagnosis of symptomatic food allergy, and might decrease the need for double-blind, placebo-controlled food challenges, the gold standard for food allergies.

FOOD CHALLENGE TESTING

Th e double-blind, placebo-controlled food challenge is performed with an incremental dose of food allergen, or placebo, given at 20-minute intervals while the patient is observed for objective signs of food allergy. Patients who tolerate the fi nal dose of this challenge then undergo an open (unblinded) challenge in which a regular-size portion of the food is eaten, in order to establish tolerance. Th e double-blind challenge test is used routinely in research, and the incremental challenges without placebo are used in the clinical setting. (Lack, 2008 ) Until recently, double-blind, placebo-controlled food challenge testing has been the gold standard for IgE-mediated food allergies. However, there have been many pitfalls in this testing.

1. Time-consuming, both for patient and clinician 2. Reproducibility – this can be aff ected by multiple variables in the process of presentation, ingestion, and absorption of food 3. Specifi city – coincidental factors are highly likely to aff ect outcomes 4. Sensitivity – false negative 458 INTEGRATIVE GASTROENTEROLOGY

5. Discrimination – false positives commonly occur 6. Lastly, so wide is the range of possible clinical responses, and the possible range of implicated substances, that a standardized form of testing is diffi cult to conceive, according to one authority (Radcliff e, 1 9 8 7 ) 7. M e c h a n i s m o f O r a l To l e r a n c e

Mucosal or oral tolerance represents the most important immune response to food antigens that aff ords systemic hyporesponsiveness, or protection from infl ammatory events and bodily disorder. Th e concept of oral desensitization draws its mechanism from oral tolerance. It has been known since the work of Besredka in 1909, and H. G. Wells in 1911, that animals fed soluble proteins lose their ability to respond to that specifi c antigen on subsequent systemic chal- l e n g e ( C h a l l a c o m b e & To m s a i , 1 9 8 7 ) .

Oral tolerance mechanics is the cornerstone of setting up a reaction, or nonreaction, against self and nonself (dietary challenge). It has been asserted that oral tolerance to dietary antigens is the result of B cells switching from IgE/IgG antibody production to IgA under the inﬂ uence of cytokines. (Suen, 2004 ).

HYPERPERMEABILITY

Th e abrogation of tolerance to otherwise innocuous food proteins may well be involved in the pathogenesis of a variety of disease states (as covered in Chapter 7. Loss of mucosal barrier integrity resulting in hyperpermeability or “leaky gut” is oft en the fi rst step in this loss of oral tolerance, by reducing tight junctions and basement membranes that form the cohesive bonding among the mucosal epithelial cells. Excessive stimulation of antigen-presenting cells favors overstimulation of T-helper type 1 cells, Th 1 cells, and a cytokine profi le that is incompatible with the induction of tolerance.

Other defense factors for the gut include low luminal pH, digestive enzymes, mucus, enteric microﬂ ora, regenerative mucosal cell rate, and glycocalyx.

A breach of any of these defense factors and loss of the integrity of the mucosa leads to aberrant antigen handling and subsequent production of Food Reactions and Their Implications in the Irritable Bowel Syndrome 459 cytokines, allowing the induction of immunological hypersensitivity (Figure 41.3 ; also see Suen, 2004 ). Crohn’s disease, ulcerative colitis and celiac disease with loss of mucosal integrity or villous atrophy, respectively, allow loss of oral tolerance. A breach of oral tolerance may also be triggered through the use of NSAIDs (nonsteroidal anti-infl ammatory drugs) which can cause microscopic and macroscopic breaks in the mucosal gut barrier to food antigens, and drives a proinfl amma- t o r y i m m u n e r e s p o n s e ( P o s t l e t h w a i t e , 2 0 0 1 ) .

7 0% of the entire immune system resides in the gut, and approximately 80 % of plasma cells (mainly immunoglobulin A [IgA]-bearing cells) reside in GALT.

GUT-ASSOCIATED LYMPHOID TISSUE (GALT)

Th e gut-associated lymphoid tissue (GALT) is the prominent part of mucosal- associated lymphoid tissue (MALT) and is the second line of defense against food antigens. As part of its protective role, GALT interacts with gastrointestinal functions in a dynamic manner. For instance, GALT can decrease intestinal permeability, orient the immune response toward luminal content, or allow either tolerance or elimination/degradation of luminal antigens. On the fl ip side, GALT can provoke damage to the intestinal mucosa, such as in celiac disease, infl ammatory bowel disease, or food allergy (Vighi et al., 2008 ).

FOOD ALLERGY AND THE IGG IMMUNOGLOBULIN CLASS

Th e IgG immunoglobulin class has an exceptionally long half-life in circulation (serum half-lives of IgG ranging from 22 to 96 days) and constitutes about 75 % of the total serum immunoglobulin pool. While IgM is involved in the primary antibody response, IgG antibodies drive the secondary antibody response. IgG antibodies are elaborated approximately one month following antigen recognition; thus, the presence of specifi c IgG generally corresponds to a “maturation” of the antibody response. IgG also plays an important role in antibody dependent cell-mediated cytotoxicity (ADCC) and is also associated with Type II and Type III hypersensitivity. Despite the substantial evidence to support a role for IgE in food allergy, there is considerable research supporting the role of IgG as a marker of delayed 460 INTEGRATIVE GASTROENTEROLOGY allergy to food antigens. Repeated exposure to an antigen can eventually produce allergy-like responses or hypersensitivities. Th ese reactions are usually delayed, with symptoms not being evident for hours or even days aft er the initial exposure. Since reactions to food antigens mediated by IgE are immediate, IgG antibodies drive these “delayed” reactions. Th e IgG antibodies may do more than just “trigger” a cascade of mediators that produce the allergy response to food. IgG antibodies have been shown experimentally to increase the permeability of the intestinal wall. Intestinal hyperpermeability has been implicated in the pathogenesis of allergic diseases, such as chronic urticaria.

Delayed Food Allergy Symptoms

The symptomatic process begins with the action of food materials in the digestive tract, continues into the bloodstream, and then affects the function of any target organ that receives the food problem. For example: • Symptoms may be limited to the digestive tract — indigestion, abdominal pain, bloating, nausea, vomiting, and diarrhea. • Symptoms may be general or systemic — fever, fatigue, sweating, and chills. • The lungs are the target organ in food-induced bronchitis and asthma. • The joints are target organs in food-allergic arthritis. • Muscles and connective tissue react with pain, stiffness, and swelling. • Weakness and reduced exertional tolerance are associated with pain. • The skin reacts with itching, rashes, hives, thickening, redness, swelling, and scaling, as in eczema and psoriasis. • The brain is the target organ when disorganized, disturbed thinking, feeling, remembering, and behaving occur.

ELISA IGG DELAYED FOOD ALLERGIES (SENSITIVITY) TESTING

ELISA IgG IgE is a quantitative/semiquantitatve in vitro analysis designed to detect and quantify IgG antibodies and IgE reactive to various food proteins. In the ELISA testing method, lyophilized food proteins are immobilized by adsorption to plastic wells, and reacted with the serum portion of the individual’s blood sample. Washing is then performed, and the plate is reacted with an HRP-labeled antihuman IgG or IgE antibody conjugate. Th e enzyme tag horseradish peroxidase facilitates a color change upon addition of its substrate, a chromagen, to allow for easy detection of antigen–antibody interaction within the wells. Th e intensity of the color change is quantifi ed via spectrophotometric Food Reactions and Their Implications in the Irritable Bowel Syndrome 461 analysis, and is proportional to the concentration of food antigen-specifi c IgG or IgE antibodies present in the serum sample (Suen, 2004 ).

The ELISA method is reported to be reproducible, reliable, and valid. (Westgard Quality Corporation, 2004 ).

SCIENTIFIC VALIDITY OF ELISA

Laboratory implementation of ELISA methodology for the detection of IgG and IgE food-specifi c antibodies must clearly identify its suitability for this purpose, in yielding reproducible and consistent results for each patient tested, on every occasion. Reproducibility is the ability of the test to reproduce the same test results for identical samples under identical test conditions. Duplicate testing provides an internal measure of control and assures reproducibility. If the testing method is precise, there should be minimal variation between the duplicate runs. Daily in-house blinded split-sample reproducibility checks constitute good laboratory practice for quality assurance. Most laboratories also participate in periodic blinded testing through an approved accredited organization to further insure reproducibility of test results.

Testing for IgG4 against Food Remains Controversial

The European Academy of Allergy and Clinical Immunology (EAACI) has announced that testing for IgG4 against foods is not recommended as a diagnostic tool.

Th e European Academy of Allergy and Clinical Immunology (EAACI) con- tends that enzyme-linked immunosorbent assay-type and radioallergosorbent- type for food antigens from serum samples show positive IgG4 results without corresponding clinical symptoms. Th ey further state that its presence should not be considered as a factor that induces hypersensitivity, but rather an indicator for immunological tolerance, linked to the activity of regulatory T-cells (Stapel, 2008 ). 462 INTEGRATIVE GASTROENTEROLOGY

A number of tests may be useful in identifying foods to which a patient is reactive, but no one test is likely to identify all reactive foods. (Herman & Drost, 2004 )

I GG FOOD SENSITIVITY TESTING IN THE IRRITABLE BOWEL SYNDROME

Patients with irritable bowel syndrome (IBS) oft en report some form of dietary intolerance and self-experiment with elimination diets. Th e utilization of food allergy testing to predict food sensitivity in IBS has been, overall, disappoint- ing for many years, when using IgE antibodies. Studies that support the use of IgG antibody testing and elimination diets for IBS are reviewed below.

Atkinson et al. ( 2004 )

Atkinson et al. were the fi rst to study IgG antibodies in conjunction with elimination diets for IBS (Atkinson et al., 2004 ). A total of 150 outpatients with IBS at the University Hospital of South Manchester, United Kingdom, were randomized to receive, for three months, either a diet excluding all foods to which they had elevated IgG antibodies by ELISA (true diet) or a sham diet excluding the same number of foods but not those to which they had antibodies. Primary outcomes measured were changes in IBS symptom severity and global rating scores. Quality of life, anxiety/depression and non-colonic symptomatology were secondary outcomes. Results: Aft er 12 weeks, the true diet resulted in a 10 % greater reduction in symptom score than the sham diet, with a mean diff erence 39 (95% confi dence intervals; p=0.024) with this value increasing to 26% in fully compliant patients (diff erence 98 (95 % CI: p<0.001; see Figure 41.4 .). Global rating also signifi - cantly improved in the true diet group as a whole (p=0.048) and even more in compliant patients (p=0.006). All other outcomes demonstrated trends favoring the true diet. Relaxing the diet led to a 24 % greater deterioration in symptoms in those on the true diet (95% CI: 18–88); p=0.003).

Based upon their ﬁ ndings, Atkinson and colleagues concluded that food elimination based on IgG antibodies may be effective in reducing IBS symptoms, and is worthy of further biomedical research. (Atkinson et al., 2004 ) Food Reactions and Their Implications in the Irritable Bowel Syndrome 463

Zar et al. ( 2005 )

Th ese investigators used the same hypothesis as the previous study by Atkinson’s team, with data from dietary elimination and food challenge studies. Investigators from the St. Georges Hospital Medical School, London, compared IgG4 and IgE titers to common food antigens in IBS and controls (Zar, Benson & Kumar, 2005 ). Results: One hundred and eight IBS (52 diarrhea-predominant; 32 constipation-predominant; 24 alternating) and 43 controls were included in this study. IgG4 and IgE titers and skin prick testing to 16 common foods including milk, eggs, cheese, wheat, rice, potatoes, chicken, beef, pork, lamb, fi sh, shrimps, soya bean, yeast, tomatoes, and peanuts were measured. Th ere was no signifi cant diff erence in IgE titers to any of these foods between IBS and controls. Serum IgG4 antibodies to common foods like wheat, beef, pork, and lamb were elevated in IBS patients. In keeping with the observation in other atopic conditions, these fi ndings suggest the possibility of similar pathophysiological role for IgG4 antibodies in IBS (Zar et al., 2005 ).

Testing for IgE food antibodies usually is not helpful for IBS, except in a small subgroup of patients with diarrhea-predominant disease and atopy. (Whorwell & Lea, 2004 ).

Drisko et al. ( 2006 )

In an open label pilot study of 15 patients with irritable bowel syndrome by Rome II criteria, subjects who had failed standard medical therapy in a tertiary medical clinic at the University of Kansas Medical Center, were tested with baseline serum IgE and IgG food and mold panels, comprehensive stool analyses (CSA) and quality of life (QOL) questionnaires (Drisko et al., 2006 ). Patients underwent food elimination diets based on the results of food and mold panels, followed by controlled food challenge. Probiotics were also introduced, and repeat testing was performed at 6 months. McCallum and his associates followed up with cohort at 1 year aft er trial completion to assess the reported intervention and for placebo eff ect. Results: Baseline abnormalities were identifi ed on serum IgG food and mold panels in 100% of the study subjects aft er food elimination and rotation diet (p<0.005). Signifi cant improvements were documented in stool frequency (p<0.005), pain (p<0.05), and IBS-QOL scores (p<0.0001). Dysbiosis 464 INTEGRATIVE GASTROENTEROLOGY

(imbalance in gastrointestinal fl ora) was identifi ed in 100 % of subjects by CSA. Th e one-year follow-up demonstrated signifi cant continued adherence to the food rotational diet (4.00+ /-1.45), minimal symptomatic problems with IBS (4.00+ /-1.17), and perception of control over IBS (4.15+ /-1.23). Th e continued use of probiotics was considered less helpful (3.40+ /- 1.60).

Yang and Li ( 2007 )

Based on their ﬁ ndings, Drisko and colleagues ( 2006 ) concluded that identifying and addressing food sensitivity in IBS patients who had not responded to medical therapy can result in a sustained clinical response, which impacts on well-being and quality of life.

Th e therapeutic eff ects of eliminating allergic foods according to food- specifi c IgG antibodies in irritable bowel syndrome study was conducted at Shandong Provincial Hospital in 55 cases with diarrhea-dominant IBS, 32 with constipation-dominant IBS, and 18 normal controls. Results : Th e positive rate of serum food-specifi c IgG antibodies was 63.5 % in patients with diarrhea-dominant IBS and 43.8 % in constipation-dominant IBS. Aft er eliminating allergic foods, the overall health score in patients with IBS increased signifi cantly compared to those before treatment. At the end of eight weeks, the symptoms relieved completely in 31.4 % of cases and remarkably in 34.3% (Yang & Li, 2007 ).

Zuo et al. ( 2007 )

Th irty-seven IBS patients, 28 functional dyspepsia (FD) patients, and 20 healthy controls participated in a study of serum food antigen-specifi c IgG and IgE antibodies. Serum IgG and IgE antibody titers to 14 common foods including beef, chicken, codfi sh, corn, crab, eggs, mushroom, milk, pork, rice, shrimp, soybean, tomatoes, and wheat were analyzed by ELISA. Serum total IgE titers were also measured. Lastly, symptoms were assessed in the study. Results: IBS patients had signifi cantly higher titers of IgG antibody to crab (P=0.000), egg (P=0.000), shrimp (P=0.000), soybean (P=0.017), and wheat (P=0.004) than controls. Serum IgG antibody titers to some common foods are increased in IBS and FD patients compared to controls (Zuo et al., 2 0 0 7 ) . Food Reactions and Their Implications in the Irritable Bowel Syndrome 465

Ou-Yang et al. ( 2008 )

Th e causes of chronic diarrhea in children are complex. Food allergy is generally viewed as an important cause of this disorder, and IgG-mediated delayed allergy plays a major role in this process. Eighty-two children with chronic diarrhea and 30 healthy controls were enrolled in the study. Serum levels of specifi c IgG antibody to 14 kinds of food were detected using ELISA. Results: In the 82 children with chronic diarrhea, 79 (96.2 %) had increased specifi c IgG levels for one or more of the 14 foods tested, compared to 8 (26.7 % ) of the controls (p <0.01). Th e majority of patients demonstrated increased specifi c IgG levels for milk (68.3% ) and egg (62.2 %). Only 2.4 % were allergic to chicken, and no patient was allergic to pork. Th e symptoms were improved in 65 patients (79.3 % ) aft er 1 week to 3 months of diet treatment (Ou-Yang et al., 2008 ).

SHORT-TERM MANAGEMENT OF IGE FOOD ALLERGIES

Anaphylactic reactions require prompt treatment of symptoms with rapid- acting antihistamines and intramuscular epinephrine, inhaled beta-agonist, and IV corticosteroids. Patients should be rapidly transported to a hospital where oxygen and IV fl uids support should be given (Muraro et al., 2007 ).28 Intramuscular epinephrine should be administered within minutes aft er an allergic reaction, with the lateral thigh as the optimal route of administration. Subcutaneous or inhaled epinephrine provides suboptimal therapeutic levels of the drug (Simons, 2004 ).

LONG-TERM MANAGEMENT OF IGE FOOD ALLERGIES

Th e management of food allergies is the avoidance of the relevant food allergens. Th e management of multiple food allergies is oft en complex, and needs the help of a trained dietician in developing a plan to avoid relevant food allergens and to prevent secondary dietary defi ciencies such as iron defi ciency anemia, rickets, osteoporosis, and impaired growth in children (Christie et al., 2002 ).

While subcutaneous immunotherapy is highly effective in patients with allergies to grass pollens and insect stings, this therapy has not been shown to be safe in patients with food allergies. 466 INTEGRATIVE GASTROENTEROLOGY

Table 41.6. Protective Roles for IgG in Host Defense Against Pathogens

Binds to pathogens inducing immune killing

Agglutination and immobilization

Complement activation (classical pathway)

Opsonization for phagocytosis

Neutralization of bacterial toxins

Oral desensitization with egg white and other foods has some effi cacy. Th is appears to increase the threshold dose of reactivity to the food, although the exact mechanism is uncertain (Buchanan et al., 2004 ). Th e bottom line is that food allergies, intolerances, and/or sensitivities are widespread in patients complaining of a multitude of symptoms, which they may attribute to food that they ate. Enlightened physicians or other healthcare providers, with the proper questioning, inspection of patient’s diet diary, or testing, can then provide them with an elimination diet and other dietary strategies, nutrients, vitamins, or medication to help ameliorate their symptoms. A visit to a health food store to buy organic may also be another recommendation for both patients and practitioners.

42 An Evidence-Based Review of Complementary and Integrative Approaches for Irritable Bowel Syndrome

OCTAVIA PICKETT-BLAKELY , ASHWINI S. DAVISON , AND GERARD E. MULLIN

key concepts

■ IBS is the most commonly diagnosed GI disorder. ■ Patients are dissatisfi ed with conventional treatment of IBS. ■ Half of IBS patients have tried CAM. ■ Probiotics may be a key component in treating IBS. ■ C B T i s b e n e fi cial in select patients with IBS. ■ Larger studies with well-defi ned outcomes are needed. ■

Introduction

rritable bowel syndrome (IBS) is a complex disorder of the gastrointestinal and nervous systems characterized by abdominal pain or discomfort I and altered bowel habits, and is diagnosed according to Rome III criteria (Table 42.1 ; Camilleri et al., 2007 ). It is the most frequently diagnosed gastrointestinal condition, with an estimated U.S. prevalence of 10 to 15% (Th ompson, 1986 ). In 2003, the estimated U.S. annual direct costs for IBS rose to $1.35 billion, resulting in an impact of $30 billion annually (excluding prescription and over-the-counter medications; also see Leong et al., 2003 ; Inadomi, Fennerty, & Bjorkman, 2003 ; Hulisz, 2004 ). IBS adversely aff ects quality of life (QOL) and work productivity, and is the second most common excuse for missing

467 468 INTEGRATIVE GASTROENTEROLOGY work (Quigley et al., 2006 ). A survey of more than 5,000 people from U.S. households found that IBS patients missed an average of 13.4 days per year from work or school due to illness. Th e average subject without a GI disorder missed only 4.9 days (Drossman et al., 1993 ). Recent research advances have provided some insight into the pathophysiology of IBS, leading to the development of targeted medical therapy. However, over the past decade, the FDA withdrew three IBS medications (Cisapride, Alosetron and Tegaserod) from the market. As a result, many patients have been dissatisfi ed with the lack of conventional medical therapies for the condition. Complementary and alternative medicine (CAM) encompasses a wide range of therapeutic modalities intended for use with, or as an alternative to, traditional medical therapy. CAM may be broadly categorized into botanicals, probiotics, psychological/mind-body therapies, and manipulation (Breuner, 2006 ). Herbal remedies are an example of botanical therapy. Within the realm of psychological and mind–body therapies are cognitive-behavioral therapy, hypnosis, and relaxation. Acupuncture, acupressure, and refl exology are considered energy manipulation techniques. A key concern for clinicians is that CAM interventions may off er nothing more than a placebo eff ect. An analysis of 31 trials of CAM in IBS patients estimated the placebo response rate to be greater than 40% (Dorn et al., 2007 ). Th is rate is similar to that seen in IBS patients enrolled in other medical trials (Akehurst. & Kaltenthaler, 2001 ; Drossman et al., 2002 ). Another drawback of research of CAM in IBS is that outcome measures are oft en determined with symptom diaries and questionnaires, which may only partially refl ect symptom relief (Meissner, Blanchard, & Malamood, 1997 ).

Table 42.1. Rome III Diagnostic Criteria for IBS

Recurrent abdominal pain or • improvement with defecation discomfort at least 3 days per month • onset associated with a change in frequency in the last 3 months, associated with of stool 2 or more of the following • onset associated with a change in form of stool

Criteria fulfi lled for the last 3 months with symptoms onset at least 6 months prior to diagnosis

Discomfort means an uncomfortable sensation not described as pain

(adapted from Drossman, 2006 ) An Evidence-Based Review of Complementary and Integrative Approaches 469

Regardless of the effi cacy of CAM for IBS, patients and practitioners are certainly interested in nonpharmacologic treatments (Cox, Lusignan, & Chan, 2004 ). In 1980s about 16% of IBS patients had sought out CAM practitioners (Smart, Mayberry & Atkinson, 1986 ). More recently, 51 % of patients with IBS reported using CAM, with out-of-pocket expenditures totaling more than $34 million annually (Haas, McClain, & Varilek, 2000 ; Kong et al., 2005 ; Herman, Craig, & Caspi, 2005 ). In view of the public interest in CAM, and patient dissatisfaction with conventional IBS therapies, clinicians should be aware of how CAM can be integrated into a patient’s medical regimen.

METHODS

MEDLINE (OVID: 1966 through September 2007), EMBASE (OVID: 1988 through September 2007) and the Cochrane Library (OVID: Issue 1, 2007), were systematically searched for evidence relevant to this chapter. References listed within related papers and recent review articles were cross-referenced for additional citations. Searches of electronic databases combined the terms functional gastrointestinal disease, irritable bowel syndrome, IBS, complementary and alternative medicine, CAM, integrative medicine, mind-body medicine, cognitive behavioral therapy, acupuncture, hypnotherapy, botanicals, herbal therapies, herbs, energy medicine, probiotics, refl exology and yoga.

STUDY SELECTION CRITERIA

Articles selected for inclusion were randomized, controlled trials, uncontrolled trials, and anecdotal data evaluating CAM therapies in patients with IBS. We specifi cally included studies that reported data on at least one of the following outcomes: bowel symptoms, disease activity, adverse events, or quality of life (QOL). Practice guidelines, meta-analyses, or systematic reviews explicitly based on randomized trials related to the guideline question were also eligible for inclusion. Articles written in a language other than English were excluded.

Botanicals

For centuries, botanicals have been used for medicinal purposes and are now a commonly used form of CAM (Tindle et al., 2005 ). Th e appeal of botanicals likely stems from their accessibility and perceived safety as “natural” products. 470 INTEGRATIVE GASTROENTEROLOGY

Table 42.2. Peppermint Oil for IBS

Author Design Pts (enrolled/ Treatment Global improvement dropout) period (weeks) vs. control

Carling et.al. 3-armed, double- 40/2 2 17/30 vs. 5/13 blind, cross over

Dew et.al. double-blind, cross 29/nr 2 24/29 vs. 5/29 over

Lech et.al. double-blind, 2 47/5 4 13/19 vs. 6/23 parallel groups

Nash et.al. double-blind, cross 41/8 2 13/33 vs. 17/33 over

Rees et.al. double-blind, cross 18/2 3 13/16 vs. 2/16 over

Lawson et.al. double-blind, cross 25/0 4 ND over

Shaw et.al Open, 2-parallel 35/0 26 3/17 peppermint groups oil, 13/18 CBT

Schneider double-blind, cross 60/13 6 Pain relief p=0.03, et.al. over vs. placebo

Pittler, M.H. & Ernst, E. Peppermint oil for irritable bowel syndrome: a critical review and metaanalysis. American Journal of Gastroenterology 93 (7), 1131-1135. Reprinted with permission from Pittler & Ernst (1998 )

Various botanical preparations have been studied in IBS, with varied results. Peppermint is one of the most well-known botanicals shown to relieve symptoms in IBS patients (Table 42.2 ; also see Pittler & Ernst, 1998 ). Of the 75 randomized trials for combination herbal therapy identifi ed in one systematic review, only three double-blind, placebo-controlled trials were considered to be high quality (Madisch et al., 2004 ; Bensoussan et al., 1998 ; Leung et al., 2006 ). A comparison of herbal formulations used in these three studies is shown in Table 42.3 . In a study of 116 patients, both standard and individualized combination Chinese herbal medicine signifi cantly improved bowel symptoms. Th e benefi t of individualized herbal treatment was maintained at 14 weeks following completion of treatment (Bensoussan et al., 1998 ). Another study in 208 patients demonstrated effi cacy with the herbal preparations STW 5 and STW 5-II. Th e most recent of the three trials randomized 119 patients to a standard preparation of traditional Chinese medicine (TCM) An Evidence-Based Review of Complementary and Integrative Approaches 471

Table 42.3. Herbal Therapies Studied in IBS

Madisch (1998) Madisch Bensoussan [(1998) Leung [(2006)

STW5 STW5-II TCM-individ, standard TCM – standard prep

Candytuft Candytuft Codonopsis pilosulae Astragalus membranaceus

Chamomile Chamomile Agastaches pogostemi Atractylodes macrocephala

Peppermint Peppermint Coicis lachryma-jobi Paeonia lactifl ora

Caraway Caraway Ledebouriellae seseloids Buplerum chinense

Licorice root Licorice root Glycyrrhizae uralensis Citrus reticulata

Lemon balm Lemon balm Bupleurum chinense Saposhnikovia divaricata

Celandine Artemisiae capillaris Murraya paniculata

Milk thistle Atractylodis Punica granatum

Angelica Angelica Portulaca oleracea

Magnoliae offi cinalis Coptis chinensis

Citri reticulatae

Ginger

Fraxini cortex

Poriae cocos

Plantaginis

Phellodendri

Saussureae vladimirae

Paeoniae lactifl ora

Coplidiis

Schisandrae extracts containing eleven herbs or placebo (Madisch et al., 2004 ). However, the use of this herbal formulation for diarrhea-predominant IBS did not improve symptoms. Unfortunately, these studies refl ect the lack of consistency in formulations, mechanisms of action, and results, oft en seen in CAM trials. Further studies substantiating the effi cacy of standard versus individualized herbal preparations for IBS would help practitioners appropriately advise patients on the effi c a c y o f b o t a n i c a l s . 472 INTEGRATIVE GASTROENTEROLOGY

Probiotics

Probiotics are dietary supplements containing live microorganisms that, when ingested, exert a benefi cial eff ect on the host. Among the most commonly utilized and studied species are lactobacillus, bifi dobacteria, and Saccharomyces boulardii (Quigley et al., 2006 ; Quigley, 2007 ; Quigley & Flourie, 2007 ). Th e association between IBS and small intestinal bacterial overgrowth (SIBO) is well established. Pimentel and colleagues demonstrated that successful treatment of SIBO with antibiotics improved IBS symptoms (Pimentel, Chow, & Lin, 2000 ). Th e results of randomized, controlled clinical trials using probiotics to treat IBS symptoms are shown in Table 42.4 . In a study by O’Mahony et al. ( 2005 ), Bifi dobacterium infantis 35624 ( B. infantis ) showed improvement in all IBS symptoms except stool frequency and consistency. Th is coincided with normalization of the proinfl ammatory cytokine profi le (elevated IL-10/IL-12 ratio) in those patients. A confi rmatory trial by the same group evaluated optimal therapeutic dosages, fi nding the daily, 108 cfu dose of B. infantis, given for 4 weeks, superior to alternative doses of B. infantis and placebo in improving abdominal pain and global symptom assessment scores (Whorwell et al., 2006 ). In the placebo group, there was decrease in composite IBS scores (6-point scale) by 1.27, versus a 2.12 point decrease in the 108 dose group (p<0.02). Th is study was well designed, with a practical primary end point of abdominal pain or discomfort. Similarly, a recent study in pediatric IBS patients showed that those treated with Lactobacillus GG were more likely to have treatment success and reduced frequency of pain compared to placebo (Gawronska et al., 2007 ). Although all of these results are provocative, the placebo response remains quite high in each of the studies. One limitation of the previously cited studies is the use of one probiotic strain. Th e microbial milieu of the gastrointestinal tract includes multiple species. Th erefore, one could surmise that an ideal probiotic regimen aimed at treating IBS symptoms would include a mixture of organisms. Kajander et al. ( 2005 ) studied a probiotic mixture containing Lactobacillus rhamnosus GG, L. rhamnosus LC705, Bifi dobacterium breve Bb99, Propionibacterium freudenreichii ssp, and Shermanii JS in IBS patients over six months. Th ere was improvement in total symptom scores composed of abdominal pain, distension, fl atulence, and borborygmi in the treatment group compared to placebo (7.7 points lower 95% CI: 13.9 to –1.6). Th is study diff ers from those previously discussed, in that the treatment period was much longer and a probiotic mixture was used. Another placebo-controlled trial comparing VSL#3 to placebo in IBS patients with signifi cant bloating found that patients had reduced Table 42.4. Randomized, Controlled Clinical Trials of Probiotics in the Treatment of IBS

Reference No. of patients Probiotic(s) mixture Treatment Period Results

[30] 103 L. rhamnosus GG, L.rhamnous LC705, B. breve 6 months 42% vs. 6% mean reduction symptom score Bb99 and P. freudenreichii ssp. Shermanii JS

[31] 48 VSl#3 4 weeks or 8 weeks Improved fl atulence in treatment group vs. placebo

[27] 77 L. salivarius UCC4331, B. infantis 35624 8 weeks Improved score for abdominal pain and bloating

[28] 362 B. infantis 35624 (doses 106 , 108 , 1010 ) 4 weeks Improved global symptom score > 20% vs. placebo (108 dose)

[32] 274 Bifi dobacterium animalis, S. Th ermophilus, 6 weeks Improved health-related QOL scores and L. Bulgaricus (yogurt) bloating

[33] 86 L. rhamnosus GG, L. Rhamnosus Lc705, P. 5 months Improved IBS score Freudenreichii, B. Animalis 474 INTEGRATIVE GASTROENTEROLOGY

fl atulence during the treatment period (Kim et al., 2005 ). In this study, colonic transit was retarded in the VSL#3 group relative to placebo. More recently, fermented milk containing Bifi dobacterium animalis, S. thermophilus and L. bulgaricus was compared to placebo in constipation-predominant IBS patients (Guyonnet et al., 2007 ). Th e health-related QOL discomfort score and bloating were improved in the both groups, though to a greater extent in the treatment group. A multispecies probiotic formulation used in a smaller study again showed improvement in composite IBS scores, specifi cally abdominal distension and pain, compared to placebo (Kajander et al., 2007 ). In summary, probiotics may prove to be a key component in the comprehensive approach to treating IBS. Future randomized studies should aim to enroll more participants, and should compare diff erent probiotic mixtures to each other, as well as controls, to see if there truly are improvements in standardized endpoints.

Energy Manipulation

In evaluating acupuncture as a therapeutic modality for IBS, a recent Cochrane review stated that the evidence is inconclusive given the poor quality of studies (Lim et al., 2006 ). Aft er this review, Schneider and colleagues ( 2007 ) published a small randomized trial evaluating acupuncture in patients with IBS symptoms. Th is study used validated QOL questionnaires, including the SF-36 and FDDQL, to assess treatment response. Both groups’ (acupuncture and sham acupuncture) global QOL scores improved, with no signifi cant diff erence between them. Unfortunately, this study was underpowered to detect a diff erence between groups. Similar fi ndings were reported by Forbes et al. ( 2005 ). Refl exology is an ancient form of natural healing that uses pressure on the soles of the feet to evoke a change in energy fl ow through the body (Blunt, 2006 ). Refl exology points are also found in the hands, and refl ect certain organs in the body. Th ough there have been reports in the lay press suggesting the effi cacy of this modality, there are very limited data on the use of refl exology for IBS symptom management. Th e fi rst trial was conducted in 34 patients in a single-blind fashion. Patients were randomized to receive six 30-minute sessions of refl exology foot massage or a non-refl exology foot massage (Tovey, 2 0 0 2 ) . Th ere was no improvement in abdominal pain, bloating, or altered bowel habits in either group. Given the paucity of data, further randomized trials should be performed before this modality is recommended for IBS patients. An Evidence-Based Review of Complementary and Integrative Approaches 475

Mind–Body Interventions

Th e pathophysiology of IBS involves dysregulation of the complex interplay between the nervous system and the viscera. Visceral hypersensitivity has been demonstrated in both animal models and humans (Dizdar, Gilja, & Hausken, 2007 ; Mayer et al., 2007 ). Th e physiological eff ects of psychological and physical stressors on gut function and brain–gut interactions are mediated by outputs of the emotional motor system (Figures 42.1 and 42.2; also see Mayer et al., 2007 ; Mayer, Naliboff , & Chang, 2001 ). Studies on corticotropin-releasing hormone (CRH) have demonstrated the relationship between stress and IBS. Symptoms in IBS patients increase with CRH, and improve with CRH receptor antagonists (Heitkemper et al., 1996 ; Posserud et al., 2004 ; Sagami et al., 2004 ; Dinan et al., 2006 ). Mind–body approaches such as meditation, relaxation, hypnotherapy, and cognitive-behavioral therapy (CBT) have also been investigated for use in IBS patients. Given the aforementioned role of stress in the provocation and perception of IBS symptoms, meditation would seem to be a logical therapeutic option. Relaxation produces physiological eff ects characterized as the hypo- metabolic physiologic state (Wallace, Benson, & Wilson, 1971 ). Th e relaxation response is a physical state of deep rest that alters physical and emotional responses to stress. One form of relaxation, mindfulness-based stress reduction (MBSR), has been shown to down regulate proinfl ammatory cytokines elevated in IBS. Carlson et al. (2003 , 2004 , 2007 ) showed improvement in neuroendocrine function, infl ammatory markers, QOL, and stress when using MBSR for cancer patients. Although there are few studies exploring meditation in IBS, one found that relaxation response meditation (RRM) was superior to placebo in improving fl atulence and belching (Keefer & Blanchard, 2001 ). Additionally, at 3-month follow-up, improved fl atulence, belching, bloating, and diarrhea persisted according to symptom diaries. One-year follow-up of this cohort showed continued reductions in abdominal pain, diarrhea, and fl atulence (Keefer & Blanchard, 2002 ). Th ese fi ndings are encouraging and justify further study of meditation as a therapeutic option in IBS. Th ere is limited data on the eff ect of yoga on IBS symptoms. One randomized, controlled study compared yoga to conventional treatment in patients with diarrhea-predominant IBS (Taneja et al., 2004 ). Twenty-two patients fulfi lling Rome II criteria of IBS were randomized to two months of yoga twice daily, or to conventional treatment with loperamide daily for two months. 476 INTEGRATIVE GASTROENTEROLOGY

Although patients in both groups experienced symptom improvement, those in the yoga group had greater improvements in scores for bowel symptoms and autonomic symptoms. Th is study was limited by small sample size and short therapeutic duration. Th e external validity of the study is also of concern, given the largely male study population. A separate group studied yoga in adolescents with IBS (Kuttner et al., 2006 ). Twenty-fi ve patients were randomized to either have the yoga intervention fi rst, or to a waiting list for a later yoga intervention. Aft er four weeks of daily yoga, patients had lower levels of functional disability and anxiety. Patients with IBS have alterations in visceral sensation and hyperalgesia that have been targeted by many diff erent therapies (Posserud et al., 2007 ). Body awareness therapy (BAT) has been evaluated to help these patients deal with body image and tension. BAT focuses on reducing body tension by focusing on movements, breathing, coordination, and posture. It has been studied in female victims of sexual abuse, patients with pain disorders, and outpatient psychiatric patients (Green et al., 2001 ). In one trial, 12 weeks of BAT led to improvement in gastrointestinal and psychological symptoms, especially in patients with constipation-predominant IBS (Eriksson et al., 2007 ). A 24-week study was conducted by the same group to evaluate the eff ect of BAT on body tension in IBS patients (Eriksson et al., 2007 ). Patients received two hours of BAT over 24 weeks, with a focus on body tension during movements that are a part of daily life. In comparison to healthy controls, IBS patients had higher levels of body tension, stress markers, gastrointestinal symptoms, and psychological complaints at baseline. Aft er 24 weeks, patients with IBS reported improvements in pain, coping ability, GI symptoms, psychological symptoms, and somatic complaints. Th ey also had decreased saliva cortisol levels, possibly indicating a reduction in overall stress levels. Hypnotherapy is another form of CAM, in which the induction of hypnotic states is achieved by deep relaxation, mental imagery, or other techniques (Gonsalkorale, 2006 ; Gonsalkorale, Houghton, & Whorwell, 2002 ; Gonsalkorale et al., 2003 ; Gonsalkorale, Toner, & Whorwell, 2004 ; Gonsalkorale & Whorwell, 2005 ). Gut-directed hypnotherapy (GDH) is a more specifi c intervention that has been studied in IBS patients (Gonsalkorale, 2006 ; Gonsalkorale, Houghton, & Whorwell, 2002 ; Whorwell, Prior, & Faragher, 1984 ; Prior, Colgan, & Whorwell, 1990 ; Lea et al., 2003 ; Simren et al., 2004 ). Improved tolerance of rectal balloon distension has been demonstrated in patients with diarrhea-predominant IBS aft er GDH (Prior, Colgan, & Whorwell, 1990 ). Th e earliest RCT investigating hypnotherapy in IBS showed a more dramatic improvement in IBS symptoms of abdominal pain, distension, general well-being, and bowel habit in comparison to psychotherapy (Whorwell, Prior, & Faragher, 1984 ). In addition, there were no relapses noted An Evidence-Based Review of Complementary and Integrative Approaches 477 over the course of the 3-month follow-up period. Gonsalkorale et al. published their experience in a cohort study of IBS patients undergoing hypnotherapy in a specialized center devoted to providing this service (Gonsalkorale, 2006 ; Gonsalkorale, Houghton, & Whorwell, 2002 ). Patients underwent 12 hypnotherapy sessions over the course of 3 months and were required to practice techniques between sessions. Th ey reported marked improvement in symptom measures of pain, bowel habit dissatisfaction, bloating, and life interference. Although many of the symptom parameters were subjective, the symptom ratings of bowel habit dissatisfaction correlated with actual changes in bowel habits. A follow-up study by the same group evaluated the symptom scores more than one year aft er hypnotherapy and showed that 81% reported sustained clinical improvement (based on symptom scores) initially experienced with hypnotherapy (Gonsalkorale et al., 2003 ). Th ere were similar improvements in quality of life, depression, and anxiety. Th e authors later reported that symptom improvement in IBS patients receiving GDH is associated with cognitive changes (Gonsalkorale, Toner, & Whorwell, 2004 ). Further studies are needed to validate hypnotherapy as a treatment for IBS patients. Cognitive-behavioral therapy (CBT) is a form of psychotherapy aiming to correct erroneous thoughts and maladaptive behavior (Toner et al., 1998 ). Th e application of CBT to IBS treatment is described in the literature (Hutton, 2005 ). Boyce et al. (2000, 2003) compared conventional treatment to CBT and relaxation therapy. Th ere was no signifi cant diff erence in bowel symptom frequency scores among the three treatment arms (conventional treatment alone, conventional treatment with CBT, and conventional treatment with relaxation therapy). Th e authors concluded that the combination of CBT and relaxation therapy off ered no additional benefi t over conventional medical therapy alone for IBS. Greene and Blanchard (1994 ) compared CBT with symptom monitoring control and noted improved composite symptom reduction and depression. A recent study by the same group compared CBT to psychoeducational support group therapy and intensive symptom monitoring (Blanchard et al., 2 0 0 7 ) . Th e authors reported improved gastrointestinal composite symptom scores, and individual symptoms such as bowel regularity, abdominal pain, and fl atulence. Th ree-month follow-up data also indicated maintenance or continued improvement of all IBS symptoms. As with many IBS studies, selection bias and placebo eff ect must be kept in mind when interpreting these data. Indeed, highly motivated patients are more likely to seek participation in clinical trials. Additionally, underlying psychiatric illness portends a worse prognosis for response to CBT (Blanchard et al., 1992 ). Preexisting psychiatric disease was one exclusion criterion for the trial. Although there are indicators 478 INTEGRATIVE GASTROENTEROLOGY that CBT is potentially benefi cial in the treatment of IBS, physicians must be highly selective in deciding which patients should pursue this therapy.

Discussion

IBS is a common gastrointestinal disorder that truly aff ects a patient’s quality of life. Current management focuses on symptom-specifi c therapy, but has left many patients and providers disappointed. For patients with IBS, some forms of CAM may be useful adjuncts to conventional treatments. Although there is inconsistent evidence regarding some CAM methods, patients and practitioners continue to be interested in these therapies. Primary care providers and gastroenterology specialists need to be aware of these options in order to properly advise their patients. In the future, perhaps a better approach to IBS treatment will involve a combination of CBT with conventional symptom- based therapy, or a behavioral multimodality approach (Schwarz, Blanchard, & Neff , 1986 ). Stress, abuse, and emotional feelings infl uence bowel symptoms via activation of the brain’s central circuitry called the emotional motor system (EMS), to produce autonomic and neuroendocrine responses. Bowel symptoms then cause more distress, triggering the release of mediators (cytokines, cortisol and adrenaline) that act on the EMS, producing a feed-forward cycle of bowel symptoms and emotional distress.

43 Nutrition Strategies for the Treatment of IBS and the Prevention of Digestive Complaints

ASHLEY KOFF

key concepts

■ S p e c i fi c dietary choices can correct the disruption of motility that characterizes irritable bowel syndrome (IBS). ■ An integrative approach allows today’s practitioner to move beyond recommendations of symptom management to recommendations for treatment. ■ An anti-infl ammatory diet provides the framework of the ideal dietary choices for IBS patients. ■ B e h a v i o r m o d i fi cations of IBS patients, as well as practitioners, are necessary to achieve sustainable long-term results. ■

Introduction

rritation of the gastrointestinal tract manifests disruptions in normal digestive function, laying the foundation for health problems as well as I detracting from quality of life. Research and anecdotal evidence demonstrates a link between diet and digestive system function (Lipski, 1999 ). Th us, dietary modifi cations are an integral part of IBS treatment. Historically, protocols for irritable bowel syndrome (IBS), including diet recommendations, focused on symptom relief only and tended to be “one size fi ts all.” Today, the opportunity exists to employ an integrative approach to IBS that focuses on

479 480 INTEGRATIVE GASTROENTEROLOGY treatment, with sustained digestive wellness as the achievable end goal. To eliminate digestive irritation, the practitioner must understand contributing factors and develop eff ective implementation strategies, taking a personalized approach.

Dietary Recommendations

While the causes of IBS may not be clear, the defi nition, which includes “a disruption of the digestive tract’s motility resulting in chronic symptoms such as constipation, diarrhea, cramping pain, distention and fl atulence,” provides key insights into how dietary choices may aid or exacerbate these symptoms. Whereas “disruption of the digestive tract’s motility. . .” hones in on a need for IBS dietary guidance to optimize motility, the latter portion of the defi nition (“resulting in chronic symptoms”) reveals the need to address factors that contribute to ongoing GI disturbance.

Beyond the deﬁ nition, IBS recommendations must include behavior modiﬁ cations— both for the practitioner and the patient— to achieve long- term, lasting results.

Th us, IBS dietary recommendations stem from a two-pronged approach: One prong examines the key words of the IBS defi nition, and the other prong addresses behavior modifi cations.

The IBS Types

CONSTIPATION

Constipation can occur for diff erent reasons: dehydration, medication, quit- ting smoking or caff eine, increased fi ber without suffi cient fl uid, lack of fi ber, magnesium defi ciency (can be conditional or clinical), excessive calcium supplementation, lack of activity (especially that which moves the lower abdomen), menstrual cycle, or historic use of laxatives. It is important to ask the patient questions about each of these, so that recommendations can be tailored for optimal results. Nutrition Strategies for the Treatment of IBS 481

Recommending an increase in ﬁ ber for all constipation patients is not an effective strategy. In many people, it can have the reverse, and undesirable, effect of worsening bloating and ﬂ atulence, and even constipation (Bijerk, 2004 ; Koff, 2005).

For these patients, it may actually be necessary to reduce fi ber and suggest magnesium-rich foods, modify their supplementation, and suggest motility- enhancing stretches to yield optimal results. For IBS constipation patients, the fi rst step is to identify the potential cause of the constipation, and then begin with individualized strategies to alleviate it.

DIARRHEA

For those patients who suff er from increased motility resulting in loose stools, frequency and bowel control issues, dietary approaches may also help achieve regularity. Diarrhea-dominant IBS patients typically reduce their dietary choices to minimal variety, and oft en low-nutrient density, by avoiding fi ber and non-animal sources of protein and fat, and by choosing refi ned grains and other higher glycemic carbohydrates. While perhaps eff ective at managing diarrhea, such dietary choices not only fail to control symptoms in the long term, they also contribute to increased risk of other chronic diseases (e.g., obesity, diverticulosis, elevated cholesterol, heart disease, and diabetes) (McCoubrey, 2008 ).

The best plan for diarrhea-dominant IBS patients incorporates nutrient- dense choices that help heal their digestive tract, modiﬁ cation of their supplementation plan to provide optimal nutrient intake, and evaluation of their diet for known gastric irritants that contribute to loose stools.

ALTERNATING

For these patients, who experience both constipation and diarrhea in alternating cycles, following any one set of dietary guidelines oft en results in a full pendulum swing back to their other set of symptoms. Potential areas to explore for these patients are hormonal triggers, especially menstrual cycles for 482 INTEGRATIVE GASTROENTEROLOGY women, stress, and food allergies. Furthermore, teaching these patients to only partially modify their food and supplement intake, as symptoms shift from one to the other, may dramatically reduce the severity of their symptoms, allowing for a greater period of normalcy and ultimately enabling healing and digestive wellness.

Part 1: Core Goals: Motility

Several factors, such as food processing, diet trends, nutrient quality of soils, and medication use in the last century, are collectively responsible for an exponentially negative impact on the digestive tract motility of Americans. For example, the refi ning of grains to fl our signifi cantly reduces its content of magnesium, a powerful motility agent. Similarly, dietary trends such as no- or low- carbohydrate plans also aff ect the intake of nutrients found in carbohydrates (e.g., fi ber, magnesium), which play major roles in motility. Th e increase in the use of preservatives — such as sugar, salt, and chemical preservatives — to achieve extended shelf stability and create ready-to-eat food options, oft en replaces motility-regulating nutrients found naturally foods prior to processing. Th e explosion of the non-water-based beverage industry contributes to dehydration, which also negatively aff ects digestive tract motility. Many of these beverages contain caff eine, a powerful motility agent, which further exacerbates their impact on the digestive tract’s motility control. Th e use of antibiotics and other medications that aff ect gut fl ora also plays a role in d i g e s t i o n a n d m o t i l i t y .

When the effects of any known irritant or challenge to optimal motility accumulate, the result is exponentially negative. Disruption of digestive tract motility becomes evident as constipation, diarrhea or an alternation of the two.

Th e following reviews nutrition recommendations to address digestive tract motility issues for IBS patients.

MINERALS

A balance of minerals is necessary for optimal cellular function, especially in the digestive tract. Th is applies to both food and supplement sources. Nutrition Strategies for the Treatment of IBS 483

1. Calcium/Magnesium: While calcium has a tightening (contracting) eff ect on the body’s muscles, magnesium acts as Mother Nature’s muscle relaxant. Together, these two minerals create normative muscle contractions— contracting and relaxing the muscle— including those of the digestive tract responsible for normalizing bowel function. In a person suff ering from chronic constipation, practitioners should fi rst conduct an assessment of calcium and magnesium balance. As mentioned previously, food processing (especially of grains) plays a major role in magnesium reduction, as do low-carbohydrate diets, which exclude many of the richest sources of magnesium. Today’s food and health trends favor calcium dominance. Beyond reduction or elimination of magnesium-rich carbohydrates, low-carbohydrate plans include calcium-rich foods (e.g., cheese, full-fat dairy products). News reports further promote the benefi ts of calcium for weight loss and bone density, emphasizing food choices for patients to improve calcium intake, oft en without mention of magnesium. Finally, the popularity of coff ee, tea drinks, and smoothies made with calcium- rich and calcium-fortifi ed beverages further increases calcium intake in the absence of magnesium.

Beyond dietary choices, calcium–magnesium balance must factor into the minerals patients obtain through nutrient supplementation. Oft en told to take a “calcium supplement,” not a “mineral supplement,” patients unknowingly omit other minerals, including magnesium; if these products include magnesium, they oft en do it at a ratio of at least 2:1 in favor of calcium. When combined with dietary changes that also typically favor calcium intake, such supplementation exacerbates an imbalance that aff ects digestive tract motility.

For the IBS constipation patient, a needs assessment should certainly include the level of calcium necessary for maintaining bone health while balancing the need for sufﬁ cient magnesium to enable optimal motility.

Additional attention should be paid to establishing a desirable balance between dietary calcium intake (compared to magnesium), supplemental calcium, and both sources of magnesium.

a . Foods rich in calcium: 1 . N a t u r a l l y : a. Dairy : yogurt, cheese, cream 484 INTEGRATIVE GASTROENTEROLOGY

b . Nondairy : green leafy vegetables, almonds, pistachios, black- strap molasses, broccoli, fi gs, tofu, sea vegetables 2. Fortifi ed: orange juice, milk alternatives (rice, soy, etc.), English muffi ns, breads, cereals b . Foods & Supplement sources of magnesium: 1. Leafy greens (arugula, spinach, Swiss chard), seeds (pumpkin, sesame, fl axseed, sunfl ower), tahini, summer squash, okra, barley, salmon, quinoa, beans (black, pinto), dried unsweetened coconut, chocolate (cacao) 2. Supplements: glycinate and citrate; Natural Calm 2. Sodium/Potassium: Th e balance of these minerals aff ects cellular hydration, with potassium responsible for maintaining intracellular hydration and sodium responsible for extracellular water balance. Hydration plays a critical role in the optimal functioning of the digestive tract. If a patient’s diet is potassium defi cient or sodium rich (creating a conditional potassium defi ciency), dehydration will inhibit optimal function of the colon. Many patients turn to laxatives to address this issue, but optimizing potassium/sodium balance and, of course, improving overall water intake, can produce positive results by enabling the body’s normal cellular function. a. Foods rich in potassium: coconut water, spinach, tomatoes, cantaloupe, papaya, carrots, beets, winter squash, white potato, banana, yogurt b. Foods high in sodium: salt, processed foods, soups, sauces, soda, pickled and cured foods (pickles, olives, hot dogs, jerky), soft drinks, sparkling water 3. Iron: Th is mineral is critical for cell growth and function. During certain life stages (childhood, adolescence, pregnancy), the body’s increased needs may require additional intake of iron-rich foods and/ or supplementation. Additionally, many vegan and vegetarian patients supplement their food intake with iron; this issue has increased relevance with growing awareness of the health benefi ts of vegetarian c h o i c e s .

While increased consumption of iron-rich foods doesn’t commonly generate constipation, the opposite is true of iron supplementation; constipation is a known side effect. Nutrition Strategies for the Treatment of IBS 485

Th e benefi t of combining vitamin C-rich foods with iron-rich foods goes beyond increasing absorption of the iron; it can also help minimize the iron’s constipating eff ect. Supplement manufacturers have taken advantage of this knowledge by creating an iron supplement that is known to be eff ective without creating constipation in most people (Floradix).

a . Foods rich in iron: shrimp, venison, beef, calf’s liver, greens (spinach, chard), cooked beans, sesame seeds b . Foods rich in vitamin C: bell peppers, parsley, broccoli, strawberries, lemon juice, caulifl ower, papaya, kiwi, orange, cantaloupe, raspberries, pineapple, green beans, kale

Fiber, stimulants, water, lubricants, and chemical compounds all aff ect motility as well.

FIBER

Th e kind and quantity of fi ber, as well as the frequency of intake, play important roles in motility. Th is can be both positive and negative for IBS patients. While daily fi ber intake is critical to regularity and digestive health, the type of fi ber one introduces to an irritated bowel— and how one introduces it— can mean the diff erence between success and distress. Th e following provides the keys to success for fi ber introduction for IBS patients:

1. Fiber intake basics (even for the non-IBS patient) a. Introduce in small increments, whether in food form or supplement (Miskovitz, 2005 ). For example, begin with a baked apple without the skin, then baked apple with the skin, then a fresh apple with the skin; or, half a teaspoon of a supplement daily for a week, then half or one teaspoon twice daily, and so on. b. Adding fi ber to a dehydrated system will prove unsuccessful. Th e fi ber requires moisture to move throughout the digestive tract. (In some instances, this technique has been used to help the loose- stool patient decrease bowel movement frequency. Th is strategy should not be used long term.) 2. IBS-specifi c a. Limit wheat bran (Lipski, 1999 ). Wheat tops the list of known shared irritants among IBS patients, so supplementing with it is counterintuitive (Francis, 1994 ). 486 INTEGRATIVE GASTROENTEROLOGY

b. Use diff erent fi bers (emphasize soluble fi ber) for constipation (oat bran, fl axseed, psyllium, etc.) versus diarrhea (rice bran) (Bijerk, 2 0 0 4 ) . c. Many IBS suff erers feel their worst in the morning. Adding fi ber to an acutely irritated system may be less successful than incorporating it throughout the day, or taking a supplement at night.

Th e following is a list of recommended fi ber-rich foods and supplements:

1. Fiber-rich foods: berries, greens, beans (smaller beans are usually better for IBS patients), apples, pears, oats, fl axseeds 2. Fiber supplements: Citrucel, Genesis Today 4 Fiber, Konsyl, Fiber Choice, oat bran, rice bran, psyllium

WATER

Th e digestive tract requires water to facilitate nutrient absorption and cellular activity, including muscle contractions and waste removal (Miskovitz, 2005 ). Yet many people consume insuffi cient quantities of water. Two common issues arise: First, many complain that they don’t like the taste of water. Second, they are confused about how much water to consume. With regard to the fi rst issue, partial blame rests with the popularity of non-water-based beverages, to which the “taste” of water may pale by comparison. To resolve confusion about the right amount of water and to obtain actionable results, patients should be given their desirable water intake. Identifying what’s desirable for each individual also takes into account hydration needs, overall health benefi ts of exchanges (non-water-based beverages to water-based ones, reduction of stimulants, etc.), and what feels doable to them without generating stress. (Having to go to the bathroom more frequently, even if to urinate, may not be well received by, nor benefi cial for, IBS patients if it produces additional stress).

The majority of “good-tasting” beverages play a role in health issues, such as obesity and chronic disease. These products (even artifi cially sweetened, noncaloric ones) raise the bar for satisfaction by acclimating taste buds to higher intensities of sweetness or fl avor than exist naturally. These beverages can overwhelm the digestive tract, contribute to gas and bloating, and feed bad bacteria. They are not a signifi cant source of fi ber, which further contributes to digestive tract “laziness” and may yield energy storage (fat), encourage suboptimal blood sugar levels, and hamper optimal digestion. Nutrition Strategies for the Treatment of IBS 487

Th e following water-based beverages and foods can help patients increase their daily water intake:

1. Water-based beverages: herbal tea, water with lemon/lime juice (1 oz. juice to 8 oz. water) 2. Water-based foods: cucumber, celery, tomatoes, iceberg lettuce, bamboo shoots, apple, watermelon, homemade broth (made with water and spices, not salt)

LUBRICANTS

Lubricant foods and herbs help the stool move through the digestive tract. Known as demulcents, these herbs, seeds, and oils lubricate the digestive tract, thereby relieving irritation. Practitioners should teach patients to incorporate demulcents into their meals, as well as to explore the use of herbal supplements.

1. Demulcents: okra, fl axseed, oat, kelp, cactus, natto, toasted sesame oil, olive oil, acacia, chia seeds.

CHEMICAL COMPOUNDS

Chemical compounds are a signifi cant factor in motility disruption. Numerous medications, either intentionally or as a side eff ect, override the body’s motility-regulating capabilities. Consider other sources of chemicals, as well as natural stimulants, that a patient may consume regularly or that the patient used to c o n s u m e r e g u l a r l y .

Caffeine, nicotine, and herbal laxatives are all stimulants and thereby affect the motility of the digestive tract. The digestive tract appears to adapt to the routine use of these substances, thus developing a reliance on the substance for motility messages.

Th e problem intensifi es when patients discontinue their intake of these substances. Without adequate support, food choices, and possible nutrient supplementation prior to or during discontinuation, digestive tract motility may simply stall, producing or worsening constipation. It can take a great deal 488 INTEGRATIVE GASTROENTEROLOGY of eff ort to retrain the body’s signaling and response. Th e chronic consumption of medications that aff ect the GI, and the use of stimulants, can have a singular or cumulative eff ect on a patient’s GI motility.

Part 2: Factors that Result in Chronic Symptoms

Th e “chronic” nature of gastrointestinal disturbances in the absence of structural dysfunction satisfi es the criteria for an IBS diagnosis. To identify and address the root causes of ongoing digestive irritation, practitioners must evaluate the patient for frequent consumption of known gastric irritants, potential food allergies, gut dysbiosis, and subclinical infl ammation. A multifactorial approach allows the provider to address the patient’s symptoms and to make signifi cant inroads on the healing path to digestive wellness.

1. Known Gastric Irritants and Food Allergies

Research shows that IBS suff erers appear to share certain factors that contribute to chronic irritation of the digestive tract. While IBS patients may have individual intolerances, several intolerances appear to occur in the majority of patients (Lipski, 1999 ).

The most common irritants, or “triggers,” include wheat, corn, alcohol, dairy, coffee, caffeine (including chocolate), citrus fruits, sugar, and sugar alcohols (Koff, 2005).

For guidance on teaching patients about modifi cation options, see the “Usual Suspects” section of Recipes for IBS (Koff , 2005). Many practitioners and patients should also consider food allergy testing. Anecdotally, I fi nd the majority of IBS patients initially intolerant to a wide range of foods (oft en confi rmed by testing), with their list typically including foods frequently consumed. Because these are IBS patients and their digestive systems are irritated, it follows that the body may not tolerate a majority of the food introduced into it. Th us, before testing for food allergies (which can be costly and overwhelm- ing), I recommend trial eliminations or reductions of known irritants, while simultaneously addressing the motility issues as previously discussed. Additional trial eliminations can be used on a case basis, with care taken to maintain a nutrient-rich nutrition plan. Nutrition Strategies for the Treatment of IBS 489

2. Gut Dysbiosis

Dietary choices, antibiotic use, and low-grade antibiotic exposure collectively contribute to the potential for a gut fl ora imbalance. Discussed elsewhere in this book by Dr. Gerald Friedman (Chapter 29), probiotic supplementation should be part of the treatment for IBS. Clinical research demonstrates the value of strain specifi city in the selection of the right probiotic (Huff nagle, 2007 ). Th e Bifantis strain appears to be the sole probiotic strain to address the entire spectrum of IBS symptoms. Food sources alone will likely not yield the same results as probiotic supplementation for IBS patients, for two reasons. First, many probiotic-containing foods and food products fall under the “known irritants” food list. Second, the quantity of probiotic shown to be eff ective for IBS patients proves challenging to consume in foods. Appropriate food sources of probiotics still should be used to improve overall gut fl ora balance (Wald, 2008 ). Food sources of probiotics and prebiotics include:

a. probiotic (natural) : cultured (fermented) vegetables, kimchi, raw sauerkraut, yogurt, dairy kefi r, coconut water kefi r, fermented soy (tempeh, miso, natto) b . prebiotic: Jerusalem artichoke, chicory root, asparagus, oats, raw honey, barley, fl axseeds (ground), onions

3. Infl ammation

It is increasingly apparent that an anti-infl ammatory diet is best for patients suff ering from IBS (Huff nagle, 2007 ). As Dr. Andrew Weil ( 2005 ) discusses in his book, Healthy Aging, there is increasing acceptance by the scientifi c community that subclinical infl ammation plays a role in “so-called functional diseases (where there is) real suff ering without objective changes in body structure that physicians can document.” Historically, patients with digestive disturbances avoid whole categories of nutrient-rich foods in an eff ort to minimize their symptoms (McCoubrey, 2008 ). Such eff orts likely shift the balance away from an anti-infl ammatory approach to one where nutrient-poor choices and a lack of variety promote increased risk for chronic disease.

In essence, the danger of an IBS patient’s dietary plan that only focuses on how to reduce symptoms is that such a dietary plan likely increases the patient’s risk for chronic disease. Because chronic infl ammation plays a role in IBS, patients would benefi t an anti-infl ammatory diet which focuses on the quality of macronutrients to achieve nutrition for optimal health. 490 INTEGRATIVE GASTROENTEROLOGY

At the core of an anti-infl ammatory diet is the notion of choice: Th e foods one chooses not to eat are equally important as what one does eat. What does emphasizing choice mean? It means that the patient isn’t told he or she can’t eat certain foods. Rather, with education about how certain foods aff ect their system, patients choose to include healing foods most oft en and choose not to eat (or to eat less oft en) those foods likely to produce or exacerbate irritation.

Part 3: Behavior Modiﬁ cations for Long-Term Results

An irritated digestive system needs time off to heal. It is critical to explore how to accomplish the dietary recommendations for IBS, which focus on getting the necessary nutrients, while simultaneously learning to keep the gut under - whelmed. Achieving and maintaining an under whelmed digestive tract is the key dietary objective for IBS suff erers, regardless of their IBS “type.” Th is section provides implementation strategies for necessary behavior modifi cations.

• Aim to achieve a consistent nutrient supply. When a patient con- sumes nutrients at regular intervals, the body does not have to function at an energy defi cit, which helps minimize irritation. In an energy defi cit, the body sends urgent messages for energy, thus creating potential traps such as refi ned carbohydrate cravings, caff eine and soda consumption, and excessive nutrient intake.

To achieve regular intervals of intake, use the analogy that the body is designed like a race car— it routinely needs nutrient-balanced pit stops at regular intervals throughout the day.

In my practice, I don’t use the terms “meal” or “snack.” Instead, I use “eating occasion,” which correctly focuses the patient on the desired goal — taking in nutrients — rather than focusing on portion size and time of day. Example: “We want an eating occasion within 45 minutes of waking up” versus “Eat breakfast.” An eating occasion can be soup, a beverage, fi sh and vegetables, but breakfast oft en connotes a “breakfast” food such as high-fi ber cereal, muffi n, juice, etc.

• Aim for macronutrient balance at each “eating occasion.” Understanding and implementing macronutrient balance at each “eating occasion” helps generate physiologic as well as mental satisfaction. Practitioners should fi rst teach patients what fats, carbohydrates, and Nutrition Strategies for the Treatment of IBS 491

proteins are, where they are found, and portion sizes to help patients view foods as providers of nutrient complexes that off er energy and taste, and support the body’s numerous functions.

Example: Choose half a sandwich and salad; then, three hours later, have a piece of fruit with peanut butter —instead of eating a whole sandwich and an apple at once.

• Improve eating mechanics. Adjusting one’s eating mechanics is seemingly the simplest change, and one that yields signifi cant results. However, it is also the one modifi cation (or series of modifi cations) with which patients struggle the most. It requires undoing years of habits and environmental infl uences. With busy lives, it can be diffi - cult to learn to slow down. Th at certainly applies to eating mechanics. Chewing, taking smaller bites, and pausing between bites will improve digestion and absorption almost immediately (Lipski, 1999 ). Similarly, behaviors such as drinking with straws or guzzling directly from a bottle can translate to added bloating or fl atulence. When advising patients to modify their eating mechanics, providing explanations instead of listing foods and behaviors on a “No” list should dramatically improve compliance.

Examples:

a. Instead of saying, “no Perrier,” advise patients that they should “Limit carbonated beverages, as taking in gas is likely to produce more gas.” Suggest that patients drink iced herbal tea, or add lemon or lime to fl at water, as their regular beverage choices; not only will eliminating the carbonation reduce irritation, but the herbal tea, lemon, and limes help improve digestion. b. Instead of saying, “Chew more slowly,” say “Chew more, because your teeth help break down the food so that it comes through your digestive tract in a form that is easier for your system to use. If you are in a rush, choose items that require less chewing, such as soups, scrambled eggs, mashed or cooked vegetables (versus raw) or oatmeal.”

• Create awareness. While IBS aff ects millions of Americans, each person’s digestive tract is his or her own, and his or hers to explore. Using a food–symptom journal can help each patient refi ne general IBS nutrition guidelines into a personalized nutrition plan. Personalization is the key to long-term digestive wellness for optimal health. 492 INTEGRATIVE GASTROENTEROLOGY

• Practitioners also need behavior modifi cations. Our patients aren’t the only ones whose habits have built up over the years. Th e key is to shift to a teaching role versus a prescribing role. In doing so, patients receive education, which empowers them and enables them to make choices. To accomplish this, practitioners need resources and references such as those presented in this book.

Conclusion

An exploration of the multifactorial dietary infl uences on the digestive tract demonstrates the potential impact for IBS recommendations to move beyond symptom management to eff ective treatment for sustained digestive wellness. Th e dietary recommendations described should allow the practitioner to identify areas of opportunity for each patient that, in concert with other recommendations, lay the foundation for a healing plan for digestive wellness and optimal health. 44 Alternative Approaches to the Patient with Inﬂ ammatory Bowel Disease

LEO GALLAND , KATARZYNA KINES , AND GERARD E. MULLIN

key concepts

■ I n fl ammatory bowel disease (IBD) is characterized by idiopathic chronic intestinal infl ammation, oxidative injury to tissues, and frequent nutritional defi ciencies. ■ Impairments in tissue antioxidant defenses poses vulnerability threats to uninvolved intestine–supplementation with antioxidants may help spare further damage. ■ Functional foods and nutraceuticals attenuate infl ammatory mediators such as tumor necrosis factor alpha (TNF-α ) and nuclear factor kappa beta (NFkB). Supplementation should be considered for patients with IBD. ■ Probiotics can direct the immune system toward a favorable response in IBD and the data supports its effi cacy and safety. ■ Prebiotics derived from food can support and sustain the growth of benefi cial/friendly bacteria. Research studies show that prebiotics can induce remission and maintain response in colonic disease. ■ Th erapeutic modalities that integrate anti-infl ammatory nutrients into the diet of patients with IBD should be considered by clinicians who manage these complex and challenging d i s e a s e s . ■

493 Introduction

rohn’s disease (CD) and ulcerative colitis (UC) are chronic intestinal diseases that have in common uncontrolled intestinal infl ammation C and mucosal injury causing systemic illness, poor quality of life, immunosuppressant medication use, surgical intervention, and an increased risk for gastrointestinal and systemic cancer(s). Th e gross and histological lesions associated with IBD are thought to result from an inappropriate activation of the mucosal immune system, causing the release of noxious biochemi- cals with consequent tissue injury and intestinal symptoms.

There are a multitude of theories as to the etiology and pathogenesis of IBD. The common thread is a genetically improperly programmed overactive immune response, after an initial insult to the gut (Figure 44.1 ).

In CD, genetic variants confer susceptibility vis-a-vis the immune system’s interaction and reaction to constituent enteric fl ora along with regulatory defects in the mucosal immune response. Ultimately a breakdown of the protective mucosal barrier that separates immune response cells from the contents of the intestinal lumen occurs which drives the process in a feed-forward manner. Th e normal fl oras of the gut lumen act as triggers for the infl ammatory response and appear to play a central role in pathogenesis (Podolsky, 2002 ). In both Crohn’s disease and ulcerative colitis, an increased number of surface- adherent and intracellular bacteria have been observed in mucosal biopsies (Darfeuille-Michaud et al., 1998 ; Swidinski et al., 2002 ). Th e immune responses provoked by these bacteria, however, are diff erent in the two disorders (MacDonald, DiSabatino, & Gordon, 2005 ). In Crohn’s Disease, the immune response in CD is driven by lymphocytes with a type 1 helper-T-cell (TH1) phenotype and their cytokines: interleukin-2 (IL-2) and gamma-interferon ( γ − IFN). Th ese TH-1 products promote a self- sustaining cycle macrophage activation that includes interleukin 12 (IL-12), which further increases TH-1 activity, interleukins 1 and 6 (IL-1, IL-6) and tumor necrosis factor alpha (TNF-α ), which create a broader infl ammatory response. Ulcerative colitis is associated with lymphocytes that organize the infl ammatory response in UC demonstrate an atypical type 2 helper-T-cell (TH2) phenotype, with interleukin-5 (IL-5) as a distinctive cytokine mediator (Fuss et al., 1996 ). Alternative Approaches to the Patient with Inﬂ ammatory Bowel Disease 495

Malnutrition is a major reversible complication of infl ammatory bowel disease (IBD). The mechanisms of malnutrition include: • anorexia resulting from the systemic effects of IL-1 • a catabolic state induced by TNF-alpha • malabsorption due to disease or surgical resection • nutrient losses through the infl amed and ulcerated gut • small bowel bacterial overgrowth resulting from strictures or fi stulas • increased nutrient utilization and requirement due to higher intestinal cell turnover, infl ammation, fever, and infection • Blood loss or wound healing requirements • the side effects of drug therapy (Gassull, 2003 )

• I n fl ammation increases oxidative stress in the bowel mucosa and decreases levels of antioxidants (Figure 44.3; see Simmonds & Rampton, 1993). • Zinc and copper, or the zinc-dependent and copper-dependent enzyme, superoxide dismutase (Cu-Zn SOD), are reduced in mucosal biopsies from patients with both types of IBD (Lih-Brody et al., 1996 ). • Oxidative stress caused by infl ammation decreases the mucosal concentration of vitamin C (Buffi nton & Doe, 1995 ). • Plasma levels of vitamins A and E are lower, and plasma levels of the oxidative stress marker, 8-hydroxy-deoxy-guanosine (8-OHdG) are higher, in IBD patients than in controls (D’Odorico et al., 2001 ). • Compared to controls, children and adults with IBD have lower blood levels of zinc and selenium, mineral cofactors of antioxidant enzymes (Ojuawo & Keith, 2002 ; Hendricks & Walker, 1988 ; Hinks, Inwards, Lloyd, & Clayton, 1988 ). • Adults with UC may show lower levels of beta-carotene, magnesium, selenium, and zinc (Geerling, Badart-Smook, Stockbrugger, & Brummer, 2000 ). • Micronutrient defi cits may favor self-perpetuation of IBD by causing defects in the mechanisms of tissue repair (Gassull, 2004 ). Micronutrient defi ciencies may also contribute to some complications of IBD, such as growth retardation, osteopenia, urolithiasis, and thromboembolic phenomena (Gassull, 2003 ).

In CD, abnormal mucosal barrier function may play a primary role in pathogenesis. • Small intestinal permeability is increased among healthy ﬁ rst-degree relatives of patients with CD (Hollander et al., 1986 ) and is increased in nonin- ﬂ amed enteric tissue obtained from patients (Peeters et al., 1994 ). 496 INTEGRATIVE GASTROENTEROLOGY

• Aspirin, a drug which increases intestinal permeability of healthy controls, causes an exaggerated increase in intestinal permeability of ﬁ rst-degree relatives of patients with CD (Hilsden, Meddings, & Sutherland, 1995 ). • The rate of relapse among patients who have entered remission is directly proportional to the degree of small intestinal hyperpermeability measured with chemical probes (Wyatt et al., 1993 ). • Hyperpermeability is associated with polymorphism of genes, associated with regulation of epithelial barrier function (MacDonald, DiSabatino, & Gordon, 2005 ); it increases exposure of the intestinal immune system to luminal antigens.

DIETARY ASSOCIATIONS AND IBD

No consensus has emerged, however, regarding the role of dietary patterns as antecedents of infl ammatory bowel disease (Loft us, 2004 ). Increased refi ned sugar intake and high overall carbohydrate intake has been associated with the development of Crohn’s disease (Reif et al., 1997 ). Increased consumption of chemically modifi ed fats (such as those found in margarine) may be involved in the etiology of ulcerative colitis (Epidemiology Group, 1994 ). High consumption of a fast food diet is an antecedent of both ulcerative colitis and Crohn’s disease (Persson, Ahlbom, & Hellers, 1992 ). Th ere is an inverse association between dietary intake of vegetables, fruits, fi sh, fi ber, and omega-3 fatty acids, and the subsequent development of Crohn’s disease in children (Amre et al., 2007 ). Interestingly, studies in Japan indicate that the rise in CD in Japan strongly correlates with increased total fat, animal fat, ratio of omega-6 to omega-3, with increased animal protein (but not fi sh protein) being the strongest independent factor. It inversely correlates with vegetable protein (Shoda et al., 1996 ).

FORMULA FEEDING AND IBD

Short duration of breastfeeding or the absence of breastfeeding) may be an antecedent of infl ammatory bowel disease. Breastfeeding may protect against enteric infections during infancy, aid with early development of a competent gastrointestinal immune system, or delay exposure to foreign antigens such as cow’s milk. Several studies have found that people who develop infl ammatory bowel disease are less likely to have been breastfed than controls (Cashman & Shanahan, 2003 ; O’Sullivan & O’Morain, 2006 ). Intolerance to cow’s milk has also been implicated as antecedent precursor of IBD although the data are somewhat confl icting Alternative Approaches to the Patient with Inﬂ ammatory Bowel Disease 497

(Cashman & Shanahan, 2003 ). Patients with a history of milk allergy during infancy who subsequently developed ulcerative colitis did so at an earlier age than those without a history of milk allergy (Glassman, Newman, Berezin, & Gryboski, 1990 ). Allergy to milk proteins still remains a possible cause of dairy sensitivity or milk intolerance in a small percentage of infl ammatory bowel disease patients. Several studies have demonstrated an association between allergic symptoms asthma, rhinitis, and the subsequent development of infl ammatory bowel disease, particularly ulcerative colitis (Ceyhan, Karakurt, Cevik, & Sungur, 2003 ; D’Arienzo et al., 2002 ; Weng, Liu, Barcellos, Allison, & Herrinton, 2007 ).

INTESTINAL PERMEABILITY AND IBD

Th e intestinal mucosal barrier has evolved to maintain a delicate balance between absorbing essential nutrients while preventing the entry and responding to harmful contents. In IBD, disruptions of essential elements of the intestinal barrier lead to permeability defects, immune system activation resulting in tissue damage. Th e epithelial phenotype in active IBD is very similar in CD and UC. It is characterized by increased secretion of chloride and water, leading to diarrhea, increased permeability via both the transcellular and paracellular routes, and increased apoptosis of epithelial cells. Abnormal gut permeability is a feature of established Crohn’s Disease whether active or quiescent (Buhner et al., 2006 ; D’Inca et al., 2006 ). Relatives of patients with Crohn’s Disease demonstrated increased permeability suggesting that increased permeability is an antecedent of disease while hyperpermeability has been shown to precede the development of frank disease (Irvine & Marshall, 2000 ). Th erapeutic restoration of the mucosal barrier could conceivably protect and prevent antigenic overload of the mucosal immune system due to intestinal “leakiness (Salim SY, Soderholm JD, 2010 ).

LOW VITAMIN D STATUS AND IBD

Vitamin D is now widely recognized as a regulator of the immune system. Vitamin D is an immunoregulatory biochemical which acts in part by inducing T regulatory cells to downregulate TH-1 responses. Defi ciency of vitamin D may also be antecedent precursor of infl ammatory bowel disease (Lim, Hanauer, & Li, 2005 ). Epidemiologic studies have observed that the incidence of infl ammatory bowel disease is higher in populations with lower vitamin D levels (northern latitudes) and relapses occur more commonly in autumn and winter months, when levels of sunlight are low. Experimental evidence of a possible role of vitamin D in IBD stems from work in animal models of the 498 INTEGRATIVE GASTROENTEROLOGY disease whereby the active form of this nutrientinhibits the development of infl ammatory bowel disease (Froicu & Cantorna, 2007 ). Furthermore, the absence of the vitamin D receptor is associated with activation of the innate immune system and the development of colitis. Clinical trials utilizing vitamin D as a therapeutic intervention are presently underway. A recent trial of vitamin D for Crohn’s Disease showed that supplementation with 1200 international units of vitamin D3 signifi cantly increased serum vitamin D levels and reduced the risk of relapse from 29% to 13 %, (P = 0.06) (Jø rgensen SP, Agnholt J, Glerup H et al., 2010 ). Larger studies are required.

OTHER FACTORS THOUGHT TO BE PRECURSORS OF INFLAMMATORY BOWEL DISEASE

• Oral contraceptives or hormone replacement therapy (Godet, May, & Sutherland, 1995 ) • Perinatal passive smoke exposure (Russell et al., 2005 ) • Childhood smoke exposure (passive or active; see Mahid, Minor, Stromberg, & Galandiuk, 2007) • Smoking (for Crohn’s disease; see Cosnes, 2004 ) • Prematurity (but not mode of delivery; see Sonntag et al., 2007 ) • Appendectomy (for Crohn’s disease; see Cosnes, Seksik, Nion- Larmurier, Beaugerie, & Gendre, 2006) • Treatment of acne with isotretinoin (Reddy, Siegel, Sands, & Kane, 2 0 0 6 )

Alternative Therapies

The speciﬁ c carbohydrate diet (www.scd.org) is a food-based approach to enteral nutrition for patients with inﬂ ammatory bowel disease that has been used by patients with CD and UC, with anecdotal reports of long-term remission without medication (Nieves & Jackson, 2004 ).

SPECIAL DIETS USED FOR IBD

The Speciﬁ c Carbohydrate Diet for Crohn’s Disease

Th e specifi c carbohydrate diet (SCD) is a strict grain-free, lactose-free and sucrose-free diet that was designed for people with Crohn’s disease, ulcerative Alternative Approaches to the Patient with Inﬂ ammatory Bowel Disease 499 colitis, celiac disease, infl ammatory bowel disease (IBD) and irritable bowel syndrome (IBS). Th e specifi c carbohydrate diet was developed by Sydney Valentine Haas, MD. Elaine Gottschall helped to popularize the diet aft er using it to help her daughter recover from ulcerative colitis leading her to write a book Breaking the Vicious Cycle: Intestinal Health Th rough Diet (Gottschall, 1 9 9 4 ) . Th e purported mechanism of action of enteral feeding as therapy for IBD is related to improvement of nutritional status, favorable alteration in ileocecal fl ora and fermentation by the proper choice of nutritious sources of carbohydrate (Gottschall, 1994 ). Th e SCD is far more eff ective for patients with CD than UC. In practice, the SCD consists of meat, poultry, fi sh, eggs, most vegetables and fruits, nut fl ours, aged cheese, homemade yogurt, and honey. Forbidden foods include all cereal grains and their derivatives (including sweeteners other than honey), legumes, potatoes, lactose-containing dairy products and sucrose. Related studies have found that high sucrose intake predisposed to CD (Matsui et al., 1990 ; Martini & Brandes, 1976 ; Th urnton, Emmett, & Heaton, 1979 ; Mayberry, Rhodfes, & Newcombe,) and that control of disease was enhanced by its avoidance (Heaton, Th ornton, & Emmett, 1979 ).

FODMAPs and Crohn’s Disease

A new hypothesis is proposed, by which excessive delivery of highly fermentable but poorly absorbed short-chain carbohydrates and polyols (designated FODMAPs–Fermentable Oligo-, Di- and Mono-saccharides And Polyols) to the distal small intestinal and colonic lumen is a dietary factor underlying susceptibility to Crohn’s disease. Th e subsequent rapid fermentation of FODMAPs in the distal small and proximal large intestine induces conditions in the bowel that lead to increased intestinal permeability, a predisposing factor to the development of Crohn’s disease. Evidence supporting this hypothesis includes the increasing intake of FODMAPs in western societies, the association of increased intake of sugars in the development of Crohn’s disease, and the previously documented eff ects of the ingestion of excessive FODMAPs on the bowel (Gibson PR, Shepard SJ, 2005 ).

Effective diet therapy for IBD must be individualized according to food preferences and diagnosis. Patients with CD are more likely to be food-sensitive than patients with UC. 500 INTEGRATIVE GASTROENTEROLOGY

Diets that induce remission of CD do not usually induce remission of UC, although they improve patients’ nutritional status and prevent complications related to surgery. Recent dietary approaches to treatment of UC have examined the therapeutic potential of short-chain fatty acids (SCFA), butyric acid in particular (Dionne et al., 1998 ). SCFA’s: Nourish the colonic epithelium, lower intraluminal pH, favor the growth of Lactobacilli and Bifi dobacteria (considered to be benefi cial organisms, or probiotics) and inhibit the growth of Clostridia, Bacteroides, and Escherichia coli, potential pathogens. In addition to serving as the preferred energy substrate for colonic epithelial cells, butyrate has a true anti-infl ammatory eff ect, preventing activation of the proinfl ammatory nuclear transcription factor, NF-k-B (Inan et al., 2000 ). When added to 5-ASA enemas, butyrate (80 mM per liter), induces remission in ulcerative proctitis that is resistant to combined 5-ASA/hydrocortisone enemas (Vernia et al., 2003 ). Because butyrate is normally produced by bacterial fermentation of indigestible carbohydrate in the colon, studies have examined the eff ect of fi ber supplementation on the course of UC. Th ese studies are described below in the section on Prebiotics (Table 44.1 ).

Table 44.1. Prebiotics in Ulcerative Colitis

Author Year Fiber Study Outcome

Fernandez- 1999 Plantago Ovata seed Fiber + /- = to Mesalamine Banares fi ber 10 gm Mesalamine

Kanauchi 2002 30 gm barley Mod to active disease activity

2003 UC

Hallert 2003 Oat bran 60 gm In remission abd pain

(20gm fi ber) Increase fecal butyrate

Welters 2002 Inulin 24 gm IAPA pouch infl ammation

In these four RCTs, prebiotics were looked at for their eff ect on ulcerative colitis. Th e rationale for performing these studies is that short-chain fatty acids (acetate, propionate, butyrate), which are metabolized into acetyl CoA and are the primary energy source for the colon and necessary to maintain integrity, are defi cient in ulcerative colitis. As you can see in this table, in all four studies patients benefi ted from using prebiotics. NB: Barley foodstuff s are also very high in glutamine, which may benefi t the small bowel as a primary fuel source. Alternative Approaches to the Patient with Inﬂ ammatory Bowel Disease 501

Low Sulfur Diet in UC

• Patients with UC are not defi cient in butyrate, but appear unable to utilize it, perhaps because organic sulfi des produced by their enteric fl ora inhibit the epithelial effects of butyrate (Roediger, Duncan, Kapaniris, & Millard, 1997 ; Roediger, Moore, & Babidge, 1997 ). • Protein consumption is a major determinant of sulfi de production in the human colon (Magee, Richardson, Hughes, & Cummings, 2000 ). • For patients with UC in remission, the risk of relapse is directly infl uenced by higher consumption of protein, especially meat protein, and by total dietary sulfur, and sulfates (Jowett et al., 2004 ). • A low sulfur diet has been advocated for maintenance of remission in UC. • The low sulfur diet, which is markedly different from the specifi c carbohydrate diet used for treatment of CD, eliminates beef, pork, eggs, cheese, whole milk, ice cream, mayonnaise, soy milk, mineral water, nuts, cruciferous vegetables, and sulfi ted alcoholic beverages. • Controlled studies have not been performed, but a small preliminary study demonstrated the feasibility and safety of a low sulfur diet for patients with UC over a 5-year period (Roediger, 1998).

Th e diff erences in dietary response patterns between patients with CD and patients with UC make clarity of diagnosis essential for proper nutritional therapy.

EXCLUSION DIETS

Exclusion diets eliminate specifi c symptom-producing foods and have been used to maintain remission of a number of digestive diseases including the irritable bowel syndrome (IBS) and IBD.

Crohn’s Disease and Exclusion Diets

Although self-reported food intolerance is common among patients with IBD (Ballegaard et al., 1997 ), most of the data from controlled studies has been gathered from patients with CD.

The East Anglia Multicenter Controlled Trial

Investigators who conducted the East Anglia Multicenter Controlled Trial observed that 84% of patients with active CD entered clinical remission 502 INTEGRATIVE GASTROENTEROLOGY aft er two weeks of a liquid elemental diet produced a signifi cant decrease in erythrocyte sedimentation rate and C-reactive protein, and an increase in serum albumin. (Riordan et al., 1993 ). Patients were then randomized to receive treatment with prednisolone or treatment with a specifi c food exclusion diet. To determine which foods each patient needed to avoid, a structured series of dietary challenges was conducted. Patients would introduce foods of their choice, one at a time. Any food that appeared to provoke symptoms was excluded from further consumption; foods that did not provoke symptoms were included into a maintenance diet. At six months, 70 percent of patients treated with diet were still in remission, compared with 34 percent of patients being treated with prednisolone. Aft er two years, 38 percent of patients treated with specifi c food exclusion were still in remission, compared to 21 percent of steroid-treated patients. In previous uncontrolled studies, some of the same authors had used a diet consisting of one or two meats (usually lamb or chicken), one starch (usually rice or potatoes), one fruit and one vegetable instead of the elemental diet, in order to induce remission. Structured food challenges were then used to construct a maintenance diet free of symptom-provoking foods. Compliance with the specifi c food elimination diet was associated with a rate of relapse of under 10 percent per year (Alun Jones, Workman, & Freeman, 1985). Individual foods found most likely to provoke symptoms in this study were wheat, cow’s milk and its derivatives, cruciferous vegetables, corn, yeast, tomatoes, citrus fruit, and eggs.

Crohn’s Disease and Dietary Yeast Elimination

A large proportion of CD patients develop antibodies to baker’s and brewer’s yeast, Saccharomyces cerevisiae (ASCA; see Barnes et al., 1990 ). Lymphocytes of ASCA-positive patients proliferate aft er stimulation with mannan, an antigen common to most types of yeast. Lymphocyte proliferation of ASCA- positive patients is associated with increased production of the key infl ammatory mediator, TNF- α (Konrad et al., 2004 ). Rectal exposure to yeast and citrus antigens produced increased rectal blood fl ow and submucosal edema in CD patients, when compared to controls (Van Den Bogaerde et al., 2002 ). Patients with stable chronic CD experienced a signifi cant reduction in the CD activity index during 30 days of dietary yeast elimination and a return to baseline disease activity when capsules of S. cerevisiae were added to their diets (Barclay, McKenzie, Pennington, Parratt, & Pennington, 1992 ). Most recently, a study analyzed IgG antibodies to common foods in Crohn’s disease and and healthy controls. In Crohn’s Disease 84 and 83 % of the patients, respectively, IgG antibodies against processed cheese and yeast were detected. Alternative Approaches to the Patient with Inﬂ ammatory Bowel Disease 503

Th e daily stool frequency signifi cantly decreased by 11 % during a specifi c diet compared with a sham diet. Abdominal pain reduced and general well-being improved (Bentz S, Hausmann M, Pilberger H, Kellermer S et al, 2010 ).

SUPPLEMENTS

Nutritional supplements may be used to correct or prevent the defi ciencies that are common among patients with infl ammatory bowel disease (Table 44.2 .) or to achieve an anti-infl ammatory eff e c t .

Folic Acid

5-ASA derivatives, sulfasalazine in particular, impair folic acid transport (Mason, 1989 ). Reduced folic acid in patients with IBD is associated with hyperhomocysteinemia (Chowers et al., 2000 ), a risk factor for deep vein

Table 44.2. Malnutrition in IBD

Deﬁ ciency CD UC Treatment

Negative nitrogen balance 69% Unknown Adequate energy and protein

Vitamin B12 48% 5% 1000 mcg/d x 7 d then Q mo

Folate 67% 30% –40% 1 mg/d

Vitamin A 11% Unknown 5,000–25,000 IU/d

Vitamin D 75% 35% 5,000–25,000 IU/d

Calcium 13% Unknown 1,000–1,200 mg/D

Potassium 5% –20% Unknown Variable

Iron 39% 81% Fe Gluconate 300 mg TID

Zinc 50% Unknown Zn Sulfate 220 mg daily or BID

Th is table illustrates the frequency of vitamin and mineral insuffi ciencies in patients with IBD. Of note, patients with Crohn’s disease are vulnerable to vitamin B12, folate, zinc, and vitamin D defi ciency due to their small bowel disease and malabsorption of fat, and diminished surface area for absorption due to damage to the surface epithelium. Th us, all patients with IBD should be screened annually for vitamins and minerals as shown here, to avoid defi ciencies of these micronutrients. 504 INTEGRATIVE GASTROENTEROLOGY thrombosis (Den Heijer et al., 1996 ), an extraintestinal complication of infl ammatory bowel disease. One study found that a high dose of folic acid (15 mg/day) reversed sulfasalazine-induced pancytopenia in two patients (Logan, Williamson, & Ryrie, 1986 ). Folic acid has been studied for its ability to circumvent dysplasia as a consequence of longstanding IBD with disap- pointing results (Table 44.3 .).

Vitamin B12

Because vitamin B12 absorption may be impaired by ileal infl ammation and by small bowel bacterial overgrowth, defi ciency of vitamin B12 has long been described as a potential complication of CD (Beeken, 1975 ). Lower vitamin B12 levels are associated with increased serum homocysteine in patients with CD (Romagnuolo, Fedorak, & Dias, 2001 ). Ischemic strokes in a woman with CD were associated with vitamin B12-reversible hyperhomocysteinemia (Penix, 1998 ). Cobalamin injection can correct the megaloblastic anemia associated with CD (Abe, Wakabayashi, & Hirose, 1989 ). One needs to correct defi ciencies of low B12 status prior to supplementing with folic acid or risk precipitating neurological defi cits.

Table 44.3. Folate Does Not Prevent IBD-Related Cancer or Dysplasia

Senior Author Cases/ End point RR/OR Signiﬁ cant Controls Protection?

Lashner 1997 29/69 Cancer or dysplasia 0.54 RR NO

Pardi 2003 11/52 Cancer or dysplasia 0.68 RR NO

Smith 2006 2/22 Dysplasia NA NO

Lashner 1989 35/64 Cancer or dysplasia 0.38 OR NO

Lashner 1993 6/61 Cancer or dysplasia 0.82 OR YES

Rutter 2004 68/136 Cancer or dysplasia 0.40 OR NO

Folate is commonly defi cient in ulcerative colitis and Crohn’s disease. Folate is felt vis-a-vis methyl donation to be “chemopreventive”; however, there is evidence to suggest that at higher doses folate may be cancer promoting (Sauer, Mason, & Choi, 2009 ). Th is table shows that folate, in 5 of 6 studies, does not prevent IBD-related dysplasia. Th us, for IBD it is best to test individuals for folate status using RBC folate, and only supplement to suffi ciency using the dietary reference intake (DRI) of 400 micrograms daily as a guideline for therapy. Alternative Approaches to the Patient with Inﬂ ammatory Bowel Disease 505

Vitamin B6

Median vitamin B6 levels are signifi cantly lower in patients with IBD than controls; low levels are associated with active infl ammation and hyperhomocysteinemia (Saibeni et al., 2003 ). Although some homocysteine is removed by folate-B12-dependent rem- ethylation, the bulk of homocysteine is converted to cystathionine in a reaction catalyzed by vitamin B6. Ischemic stroke and high grade carotid obstruction in a young woman with CD were attributed to hyperhomocysteinemia, vitamin B6 defi ciency, and a heterozygous methylenetetrahydro- folate reductase gene mutation. Th e authors believed that vitamin B6 defi ciency was the principal cause of hyperhomocysteinemia in this patient (Younes- Mhenni et al., 2004 ). Low B6 status can cause neuropathy, oft entimes falsely attributed to low B12 status in Crohn’s Disease.

Vitamins E and C

Blood levels of vitamins E and C are oft en reduced in patients with IBD (Fernandez-Banares et al., 1989 ). Low Vitamin E status can fi rst present with neurological sequelae, and should be suspected in Crohn’s Disease with intestinal malabsorption of long chain fats. Administration of alpha-tocopherol 800 IU per day and vitamin C 1000 milligrams per day to patients with stable, active CD decreased markers of oxidative stress but had no eff ect on the CD activity index (Aghdassi et al., 2003 ). In combination with Selenium, vitamin E has been shown to protect animals against experimental colitis (Protective eff ects of selenium and vitamin E combination on experimental colitis in blood plasma and colon of rats. Bitiren M, Karakilcik AZ, Zerin M, Ozardali I et al, 2009).

Vitamin A

Although levels of carotenoids (Rumi et al., 2000 ) and retinol (Bousvaros et al., 1998 ) are diminished in patients with active CD, low levels may not be entirely related to malabsorption, but to infl ammation (Reimund et al., 2005 ; Sampietro et al., 2002 ) and a reduction in circulating retinol binding protein (Janczewska et al., 1991 ).In experimental colitis, all-trans retinoic acid ameliorates intestinal injury by shift ing the immune response from a Th 1 to a Th 2 cytokine profi le All-trans retinoic acid ameliorates trinitrobenzene sulfonic acid-induced colitis by shift ing Th 1 to Th 2 profi le (Bai A, Lu N, Zeng H, Li Z et al., 2010 ). 506 INTEGRATIVE GASTROENTEROLOGY

Vitamin D and Bone Status in Inﬂ ammatory Bowel Disease

IBD is associated with a high prevalence of defi ciencies of vitamin D, vitamin K and bone mineral density (Kuwabara A, Tanaka K, Tsugawa N, Nakase H et al. Osteoporos Int. 2009 Jun;20(6):935-42. Reduced blood levels of 25-OH cholecalciferol, the major vitamin D metabolite, are common in patients with CD, and are related to malnutrition and lack of sun exposure (Harries et al., 1985 ; Vogelsang et al., 1989 ). Administration of vitamin D, 1000 IU per day for one year, prevented bone loss in patients with active CD (Vogelsang, Ferenci, Resch, Kiss, & Gangl, 1995 ). Th e major causes of bone loss in IBD, however, are the eff ects of infl ammatory cytokines and glucocorticoid therapy (Trebble et al., 2004 ), not vitamin D status. Calcitriol (1,25-dihydroxycholecalciferol), the most active metabolite of vitamin D, may actually be increased in patients with infl ammatory bowel disease as intestinal macrophages increase its synthesis. Elevated calcitriol is associated with increased risk of osteoporosis, and may serve as a marker of disease activity (Abreu et al., 2004 ). Hypercalcemia is a rare complication of excess calcitriol, and serum calcium should be monitored in patients with IBD receiving vitamin D supplements (Tuohy & Steinman, 2005 ).

Vitamin K and Bone Status in Inﬂ ammatory Bowel Disease

Biochemical evidence of vitamin K defi ciency has been found in patients with ileitis and in patients with colitis treated with sulfasalazine or antibiotics (Krasinski et al., 1985 ). Serum vitamin K levels in CD are signifi cantly decreased compared with normal controls and are associated with increased levels of undercarboxylated osteocalcin, indicating a low vitamin K status in bone. In patients with CD, undercarboxylated osteocalcin is inversely related to lumbar spine bone density (Schoon et al., 2001 ). A sensitive method for measuring the serum level of protein-induced by vitamin K absence or antagonist II (PIVKA-II) has become widely available (Kuwabara A, Tanaka K, Tsugawa N et al, 2009 ). In a recent study, Compared with ulcerative colitis (UC) patients, CD patients had signifi cantly lower plasma vitamin K and 25OH-D concentrations; signifi cantly higher serum levels of PIVKA-II, and undercarboxylated osteocalcin; and signifi cantly lower bone mineral density scores at almost all measurement sites. Th e rate of bone resorption in CD is inversely correlated with vitamin K status, suggesting that vitamin K defi ciency might be another etiological factor for osteopenia of infl ammatory bowel disease (Duggan et al., 2004 ). Alternative Approaches to the Patient with Inﬂ ammatory Bowel Disease 507

Optimal dose of vitamin K for correction of defi ciency is not known. Patients with active small bowel disease may not absorb oral vitamin K, even at high dosage (Fugate & Ramsey, 2004 ).

Calcium and Bone Status in Inﬂ ammatory Bowel Disease

In experimental animals, low dietary calcium increases severity of IBD (Cantorna, Zhu, Froicu, & Wittke, 2004 ). Calcium supplementation is recommended for maintaining bone density in patients with IBD though there is confl icting data regarding its effi cacy. Calcium supplementation (1000 milligrams per day) with 250 IU of vitamin D per day, conferred no signifi cant benefi t to bone density at one year in patients with corticosteroid-dependent infl ammatory bowel disease and osteoporosis (Bernstein et al., 1996 ). However, a more recent study showed that daily supplementation with calcium (500 mg) and vitamin D (400 I.U.) increased bone mineral density Siffl edeen JS, Fedorak RN, Siminoski K et al., 2005).

Zinc

Zinc is an important cofactor for antioxidant defenses. Copper-zinc superoxide dismutase is impaired in patients with clinically active IBD whose intestinal mucosal biopsies demonstrate increased oxidative stress. Low plasma zinc is common in patients with CD and may be associated with clinical manifestations such as acrodermatitis, altered taste and smell, decreased activity of zinc-dependent enzymes like thymulin and metallothionein and reduction in muscle zinc concentration and poor taste acuity. Zinc absorption is impaired and fecal zinc losses are inappropriately high (Griffi n, Kim, Hicks, Liang, & Abrams, 2004 ). Zinc status is very important to monitor in children and adolescents as zinc defi cient adolescents with CD grow and mature more normally when zinc defi ciency is treated. Correction of zinc defi ciency as a specifi c intervention for IBD has been associated with global clinical improvement (Hendricks & Walker, 1988 ). Zinc supplementation may improve immune function, epithelial renewal and maintain mucosal integrity. zinc has been shown to improve barrier function in CD, although the inherent mechanisms are unknown (Hering & Schulzke, 2009 ). High dose supplementation with zinc sulfate, 110 milligrams three times a day for eight weeks, signifi cantly decreased small intestinal permeability in CD for a period of twelve months (Sturniolo, Di Leo, Ferronato, D’Odorico, & D’Inca, 2001 ). In CD patients with active disease, zinc sulfate, 200 milligrams per day (but not 60 milligrams per day) signifi cantly increased plasma zinc and thymulin activity (Brignola et al., 1993 ). 508 INTEGRATIVE GASTROENTEROLOGY

Zinc competes with copper, iron, calcium, and magnesium for absorption. When administering high doses of zinc, consider administering a multimin- eral at a separate time of day. Zinc will be absorbed best if not taken at the same time as calcium, magnesium, or iron.

Selenium

Like zinc, selenium is an important cofactor for antioxidant enzyme systems such as Se-dependent glutathione peroxidase, which is impaired in IBD. Low selenium levels in patients with Crohn’s disease are associated with increased levels of TNF-α and decreased levels of the antioxidant enzyme, glutathione peroxidase (GSHP; see Reimund, Hirth, Koehl, Baumann, & Duclos, 2000). Patients with small bowel resection are at risk for severe selenium defi ciency and monitoring of selenium status and selenium supplementation has been recommended for this group in particular (Rannem, Ladefoged, Hylander, Hegnhoj, & Jarnum, 1992 ). Patients on enteral feeding with liquid formula diets experience decreased selenium concentrations proportional to duration of feeding, suggesting that additional selenium supplementation is also needed by them (Kuroki, Matsumoto, & HIida, 2003 ).

Magnesium

Magnesium defi ciency is a potential complication of IBD, a result of decreased oral intake, malabsorption and increased intestinal losses due to diarrhea. Urinary magnesium and RBC magnesium are better predictors of magnesium status than serum magnesium in this setting (Galland, 1988 ). Reduced urinary magnesium excretion is a signifi cant risk factor for urolithiasis, one of the extraintestinal manifestations of IBD (Böhles et al., 1988 ). For patients with IBD, the urinary ratio of magnesium and citrate to calcium is a better predictor of lithogenic potential than urinary oxalate excretion (McConnell et al., 2002 ). Supplementation with magnesium and citrate may decrease urinary stone formation, but diarrhea is a dose-related, limiting side eff e c t .

Chromium

Chromium is an important cofactor for glucose tolerance. Levels of chromium are oft en overlooked in patients with infl ammatory bowel disease who are on Alternative Approaches to the Patient with Inﬂ ammatory Bowel Disease 509 glucocorticosteroid therapy. Glucocorticoid therapy increases urinary chromium excretion and chromium picolinate, 600 micrograms per day, can reverse steroid-induced diabetes in humans, with a decrease in mean blood glucose from 250 milligrams per dl to 150 milligrams per dl. Chromium supplementation may be of benefi t for patients receiving glucocorticoids who manifest impaired glucose tolerance (Ravina et al., 1999 ).

Iron

Anemia occurs in about 30 percent of patients with IBD (Gasche, Lomer, Cavill, & Weiss, 2004 ). Its causes include: iron defi ciency due to blood loss, cytokine-induced suppression of erythropoiesis from chronic infl ammation and side eff ects of medication. Iron defi ciency actually increases the IFN-γ response in TH-1 driven infl ammation and may contribute to aggravation of Crohn’s disease Lih-Brody L, Powell SR, Collier KP, Katz R et al., 1996). Oral iron supplements may increase oxidative stress in the gut via Fenton chemistry. Very high dose iron supplementation consistently aggravates experimental colitis in rodents (Oldenburg et al., 2001 ). Th e relative risks and benefi ts of oral iron supplementation for patients with IBD are uncertain.

ESSENTIAL FATTY ACIDS

PHYSIOLOGY AND BACKGROUND

Essential fatty acids (EFA) refer to dietary constituents that cannot be synthesized endogenously and must be obtained via the diet for optimal health. Biochemical studies indicate that 25 percent of patients with IBD show evidence of essential fatty acid defi ciency (Siguel & Lerman, 1996 ). In experimental animals, fi sh oil feeding ameliorates the intestinal mucosal injury produced by methotrexate (Vanderhoof et al., 1991 ). In tissue culture, omega-3 fatty acids stimulate wound healing of intestinal epithelial cells (Ruthig & Meckling- Gill, 1999 ). It is interesting to note that omega-6 EFAs are markedly more common in the current Western diet and may have a proinfl ammatory eff ect. Omega-3 EFA are found in a wide variety of foods including, fl ax seeds, eggs of hens on a diet rich in fl ax seed (otherwise one yolk has only 0.2 g omega 3), walnuts (other nuts do not have suffi cient amounts for a therapeutic eff ect, FYI e.g. 1 tbsp of almond butter = 0.06g; walnuts: 1 cup = 10.6g), cultivated plants (FYI e.g. kale–1 cup chopped kale = 0.12 g omega 3), berries (e.g. 1 cup raw 510 INTEGRATIVE GASTROENTEROLOGY strawberries = 0.09g, while blueberries 0.08g, which is traces; berries are not a reliable source of omega 3, hemp seeds and fi sh (deep water fatty fi sh such as mackerel, herring, sardines, wild caught salmon) FYI, 3 oz. wild Atlantic salmon cooked in dry heat = 1.88g. Long-term of fi sh oil use raises theoretical concerns for possible; increased bleeding lipid peroxidation and toxicity of mercury and halogenated biphenyls. Fish oil can be administered as either raw fi sh oil or as an enteric-coated capsule. A dose of up to 3 grams per day of EPA plus DHA has been determined to be safe for general consumption. Omega-3 EFA appears to work through a plethora of mechanisms (Figure 44.4 .). Eicosanoids appear to aff ect both the cyclooxygenase (COX) pathway (primarily COX-2) and the 5-lipoxygenase pathway (Figure 44.4 .). Prostaglandin

E2 is a proinfl ammatory, nociceptive factor that is produced through the COX-2 pathway while arachidonic acid (AA) is the usual substrate for this pathway. EPA is a chemical homologue that diff ers from AA by only the presence of the n3 double bond. Th erefore, EPA represents both an inhibitor of AA and an alternate substrate for COX. EPA also results in inhibition of the 5-lipoxygenase pathway and decreased production of proinfl ammatory leukotriene B4 . EPA and DHA can themselves act as substrates for the formation of novel protective mediators (termed E-series and d -series resolvins) that may have direct anti-infl ammatory eff ects (Figure 44.5 .). Furthermore, omega-3 EFA regulates transcription factors such as peroxisome proliferator- activated receptors (PPARs) with resultant downregulation of infl ammatory processes as well as inhibition of NFkB expression and downregulation of the proinfl ammatory cytokines IL-1β and TNF-α .

CLINICAL TRIALS

Ulcerative Colitis

Numerous studies have evaluated the eff ects of fi sh oil on ulcerative colitis. Several early studies supported the notion that enteral fi sh oil supplements led to improvement in IBD in animal models. Th e fi ndings of animal studies were corroborated in small clinical trials (Table 44.4 ). Th e methodology and endpoints have been varied in these clinical studies and it is diffi cult to directly compare the results obtained. When clinical scores were used as an outcome (Disease Activity Index, Ulcerative Colitis Activity Index or undefi ned “clinical score”), three of fi ve studies showed signifi cant clinical improvement in the fi sh oil arm of the study at some point during the course of therapy (although only two). When endoscopic endpoints were used Alternative Approaches to the Patient with Inﬂ ammatory Bowel Disease 511

Table 44.4. Fish Oils and Remission in UC

Study EPA DHA Clinical Endo

Almallah 1998 3.2 g/d 2.4 g/d p<0.05 p=0.013

Aslan 1992 2.7 g/d 1.8 g/d ∗ p<0.05 NR

Stenson 1992 3.24 g/d 2.16 g/d p=0.001 p=0.054

In ulcerative colitis, 3 RCTs looked at whether fi sh oils could induce remission of disease — in all 3 studies, using a range of therapeutic doses of n3 fatty acids (combined EPA-DHA over 3 grams) showed statistical clinical benefi t. to evaluate the role of fi sh oil in the treatment of ulcerative colitis, all studies showed statistically signifi cant improvement in the study group that received fi sh oil supplementation. Future studies should assess the eff ects of pharmaceutical grade enteric-coated n–3 fatty acids on clinical outcomes in IBD, including requirements for corticosteroids. Recently, a randomized controlled trial evaluated a “nutritionally balanced oral supplement” (UCNS) enriched with fi sh oil, fructooligosaccharides, gum Arabic, vitamin E, vitamin C and selenium was found to improve disease activity and medication use in patients with mild to moderate ulcerative colitis. Th e group treated with the supplement containing fi sh oil showed a signifi cantly greater rate of decrease in the dose of prednisone required to control clinical symptoms when compared to the group that received placebo. Th is type of integrated approach with synergistic nutraceuticals may achieve superior outcomes in future IBD studies.

FISH OIL AND CROHN’S DISEASE

Th e Cochrane Collaboration recently published a systematic review evaluating this topic. Evaluated 214 publications and identifi ed 15 randomized controlled trials. Only four studies were of suffi cient quality to be included in the analysis (Table 44.5 ). Enteric-coated omega-3 EFA supplementation reduced the one-year relapse rate by half with an absolute risk reduction of 31 % and a number needed to treat (NNT) of only 3. A much larger RCT asked whether n3 fatty acids could sustain remission once it is achieved (Figure 44.6 .). Subsequently, two randomized, double-blind, placebo-controlled studies (Epanova Program in Crohn’s Study 1 [EPIC-1] and EPIC-2) were conducted between January 2003 and February 2007 at 98 centers in Canada, Europe, Israel, and the United States. Data from 363 and 375 patients with quiescent Crohn’s disease were evaluated in EPIC-1 and EPIC-2, respectively. Patients with a 512 INTEGRATIVE GASTROENTEROLOGY

Table 44.5. Fish Oils and CD

Author Patients Time Intervention Outcomes

Belluzzi 1996 39/39 1 year 1.8 g EPA CDAI<150 0.9 g DHA

Lorenz-Meyer 1996 70/65 1 year 3.3 g EPA CDAI<150 1.8 g DHA

Belluzzi 1997 26/24 1 year 1.8 g EPA CDAI<150 0.9 g DHA

Romano 2005 18/20 1 year 1.2 g EPA PCDAI 0.6 g DHA <20

In Crohn’s disease, 4 RCTs all showed clinical effi cacy for achieving remission.

Crohn’s Disease Activity Index (CDAI) score of less than 150 were randomly assigned to receive either 4 g/d of omega-3 free fatty acids or placebo for up to 58 weeks. No other treatments for Crohn’s disease were permitted. Clinical relapse, as defi ned by a CDAI score of 150 points or greater and an increase of more than 70 points from the baseline value, or initiation of treatment for active Crohn’s disease. In both EPIC-1 and EPIC-2, there were no signifi cant diff erences in the CD relapse rate for placebo versus fi sh oils. A second metaanalysis by the Cochrane group combined the data from their original report along with the results from EPIC-1, EPIC-2 showed a marginal benefi t for enteric-coated fi sh oil for the maintenance of Crohn’s Disease (Turner D, Zlotkin SH, Shah PS et al., 2009 ). A recent metaanalysis echoed the marginal benefi t for enteric coated fi sh oils for the maintenance of Crohn’s disease. (Turner D, Shah PS, Steinhart AH, Zlotkin S et al, 2010) (fi gure 44-x).

Glutamine

Glutamine appears to have a special role in restoring normal small bowel permeability and immune function. Patients with intestinal mucosal injury secondary to chemotherapy or radiation benefi t from glutamine supplementation with less villous atrophy, increased mucosal healing and decreased passage of endotoxin through the gut wall (van der Hulst et al., 1993 ). Although integrative practitioners oft en advocate glutamine therapy for treatment of infl ammatory bowel disease, controlled studies have shown no benefi t from glutamine supplementation at doses as high as twenty grams per day in patients with CD (Akobeng et al., 2000 ; Den Hond et al., 1999 ). Glutamine excess aggravates experimental colitis in rodents (Shinozaki, Saito, & Muto, 1997 ). Glutamine is commonly used in commercially available nutraceutical medical foods for improving gut barrier health. Alternative Approaches to the Patient with Inﬂ ammatory Bowel Disease 513

N-Acetylglucosamine (NAG)

NAG is a substrate for synthesis of glycosaminoglycans, glycoproteins that protect the bowel mucosa from toxic damage. Synthesis of NAG by N-acetylation of glucosamine is impaired in patients with IBDD (Burton & Anderson, 1983 ). In a pilot study, NAG (3 to 6 grams per day for for more than two years) given orally to children with refractory IBD produced symptomatic improvement in the majority of patients and an improvement in histopathology (Salvatore et al., 2000 ). In children with distal colitis or proctitis, the same dose of NAG was administered by enema with similar eff ects.

Probiotics

Table 44.6. Probiotics in Ulcerative Colitis

Study Probiotic Result

Kruis et al . (1997) Escherichia coli Nissle 1917 Equal to mesalamine Venturi et al. (1999) E. coli Nissle 1917 Equal to mesalamine Rembacken et al . (1999) E. coli Nissle 1917 Equal to mesalamine Gustlandi et al . ( 2003 ) S. boulardii Equal to mesalamine Ishikawa et al . (2003) Bifi dobacterium Milk Superior to placebo Borody et al . (2003)∗ Stool enema Improved Kruis et al . (2004) E. coli Nissle 1917 Superior to conventional medications Kato et al . (2004) Bifi dobacteria Milk Superior to placebo

Furrie et al . ( 2005 ) Bifi dobacteria + fi ber Improved

Th is table summarizes the data for randomized clinical trials of probiotics in ulcerative colitis. In 4 of the studies, probiotics were found to be equal to mesalamine; in 1 study superior to medications; in 2 studies superior to placebo; and in 2 studies improved. Borody, using fecal transfer or “bacte- riotherapy” to change fl ora, permanently improved patients with resistant disease to conventional medications. In a small group of 6 patients with refractory UC gave broad-spectrum antibiotics and PEG to clear bowel. Th en given freshly prepared fecal enema from a healthy donor. Reported reversal of all symptoms by 4 months and sustained reversal of 1–3 years. J. Clinical Gastroenterology 2003 37:42-47. In these studies, the mechanisms for UC benefi t were noted in biopsy specimens. Probiotics were noted to decrease proinfl ammatory TNF, NFkB, while increasing in IL-10 It is important to note that changes in fl ora observed only temporarily (transiently) change the total fl ora without permanently changing the fl ora-thus as, he probiotics are working on the gut barrier and immune system to establish an eff ect not by merely repopulating the gut. Th e strains given in these studies vary widely and individual hosts may selectively respond to various preparations. 514 INTEGRATIVE GASTROENTEROLOGY

Probiotics are benefi cial microorganisms. Th eir therapeutic use in IBD is attracting considerable attention, because of the recognition that alteration of intestinal microfl ora may modulate intestinal immune responses (O’Sullivan e t a l . , 2 0 0 5 ) .

Immunoregulatory Roles for Probiotics in IBD • Upregulate Th2 cytokines (IL-10) • Downregulate Th1 cytokines (IL-12) • Inhibit IFNg by T-cells • Inhibit NFkB • Stabilize IkB levels • Induce T-regs

Because of the large number of probiotic preparations available, this section will only discuss those preparations that are commercially available in the United States and that have been studied in clinical trials of patients with IBD. More data exist for their benefi ts in UC than in CD. For a more comprehensive discussion of probiotics, please see Chapter 28.

VSL-3

Is a proprietary mixture of Lactobacillus acidophilus, L. bulgaricus, L. casei, L plantarum, Bifi dobacteriium brevis, B. infantis, B. longum and Streptococcus salivarius ssp thermophilus, supplied in sachets containing 900 billion organisms each. When added to therapy with the 5-ASA derivative balsalazide, VSL-3 (one sachet twice a day) induced faster remission of active UC than balsalazide or mesalazine alone (Tursi et al., 2004 ). In an uncontrolled trial, two sachets of VSL-3 twice a day for six weeks as monotherapy yielded clinical and endoscopic remission of mild to moderate UC in 54 percent of patients treated (Bibiloni et al., 2005 ). VSL-3 also prevents relapse of pouchitis (post- colectomy infl ammation of the ileal pouch; see Gionchetti et al., 2000 ), with two sachets once a day producing remission rates far better than placebo over a one-year period (Mimura et al., 2004 ). A survey done at the Cleveland Clinic, however, found poor compliance with this therapy in patients not participating in clinical trials (Shen et al., 2005 ). In children, VSL-3 has been shown to induce remission with moderate activate disease and maintain remission (Huynh HQ, deBruyn J, Guan L, Diaz H et al 2009 ; Miele E, Pascarella F, Giannetti E, Quaglietta L, 2009 ). Overall, a metaanalysis shows benefi t for Alternative Approaches to the Patient with Inﬂ ammatory Bowel Disease 515 using probiotics for the maintenance of remission in ulcerative colitis (Figure 44-x; Sang LX, Chang B, Zhang WL, Wu XM et al, 2010).

LACTOBACILLUS GG

Lactobacillus rhamnosus var GG at a dose of 10 to 20 billion organisms per day, was found to prevent onset of pouchitis in patients with ileal pouch-anal anastomosis during the fi rst three years aft er surgery in a placebo-controlled trial (Gosselink et al., 2004 ). Lactobacillus GG has been ineff ective in inducing or maintaining remission of patients with CD (Schultz et al., 2004 ) or in preventing relapse of CD aft er surgical resection (Prantera et al., 2002 ).

SACHHAROMYCES BOULARDII

Th is plant-derived yeast has shown benefi t in the treatment or prevention of:

• traveler’s diarrhea (McFarland & Bernasconi, 1993 ) • C. diffi cile diarrhea (Surawicz CM, McFarland LV, Elmer G, 1989a ) • antibiotic-induced diarrhea (Surawicz CM Elmer GW, Speelman P, 1989b ).

Experimental data suggest that the yeast owes its antibacterial eff ects to stimulation of secretory IgA secretion (Buts et al., 1990 ) and macrophage activation (Machado Caetano et al., 1986 ). Despite its stimulation of mucosal immune responses and its antigenic sim- ilarity to baker’s yeast, S. boulardii has shown benefi t in both UC and CD. Th e addition of S. boulardii (250 milligrams three times a day) to maintenance mesalazine therapy of patients with chronic, active UC was associated with induction of remission within four weeks in 17 out of 25 patients (Guslandi, Giollo, & Testoni, 2003 ). In a placebo-controlled trial, the same dose was given to patients with stable, active CD and mild to moderate diarrhea. S. boulardii reduced the frequency of diarrhea and the clinical activity index when given over a ten-week period, with benefi ts apparent within two weeks (Plein & Hotz, 1993 ). When added to mesalazine therapy of patients with CD in remission, S. boulardii (1000 milligrams per day) reduced the frequency of relapse from 37.5% to 6.25% during six months, when compared to mesalazine alone (Guslandi et al., 2000 ). Two studies have demonstrated that patients with CD having altered intestinal permeability normalized their markers of mucosal 516 INTEGRATIVE GASTROENTEROLOGY integrity following S. boulardii therapy. Although S. boulardii is considered non-pathogenic, case reports of S. boulardii fungemia have been described in critically ill or immunocompromised patients exposed to S. boulardii. At least eighteen reports of this complications have been published, including one in which airborne spread of S. boulardii occurred in an intensive care unit (Cassone et al., 2003 ). S. boulardii has been shown to improve intestinal permeability in Crohn’s disease that is in remission (Garcia Vilela E, De Lourdes De Abreu Ferrari M, Oswaldo Da Gama Torres H, Guerra Pinto A et al, 2008).

Prebiotics

DEFINITIONS AND PHYSIOLOGICAL EFFECTS

Prebiotics are nondigestible food ingredients that stimulate the growth or modify the metabolic activity of intestinal bacterial species that have the potential to improve the health of their human host. Criteria associated with the notion that a food ingredient should be classifi ed as a prebiotic are that it remains undigested and unabsorbed as it passes through the upper part of the gastrointestinal tract and is a selective substrate for the growth of specifi c strains of benefi cial bacteria (usually Lactobacilli or Bifi dobacteria ), rather than for all colonic bacteria. Prebiotic food ingredients include bran, psyllium husk, resistant (high amylose) starch, inulin (a polymer of fructofuranose), lactulose, and various natural or synthetic oligosaccharides, which consist of short chain-complexes of sucrose, galactose, fructose, glucose, maltose or xylose (Table 44.1 ) Th e best known eff ect of prebiotics is to increase fecal water content, relieving constipation. Bacterial fermentation of prebiotics yields short-chain fatty acids like butyrate. Fructooligosaccharides (FOS) have been shown to alter fecal biomarkers (pH and the concentration of bacterial enzymes like nitroreductase and beta-glucuronidase) in a direction that may convey protection against the development of colon cancer (Galland, 2005 ). Several studies have suggested benefi ts of various prebiotics for the treatment of patients with ulcerative colitis (Table 44.1 ): Effi cacy of Prebiotics in IBDOat bran, 60 grams per day (supplying 20 grams of dietary fi ber), increased fecal butyrate by 36 per cent in patients with UC and diminished abdominal pain (Hallert et al., 2003 ). A dietary supplement containing fi sh oil and two types of indigestible carbohydrate, FOS and xanthum gum, allowed reduction of glucocorticoid dosage when compared to a placebo, in patients with steroid-dependent UC (Seidner et al., 2005 ). A Japanese germinated barley foodstuff (GBF) containing hemicellulose-rich Alternative Approaches to the Patient with Inﬂ ammatory Bowel Disease 517 fi ber, at a dose of 20 to 30 grams per day increased stool butyrate concentration (Bamba, Kanauchi, Andoh, & Fujiyama, 2002 ) , decreased the clinical activity index of patients with active UC (Kanauchi et al., 2003 ) and prolonged remission in patients with inactive UC (Hanai et al., 2004 ). Wheat grass juice, 100 milliliters twice daily for one month was tested in a small placebo-controlled trial of patients with distal UC (Ben-Ayre et al., 2002 ). Interestingly, use of wheat grass juice was observed to be associated with a signifi cant reduction in rectal bleeding, abdominal pain and disease activity as measured by sigmoi- doscopy. A mixture of B. longum and inulin-derived FOS administered for one month as monotherapy to patients with UC produced improvement in sig- moidoscopic appearance, histology, and several biochemical indices of tissue infl ammation when compared to a placebo control (Furrie et al., 2005 ). Prebiotics appear to provide benefi t to patients with ulcerative colitis.

Bovine Colostrum

Colostrum is the fi rst milk produced aft er birth and is particularly rich in immunoglobulins, antimicrobial peptides (e.g., lactoferrin and lactoperoxi- dase), and other bioactive molecules, including growth factors. Recent studies suggest that the peptide growth factors in colostrum might provide novel treatment options for a variety of gastrointestinal conditions (Playford, Macdonald, & Johnson, 2000 ). Colostrum enemas, 100 milliliters of a 10 percent solution, administered twice a day by patients with distal UC, proved superior to a control enema in promoting healing; all patients were also taking a fi xed dose of mesalazine (Khan et al., 2002 ). Studies of oral colostrum in IBD have not been reported, but 125 milliliters three times a day fed to healthy human volunteers was shown to prevent the increase in intestinal permeability produced by indomethacin (Playford et al., 2001 ), suggesting that peptide growth factors survive passage through the stomach and upper small bowel. Dehydroepiandrosterone (DHEA). DHEA is the steroid hormone produced in greatest quantity by the human adrenal cortex, circulating primarily in the sulfated form, DHEA-S. DHEA has interesting eff ects that may be relevant to IBD. DHEA inhibits activation of nuclear factor kappa B (NF-kB), which is known to be activated in infl ammatory lesions. Patients with IBD have lower levels of DHEA-S in serum and intestinal tissue than controls (de la Torre et al., 1998 ), partially associated with prior treatment with glucocorticoids (Straub et al., 1998 ). In men with IBD, low DHEA-S is associated with increased risk of osteoporosis (Szathmari et al., 2002 ). DHEA has been tested in clinical trials for IBD. In a pilot study, six of seven patients with refractory CD and eight of thirteen patients with 518 INTEGRATIVE GASTROENTEROLOGY

refractory UC responded to DHEA (200 milligrams per day for 56 days) with decrease in the clinical activity index (Andus et al., 2003 ). A case report demonstrated benefi t of the same dose of DHEA in a woman with severe refractory pouchitis, with relapse occurring 8 weeks aft er discontinuation of DHEA (Klebl et al., 2003 ). Th us, DHEA may show promise as a therapeutic adjunct in IBD. Future trials are warranted.

Melatonin

Th e gastrointestinal tract is a major source of extrapineal melatonin, which is produced in mucosal serotonin-rich enterochromaffi n cells. In the gut, melatonin may aff ect mucosal function, lymphocyte activation and motility. Melatonin may protect gut mucosa from ulceration by its antioxidant action, stimulation of the immune system and by fostering microcirculation and epithelial regeneration (Bubenik 2001 ). Melatonin is being studied as therapy for UC in humans (Malhotra et al., 2004 ). In rats with experimental colitis, melatonin reduces colonic infl ammatory injury through inhibition of NF-kB sig- nalling (Li et al., 2005 ). An appropriate human dose has not been determined. Melatonin doses for other conditions vary from one milligram for prevention of jet lag to 30 milligrams per day in the treatment of patients with cancer.

Botanicals

In traditional Chinese medicine and Ayurveda, herbal extracts are the mainstay of treatment for IBD and appear to be eff ective when used by practitioners trained in those systems. Botanicals commonly taken by patients with IBD include:

• S l i p p e r y e l m • F e n u g r e e k • D e v i l ’ s c l a w • Gingko biloba • Angelica sinensis (Dong quai) • L i c o r i c e .

Th ese herbs express antioxidant or anti-infl ammatory activity in vitro (Figure 44.7 ; see also Kang et al., 2005 ; Langmead et al., 2002 ; Dong et al., 2 0 0 4 ) . Alternative Approaches to the Patient with Inﬂ ammatory Bowel Disease 519

POLYPHENOLS

Polyphenols are phytochemicals that are found in food substances produced from plants. Polyphenols are separated from essential micronutrients in that a defi ciency state has not been identifi ed nevertheless, they are believed to play a biologically active role, and have been shown to be potentially immune- modulating (Shapiro, Singer, Halpern, & Bruck, 2007 ) Four polyphenols in particular have a preponderance of evidence in the role of immune modulation and will be addressed in this chapter: resveratrol, epigallocatechin, curcumin and boswellia (Table 44.7 ; see Mazzon et al., 2005 ). 148

RESVERATROL

Resveratrol is most abundant in the skin of red grapes— contributing to a high concentration in red wine and grape juice (Athar et al., 2007 ). Resveratrol is a

Table 44.7. Polyphenols in IBD

Polyphenol # of Route, dose Results Studies

Resveratrol 2 5–10 mg/kg 2/2 improvement: clinical, path, 2/2 IG mediators, cytokines

EGCG 3 5 gm/l, 50 mg/kg/D 3/3 improvement: clinical, path, 1 IP, 2 PO mediators, cytokines

Curcumin 6 2 % , 30–300 mg/kg/D 6/6, improvement: clinical, path, 6 PO, 1 IP mediators, cytokines, markers 4/7 ↑ survival

Boswellia 3 5.0–34.2 mg/kg/D, 2/3 improvement: clinical, 2 PO, 1 IP macroscopic, microscopic, mediators; 1/3 no improvement

Th is table illustrates rodent studies of chemical-induced colitis and protection by polyphenolic compounds (polyphenols). Resveratrol, EGCG (found in green tea), and curcumin were found to protect the colon from chemical-induced injury, while quercetin produced mixed results. Research has shown the quercetin may become metabolized and inactivated locally in the gut tissues. Reprinted from Scholz & Williamson ( 2007) with permission from Verlag Hans Huber. 520 INTEGRATIVE GASTROENTEROLOGY potent inhibitor of cyclooxygenase activity in vivo (Khanduja, Bhardwaj, & Kaushik, 2004 ). In rodent models of infl ammatory colitis, resveratrol has been shown to reverse weight loss, increase stool consistency, improve mucosal appearance, improve histopathology, decrease infl ammatory infi ltrate, and decrease mucosal levels of IL-1B, COX-2, and PGD2 (Martin, Villegas, La Casa, & de la Lastra, 2004 ). Table 44.7 summarizes the work of resveratrol administration in animal models of IBD. To date, resveratrol has not yet been studied in human subjects w i t h I B D .

CATECHINS

Th ese compounds are particularly abundant in green (non-fermented) tea, whereas black tea contains theafl avins and thearubigins (Cabrera, Artacho, & Gimenez, 2006 ). Th ey work through a combination of both antioxidant eff ect and alteration of intracellular signaling (primarily through inhibition of the NF-kB pathway). Catechins are eff ective free radical scavengers in vitro (Heijnen et al., 2001 ). Catechins can modulate and inhibit NF-kB activity (Nomura, Ma, Chen, Bode, & Dong, 2000 ). Table 44.7 summarizes the work of catechin administration in animal models of IBD

CURCUMIN

Turmeric, the major spice in curry, is a natural spice made from the herb Curcuma longa, a member of the ginger family. Besides being a culinary staple, it has been used in Ayurvedic medicine since ancient times. Th e major chemical constituents of turmeric are curcuminoids, the most prominent of which is curcumin. Recently, investigational focus has shift ed toward the role of curcumin as an intracellular signaling agent and studies have demonstrated that curcumin, much like green tea polyphenols, is an inhibitor of NF-kB and leads to downstream regulation and inhibition of proinfl ammatory genes and cytokines (Figure 44.8 ; see also Jobin et al., 1999 ). Administration of curcumin has also been reported to modulate a host of other cytokines and signaling pathways including iNOS, MMP-9, TNF-a, JNK, p38, AKT, JAK, ERK and PKC (Duvoix et al., 2005 ). Four studies involving curcumin administration to murine colitis models showed clinical and histo- pathological improvement and, where measured, decreased infl ammatory cytokine production (Table 44.6 ; also see Sugimoto et al., 2002 ; Kim et al., 2005 ; Deguchi et al., 2007 ). Th ese fi ndings were echoed in three studies Alternative Approaches to the Patient with Inﬂ ammatory Bowel Disease 521

involving rodent models of colitis (Jian et al., 2005 ; Zhang, Deng, Zheng, Xia, & Sheng, 2006 ; Sugimoto et al., 2002 ). Holt and colleagues reported in 2005 the preliminary results of a pilot study involving open-label administration of curcumin preparation to fi ve patients with ulcerative colitis and fi ve patients with Crohn’s disease. Of the ten patients, nine reported improvement at the conclusion of the two-month study. Four of the fi ve patients with ulcerative colitis were able to decrease or eliminate their medications (Holt, Katz, & Kirshoff , 2005 ). In a larger, randomized, double- blind multicenter trial involving 89 patients with quiescent ulcerative colitis, administration of 1 gram of curcumin twice daily resulted in both clinical improvement and a statistically signifi cant decrease in the rate of relapse (Hanai et al., 2006 ). Given its excellent safety profi le, plausible mechanism for aff ecting infl ammation, and the results above, curcumin is poised to have a prominent role in the future management of IBD.

BOSWELLIA

Th e Ayurvedic herb, Boswellia serrata (Indian frankincense) contains boswellic acids, which inhibit leukotriene biosynthesis in neutrophilic granulocytes by noncompetitive inhibition of 5-lipoxygenase (Ammon, 2002 ). During a small six-week trial, 350 milligrams three times a day of Boswellia gum resin was as eff ective as sulfasalazine 1000 milligrams three times a day in reducing symptoms or laboratory abnormalities of patients with active UC (Gupta et al., 2 0 0 1 ) . Th e rate of remission was 82 percent with Boswellia and 75 percent with sulfasalazine (Gupta et al., 1997 ). A proprietary Boswellia extract, H15, was found as eff ective as mesalazine is improving symptoms of active CD, in a randomized, double-blind study from Germany (Gerhardt et al., 2001 ).

ALOE VERA

Aloe vera gel has a dose-dependent inhibitory eff ect on production of reactive oxygen metabolites, prostaglandin E2 and (at high doses) IL-8 by human colonic epithelial cells grown in tissue culture (Langmead, Makins, & Rampton, 2004 ). Oral aloe vera gel, 100 milliliters twice a day for four weeks, produced a clinical response signifi cantly more oft en than placebo (response ratio 5.6) in patients with UC (Langmead et al., 2004 . Remission occurred in 30 percent of patients taking aloe vera gel and 7 percent of patients receiving placebo. Aloe also reduced histological disease activity, whereas placebo did not. No signifi cant 522 INTEGRATIVE GASTROENTEROLOGY side eff ects were described, although it should be noted that aloe vera gel is oft en used as a laxative. Acemannan, an extract of Aloe vera, concentrated to a mucopolysaccharide (MPS) concentration of thirty percent of solid weight, has been demonstrated to reduce symptoms and indices of infl ammation in controlled studies of patients with UC (Robinson, 1998 ).

Mind–Body Therapies

Although it is widely believed that stress aggravates IBD, a German study found no relationship between stressful life events, feelings of pressure or confl ict or fear of separation and symptoms of CD or UC (von Wietersheim, Kohler, & Feiereis, 1992 ). A prospective study did not validate the notion that stressful life events can trigger relapse (North, Alpers, Helzer, Spitznagel, & Clouse, 1991 ). Th ree prospective studies of diff erent types of psychotherapy for patients with IBD failed to show any improvement in medical outcome compared with standard care (Maunder & Esplen, 2001 ; Jantschek et al., 1998 ; Schwarz & Blanchard, 1991 ). Adaptive adjustment to IBD has been conceptualized as a process involving the interaction of three challenges: illness uncertainty, loss and change, and suff ering (Maunder & Esplen, 1999 ). Enhancement of adaptive adjustment and prevention of psychosocial distress should play an important role in the treatment of patients with IBD. Interventions of potential value include: enhancing problem-solving and coping skills, enhancing the positive appraisal of uncertainty, increasing personal control, and increasing social support ( D u d l e y - B r o w n , 2 0 0 2 ) .

An easily taught, “patient centered” self-management intervention addresses the adaptive challenges of living with IBD and improves clinical outcome, dramatically reducing doctor visits and hospitalization rates.

Th is educational tool eff ectively addresses the adaptive challenges of living with IBD. During a 15 to 30 minute consultation, physicians designed personalized self-management strategies for each patient. Th e goal was to ensure that patients could recognize relapse and that patients and physicians could agree on a mutually acceptable treatment protocol for the patient to initiate at onset of a relapse. Physicians specifi cally asked patients about the symptoms they had experienced during past relapses and reviewed past and current treatments that had been used to control symptoms, emphasizing the specifi c eff ectiveness of each and its acceptability to the patient. Compared to a control Alternative Approaches to the Patient with Inﬂ ammatory Bowel Disease 523 group that received customary care, the intervention group required one-third as many doctor visits and one-third as many hospitalizations. Th e diff erence in outcome was not related to specifi c treatments employed but rather to the empowerment of patients to be actively involved in managing their own care (Robinson et al., 2001 ).

The efﬁ cacy of 5-ASA derivatives in inducing remission of IBD can be enhanced by ﬁ sh oils supplying 4000 milligrams of EPA plus DHA per day, and by probiotics (VSL-3, 2 packets a day, or S. boulardii 250 milligrams 3 times a day).

Adverse Events with Corticosteroids

• Early events – Cosmetic side effects (acne, moon facies, edema), sleep disturbance, mood disturbance, glucose intolerance, dyspepsia • Events with prolonged use (usually > 12 weeks) – Posterior sublenticular cataracts, osteoporosis, osteonecrosis of the femoral head, myopathy, susceptibility to infections • Events with withdrawal – Acute adrenal insufﬁ ciency, myalgias, malaise, arthralgias, increased intracranial pressure

Adverse Events with Biologic Agents ( Clark et al., 2007 )

• Increased risk of opportunistic infections, including tuberculosis • Development of autoimmunity (antinuclear and anti-DNA antibodies) • Infusion and injection site reactions • Development of antibodies against therapies • Neurological disorders such as optic neuritis, seizure, and new onset or exacerbation of central demyelinating disorders, including multiple sclerosis • Congestive heart failure • Lymphomas and other malignancies

Acupuncture

Acupuncture and moxibustion are commonly employed by practitioners of Chinese medicine for treatment of ulcerative colitis. Uncontrolled studies 524 INTEGRATIVE GASTROENTEROLOGY from China claim excellent results (Yang & Yan, 1999 ; Zhang, 1998 ). One small study of moxibustion found evidence of enhanced cellular immunity and decreased antibody production associated with improvement of diarrhea in patients with ulcerative colitis (Wu et al., 1997 ), suggesting downregulation of the TH-2 response network. A review of studies from both the Chinese and Western literature supports the effi cacy of acupuncture in the regulation of gastrointestinal motor activity and secretion through opioid and other neural pathways (Li, Tougas, Chiverton, & Hunt, 1992 ). Controlled clinical trials of patients with infl ammatory bowel disease have not yet been conducted.

Preventive Prescription

Despite abundant speculation about the reasons for the dramatic increase in incidence of IBD in industrialized nations over the past century, no convincing strategy for primary prevention has been devised. Secondary prevention may benefi t from the following interventions:

• Prolonged use of 5-ASA derivatives and folic acid (typically one milligram per day) to maintain remission and prevent colon cancer. Fish oils supplying about 5000 milligrams per day of omega-3 fatty acids and S. boulardii 1000 milligrams per day may enhance effi cacy of 5-ASA derivatives in maintenance of remission. • Folic acid, vitamin B6, and vitamin B12 at doses that keep circulating homocysteine low, to prevent thrombotic complications. • Vitamin D (1000 international units per day) and vitamin K (optimal dosage unknown) to prevent bone loss. • A s p e c i fi c food exclusion diet, individually tailored (described above), cessation of tobacco use, and reduced consumption of sucrose, for maintenance of remission in patients with CD. • An anti-infl ammatory diet for maintenance of remission in patients with ulcerative colitis. • Dietary restrictions are very common in patients suff ering from IBD, both iatrogenic and self-imposed, also possibly as a result of confusion by confl icting information in media. • Patients may have decreased nutritional intake from pain, bleeding, or severe diarrhea, and as a result, many patients eat only when absolutely necessary. • Food sensitivities may be particularly diffi cult to assess through the standard elimination diet, as it leads to more calorie restriction. Alternative Approaches to the Patient with Inﬂ ammatory Bowel Disease 525

• Finally, IBD is emotionally diffi cult, especially when various medications produce a limited eff ectiveness. As a result, individual nutritional counseling becomes essential for moral support, education, and guidance, and can be a source of needed reassurance and c o m p l i a n c e .

45 Obesity

LAWRENCE J. CHESKIN AND KATRINA SEIDMAN

key concepts

■ Th e prevalence of obesity has skyrocketed in the past 20 years, particularly among the extremely obese and children. ■ While genetic and medical causes of obesity exist, the vast majority of treatment needs to be directed toward modifi able dietary and physical activity behaviors. ■ An individualized approach to treatment of the obese patient is most useful, and takes into account his or her dietary and medical history and specifi c problem areas related to food choices, triggers for eating, and physical activity level. ■ While a number of over-the-counter medications and botanicals purport to control appetite or body weight, most are ineff ective or lack effi cacy data. ■ A few prescription anorexic-inducing medications — and one fat-blocking medication —provide a modest benefi t over placebo, though their eff ectiveness tends to diminish over time. ■ B a r i a t r i c s u r g e r y i s t h e m o s t e ff ective available treatment, though it is not a fi rst-line treatment because of the risks involved and because surgery patients also frequently regain l o s t w e i g h t . ■

526 Introduction

n the past generation, the prevalence of obesity has nearly doubled: Two- thirds of American adults are now overweight or obese, and if current I trends continue, we will essentially all be overweight by 2030. (Wang et al., 2008 ) Obesity has reached epidemic proportions in the United States. Th e recent increase in prevalence is even more dramatic among children and the extremely obese. Even developing nations are seeing an increase in obesity, in part related to adoption of Western diet and exercise patterns. What is causing this epidemic? In the United States, although the percent of energy intake derived from fat is decreasing (from a high of 40 % to about 32 % today), total daily caloric intake is increasing, and refi ned carbohydrate intake has increased. In addition, increasing numbers of adults and children are sedentary; one-quarter of adults engage in virtually no physical activity aside from activities of daily living. Despite recent discoveries in the molecular genetics of obesity, a major role for genetic infl uences is not a likely explanation for the rapid recent changes in the prevalence of obesity. Obesity is a close second to cigarette smoking as the most important modifi able medical risk factor for diseases of virtually every organ system, including certain cancers (Table 45.1 ). Obesity is the most important risk factor in the development of Type 2 diabetes. Th e risk of complicating medical conditions increases with the degree of obesity, although for some complications — notably coronary artery disease, Type 2 diabetes and stroke — the risk correlates best with the regional distribution of fat. Central (visceral) deposition of fat (the “apple-shape” pattern), seen more commonly in men, increases risk, while excess fat in the lower body (thighs, hips and buttocks), seen more commonly in women (the “pear-shape” pattern), is associated with a lower risk of such c o m p l i c a t i n g c o n d i t i o n s . Obesity also increases overall mortality, and has recently been shown in Framingham, MA and other populations to shorten life expectancy by at least several years. In addition to the medical risks, and oft en more motivating for many people seeking to lose weight, are the unfortunate psychosocial consequences of obesity. Th ere is widespread prejudice against obese individuals, even detectable in the opinions of young children. Th e resulting social and job discrimination contributes to low self-esteem and the high rate of depression among obese people who seek treatment. Notable also is the greater social stigma borne by obese women compared with obese men in our society, and the higher prevalence of obesity among those of low socioeconomic status, African Americans, Latinos, and Native Americans. For example, about 80% 528 INTEGRATIVE GASTROENTEROLOGY

Table 45.1. Major Health Risks of Obesity

Type 2 diabetes mellitus

Hypertension

Coronary artery disease

Dyslipidemias

Strokes

Carcinoma (especially endometrial, colorectal, esophageal, breast)

Sleep apnea

Gallbladder disease

Gastroesophageal refl ux disease

Nonalcoholic fatty liver disease

Osteoarthritis

Gout

Infertility

Th romboembolism

of middle-aged African-American women in the United States are overweight or obese. We all know obesity when we see it, but obesity is technically defi ned as an excess of body fat (> 25% of body weight for men and > 30% for women) rather than an excess of body weight per se. However, the measurement of percent body fat is more diffi cult to obtain, and not as intuitive as body weight. Th us, relative weight is a reasonable surrogate measure for adiposity (percent of body weight constituted by fat). Weight adjusted for height, or body mass index (BMI), defi ned as weight in kilograms divided by the square of the height in meters, is very useful for defi ning and grading the severity of obesity and its attendant risks. BMI is now the standard measure of relative weight, though it may be a poor refl ector of the actual degree of adiposity in very muscular individuals (e.g., certain types of athletes and laborers), and may understate adiposity in very sedentary individuals with little muscle mass. Th e latter is called sarcopenic obesity— a normal or low BMI with increased percent body fat and reduced lean body mass. A BMI of 25 to 30 kg/m2 is defi ned as overweight, 30 to 40 kg/m2 as obese, and 40 kg/m2 as extremely/morbidly obese. It is probably best to encourage Obesity 529 weight loss for medical reasons only, especially if the patient is young, already suff ers from complicating medical conditions, or has a strong family history of diabetes, cardiovascular, or cerebrovascular disease. For those with cosmetic/ trivial obesity, the benefi ts (and motivators) for successful weight loss are perhaps more psychosocial than medical. Th ese patients should be encouraged to focus on a healthier (low refi ned carbohydrate, low saturated fat, high fi ber) diet and increased physical fi tness, rather than just the number on the scale. In the case of abdominal fat deposition, however, even mild excess adiposity may pose a medical problem. It should be noted that visceral obesity can exist even in the absence of overall obesity (i.e., at BMIs below the cut-off point for obesity, or even below the cut-off point for overweight). A waist circumfer- ence of more than 40 inches for men, and more than 35 for women, suggests the diagnosis of abdominal obesity, and can be easily measured with a tape rule around the narrowest point above the navel. Fortunately, this metabolically active abdominal fat is usually fi rst to diminish with weight loss. Th e pear shape is both safer and more durable than the apple, as many women who diet have learned. From an evolutionary perspective, lower-body obesity may have conferred a selective advantage by helping to ensure survival through times of food shortage; lower body fat deposits are easily and selectively mobilized only under the hormonal infl uences of pregnancy and breastfeeding. Despite the inescapable fact that strong genetic infl uences on adiposity exist (as evidenced by adopted child and twin studies, as well as the increasing number of genetic markers being discovered), genetics does not appear to account for the majority of variability in BMI seen in the population, nor is it an insurmountable barrier in most of those who were fortunate (or unfortunate) enough to draw the genes leading to metabolic effi ciency in the lottery of conception. Both the environment and learned behaviors are extraordinarily important as modifi ers of genetic predisposition, and are good places to focus t r e a t m e n t .

Do not allow your patient to accept obesity as their genetic destiny. While genetic factors do inﬂ uence who is most susceptible to becoming obese, obesity can only occur when caloric intake exceeds expenditure — and both sides of this energy balance equation are eminently alterable for almost everyone!

Treatment

Perhaps no other fi eld of medicine today is as subject to the fads and hype, as well as to unreasonable patient expectations, as is obesity treatment. Part of 530 INTEGRATIVE GASTROENTEROLOGY the reason lies in the inherent diffi culty of reconciling a society whose main fuels are high-density and tasty, with an ideal body form typifi ed by the Barbie doll. Given that our profession is unlikely to have any say in what body form people are striving for, the next best approach is to encourage reasonable goal weights for our own patients, press those who really need to lose weight to do so, and steer them toward safe, comprehensive treatment options. Th e components of a comprehensive approach to weight loss are listed in Table 45.2 . Th e omission of any of these components is likely to adversely aff ect long-term results. Th e long-term success rate, defi ned as losing weight and keeping most of it off for 5 years, is low; perhaps 5% to 15 % from the limited data provided by published studies. Although this rate is clearly poor, it must be viewed in context and compared with our similarly poor success in treating other chronic conditions and addictions, for example, cigarette smoking and drug abuse. In fact, if one views the chronic pleasurable overconsumption of food energy as a kind of addiction, an instructive distinction between food and other reinforcing substances appears. Th e cigarette smoker need never smoke again; the obese person, however, must learn to coexist with the off ending substances in order to live. As such, we cannot expect many complete cures, and we will need to be constantly on the alert for relapses in those who appear to be in remission.

Medical Assessment

Th e fi rst step in treating the obese patient is the medical evaluation. Th e patient may desire weight loss, or may be reluctant. By all means, encourage the reluctant patient who has medical complications of obesity to lose weight, but recognize that any attempt at weight loss will be almost certain to fail if the patient is not self-motivated to change. Another important ingredient for success is

Table 45.2. Components of Comprehensive Weight Control Programs

Medical assessment and monitoring

Behavioral assessment and modifi cation

Dietary assessment and modifi cation

Physical activity assessment and modifi cation

Long-term maintenance support Obesity 531 called self-effi cacy, and is the patient’s belief that this change is attainable. Negative expectations are oft en a self-fulfi lling prophecy.

INTEGRATIVE ASSESSMENT

Begin with a complete history and physical. Th e weight history may be of value in identifying precipitants of weight gain, and may suggest both avenues of treatment to pursue and avenues to avoid. For example, a change in job leading to a reduction in physical activity may be detected. Also of interest is whether the onset of obesity was in childhood or later in life. Although only about a fi ft h of obese adults were obese children, about four-fi ft hs of obese children go on to become obese adults. Obesity in childhood can result in an increase in average cell number, not just size, while this occurs less frequently in adults, usually only when rapid weight gain occurs. Treatment of the hyperplastic form of obesity is said to be more diffi cult because weight reduction does not greatly reduce the number of fat cells, only their average size. Other information that can be gleaned from the weight history include postpartum weight gain (the average woman weighs about 10 lbs. more 2 years postpartum compared to pre-pregnancy, but the amount is extremely variable); weight gain aft er smoking cessation (average gain of about 6 lbs., again highly variable, and the most common excuse women give for not wanting to quit smoking); and evidence of yo-yo dieting and eating disorders such as binge eating (consuming inordinately large amounts of food within a specifi ed period, three times a week or more, in private, for more than 1 year with loss of control and negative emotional sequelae); or bulimia nervosa (bingeing plus purging, either by vomiting, use of diuretics, or excessive exercise). When an eating disorder is suspected, referral to a center experienced in the treatment of these problems is recommended. Th e history should also include questions to help rule out endocrine conditions that can lead to obesity, such as hypothyroidism, hyperadrenalism, and neuroendocrine tumors, although even the most common of these, hypothyroidism, is rarely a signifi cant cause of obesity in adults. Also inquire about drugs that may be associated with weight gain, such as sulfonylureas, insulin, steroids, most psychotropics, and anti-seizure medications. (Cheskin et al., 1999 ) Also assess for symptoms suggestive of diseases that oft en complicate obesity, such as Type 2 diabetes, coronary artery disease, hypertension, and sleep apnea. Symptoms and signs of depression should also be sought, as depression commonly accompanies severe obesity and may require additional treatment. Childhood or adult sexual or physical abuse is also common. Because it is usually not volunteered, it needs to be specifi cally elicited aft er 532 INTEGRATIVE GASTROENTEROLOGY rapport has been established with the patient. Th e family history is of particular interest for endocrine disorders, extreme obesity, and its complications.

PHYSICAL EXAMINATION

Th e physical examination may be somewhat limited when the patient is extremely obese, but it can yield evidence of endocrine causes and detect complicating conditions. It is necessary to obtain not only an accurate weight and height for calculation of the BMI, but also tape measurement of the waist cir- cumference, which, as noted, is an important modifi er of the risk in obesity.

LABORATORY EXAMINATION

Laboratory evaluations should serve to screen for the complications of obesity. Blood chemistries should include, in particular, counts of fasting serum glucose, cholesterol, and triglycerides and liver function tests. A thyroid-stimulating hormone (TSH) should be obtained, and other endocrine and metabolic tests i f a p r o b l e m i s s u s p e c t e d .

Fewer than 5% of obese adults will have a newly identiﬁ ed medical cause of weight gain, such as hypothyroidism, and fewer still will see resolution of their weight problem with treatment of any newly identiﬁ ed conditions.

Behavioral Assessment

It is critical to gain a sense of the behavioral triggers to obesity. Th is can be accomplished by referral to an appropriately skilled behavioral psychologist and/or through your own discussions with the patient. First, it is important to assess the impact of the obesity itself on the patient’s level of functioning and quality of life. Some very important aspects of the patient’s problem may only emerge with specifi c inquiry: For example, the patient may have withdrawn from all unnecessary social interactions, may no longer be able to enjoy certain activities or interests because of weight gain, or may have suff ered job discrimination, to name a few possibilities. Also related to quality of life are the patient’s expectations about what changes will occur with successful weight control. Although it may be motivating for the patient to believe that life will improve with weight loss, disappointment may follow Obesity 533 unless the changes likely to occur have been placed in proper perspective. Medical benefi ts can certainly be expected with weight loss in many of those suff ering from medical complications of obesity. For example, patients with Type 2 diabetes can oft en discontinue insulin or oral agents, antihypertensive medications may become unnecessary, and sleep apnea usually disappears with as little as 10% to 15 % loss of initial weight. On another level, however, although self-assurance oft en increases, the wallfl ower does not become the life of the party and the average, competent worker does not get a promotion upon losing weight. Encourage obese patients toward a balanced view by reminding them that societal prejudices about body weight and character are in no way based on fact, and that they are the same good people whether they weigh 300 or 150 lbs.

BEHAVIORAL FACTORS

In exploring specifi c behaviors, it is useful to assist the patient in identifying their specifi c triggers to eating. Th ese eating cues are situations or feelings that lead to eating, oft en in an inappropriate way. In our society, physical hunger is rarely a signifi cant part of life, even for the poorest among us. In fact, physical hunger is not an important eating cue for many people, in part because they rarely let themselves get to the point of true hunger. Instead, they may eat in response to a host of other cues, most of which are inappropriate. Th e most common eating cues cited are: habit (“It’s noon so I guess I’ll have lunch” or “I have a jelly doughnut and coff ee in the car on the way to work”); stress (“I’ve got to fi nish this paper, and eating while I write helps me concentrate”); boredom (“Th ere’s nothing else to do”); emotions (“I eat when I’m depressed or upset”); and food as a reward (“Aft er a hard day, I deserve a rich dessert”). Underlying some of these cues is the association of food with love, caring, and comfort, which may have its antecedents in early childhood but persists into adult life and is pervasive in our culture. Th e patient should be helped to recognize that using food to deal with stress, boredom, and emotions is, at best, ineff ective. Th e stressful situation does not resolve with eating. In fact, eating may worsen the problem by distracting a person from dealing directly with the situation. Unfortunately, simply telling a patient not to eat when under stress is generally ineff ective, given the long-ingrained nature of using food inappropriately by many obese patients. Instead, use the following 3-step approach. First, recommend a period of observation and recording to enable the patient to recognize the cue. For instance, you can ask the patient to wear his or her watch upside-down as a reminder to ask, “Why am I reaching for the food at 534 INTEGRATIVE GASTROENTEROLOGY this time?” If the patient is not physically hungry, one of the possibly inappropriate eating cues is most likely occurring, and its nature should be recorded. Second, suggest the substitution of other responses for inappropriate eating. For stress, this might be writing down what the stress is, formulating a plan for doing something about it, doing something (besides eating) to relieve the stress on the spot, or, at the very least, substituting the cookies with a walk around the block or a call to a friend. Th e third step is repetition, continuing to practice making appropriate responses to the problematic cue. Th e rewards of substituting a new behavior include the positive responses of others to the change in approach — not just to eating, but to life — that the patient makes. Although some degree of behavior change is necessary, not every maladaptive behavior must be completely eliminated, nor must every rich food be replaced by celery sticks. While losing a large amount of weight in a reasonable amount of time does require a fairly aggressive diet program, maintaining a new lower weight does not. If the patient can learn to even partially control a few of his or her more important inappropriate eating behaviors, and to shift to a diet somewhat lower in calories than baseline, that is oft en suffi cient to maintain weight in the new, lower range.

DIETARY MODIFICATION

Another behavior of interest in obesity is dietary restraint. Restrained eaters believe that they must exercise a good deal of control over their eating— they are always conscious of what they can and cannot eat. Unrestrained eaters do not control their eating to any great extent. Restrained eating may lead to some paradoxical sequelae: Once restraint is relaxed, an exaggerated response may follow (all-or-nothing behavior). Such patients may be superb dieters, but are equally superb at overeating once the diet has been “broken.” Although a certain amount of control and monitoring is necessary to maintain weight control, a high level of dietary restraint may be more problematic than a low level in the long run. One solution is to couple the teaching of ways to control inappropriate eating cues with dietary changes that emphasize foods lower in fat and calories, and higher in fi ber and water content (i.e., low energy-density foods), so that lower restraint is required to maintain a given intake. Skipping meals when the patient is physically hungry should be discouraged.

“What’s hunger got to do with it?” Most obese individuals experience no more physical hunger than do lean people, but may misinterpret learned Obesity 535

habits and situations that lead to eating as “hunger.” A major breakthrough in the ability to control unnecessary eating can result when individuals learn to accurately distinguish physiological from learned forms of hunger.

Dietary Assessment

Although most aspects of diet are more properly characterized as behaviors, the need remains to understand patients’ tastes and food choices. Although the physician can and should get some idea of the patient’s diet, a formal dietary assessment is best done by a dietitian, using either a prospective or retrospective food diary. Th e results of a food diary must be interpreted with caution, as both retrospective underreporting and prospective restrained eating are more common among obese individuals (and may in fact explain some of the propensity towards obesity, if the obese are less aware of the foods and quantities they choose). Despite these shortcomings, the information gathered can be very useful. For example, the macronutrient composition of a patient’s diet will oft en be weighted toward fats, simple carbohydrates, and protein. By cutting fat and increasing intake of complex carbohydrates, especially vegetables and fruit, such patients can considerably increase the volume of food they consume as they attempt to reach and maintain a lower weight. A helpful tool in altering the composition of the patient’s diet is the technique of gradual change. For example, a patient reluctant to switch from whole milk to skim milk could fi rst try 2% milk, get used to this for a month or so, then move on to 1% fat milk for another month. At this point, the patient should notice that the once-favored whole milk will now taste too oily. At some later date, the fi nal step to skim milk can be made with few feelings of deprivation, demonstrating that taste preferences are acquired and eminently changeable, even in later life. Recommend scouring the supermarket aisles (at a time when the patient is not hungry) for tasty, low-fat, low-calorie alternatives to favored foods. Encourage the patient to explore the wide variety of foods now available, and to focus on the good taste of the new choice rather than comparing it to the “real thing.” Th e presentation of nutritional information on food labels is becoming more and more useful, listing not just grams of fat, for example, but also the percentage of the daily dietary fat allotment those grams represent. Th e patient should be taught to read labels and to stay within the calorie “budget.” 536 INTEGRATIVE GASTROENTEROLOGY

Th is is also a good time to improve the dietary habits of the patient’s family, something that is particularly easy to do when the patient is the primary cook and food shopper. Including the family in this process not only improves their diet, but also makes it easier for the patient if the home can be a temptation- free zone. If other members of the family insist on consuming junk food, they can be instructed to partake outside the home, or to put only individually packaged items in the cupboard. Small-size purchases of rich desserts and the like are desirable in general — the smaller the dietary indiscretion, the less severe the consequences. Unfortunately, portion sizes have risen greatly in the United States in recent years, especially in meals consumed outside the home. Specifi c types of diets are discussed under “Types of Diets” below.

Food preferences are mostly learned, rather than inherent, and are thus quite alterable. With repeated exposure to lower calorie, more healthful foods, taste preferences change. You may have experienced this yourselves, perhaps in switching from whole milk to reduced-fat or skim milk.

Exercise Assessment

Exercise alone is not a terribly eff ective method for shedding weight. It is diffi cult for the untrained person to do enough of it and most, if not all, of the expended energy is compensated by increased caloric intake. Exercise is, however, an excellent aid to maintaining a lower weight aft er weight loss, enabling a person to eat somewhat more than a non-exerciser and still maintain their weight. Regular aerobic exercise and strength training will also improve cardiovascular fi tness, reduce adipose tissue depots (especially visceral fat), and promote growth of metabolically more active muscle tissue. An exercise assessment should include an exploration of the patient’s usual degree of physical activity, any limiting factors such as joint disease or previous injuries, types of physical activity the patient fi nds enjoyable, and a measurement, preferably by an exercise specialist, of the current fi tness level. An exercise stress test is not required unless cardiovascular disease is suspected. A rule of thumb in devising an exercise regimen that will be most likely to be followed is to utilize a phased-in approach. Most obese individuals start out with a limited capacity to exercise. Rather than suggesting a type or level of activity that is high, and unlikely to lead to sustained adherence, make sure that the plan fi ts into the patient’s schedule and lifestyle. Obesity 537

Th e fi rst phase consists of increasing the amount of everyday physical activity, so-called “lifestyle” activity, rather than prescribing a formal exercise regimen. Lifestyle activities include taking the stairs in gradually increasing increments, parking the car farther away from the destination, walking the dog farther, and the like. Th is step alone may double the level of physical activity in a very sedentary individual. Th e next phase is a structured walking plan. People are most likely to adhere to a plan if the walk is scheduled during a break or lunchtime at work, or when the daily energy level is oft en the highest (for example, early morning, as opposed to evening aft er a long day’s work). Having a companion to walk with and a place to walk indoors are also helpful in increasing compliance. A patient should make a minimum of 20 to 30 minutes available for each session of exercise. Studies suggest that an hour is best for weight control, and 90 minutes for weight loss. Th e intensity of the exercise is not critical to the burning of calories: Walking at a leisurely pace for one hour is roughly equal to walking briskly for half an hour. Allow the patient to set the pace. Initially, it may be quite slow, but in the absence of severe cardiopulmonary or joint disease, most patients soon fi nd the going easier and faster. Goal setting can strengthen this process. Have the patient keep a log of the time spent walking and the distance covered aft er each session. Th e patient can then see the progress being made and set the goal a bit higher regularly. Next, the types of activities performed should be broadened. Walking or jogging can and should remain a component of the plan, but with the addition of other forms of aerobic exercise. Recommend aerobics classes, stationary or outdoor bicycling, swimming, a cross-country skiing machine, or just about anything else that will burn calories and be enjoyable to the patient. Strength/ resistance training of large muscle groups is an important component to include, as this can build muscle mass and raise resting metabolic rate, an aide to future weight control. Team or racquet sports and golf can be suggested to provide social interaction and thus increase the likelihood of long-term adherence to the exercise plan. Again, the most important criterion for a good exercise plan is that it be one that the patient is likely to follow and be comfortable w i t h a s a l i f e l o n g h a b i t .

Despite the multiple medical beneﬁ ts of exercise, exercise in the absence of concurrent dietary change is a remarkably ineffective way to lose weight for most people. This is probably because exercise elicits hunger, thus largely counterbalancing the calories burned in the exercise. Without this feature, manual laborers would be doomed to steady starvation! 538 INTEGRATIVE GASTROENTEROLOGY

Types of Diets

It is best to instill in your patients a degree of skepticism about commercially advertised weight-control diets. Many are based on very limited menus, the rationale being that monotony helps curb consumption. Some involve use of diuretic agents. In fact, any substantially reduced-calorie diet will initially cause diuresis, which will be regained as soon as the period of severe caloric restriction ends. Aft er the diuretic phase, the amount of weight loss to be expected on any diet obeys a simple formula. Lipolysis of one pound of adipose tissue yields about 3,500 kilocalories; it is therefore necessary to restrict energy intake and/ or increase energy output by about 500 kilocalories per day to lose one pound of fat per week. Because some muscle may also be lost, and muscle is poorer in energy than fat, the rate of weight loss may be somewhat higher than predicted. However, two counterbalancing factors are at work. First, with sustained caloric restriction, a moderate reduction in metabolic rate occurs. Th is decrease makes weight loss somewhat more diffi cult to achieve, but caloric requirement, corrected for the new, lower weight, appears to return the prediet level within a few months of resuming a eucaloric diet. Second, because lower weight means reduced caloric need, the same caloric intake will represent less of a defi cit as the patient continues to lose weight. A regular program of physical activity, especially one that includes resistance exercise, can partially counteract both these factors by helping blunt the decrease in metabolic rate and by building muscle mass, which is more metabolically active and therefore has a higher caloric requirement, even at rest, than an equal weight of adipose tissue. How much of a caloric defi cit should be recommended, and in what form should the calories be taken? Th e answer depends on the degree of obesity, the presence or absence of comorbidities such as Type 2 diabetes, the results of the behavioral assessment and, to some extent, the patient’s preferences. In any case, it is important to remind the patient that the diet is only part of the overall plan, and will fail in the long term unless accompanied by sustained changes in behavior. For patients who are overweight or moderately obese (BMI of 25 to 32), I recommend a caloric defi cit of 500 to 750 calories per day to achieve 1 to 1.5 pounds of weight loss per week. A dietitian can design a low-calorie, food- based diet that is either balanced-defi cit (reducing total number of calories while keeping proportions from carbohydrate, fat, and protein roughly the same as before), or fat-defi cit, with most of the caloric reduction resulting from restriction of fat intake. Th e latter approach is preferable because the Obesity 539 typical American diet is too high in fat, especially saturated and trans fats, and simple sugars. Also, a greater volume of food can be eaten on a diet that emphasizes fi ber-rich complex and vegetable-source carbohydrates and reduces fat to less than 30% of calories consumed. Patients with a BMI of 33 to 40 will also benefi t from a fat-and-calorie- reduced diet. It is important, however, to recognize that at this level of caloric restriction it will take more than a year to attain a weight loss of 50 to 70 pounds. Few patients can sustain this degree of restriction for that long; therefore, for a limited period of time, a very-low-calorie diet (VLCD) of fewer than 800 calories per day may be needed. Th e VLCD is justifi ed particularly if the patient already suff ers from comorbidities that are likely to be alleviated with signifi cant weight loss. VLCDs can consist of food, commercially available liquid supplements, or a combination of both. With full compliance, the amount of weight lost on a VLCD ranges from 2.5 to 4 pounds per week, depending on body mass and level of physical activity. Th e initial diuretic phase may be pronounced and accompanied by lightheadedness, headache, or fatigue, which are usually transient. Later symptoms may include constipation and intolerance of cold. Electrolyte abnormalities are rare, but serum should be monitored occasionally, and more frequently if the patient is prone to electrolyte problems because of renal insuffi ciency or diuretic use. Because of the greater stress on the body and greater need for monitoring of true VLCDs, I prefer to keep the caloric intake above 800 to 1,000 kilocalories per day. Gallstones may occur or become symptomatic, probably due to gallbladder stasis and a decrease in bile acids, which occurs during or immediately aft er any severely restricted (especially fat-restricted) diet. To prevent stasis, the patient can add to the diet a tablespoon of a fat (preferably an unsaturated fat such as canola or olive oil), taken in one daily dose, which will allow the gallbladder to contract. A VLCD should be administered only under a physician’s supervision and with full attention to the behavioral changes necessary to sustain the weight loss that this regimen will produce. In extreme (“morbid”) obesity corresponding to a BMI of 40 kg/m2 or more, the only practical initial diet for most patients is a highly restricted diet with careful medical monitoring and long-term follow-up. It should be noted, however, that even a modest weight loss can yield substantial health benefi ts for morbidly obese patients. Sleep apnea oft en disappears with as little as a 10% loss in weight, and with even 5% weight loss, hypertension, diabetes, and hyperlipidemias may also improve signifi cantly. I do not view, nor let my patients view, modest weight loss as a failure or a waste of time. Th e same is true for patients with lesser degrees of obesity. 540 INTEGRATIVE GASTROENTEROLOGY

The glycemic index, a measure of speed of absorption of carbohydrates, is increasingly popular in constructing diets. Data are mixed at this point, but foods with high complexity and high-ﬁ ber content may well prove to be particularly helpful in controlling appetite and metabolic complications of overeating.

Drugs and Surgery

Adjunctive anorectic medications may be useful for the obese patient, either from the start, to enhance compliance with the diet, or later, when compliance begins to waver or hunger becomes more prominent. Th ere is little doubt that such medications signifi cantly increase weight loss during the period in which they are used, and may help maintain some weight loss (although regain tends to occur even with continued use). Commonly used anorectic drugs are phen- termine and sibutramine. One reasonably eff ective agent, ephedra, is no longer available because it has been associated with adverse cardiovascular events. Th e true amphetamines, diuretics, and thyroid medications should generally not be prescribed for weight loss. An agent that holds some appeal to me as a gastroenterologist is orlistat (sold by prescription as Xenical, and in a nonprescription strength as Alli). Th is is the only nonsystemically acting obesity medication currently available. It acts in the lumen of the small bowel by binding to lipases, and thus causes malabsorption of about 30% of ingested fat for the prescription strength, and 25 % of ingested fat for the over-the-counter strength. Along with dietary fats, these agents also block the absorption of fat- soluble vitamins and cholesterol. Th is has two consequences: A multivitamin supplement must be taken at a time when the orlistat or Alli is not being taken to prevent defi ciencies, and there seems to be a greater degree of reduction in cholesterol levels for a given amount of weight loss compared with weight loss resulting from diet alone. While orlistat and Alli have no appetite-curbing eff ects, they may have an Antabuse-like eff ect, in that consumption of more than a moderate amount of fat at a sitting will result in unpleasant GI consequences. I view these agents as more suitable for patients who are having diffi culty avoiding junk food and fats than for patients with increased physical hunger. Whether obesity should be considered a chronic disease and treated on a long-term basis with anorectic or other drugs is in part a philosophical issue. I use these agents only aft er attempts at dieting have failed, or when progress is stalled in patients who are severely obese and/or who suff er from comorbid conditions, or if physical hunger is a problem during the diet. Herbal medications are also widely used for weight control. Agents that appear to have limited effi cacy include fi ber supplements and ephedra-like Obesity 541 agents (e.g., citrus aurantium). Agents that do not appear to have a clinically signifi cant eff ect include DHEA, Hoodia gordonii, and chitin/chitosan. Th e latter is a polymer of glucosamine that can bind fat in the GI tract, thus blocking fat absorption; in randomized controlled trials, however, there was no signifi cant weight loss with chitin compared to placebo. While the mechanism of chitin is plausible, it appears to be ineff ective at reasonable doses, and could block absorption of fat-soluble vitamins. Chromium picolinate is oft en an ingredient in OTC weight loss formulations, but the FTC recently concluded that there is insuffi cient evidence of any eff ect on weight, body composition, metabolic rate, and appetite. Th e evidence on conjugated linoleic acid is mixed, but may prove to have some modest eff ect in weight control. It is important to recognize that herbal agents are still drugs: Natural products can be as toxic as synthetic products. Not all natural, orally consumable ingredients are subjected to the degree of scientifi c scrutiny that pharmaceuticals undergo, but it is best to insist on some degree of safety and effi cacy testing for such products. Th e surgical treatment of morbid obesity has improved considerably since the days of the jejunoileal bypass and jaw wiring. Generally, patients are referred for surgery only if they have a BMI of 40 or greater, or of 37 or greater if there are signifi cant coexisting medical complications of obesity and they have failed to lose or maintain weight loss with a comprehensive nonsurgical approach. Probably the best procedure currently available is the gastric bypass, preferably performed laparoscopically. Th is procedure combines stapling of the stomach to make a small-capacity proximal gastric pouch, along with a short-segment bypass of the proximal small bowel created by a Roux-en-Y loop. Results are quite good in the short term. Long-term results, as with all methods of weight loss, depend largely on the patient’s ability to make behavioral changes. Th erefore, aside from access to a hospital with adequate experience in this procedure, the best chance of long-term success is to refer the patient to a center that off ers and insists upon extensive preoperative evaluation and long-term maintenance therapy consisting of regular sessions in dietary management and behavioral modifi cation. Do not make the mistake of viewing surgery as a treatment that does not require the patient’s active involvement — an unmotivated or unguided patient can and will defeat the p r o c e d u r e .

While medications and surgery are often the mainstays of treatment of most health conditions, obesity is one area in which changes in lifestyle, when sustained, are safer and more effective, and thus must be considered the ﬁ rst line of treatment. 542 INTEGRATIVE GASTROENTEROLOGY

Maintenance

Th e physician and the patient both know that the long-term results of attempts at weight loss are oft en poor. It is therefore important to expose the patient, at the beginning of treatment, to the attitudes and behaviors that are likely to foster long-term maintenance of weight loss. Th ese may be summarized as follows: Readiness: Correct timing for change is vital. It is folly to begin a diet when you are not yet convinced of the need to do so, or are in the midst of a stressful life event such as divorce. Setting reasonable goals: Aiming for attainable rather than an “ideal” body weight is advisable. A reasonable long-term goal might be the lowest weight the patient has successfully maintained for one year or more during the previous ten years. Reliable support systems: Obtaining helpful assistance aids in both weight loss and maintenance. Th is usually involves seeking out a friend or relative who knows how to listen and not just give advice. Building in maintenance: Planning and executing behavioral changes from day one is essential. Becoming invested in one’s goals: Learning how to talk to oneself in a positive way in order to enhance commitment to self-set objectives is a useful technique. Making gradual changes: Modifying food choices and level of physical activity reduces the sense of deprivation, and may make the process of change easier and the changes themselves more likely to be permanent. Keeping records: Recording weight, foods eaten, exercise, and precipitants of inappropriate eating is an excellent way to identify problem areas and to spot a relapse before it gets out of hand, thereby improving the chances of long-term success. Making it enjoyable: Th is is self-explanatory. It is much easier to comply with the new behaviors if they can be enjoyed. If your patient cannot stand to exercise, do not tell him or her to do it anyway. Instead, suggest taking a child to the park or walking around the mall to people-watch. Th e achievement of a positive change in lifestyle is, by itself, very reinforcing and should not be discounted as a source of satisfaction and enjoyment. Being fl exible : Th is applies to both the physician and the patient. If an approach that has been given a fair trial is not working, or if the patient’s circumstances change (a new job, for example), the weight loss plan may need to c h a n g e , t o o . Obesity 543

Studies have shown that people who are successful at losing weight and keeping it off long term share certain behaviors: in short, they regularly monitor their weight, what they eat, and their physical activity; they usually follow low-calorie, low-fat diets; and they exercise regularly. Emulating the habits of successful weight maintainers holds much promise for those struggling with weight control.

Summary (Expert Opinion)

In closing, it should be clearly accepted that helping patients lose weight and keep it off requires a comprehensive and sustained eff ort that involves devising an individualized approach to diet, behavior and exercise, as described in detail above. Although it is true that only the patient can do this work, this is one area where the diligent and caring physician, with a commitment to the principles of integrative medicine, can make a major diff erence.

46 Nutrition and Colorectal Health

MITRA RANGARAJAN AND GERARD E. MULLIN

key concepts

■ Colorectal cancer is a leading cause of cancer-related deaths in the United States. ■ Th e goal of screening programs is early detection of pre-invasive lesions or early cancer. ■ Chemoprevention has emerged as a promising and pragmatic medical approach to reduce the risk of cancer. ■ Diet plays an important part in the prevention of colon cancer. ■

Introduction

olon cancer is ranked as the third leading cause of death from cancer. Colorectal cancer is a disease with high mortality rate secondary to C diagnosing the condition at a late stage. Th erefore, attention is now focused on preventive strategies, which include early detection of treatable precursor lesions of this disease. Endoscopic polypectomy has been shown to reduce the incidence of colorectal cancer. However, it is not practical to employ this strategy for the population as a whole. Screening the general population would require extensive manpower and monetary resources, and its success is fully dependent on the compliance of the population. Th e American Cancer Society estimates the incidence of all cancers to be approximately 1,479,350 cases. An estimated 9% of all cancer mortality is sue to colorectal cancer. Mortality rate for colon cancer has steadily declined, refl ecting improvements in early detection and treatment. However, we are yet

544 Nutrition and Colorectal Health 545

Table 46.1.

BP: 115/69

RR: 16

Pulse: 72

HT: 67 in

WT: 178 lbs

BMI: 28

Temp: 98.6

to prevent the incidence of colon cancer. Th is is largely due to the lack of implementation of preventative strategies. Th e precursor for colon cancer is the formation of adenomas. Adenomas are more common than colon cancer, especially in individuals over the age of 50. Th erefore, the best strategy to prevent colon cancer is to prevent the formation of adenomas. Colorectal cancer is another condition whereby Western diets high in saturated fat and red meat, low in fi ber, and compounded by sedentary lifestyles with high obesity rates, contributes towards a greater susceptibility. Colorectal cancer is the most common cancer of the digestive organs, accounting for more than 60 % of all digestive organ cancers and 25% of all cancer mortality in the United States (Boyle & Ferlay, 2005 ). In 2004, more than 660,000 Europeans were living with a diagnosis of colon cancer. Colorectal cancer is the second most common cancer in Europe and the United States. Colon cancer is rare in Africa and Asia (except Japan), as with diverticular disease. In both conditions, a high-fi ber diet appears to be protective. For colorectal cancer, a high-fat SAD is a risk factor for disease development

Table 46.2. Complete Blood Count

WBC 4670/mm3

Hemoglobin 3.76 M/mm 3

Hematocrit 32.4%

MCV 86.2 fl

RDW 18.2%

Platelet 242 K/mm3 546 INTEGRATIVE GASTROENTEROLOGY and recurrence (Rennert, 2007 ). Th e seven Western behavioral risk factors associated with an increased risk for colorectal cancer include:

• S m o k i n g • L o w p h y s i c a l a c t i v i t y • Low fruit and vegetable intake • High caloric intake from fat • O b e s i t y • H i g h a l c o h o l i n t a k e • Low intake of multivitamins (Coups, Manne, Meropol, & Weinberg, 2 0 0 7 )

THE SAD FACTS

The standard American diet (SAD) is low in nutrient quality and is a major risk factor for colorectal cancer.

QUESTIONS

1. What are your diagnostic considerations? 2. Which laboratories would you order at this point?

QUESTION

What would you do or order next?

Author’s Approach to Her Digestive Health Issues 1. Short-term: i. Surgical opinion ii. Dietary counseling iii. Stress management: Mind–body rebalancing

Kristin’s Digestive Health Issues 1. Long-term: A Prevention of colorectal cancer recurrence Nutrition and Colorectal Health 547

Integrative Approaches to the Prevention of Colorectal Cancer Recurrence

CHEMOPREVENTION

QUESTION

Which of the following is not associated with a higher prevalence of colorectal cancer in the United States? 1. Regular exercise 2. High intake of red meat 3. High intake of saturated fat 4. Strong family history of colorectal cancer

Chemoprevention is a way to prevent or delay the development of benign or malignant lesions by taking medicines, vitamins, or other agents. Cancer chemoprevention was fi rst defi ned by Sporn in 1976 as the use of natural, synthetic or biologic chemical agents to reverse, suppress or prevent carcinogenic progression to invasive cancer (Sporn MB, Dunlop NM, Newton DL, Smith JM, 1976 ). Potential chemopreventive agents for colorectal cancer include nonsteroidal anti-infl ammatory drugs (NSAIDs), vitamins, and hormones, as listed in Table 46.3 . As well, dietary factors and exercise have been implicated in the primary prevention of colon cancer.

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS

NSAIDs, cyclooxygenase-2 (COX-2) inhibitors, and aspirin have all been studied in prevention of colon cancer. Strong support for a chemopreventive eff ect of NSAIDs is provided by in vitro experiments, animal models, epidemiological studies, and clinical trials (DuBois, Giardiello, & Smalley, 1996 ). Th e mechanism of action of NSAIDs is inhibition of cyclooxygenase, which is a key enzyme in conversion of arachidonic acid to prostaglandins, prostacyclin, and thromboxanes. Prostaglandins aff ect cell proliferation and tumor growth through activation of second messengers in signal transduction pathways, and prostaglandin levels are increased in many cancers, including colorectal adenomas and adenocarcinomas (Giardiello, Off erhaus, & DuBois, 1995 ). COX-1 is present in most tissues, whereas COX-2 is expressed in response to growth factors, cytokines, mitogens, and tumor promoters. Much of the initial 548 INTEGRATIVE GASTROENTEROLOGY

Table 46.3. Potential Chemopreventive Agents

NSAIDs

Sulindac

Celecoxib

Aspirin

Ursodeoxycholic acid

Hormones

Estrogen

Medroxyprogesterone acetate

Vitamins/Antioxidants

Calcium

Folate

Selenium

Curcumin

Vitamin D

Supplements/Sunshine

Curcumin

Ginger

Glucosinolates

Sulforaphane and indole-3-carbinol (I3C) data on NSAIDs and chemoprevention of colon cancer in humans came from literature on familial adenomatous polyposis (FAP), which is an autosomal dominant disorder characterized by innumerable colorectal adenomas and eventual carcinoma. Multiple studies have evaluated sulindac in FAP, and all report either complete or partial regression of adenomas aft er three to six months of treatment with sulindac at doses of 300 to 400 mg per day (Keller & Giardiello, 2003 ). NSAIDs such as sulindac have gastrointestinal toxicity that may limit its use for prevention in colorectal cancer. Th is led to studies on COX-2 inhibitors. Cyclooxygenase-2 is expressed in infl ammatory states, premalignant lesions, and colorectal cancer. COX-2 inhibitors were speculated to have a role in chemoprevention of colon cancer. Celecoxib led to polyp regression in FAP, which led to investigation of NSAIDs in sporadic adenomas and Nutrition and Colorectal Health 549 colorectal neoplasia (Table 46.3 ; see Steinbach, Lynch, Phillips et al., 2000 ). Epidemiologic studies have shown a reduction in colorectal cancer in individuals taking NSAIDs A series of case-control studies revealed a 40 % to 50 % reduction in the risk of colonic adenomas or colorectal cancer among patients taking aspirin (DuBois, Giardiello, & Smalley, 1996 ). Giovannucci and associates measured cancer incidence in a cohort of women and found that regular aspirin use, at doses similar to those recommended for cardiovascular disease prevention, reduced risk of colorectal cancer — but this eff ect may require greater than a decade of use to occur (Giovannucci, Rimm, Stampfer et al., 1994 ). In a prospective cohort study involving 47,900 males in the United States, Giovannucci and associates showed that regular use of aspirin decreased the incidence of adenomas. Th e major trials evaluating the use of aspirin in the chemoprevention of colorectal cancer are displayed in Table 46.4 .

CALCIUM

Vitamins, including calcium, vitamin D, folate, and selenium have also been implicated in chemoprevention of colon cancer. Dietary calcium has been hypothesized to neutralize fatty acids and free bile acids, which have an irrita- tive eff ect on the colonic epithelium (Newmark & Heaney, 2006 ). Numerous murine studies have shown that calcium decreases colonic mucosal hyperpro- liferation, decreases markers of colorectal mucosal proliferation, and inhibits colonic tumor development (Lipkin, 1999 ). Th ough two early meta-analyses showed little or no protection against colorectal cancer with calcium (Bergsma- Kadijk, van’t Veer, Kampman, & Burema , 1996 ; Martinez & Willett, 1998 ), numerous subsequent prospective cohort studies have reported modest decrease of colorectal cancer in high-intake calcium groups compared to low-intake groups (McCullough et al., 2003 ; Wu, Willett, Fuchs, Colditz, & Giovannucci, 2002 ; od et al., 2005; Baron et al., 1999a, 1999b). In a pooled analysis of 10 prospective studies looking at intake of dairy foods, calcium and colorectal cancer, Cho and colleagues concluded that increased consumption of milk and calcium were related to a lower risk of colorectal cancer. Th is data, along with other previous experimental studies that demonstrate a benefi cial eff ect of calcium supplementation on colonic epithelial cell turnover and colorectal adenoma recurrence, support the concept that moderate milk and calcium intake decreases the risk of colorectal cancer (Cho, Smith-Warner, & Spiegelman, 2004 ). Finally, a meta-analysis of three randomized controlled trials (Shaukat, Scouras, & Schunemann, 2005 ) suggested that calcium prevents recurrent colorectal adenomas with an overall relative risk of 0.80 (95% CI, 0.68–0.93). Calcium has recently been associated with higher ischemic 550 INTEGRATIVE GASTROENTEROLOGY

Table 46.4. Major Trials of Chemoprevention in Colorectal Cancer with Aspirin

First Author Date Study Design Patients Effect

Th un 1997 Prospective 662,424 patients Regular aspirin cohort providing use associated information on with reduced risk frequency and of colorectal duration of aspirin cancer use

Giovannucci 1994 Prospective 89,446 women Regular, long-term cohort reporting number of aspirin use consecutive years of associated with aspirin use reduced risk of colorectal cancer

Giovannucci (YEAR) Prospective 47,900 males in U.S. Result: lower Cohort Questionnaire sent incidence of in 1986, 1988, and colorectal 1990 about use of adenomas in aspirin and aspirin occurrence group using of cancer

Sturmer 1998 Prospective 22,071 male No association of cohort following physicians randomly aspirin use with randomized assigned aspirin use colorectal cancer placebo protection controlled

Baron 2003 Randomized, 1,121 patients with Low-dose aspirin placebo sporadic adenomas prevents controlled randomized to recurrence of aspirin or placebo adenomas

Sandler 2003 Randomized, 635 patients with Daily aspirin use placebo previous colorectal associated with controlled cancer with curative reduction of resection adenomas in randomized to patients with aspirin or placebo previous colorectal cancer

Benamouzig 2003 Randomized, 272 patients with Daily aspirin use placebo sporadic adenomas associated with controlled randomized to reduction in soluble aspirin or recurrent placebo adenomas Nutrition and Colorectal Health 551 cardiovascular events in post-menopausal women (Bolland et al., 2008 ). Many more studies are required to confi rm and validate this observation. Also, recent data showing that vitamin D defi ciency appears to be a risk factor for developing cardiovascular disease would contradict these fi ndings, as many women co-supplement calcium and vitamin D together.

VITAMIN D

Th e possible eff ects of vitamin D in colon cancer prevention were fi rst brought to light when Cedric Garland and Frank Garland reported in 1980 that people who lived in sunny locations had a lower incidence of colon cancer compared to those who lived in colder regions (Garland CF, Garland FC, 1980 ). In 1989, the Garland brothers went on to furnish further evidence that defi ciency of vitamin D may pose a signifi cant risk for the development of colon cancer. Th ey analyzed air pollution data from 20 Canadian cities and found that cities where polluted air obscured vitamin d -producing sunlight had higher death rates from both colon and breast cancer. Furthermore, they pointed out that colon cancer rates were 4 to 6 times higher in North America and Northern Europe when compared to the incidence of colon cancer in countries close to the equator (Armstrong, 2006 ). Vitamin D has also been found to be inversely associated with risk of colorectal cancer (Wu, Willett, Fuchs, Colditz, & Giovannucci, 2002 ). In a prospective cross-sectional study of 3121 asymptomatic patients aged 50 to 75 years, a multivariate analysis found vitamin D to dominate calcium as a benefi cial risk factor. Dr. Freedman and colleagues studied a total of 16,818 participants in the Th ird National Health and Nutrition Examination Survey (Freedman, Looker, Chang, & Graubard, 2007 ). Levels of serum 25(OH)D were measured at baseline by radioimmunoassay. Cox proportional hazards regression models were used to examine the relationship between serum 25(OH)D levels and mortality from specifi c cancers. Colorectal cancer mortality was inversely related to serum 25(OH)D level, with levels 80 nmol/l or higher associated with a 72% risk reduction (95% confi dence interval = 32% to 89% ) compared with lower than 50 nmol/l, P(trend) = .02, supporting an inverse relationship between 25(OH)D levels and colorectal cancer mortality. Overall, a meta-analysis showed that a signifi cant protective eff ect against developing colorectal cancer was conferred by vitamin D suffi ciency (Gorham et al., 2007 ).39 Th e most “natural” way to enhance vitamin D status is to soak in the rays of sunshine. Th e body can convert pre-vitamin D3 in the skin to vitamin D in the presence of ultraviolet light (UVB) from the sun, depending upon the latitude, 552 INTEGRATIVE GASTROENTEROLOGY time of day, presence of sun block, skin color, and skin concentration of 7-dehydro-cholesterol (Mullin & Dobs, 2007 ).

FOLATE

Several cohort and case-control studies have suggested a reduced risk of colorectal cancer with a higher consumption of vegetables and fruits (Lance, 2008 ). Folate is a B vitamin found in leafy green vegetables, citrus fruits, and dried beans and peas. Folic acid is involved in DNA synthesis and repair, DNA methylation, and modulation of cell proliferation, shown in both in vitro and animal studies (Mason & Levesque , 1996 ). Murine models of colorectal cancer report that folate administration is associated with decreased risk of colonic neoplasm, and epidemiologic studies show an inverse relationship between dietary folate and colorectal cancer incidence (Kim, 2007 ). Two large prospective cohort studies show an association between folate intake and reduced colorectal cancer incidence (Su & Arab, 2001 ; Giovannucci, 2002 ). In the Nurses’ Health Study, 88,756 women provided diet assessments including multivitamin use. Th is investigation found that long-term use of folate at doses greater than 400 micrograms daily was associated with a substantial decreased risk for colon cancer (Giovannucci et al., 1998 ). In the National Health and Nutrition Epidemiologic Follow-up Study (Su & Arab, 2001 ) subjects were followed for 20 years, and an inverse relationship of folate intake and colon cancer was found for men (RR 0.40; 95% CI, 0.18–0.88). Vitamin B6 appears to be inversely associated with risk of colorectal neoplasia (Wei et al., 2005 ). Despite the benefi cial eff ects of folic acid for the prevention of colorectal cancer, future studies are needed to determine the exact amount to be consumed for optimal benefi t .

SELENIUM

Selenium is an essential trace element in the human diet and is incorporated into proteins. Selenoproteins are involved in the neutralization of reactive oxygen species, and are important for the antioxidant defense of cells (Al-Taie et al., 2003 ). Selenium is found in plant foods, and the concentration of selenium in food correlates with the content of the soil where plants are grown. In ecologic studies selenium intake has an inverse relationship to colon cancer risk (Shamberger, 1985 ). In colon cancer cell lines, selenomethionine inhibits growth and Nutrition and Colorectal Health 553 decreased levels of cyclooxygenase proteins in the cells (Baines et al., 2002 ), and animal studies have consistently shown selenium has activity against colorectal cancer (Duffi eld-Lillico, Shureiqi, & Lippman, 2004 ). Th ough in vitro and animal studies show activity of selenium against colorectal cancer, epidemiologic studies have been inconsistent (Nomura et al., 1982 ; Early, Hill, Burk, & Palmer, 2002 ). However, several investigations reveal a protective relationship for selenium and colorectal adenomas and cancer (Willett et al., 1983 ; Clark et al., 1993 ). A pooled analysis of three randomized trials of 1763 individuals found an inverse association between higher blood selenium concentration and adenoma risk (Jacobs et al., 2004 ). Other vitamins have been studied as well. In a prospective, randomized trial, beta carotene and vitamins C and E failed to prevent colorectal adenomas (Greenberg et al., 1994 ).

CURCUMIN

Numerous components of edible plants, collectively termed phytochemicals , have been reported to possess substantial chemopreventive properties. Curcumin, a diferuloylmethane derived from the plant Curcuma longa, is a potent antioxidant with anti-infl ammatory and antitumor activities (Lev-Ari et al., 2005 ). Curcumin is commonly consumed as turmeric spice. Both in vitro studies and animal models have demonstrated a chemopreventive eff ect of curcumin (Li, Ahmed, Mehta, & Kurzrock, 2007 ; Kwon, Malik, & Magnuson, 2004 ). Curcumin inhibits COX-2 expression, inhibits growth in human colon cancer cell models, and suppresses nuclear factor κB, a transcription factor that controls expression of cytokines (Johnson & Mukhtar, 2007 ). Curcumin is one of the most extensively investigated and well-defi ned chemopreventive phytochemicals. Curcumin has been shown to protect against skin, oral, intestinal, and colon carcinogenesis, and also to suppress angiogenesis and metastasis in a variety animal tumor models (Surh & Chun, 2007 ). Curcumin inhibits the proliferation of cancer cells by arresting them in the various phases of the cell cycle and by inducing apoptosis. Curcumin has a capability to inhibit carcinogen bioactivation via suppression of specifi c cytochrome P450 isozymes, as well as to induce the activity or expression of Phase II carcinogen detoxifying enzymes. In patients with advanced colorectal cancer refractory to standard chemotherapy, 5 of 15 individuals given daily oral curcumin had stable disease aft er 2 to 4 months of treatment (Sharma et al., 2001 ). Furthermore, a recent study of 5 FAP patients with prior colectomy treated with oral curcumin and quercetin (fl avonoid found in green tea, onions and red wine) had a reduction 554 INTEGRATIVE GASTROENTEROLOGY in number and size of ileal and rectal adenomas aft er 6 months of treatment (Cruz-Correa et al., 2006 ). Well-designed intervention studies are necessary to assess the chemopreventive effi cacy of curcumin in normal individuals as well as high-risk groups. Suffi cient data from pharmacodynamics, as well as mechanistic studies, are necessary to advocate clinical evaluation of curcumin for its chemopreventive potential.

GLUCOSINOLATES (SULFORAPHANE AND INDOLE-3-CARBINOL [I3C])

In 1992, Johns Hopkins researcher Paul Talalay, MD, and colleagues found that an antioxidant called sulforaphane , produced in the body from a compound in broccoli, triggered the production of enzymes that helped detoxify cancer- causing chemicals. Th e discovery, published in the Proceedings of the National Academy of Sciences, attracted worldwide attention and was hailed as a major breakthrough in our understanding of the link between increased fresh vegetable consumption and reduced cancer risk (Prochaska, Santamaria, & Talalay, 1992 ). Subsequent studies found that sulforaphane prevented the development of breast and colon cancer, as well as other tumors, in mice, exhibiting a powerful role in cancer prevention and protection. Talalay’s team found that the key protective compound in broccoli (a chemical called glucoraphanin , which the body turns into sulforaphane) was 20 times more concentrated in young, 3-day-old broccoli sprouts than it is in more mature broccoli plants. More recently, the team launched a line of teas enhanced with the antioxidant SGS (sulforaphane glucosinolate). Cruciferous vegetables are a rich source of glucosinolates and their hydrolysis products, including indoles and isothiocyanates, and high intake of cruciferous vegetables has been associated with lower risk of lung and colorectal cancer in some epidemiological studies (Higdon, Delage, Williams, & Dashwood, 2007 ). Glucosinolate hydrolysis products alter the metabolism or activity of sex hormones in ways that could inhibit the development of hormone-sensitive cancers, but evidence of an inverse association between cruciferous vegetable intake and breast or prostate cancer in humans is limited and inconsistent. Organizations such as the National Cancer Institute recommend the consumption of fi ve to nine servings of fruits and vegetables daily, but separate recommendations for cruciferous vegetables have not been established. Isothiocyanates and indoles derived from the hydrolysis of glucosinolates, such as sulforaphane and indole-3-carbinol (I3C), have been implicated in a variety of anticarcinogenic mechanisms, but deleterious eff ects also have been reported in some experimental protocols, including tumor promotion over prolonged periods of exposure. Epidemiological studies indicate that Nutrition and Colorectal Health 555 human exposure to isothiocyanates and indoles through cruciferous vegetable consumption may decrease cancer risk, but the protective eff ects may be infl u- enced by individual genetic variation (polymorphisms) in the metabolism and elimination of isothiocyanates from the body. Cooking procedures also aff ect the bioavailability and intake of glucosinolates and their derivatives (Higdon, Delage, Williams, & Dashwood, 2007 ). Supplementation with I3C or the related dimer 3,3’-diindolylmethane (DIM) alters urinary estrogen metabolite profi les in women, but the eff ects of I3C and DIM on breast cancer risk are not known. Small preliminary trials in humans suggest that I3C supplementation may be benefi cial in treating conditions related to human papilloma virus infection, such as cervical intraepithelial neoplasia and recurrent respiratory papillomatosis, but larger randomized controlled trials are needed (Marshall, 2003 ).

DIET AND EXERCISE

Diet has been implicated in colon cancer, including meats, vegetables, fruit, and fi ber. Numerous prospective cohort studies have demonstrated an increase in risk of colorectal cancer in patients who consume red meat frequently (Giovannucci, Stampfer, Colditz, Rimm, Willett, 1992 ; Willett, Stampfer, Colditz, Rosner, &, Speizer, 1990 ).Red meat is associated with increased risk of colorectal cancer and increases the endogenous formation of N-nitroso compounds (NOC), DNA, and protein oxidation products, along with inhibition of apoptosis of cancer cells (Lewin et al., 2006 ; de Vogel et al., 2008 ; Lih-Brody et al., 1996 ; Cross, Pollock, & Bingham, 2002 ). Th ere does appear to be convincing evidence for a correlation between high vegetable and fruit intake and low rates of colorectal neoplasia. Th e majority of case-control and cohort studies published show a relative risk of less than 0.8 for colorectal neoplasia in subjects with the highest intake of fruits and vegetables (Gatof & Ahnen, 2002 ). Th e role of fi ber in the risk of colorectal cancer is less clear. About 60 % of epidemiologic studies have linked high-fi ber diets with a decreased risk of colorectal adenomas and cancer, and a large European prospective study showed similar results (Bingham, 2006 ; Bingham et al., 2003 ). Increase the amount of wheat bran in the diet. As an insoluble fi ber, wheat bran increases the fecal bulk and weight, as well as increasing the frequency of eliminating the fecal matter, thereby reducing the colon’s exposure to toxins, e.g., carcinogens. Two large prospective, randomized controlled studies showed that adopting a diet low in fat and high in fi ber, fruits, and vegetables 556 INTEGRATIVE GASTROENTEROLOGY did not infl uence the risk of recurrence of colorectal adenomas (Alberts et al., 2000 ; Schatzkin et al., 2000 ; Lanza et al., 2007 ; Schatzkin et al., 2007 ). Along with diet, body habitus and physical activity have been studied in relation to colon cancer. A meta-analysis of the association of physical activity and colon cancer shows an inverse association between physical activity and colon cancer. Th e author of this study concluded that if individuals participate in physical activity, they will have a 24 % reduction in the risk of developing colon cancer. Two large studies investigated dose-related response of exercise on colon cancer reduction. Th e Harvard Alumni Study followed 17,148 men for a maxi- mum of 26 years. During the study period, 225 men developed colon cancer. Th ose men who participated in physical activity equivalent to at least 30 minutes per day, 5 days per week, had a 50% reduction in colon cancer rates compared with men who were sedentary. Physical activity was defi ned in this study as both the time set aside for daily exercise, as well as other daily physical activities such as climbing stairs. Th e actual mechanism of how exercise helps prevents colon cancer is not fully understood. However, it is well known that exercise decreases intestinal transit time, therefore decreasing the exposure of dietary procarcinogens, which are activated by intestinal bacteria and transformed into carcinogens within the intestinal lining. Th is theory is not well supported by data, but nevertheless a mechanism that we must entertain in understanding the role of exercise in prevention of colon cancer. A revolutionary theory of colorectal cancer chemoprevention is that exercise strengthens the immune system by promoting the function of many types of immune cells that prevent and fi ght cancer, including natural killer cells. Another possible mechanism is that exercise imparts protection from colorectal cancer by improving insulin responses to meals. Insulin and insulin-like growth factors appear to promote the growth of colorectal cancer in laboratory and animal studies. Th us, the hyperinsulinism that is associated with obesity, Type 2 diabetes, and the metabolic syndrome (syndrome X) may be the means by which these conditions predispose toward the development of colorectal cancer. Finally, exercise is able to ward off unwanted cellular proliferation as well as decrease some factors such as prostaglandin E2, which is thought to promote colon cell proliferation. In order to make concrete recommendations with regard to the type, duration, and intensity of exercise, additional research is deemed necessary. Overall, case-control and cohort studies have demonstrated a positive association between obesity, hyperinsulinism, and cancer risk, whereas the majority of studies have shown an inverse relationship between physical activity and colorectal cancer risk (Gatof & Ahnen, 2 0 0 2 ) . ∗ Th e Mediterranean diet includes omega-3 fatty acids and olive oil, which appear to be chemopreventive. A pooled analysis of the small but ever-growing Nutrition and Colorectal Health 557 body of science of omega-3 and colorectal cancer indicates that fi sh oil does protect against the cancer (Brivio et al., 2007 ; Calviello, Serini, & Piccioni, 2007 ; Geelen et al., 2007 ). For each extra 100 g of fi sh consumed per week, the risk of colorectal cancer incidence was reduced by 3% . Th e Mediterranean diet is rich in extra-virgin olive oil (EVOO) and is associated with a lower incidence of colorectal cancer. EVOO contains phenolic extracts with potential antioxidant eff ect. Fini L et al. reported that pinoresinol- rich EVOO extracts have potent chemopreventive properties, and specifi cally upregulate the tumor suppressor p53 cascade in vitro (Fini L, Hotchkiss E, Fogliano V, Graziani G, 2008 ). Th is result was achieved at substantially lower concentrations in EVOO than with purifi ed pinoresinol, indicating a possible synergic eff ect between the various polyphenols in olive oil. ∗ ∗(http://www.doctorsfornutrition.com/) ∗ ∗ ∗ Combination of phytonutrients (e.g. curcumin, green tea extract) that attenuates proinfl ammatory and carcinogenic cascades.

MY HEALTH PLAN FOR KRISTIN

1. Diet: continue high vegetable, high-ﬁ ber, Mediterranean-based diet∗ 2. High-potency multivitamin 3. Doctor’s green and red alert ∗ ∗ 4. Calcium: 1,000 mg/d. Vitamin D: 2,000 i.u. 5. Foods with high ORAC value 6. Colonoscopy in 1 year then every 3 years; screen children at age 25 7. Weight-reduction program 8. Daily exercise (minimum 30 minutes per day) 9. KappArest from Biotics Research (2 bid) ∗ ∗ ∗ 10. Continue yoga, mind–body work, prayer, meditation, guided imagery

Conclusion

Prevention, as English clergyman Th omas Adams observed in 1618, “is so much better than healing because it saves the labor of being sick.” Preventive tools were much more sparse during the time of Th omas Adams than they are today. Despite the availability of vaccines to prevent infectious disease, and medicines to lower cholesterol and blood pressure, we are committed to dis- cover agents that can lower the risk of developing cancer and other noncommunicable diseases. 558 INTEGRATIVE GASTROENTEROLOGY

Colon cancer is ranked as the third leading cause of cancer-related death. Cancer is a leading cause of death globally. Seventy percent of the cancer deaths occur in low- and middle-class income countries, where the resources available for prevention, diagnosis, and treatment are limited. In industrialized nations such as the United States, with rising healthcare costs and the present economic crisis leaving millions without jobs and health insurance, the disease burden from cancer, especially colorectal cancer, is bound to show an upward trend. In 2008, the World Health Organization (WHO) projected the global burden of death from noncommunicable disease to rise by 17 % by the year 2018. Tackling this burden is a challenge to every nation (WHO, 2008). Preventive strategies for cancer must be considered in the context of activities that prevent other chronic diseases, especially those with which cancer shares common risk factors, such as coronary artery disease, diabetes mellitus, substance abuse, and respiratory illness. Th e common risk factors for the chronic diseases listed above include a sedentary lifestyle, a diet low in fi ber and antioxidants, but high in fat and simple sugars, tobacco and alcohol use, and overweight and obesity. Other risk factors include environmental exposure to toxins, which can be endogenous or exogenous. Cancer, especially colon cancer, is largely preventable. For primary prevention of colorectal cancer, our strategy should aim at reducing the level of the risk factors in the population as a whole. When we reduce the risk factors associated with cancer, we not only prevent the incidence of cancer, we also prevent incidence of other chronic conditions. Overweight, obesity, and sedentary lifestyle accounts for at least 274,000 deaths worldwide. As healthcare providers, the fi rst step we must undertake in preventing colorectal cancer is to have a systematic approach to the assessment of risk factors. Next, using the risk assessment to prioritize our actions, we need to identify:how many of the risk factors are modifi able and how many of the risk factors are attributable to avoidable exposure to carcinogens. Decision making in prevention strategies should consider social and economic factors. Incorporating a daily exercise routine of 30 minutes of walking does not require going to a gym. Likewise, including fi ber-rich seasonal fruits and vegetables, and adequate calcium and vitamin D, is of the utmost importance. With regard to folic acid, though the benefi ts are certainly noted, the exact amount and timing of supplementation need to be determined by further studies. In conclusion, eating healthfully, engaging in regular exercise, and taking nutritional supplements tailored to meet individual needs, are likely to help keep colorectal cancer away.

4 7 Liver Disease

MATTHEW CAVE , NAEEM ASLAM , CHRISTOPHER KULISEK , LUIS S. MARSANO , AND CRAIG J. MCCLAIN

key concepts

■ CAM therapy is widely used by patients with liver disease, and patients frequently do not divulge this use to their physicians. ■ Multiple CAM agents eff ectively prevent and treat experimental liver injury. ■ We frequently utilize zinc and magnesium supplementation for benefi cial eff ects on the liver, as well as for treating muscle cramps, an oft en overlooked but potentially debilitating complication of liver disease. ■ Several CAM therapies, such as silymarin and SAM, appear safe, but there are limited or confl icting human clinical data on effi cacy. ■ Hepatotoxicity is an important side eff ect of many CAM agents, especially weight-loss agents. ■ CAM agents may interfere with the metabolism/disposition of traditional medications. ■

Introduction

omplementary and alternative medicine (CAM) is an area of rapidly growing public interest. One estimate showed that CAM is used by C approximately 42 % of the U.S. population (Eisenberg, Davis et al., 1998 ). Major reasons for CAM use include back problems, anxiety, depression,

559 560 INTEGRATIVE GASTROENTEROLOGY headaches, and liver disease. Viral hepatitis, nonalcoholic steatohepatitis (NASH), alcoholic liver disease, (ALD) and cirrhosis of multiple etiologies have been the most studied liver disorders in clinical trials using CAM products. Th is high use of CAM by the general U.S. population is mirrored in the high use by patients with liver disease. Th is is due, in part, to lack of FDA- approved therapy for ALD and NASH, the chronic course of many types of liver diseases, and symptoms ranging from fatigue to muscle cramps. In one survey of 989 patients with liver disease seen at liver disease clinics in 6 U.S. medical centers between April 1 and August 1, 1999, 389 (39 %) reported using some form of CAM at least once during the preceding month: 21 % used herbal preparations (13 % used herbs to treat their liver disease: milk thistle, 12 % ; and licorice root, 1 % ); 18% used self-prayer; 9 % , relaxation; 8 % , multivitamins; 7 %, massage; 6% , chiropractic; and 6 %, spiritual healing (Strader, Bacon et al., 2002 ). Five variables were found to be predictive of alternative therapy use: female gender, young age, high level of education, high annual income, and geographic location. Overall, 74 % of patients reported using CAM in addition to medications prescribed by their physicians, yet 26 % did not inform their physicians regarding their CAM use (Seeff , Lindsay et al., 2001 ; Strader, Bacon et al., 2002 ). Similarly, White and colleagues reported that 35 of 76 patients (46% ) with hepatitis C (HCV) used CAM, with 24% of this group using herbal supplements.

The herb most commonly used for hepatitis C is milk thistle.

Benefi ts of CAM ranged from reduction in fatigue to improved gastrointestinal function, and no adverse eff ects of CAM were reported (White, Hirsch et al., 2007 ). Th ese studies are representative of many others reporting the wide use of CAM in liver disease (Krueger, Dryden et al., 2005 ; Hanje, Fortune et al., 2006 ; McClain, Dryden et al., 2008 ). In this article, we will review recent reports of CAM therapy in liver disease and potential hepatic toxicity, with an emphasis on mechanisms of action and clinical applications. We will only discuss biologic therapies, as these have been the main forms of CAM studied in liver disease. We will review (1) selected minerals and vitamins; (2) products involved in the hepatic methionine pathway; (3) prebiotics/probiotics; (4) polyphenols; (5) herbals; and (6) CAM hepatotoxicity. Liver Disease 561

1. Minerals and Vitamins

ZINC

Zinc is the second most abundant trace element in the body (second only to iron). Zinc is involved in multiple aspects of cell functions including metabolism, detoxifi cation, antioxidant defenses, signaling transduction, and gene regulation. Zinc participates in cell functions mainly through binding to thousands of zinc proteins including metalloenzymes. Zinc coordination has catalytic, structural, and/or regulatory roles in zinc proteins, and removal of zinc can exert deleterious eff ects on cell function, leading to cell injury/death (Goode, Kelleher et al., 1990 ; Kang & Zhou, 2005 ).

Major manifestations of zinc deﬁ ciency in humans include anorexia, skin lesions, growth retardation, neurosensory defects, and immune dysfunction (McClain, Adams et al., 1988 ).

Zinc defi ciency has been documented in multiple types of human liver diseases (Stamoulis, Kouraklis et al., 2007 ). Moreover, experimental zinc defi - ciency in animals increases susceptibility to several forms of hepatotoxicity such as lipopolysaccharide-induced liver injury (Shea-Budgell, Dojka et al., 2006 ). In patients with alcoholic liver disease, hepatic zinc defi ciency has been found to be correlated with liver dysfunction as indicated by decreased serum albumin, increased serum bilirubin, and decreased galactose elimination capacity and antipyrine clearance (Atukorala, Herath et al., 1986 ; Bianchi, Marchesini et al., 2000 ). Major mechanisms for zinc defi ciency in patients with liver disease include poor intake, decreased absorption, and increased urinary losses (McClain, Hill et al., 2006 ). Extensive recent research in experimental animals has shown that zinc supplementation protects against alcohol-induced liver injury. Zinc supplementation works through many mechanisms including decreasing abnormalities in gut barrier function caused by alcohol, decreasing endotoxemia, reducing proinfl ammatory cytokine production, reducing oxidative stress, and preserving function of critical hepatic-zinc fi nger proteins (Lambert, Zhou et al., 2004 ; Zhou, Wang et al., 2005 ; Kang, Song et al., 2008 ; Zhou, Liu et al., 2008 ). Zinc supplementation in humans with liver disease has been shown to reverse signs and symptoms of zinc defi ciency, such as altered immune 562 INTEGRATIVE GASTROENTEROLOGY

function, skin lesions, and night vision abnormalities (McClain, Marsano et al., 1991 ; McClain, Hill et al., 2006 ). Th e case for zinc therapy for liver disease is best supported in Wilson’s disease, an autosomal recessive genetic disease involving abnormalities in cellular copper export.

Zinc inhibits the absorption of copper from the gastrointestinal tract by inducing enterocyte metallothionein. Metallothionein is a protein that binds metals and has a high afﬁ nity for copper. It preferentially binds copper present in the enterocyte (absorbed from the gastrointestinal tract) and prevents it from entering the portal circulation.

Zinc is used primarily as maintenance therapy in successfully treated patients, and as fi rst-line therapy in asymptomatic patients (Brewer, Dick et al., 1998 ). Th e dose of zinc usually required to impair copper absorption and to treat Wilson’s disease is 50 mg of elemental zinc (equivalent to 220 mg zinc sulfate) three times a day. Long-term zinc supplementation in other liver diseases should be ≤ 50 mg of elemental zinc/day to avoid side eff ects such as copper defi ciency or GI distress. Unfortunately, few human studies have been performed on zinc supplementation in other forms of liver disease. One recent study suggested that chronic zinc therapy may decrease hepatic fi brosis, as evidenced by a decrease in serum Type IV collagen levels (Takahashi, Saito et al., 2007 ).

The main side effects of zinc supplementation are nausea and potential copper deﬁ ciency (if given at a dose of ≥ 220 mg zinc sulfate [50 mg elemental zinc] three times per day).

We frequently give one 220mg tablet of zinc sulfate a day in an attempt to prevent oxidative stress, infl ammation, and possibly decrease fi brosis. We utilize zinc for muscle cramps in patients with liver disease. Muscle cramps are an under-recognized and common complication of cirrhosis that may respond to zinc and/or oral magnesium supplementation (Kugelmas, 2000 ).

MAGNESIUM

Magnesium is an essential mineral involved in multiple enzyme systems, muscle function, and insulin/glucose metabolism (Wells, 2008 ). Alcoholics, including Liver Disease 563 those without liver disease, and patients with cirrhosis due to many etiologies frequently have low total body magnesium levels, sometimes with normal serum magnesium levels (Koivisto, Valta et al., 2002 ). Th is is thought to be due to a combination of factors, including poor absorption in the small bowel, enhanced urinary excretion, abnormal accumulation of saturated fatty acids in cell membranes, and malnutrition (Cohen, 1985 ).

Hypomagnesemia has been implicated in the pathogenesis of speciﬁ c disease states, especially nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Both conditions are strongly associated with insulin resistance, obesity, Type 2 diabetes mellitus, hypertriglyceridemia, and hypertension.

Magnesium levels have been shown to regulate the cellular response to insulin, with low levels of magnesium producing cellular insulin resistance (Barbagallo, Gupta et al., 1997 ). In a study that supports this magnesium/ insulin resistance link, six nondiabetic subjects were fed a low-magnesium diet for 4 weeks, and diet-induced magnesium defi ciency increased insulin resistance (Nadler, Buchanan et al., 1993 ). Oral magnesium supplementation also has been shown to improve insulin sensitivity in nondiabetic subjects (Guerrero-Romero, Tamez-Perez et al., 2004 ). Lastly, there is a signifi cant relation between low magnesium concentrations, and both hepatic infl ammation and fi brosis in NASH (Rodriguez-Hernandez, Gonzalez et al., 2005 ). A study of preeclampsia patients with muscle cramps showed improvement of cramps with magnesium supplementation (Dahle, Berg et al., 1995 ). We regularly treat muscle cramps in patients with liver disease with magnesium oxide, 400 mg orally daily. Th ere have been few clinical trials of magnesium supplementation for the treatment of liver disease, with one trial showing signifi cant improvement in the liver AST with magnesium supplementation (Poikolainen & Alho, 2008 ).

VITAMIN E

Vitamin E is a chain-breaking antioxidant. Tumor necrosis factor alpha (TNF- α ) is a proinfl ammatory cytokine important in the pathogenesis of many forms of liver injury including nonalcoholic and alcoholic liver disease (Hill, Barve et al., 2000 ; Tilg & Diehl, 2000 ); and nuclear factor kappa B (NF-κ B) is a transcription factor for TNF-α as well as multiple other 564 INTEGRATIVE GASTROENTEROLOGY

pro-infl ammatory cytokines (Schreck, Rieber et al., 1991 ; Schulze-Osthoff , Los et al., 1995 ; Hill, Barve et al., 2000 ; Tilg & Diehl, 2000 ; Arteel, Marsano et al., 2003 ). In vitro studies demonstrated increased binding activity of NF- κ B in human monocytes treated with ethanol, and subsequent studies showed that patients with alcoholic hepatitis demonstrate increased monocyte NF- κ B activation and increased production of TNF-α (Mandrekar, Catalano et al., 1997 ; Hill, Barve et al., 2000 ). In vitro vitamin E treatment of monocytes from patients with alcoholic hepatitis decreased NF-κ B activation and eff ectively inhibited TNF-α production (Hill, Devalaraja et al., 1999 ). In nonalcoholic fatty liver disease (NAFLD) there also is evidence to suggest an etiologic role for TNF-α and NF- κB. Oxidative stress has been postulated to play an etiologic role in the development of many forms of liver disease including NASH (oxidative stress acts as the “second hit” to produce NASH). Vitamin E also has been shown to block in vitro activation of stellate cells, in part by decreasing NF- κB activity (Lee, Buck et al., 1995 ). Transforming growth factor-β 1 (TGF-β 1) is a pro-fi brotic cytokine that is elevated in many forms of human liver disease. Expression of TGF- β 1 is increased in animal models of hepatic fi brosis, and in studies performed in rats with carbon tetrachloride (CCl 4)-induced liver fi brosis, treatment with vitamin E decreased levels of TGF-β and improved liver injury and fi brosis (Parola, Leonarduzzi et al., 1992 ; Parola, Muraca et al., 1992 ; Liu, Degli, Esposti et al., 1995 ). Indeed, vitamin E is eff ective in preventing many forms of experimental liver injury.

The effects of vitamin E in human liver disease such as ALD, NAFLD, and NASH are mixed.

One of the most commonly cited studies on vitamin E and NASH is an open-label pilot study of 11 children with NASH treated with vitamin E. Patients were treated with dietary instruction and high-dose vitamin E (between 400 to 1,200 international units (IU)/day) for 4 to 10 months. Five of 11 patients showed signifi cant improvement in ALT levels with the lowest dose (400 IU/day), 4 patients improved with 800 IU/day, and 2 patients treated with 1,200 IU/day showed improvement in ALT levels liver histology was not evaluated (Lavine, 2000 ). Another randomized controlled trial (RCT) studied 28 children with NASH treated with vitamin E. Groups were randomized to dietary instruction or dietary instruction plus vitamin E (400 IU/day x 2 months; 100 IU/day x 3 months), and were followed for 5 months. Vitamin E was shown to be eff ective in reducing and normalizing transaminases in children with NASH, Liver Disease 565 although no eff ect on ultrasound liver brightness was noted (Vajro, Mandato et al., 2004 ). However, in the largest study to date in children/adolescents, antioxidants (vitamin E 600 IU/day + ascorbic acid 500 mg/day) provided no additional benefi t to lifestyle modifi cation as assessed by liver biopsy and liver enzymes. Th is randomized trial of lifestyle modifi cation (± antioxidants) did show that lifestyle modifi cation with weight loss and exercise positively infl u- enced liver biopsy and liver enzymes at 2 years of intervention (Nobili, Manco et al., 2008 ). A nonrandomized, non-placebo-controlled pilot study of 22 adult Japanese patients examined patients with NAFLD and NASH treated with vitamin E. Patients were treated with dietary instruction for 6 months followed by vitamin E (300 IU/day) for 1 year. TGF- β 1 levels were signifi cantly higher in the patients with NASH when compared to patients with NAFLD or healthy subjects. Elevated TGF-β 1 in patients with NASH improved aft er 1 year of vitamin E treatment and correlated with improvements in ALT levels. In the patients with NASH, 5 of 9 also showed histologic improvement with decreased infl ammation and fi brosis aft er treatment with vitamin E (Hasegawa, Yoneda et al., 2001 ). We evaluated 16 adults with NASH treated with either dietary instruction alone or dietary instruction and 800 IU/daily of vitamin E for 12 weeks. Both groups demonstrated an improvement in BMI and signifi cant improvement in ALT; however, subgroup analysis showed no further benefi t in the patients treated with vitamin E and dietary instruction, when compared to the group receiving dietary instruction alone (Kugelmas, Hill et al., 2003 ). Th e PIVENS study (pioglitazone vs. vitamin E) sponsored by the National Institutes of Health (NIH) has enrolled almost 250 patients, and results from this trial should provide direction on vitamin E therapy for NASH (Chalasani, Sanyal et al., 2009 ). Studies in alcoholic liver disease have generally been negative concerning vitamin E therapy. A large RCT evaluated 67 patients with decompensated alcoholic cirrhosis treated with vitamin E and advised to abstain from alcohol. Patients were treated with 500 IU/day of vitamin E for 1 year; at the end of 1 year, there was no signifi cant improvement seen in liver function tests, hospitalization rates, or overall mortality when compared to placebo (de la Maza, Petermann et al., 1995 ). A recent RCT studied 51 patients with mild to moderate alcoholic hepatitis treated with 1,000 IU/daily of vitamin E for 1 year. Th ere were no signifi cant diff erences in biochemical markers (serum aminotransferases, bilirubin, albumin, prothrombin time, or creatinine) or overall mortality between the treatment group and placebo group (Mezey, Potter et al., 2004 ). Lastly, patients with HCV generally do not have improved viral response to interferon plus ribavirin therapy with the addition of vitamin E therapy (Hanje, Fortune et al., 2006 ). At the current time, we do not routinely use 566 INTEGRATIVE GASTROENTEROLOGY high-dose vitamin E therapy in liver disease (outside of clinical trials) due to confl icting data on effi cacy and some theoretic risks.

2. Products of Hepatic Methionine Metabolism

Abnormal hepatic methionine metabolism is well documented in many forms of liver disease including ALD, generally characterized by decreased hepatic S-adenosylmethionine (SAM) and folate levels, increased hepatic S-adenosylhomocysteine (SAH), and homocysteine accumulation (Figure 47.1 ). Several mechanisms have been proposed for SAM depletion in liver disease, including: inactivation of methionine adenosyltransferase (MAT – converts methionine to SAM); excessive consumption of SAM by the liver; and inhibition of endogenous methionine synthesis due to impaired homocysteine methylation (Purohit, Abdelmalek et al., 2007 ).

Folate deﬁ ciency is another well-characterized metabolic abnormality in liver disease, especially ALD.

Folate is a water-soluble vitamin that plays an integral role in methionine metabolism and DNA synthesis. Folate in its 5-methyltetrahydrofolate (5-MTHF) form can transfer a methyl group to homocysteine via a methionine synthase (MS)-catalyzed reaction to form endogenous methionine, which is a precursor of SAM. Th us, folate helps maintain normal concentrations of homocysteine, methionine, and SAM. Folate defi ciency can impair methionine metabolism, leading to hyperhomocysteinemia as well as depletion of methionine and SAM (Purohit, Abdelmalek et al., 2007 ).

In contrast to decreased SAM and folate levels, increased hepatic levels of homocysteine and SAH (two other important metabolites in hepatic methionine metabolism) are observed in many liver diseases, especially ALD.

Homocysteine is formed from methionine aft er removal of the methyl group on SAM and hydrolysis of SAH. Substantial data support the suggestion that hyperhomocysteinemia may play an important role in the development of alcohol-induced fatty infi ltration of the liver, liver injury, and hepatic fi brogenesis (Refsum, Ueland et al., 1998 ). Liver Disease 567

SAH is a direct product aft er SAM transfers its methyl groups to various compounds, via many diff erent methyltransferases, and SAH is a potent endogenous inhibitor of most methyltransferases. We have reported that increased SAH accumulation sensitized hepatocytes to TNF-induced cell death, and we postulated that increased SAH in liver disease may be an endogenous sensitizer to TNF hepatotoxicity (Song, Zhou et al., 2004).

S A M

SAM protects against multiple experimental toxin-induced liver diseases (Purohit, Abdelmalek et al., 2007 ). SAM administration attenuated alcohol- induced steatosis and restored hepatic glutathione concentrations in rats, and it attenuated ethanol-induced depletion of mitochondrial glutathione and restored mitochondrial function in hepatocytes (Feo, Pascale et al., 1986 ). In mice, SAM treatment signifi cantly attenuated acute alcohol-induced liver injury characterized by attenuation of alcohol-induced steatosis, necrosis, and increased ALT activity, all of which were associated with restoration of hepatic SAM and mitochondrial glutathione concentrations, and attenuation of lipid peroxidation (Song, Zhou et al., 2003 ). SAM may also protect by decreasing tumor necrosis factor α (TNFα ) and increasing interleukin-10. In the most comprehensive clinical study to date, the therapeutic potential of SAM was tested in a 24-month randomized, placebo-controlled, double- blind, multicenter trial of 123 patients with alcoholic cirrhosis (Mato, Camara et al., 1999 ). SAM treatment improved survival or delayed the need for liver transplantation in patients with alcoholic liver cirrhosis, especially in those with less advanced liver disease. In this trial, increased hepatic concentrations of glutathione may have contributed to the benefi cial eff ects of SAM because, in another study, oral administration of 1.2 g SAM/d for 6 months signifi cantly increased hepatic glutathione concentrations in ALD patients (Vendemiale, Altomare et al., 1989 ). While this one large multicenter study showed some benefi cial eff ects of SAM, other studies are needed to confi rm these benefi cial eff ects and to defi ne appropriate dosing schedules. Th e dose we utilize in clinical trials is 400 mg 4 times daily (1,600 mg total)

FOLATE

It is clear that folate defi ciency in micropigs accelerates alcohol-induced liver injury through multiple pathways. However, with folic acid fortifi cation in the current American diet, chronic alcohol exposure may not lead to major hepatic 568 INTEGRATIVE GASTROENTEROLOGY folate defi ciency in the United States. Whether further folate administration will attenuate human ALD or other forms of liver injury is unknown. In spite of unclear indications, we frequently supplement ALD patients with folate (1 mg/day).

BETAINE

Betaine is highly eff ective in reducing homocysteine levels and removing fat from the liver in experimental models of alcohol-induced liver injury (Ji and Kaplowitz, 2003 ). Unfortunately, good RCTs in humans are lacking, as are dose-fi nding studies in humans. Betaine is much more stable than SAM, and its absorption is much better characterized. A pilot study of high-dose betaine therapy (10 g twice a day) in NASH showed promising results (Abdelmalek, Angulo et al., 2001 ), but a larger, follow-up, randomized trial in NASH did not show signifi cant benefi t (unpublished data). Th us, further human studies are warranted, but we do not clinically supplement with betaine at the current time.

3. Polyphenols

Th e term dietary polyphenols refers to members of a large family of related organic plant molecules. Plant polyphenols frequently impart fl avor and color to fruits and other plant products. Plant polyphenols can be divided into several classes, generally depending on the number of phenol rings contained in the structure.

Polyphenols are the most abundant antioxidants consumed by humans, with a total intake as high as 1 g/day (Scalbert, Johnson et al., 2005 ).

Although many in vitro studies demonstrate robust biological eff ects from plant polyphenols, actual in vivo systemic eff ects likely may be modest, due to poor gastrointestinal absorption. Major human studies have not been performed in liver diseases, but there are exciting in vitro and animal studies. We will briefl y review the eff ects of green tea polyphenols, resveratrol, and curcumin.

GREEN TEA

Th ere is increasing interest in the role of tea (Camellia sinensis ) in maintaining health and treating disease. Although tea consists of several components, Liver Disease 569 research has focused on polyphenols, especially those found in green tea. Th ese include (-)-epicatechin (EC); (-)-epigallocatechin (EGC); (-)-epicatechin- 3-gallate (ECG); and (-)-epigallocatechin-3-gallate (EGCG). Of these, EGCG generally accounts for more than 40% of the total (Hara, 1997 ). Green tea polyphenols are potent antioxidants (Salah, Miller et al., 1995 ). EGCG usually has the greatest antioxidant activity, and it is the most widely studied polyphenol for disease prevention (Bagchi, 1999 ). Many of the putative health benefi ts of tea are presumed to be due to its antioxidant eff ects. Tea may also act as an anti-infl ammatory agent. We reported that mice fed an extract of green tea polyphenols had decreased TNF- α production, NF- κ B activation, hepatotoxicity, and lethality, in response to an injection of lipopolysaccharide (LPS; see Yang, de Villiers et al., 1998 ). Similarly, green tea polyphenols have been shown to protect against experimental alcohol-induced hepatic fi brosis and concomitantly decrease endotoxin levels in rats (Li, Zhang et al., 2004 ). Green tea (EGCG) protected against the hepatotoxin carbon tetrachloride (Chen, Tipoe et al., 2004 ). Green tea from Camellia sinensis also attenuated primary graft failure aft er liver transplantation of fatty livers in rats (Zhong, Connor et al., 2 0 0 4 ) . Th ese same investigators showed that Camellia sinensis attenuated experimental hepatic fi brosis in rats following bile duct ligation (Zhong, Froh et al., 2003 ). A recent study documented the benefi cial eff ects of EGCG on the metabolic syndrome in mice fed a high-fat diet (Bose, Lambert et al., 2008 ). Supplementation with dietary EGCG in mice fed a high-fat diet reduced body weight, percent body fat, and visceral fat, compared to mice without EGCG treatment. EGCG also attenuated insulin resistance, plasma cholesterol, and monocyte chemoattractant protein concentrations, and decreased liver weight, liver triglycerides, and plasma alanine aminotransferase concentrations in mice fed a high-fat diet (Bose, Lambert et al., 2008 ). Of some concern, however, are recent case reports of green-tea-induced hepatotoxicity in humans (Molinari, Watt et al., 2006 ).

RESVERATROL

Resveratrol has been linked to both improved fi tness and life extension in animal studies (Howitz, Bitterman et al., 2003 ; Lagouge, Argmann et al., 2006 ). Because it is found in red grapes and red wine, resveratrol was believed to be a potential mediator of the French paradox. However, recent studies suggest that the resveratrol levels in red wine are insuffi cient based on its low bioavailability to explain the French paradox. Nonetheless, resveratrol is an attractive and emerging CAM agent for liver disease. Animal models of both alcoholic and nonalcoholic fatty liver disease demonstrate that resveratrol attenuates steatosis, 570 INTEGRATIVE GASTROENTEROLOGY oxidative stress, and proinfl ammatory cytokine production through mechanisms involving activation of both 5’-AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1; see Ajmo, Liang et al., 2008 ; Rivera, Moron et al., 2008 ). Furthermore, in preclinical studies, resveratrol exerted both chemotherapeutic and chemopreventive actions against hepatocellular carcinoma (Wu, Sun et al., 2004 ; Bishayee and Dhir, 2008 ). Despite this emerging therapeutic rationale, we could not fi nd any published human clinical trials of resveratrol in liver disease. Resveratrol’s potential risk as a weak phytoestrogen is debated in the literature.

CURCUMIN

Curcumin is a yellow pigment that is found in the Indian spice turmeric, and has important inhibitory eff ects on infl ammation, angiogenesis, and tumor formation (Anand, Th omas et al., 2008 ). Curcumin has multiple mechanisms of action including acting as an antioxidant, inhibiting NF-kB activation and decreasing TNF- α and TGF- β production. Curcumin has been shown to be benefi cial in several models of hepatotoxicity including obesity, carbon tetrachloride, bile duct ligation, and endotoxin (Memis, Hekimoglu et al., 2008 ; Reyes-Gordillo, Segovia et al., 2008 ; Weisberg, Leibel et al., 2008 ). Importantly, curcumin has potent antitumor eff ects, including eff ects against hepatocellular carcinoma (Anand, Th omas et al., 2008 ). Unfortunately, curcumin, like many other polyphenols, has poor oral bioavailability that limits its chemoprevention effi cacy (Anand, Th omas et al., 2008 ). Th us, novel strategies to improve bioavailability, including nano delivery systems, liposomes, pegylation, and curcuma prodrugs, are all under active investigation (Anand, Th omas et al., 2008 ).

4. Herbals

SILYMARIN (MILK THISTLE)

Silymarin, the active ingredient extracted from Silybum marianum (also known as milk thistle), has been used by ancient physicians and herbalists to treat a variety of liver and gallbladder diseases.

A large number of animal studies have reported hepatoprotection against a diverse range of toxins including acetaminophen, carbon tetrachloride, mushroom poisoning (phalloidin), radiation, iron overload, phenyl hydrazine, alcohol, cold ischemia, and thiocetamide (Jacobs & Dennehy et al., 2002 ). Liver Disease 571

Th e elucidation of the mechanisms by which silymarin protects the liver has expanded substantially over the last two decades. Silymarin works as an antioxidant by reducing free radical production, protects against lipid peroxidation, stabilizes cell membranes, has anti-fi brotic properties, and inhibits NF-kB activation with favorable immunomodulatory eff ects (Dehmlow, Erhard et al., 1996 ; Saliou, Rihn et al., 1998 ; Manna, Mukhopadhyay et al., 1999 ; Hanje, Fortune et al., 2006 ). In the United States, silymarin is one of the most commonly used CAM agents in the treatment of liver disease. Large controlled trials of silymarin have been performed in Europe, with variable results, probably due to low- quality clinical trials (Hanje, Fortune et al., 2006 ). A recent Cochrane meta- analysis of 18 randomized trials in 1,088 patients with alcoholic and/or hepatitis B or C virus liver diseases highlights some of these issues. Th is study showed a signifi cantly decreased liver related mortality when low-quality trials were included, but no signifi cant eff ect was found in high-quality clinical trials on all-cause mortality, liver-related mortality, complications of liver disease, or liver histology (Rambaldi, Jacobs et al., 2005 ). On the other hand, a recent systematic review and meta-analysis by Saller et al. concluded that the use of silymarin is reasonable in Amanita phalloides poisoning, alcoholic liver disease (as an addition to abstinence), and Child’s A cirrhosis (Saller, Brignoli et al., 2008 ). Recently, the Hepatitis C Antiviral Long Term Treatment Against Cirrhosis (HALT-C) Trial survey reported that 504 (44% ) of 1,145 study participants who were nonresponders to chronic hepatitis C treatment had a history of herbal supplement use either prior to or at baseline evaluation. Silymarin was a constituent in 72% of the 60 diff erent herbals noted at enroll- ment, and herbal use showed no signifi cant eff ects in decreasing ALT and HCV RNA levels (Seeff , Curto et al., 2008 ).

Despite the lack of strong evidence, silymarin is still the most commonly used complementary and alternative medicine therapy for chronic liver diseases, in part because of its good safety proﬁ le. Well-designed, multicenter RCTs of silymarin are required to prove its effectiveness in chronic liver disease, and NIH-sponsored trials are ongoing.

GLYCYRRHIZIN (LICORICE ROOT)

Th e active component of Glycyrrhiza glabra (licorice root) is glycyrrhizin. Licorice root has been used for centuries in traditional medicine to treat cough, bronchitis, gastritis, and liver infl ammation. It is available over the counter in 572 INTEGRATIVE GASTROENTEROLOGY liquid, powder, and pill forms in the United States (Levy, Seeff et al., 2004 ). Glycyrrhizin has antioxidant, immunosuppressive, and anti-infl ammatory properties. It also enhances interferon production and stimulates natural killer cell activity (Shiki, Ishikawa et al., 1986 ; Shiki, Shirai et al., 1992 ; Yoshikawa, Matsui et al., 1997 ). Clinical trials using glycyrrhizin (intravenous-IV) have mostly involved the treatment of hepatitis C, specifi cally, patients who are refractory to, or intolerant of, interferon treatment. A double-blind randomized trial performed by Suzuki et al. looked at IV injections of 80 mg of Stronger Neo-Minophagan C (SNMC, the Japanese standard preparation of glycyrrhizin combined with glycine and cysteine) in patients who had histologically proven chronic active hepatitis. Aft er 1 month of treatment in 133 patients, transaminases fell by about 40% in the treatment group versus a 2 % drop in the placebo group, and no signifi cant side eff ects were noted (Suzuki, Ohta et al., 1984 ). Arase et al. showed improvement in ALT level with glycyrrhizin in patients with hepatitis C (Arase, Ikeda et al., 1997 ). Very few studies have shown enhanced antiviral eff ects with glycyrrhizin. Th e main side eff ects of glycyrrhizin treatment include fl uid retention and hypokalemia because of its mineralocorticoid eff ect (Hanje, Fortune et al., 2006 ).

Licorice root should be avoided in patients with cirrhosis, and we do not utilize it in our patients with chronic liver disease.

HERBAL COMBINATIONS

Several other herbal combinations have been reported to have effi cacy in chronic liver disease, especially in chronic hepatitis B and C. Th ese studies have come mainly from the Orient and are oft en observational in nature. Some of the most widely used of these herbal preparations are listed in Table 47-1 .

5. Prebiotics/Probiotics

Th ere are approximately 100 trillion microorganisms residing in the human bowel (Cani & Delzenne, 2007 ). Th erefore, the human body contains more prokaryotic cells than eukaryotic cells. However, there are limited data suggesting that the composition of the bowel fl ora is abnormal in patients with liver disease. For example, patients with cirrhosis primarily due to viral hepatitis had a signifi cant increase in Enterococcus , Enterobacter and Clostridium species and a signifi cant decrease in Bifi dobacterium species (Zhao, Wang et al., 2004 ). Work from our group demonstrated that patients with alcoholic Liver Disease 573

Table 47.1. Blended Herbal Preparations in Liver Disease: Method of Action and Uses

Blended Herbal Method of Action Use Preparations

TJ-9 Anti-fi brotic; inhibition of stellate cell activation; Hepatitis B; decreases hepatic lipid peroxidation; increases prevention of TNF-α and granulocyte colony stimulating factor hepatocellular (g-CSF) carcinoma

TJ-108 Reduction in HCV-RNA, hepatoprotective Hepatitis C

Herbal Blocking cyclin/cyclin-dependent kinase, Hepatitis B medicine 861 facilitating remodeling of fi brotic liver tissue

CH-100 No loss in HCV-RNA; however, decreased ALT, Hepatitis C hepatoprotective

Bing Gan Some improvement in HCV-RNA clearance Hepatitis C

Liv 52 Inhibits lipid peroxidation; decreases TNF activity Experimental liver injury; ALD

liver disease have decreased numbers of bowel bifi dobacteria, lactobacilli and enterococci compared to healthy controls (Kirpich, Solovieva et al., 2008 ). Bowel–liver interactions are well described in liver disease. Importantly, heavy alcohol use is associated with increased gut permeability, and the frequency of endotoxemia is high (McClain, Barve et al., 1999 ; Carithers & McClain, 2006 ). Lipopolysaccharide (LPS) derived from Gram-negative bowel fl ora stimulates proinfl ammatory cytokine production in Kupff er cells to mediate alcoholic hepatitis (McClain, Barve et al., 1999 ).

Pathological alterations in bowel ﬂ ora could contribute to the development and progression of liver disease, while restoring normal bowel ﬂ ora could be a viable treatment option.

Probiotics are defi ned as live microorganisms that, when administered in adequate amounts, confer a health benefi t to the host, apart from their simple caloric value. Likewise, prebiotics, such as fermented products, soluble fi ber and inulin, modulate the composition of the bowel fl ora to confer health benefi ts. Many newer commercial preparations contain both prebiotics and probiotics and are called synbiotics . 574 INTEGRATIVE GASTROENTEROLOGY

Animal studies support a variety of mechanisms of action for prebiotics and probiotics in the treatment of liver disease. Nanji et al. fi rst demonstrated that Lactobacillus GG reduced endotoxemia and alcohol-induced liver injury in rats (Nanji, Khettry et al., 1994 ). Feeding oats (prebiotic) has been shown to prevent endotoxemia and liver injury in rats fed alcohol (Keshavarzian, Choudhary et al., 2001 ). In mice injected with LPS and d -galactosamine, pretreatment with the probiotic mixture VSL#3 ™ prevented a breakdown in colon barrier function, reduced bacterial translocation, reduced tissue TNF- α levels, and signifi cantly attenuated liver injury (Ewaschuk, Endersby et al., 2007 ). In addition to reducing infl ammation, probiotics may also reduce oxidative stress. For example, intestinal B. longum and L. acidophilus reduced in vitro plasma lipid peroxidation (Lin & Chang, 2000 ). Probiotics may also infl uence bioen- ergetics and metabolism to infl uence liver disease. In a mouse model of NASH, VSL#3™ was shown to reduce the activity of Jun-N-terminal kinase (JNK), which integrates infl ammatory and metabolic signals and mediates insulin resistance (Li, Yang et al., 2003 ). Th e prebiotic, fructooligosaccharides (FOS), was recently shown to increase production of glucagon-like peptide-1 (GLP-1) by L cells in the colon, and to decrease its degradation by dipeptidyl peptidase-IV (Delzenne, Cani et al., 2007 ). Th is resulted in an increased portal vein concentration of GLP-1, with resultant hepatic insulin sensitization (Delzenne, Cani et al., 2007 ). Th erefore, prebiotics and probiotics appear to modulate infl ammation, oxidative stress, and metabolism in animal models of liver disease. Th ese mechanisms provide the rationale supporting the need for more clinical research on prebiotics, probiotics, and synbiotics in the treatment of liver d i s e a s e .

Emerging human data suggest a role for both prebiotics and probiotics in the treatment of a variety of liver diseases.

Probiotics have been reported improve liver transaminases in patients with alcoholic hepatitis who were treated with Bifi dobacterium bifi dum and Lactobacillus plantarum 8PA3 for fi ve days over abstinence alone (Kirpich, Solovieva et al., 2008 ). Th e reduction in liver enzymes occurred concomitantly with the restoration in numbers of bifi dobacteria and lactobacilli, which were decreased prior to therapy (Kirpich, Solovieva et al., 2008 ). In a pilot study, the prebiotic FOS improved transaminases and insulin resistance at 8 weeks in patients with NASH (Daubioul, Horsmans et al., 2005 ). Cirrhotic patients treated with a synbiotic preparation had signifi cantly reduced endotoxemia and arterial ammonia (Liu, Duan et al., 2004 ). Patients with alcoholic cirrhosis and NAFLD treated with VSL#3™ had signifi cantly reduced plasma levels of Liver Disease 575 the lipid peroxidation products, malondialdehyde, and 4-hydroxynonenal (Loguercio, Federico et al., 2005 ). However, only the patients with alcoholic cirrhosis had an improved plasma cytokine profi le (reduced tumor necrosis factor alpha and increased interleukin-10; Loguercio, Federico et al., 2005 ). Probiotics, and bifi dobacteria in particular, are a promising area of research in obesity and NASH. Reduced fecal bifi dobacteria in normal weight human infants was predictive of the subsequent development of childhood obesity at 7 years of age (Kalliomaki, Collado et al., 2008 ). Likewise, in mice, high-fat feeding was associated with a signifi cant reduction in cecal Bifi dobacterium spp., with signifi cant increases in body weight, adipose tissue mass, liver triglycerides, endotoxemia, and hepatic tumor necrosis factor alpha (Cani, Amar et al., 2007 ). Th e authors subsequently demonstrated that a prebiotic mixture of FOS restored the quantities of bifi dobacteria in high-fat-fed rodents to decrease endotoxemia, proinfl ammatory cytokines, insulin resistance, and fatty liver (Daubioul, Taper et al., 2000 ; Cani, Neyrinck et al., 2007 ). Th is is a rapidly evolving area. Because of well-documented gut–liver interactions, we feel this will be an important area for research into CAM intervention in liver disease in the future.

6. CAM Hepatotoxicity

Hepatotoxicity from herbal products may be diffi cult to diagnose and is likely underreported. Reasons for CAM toxicity include lack of well-designed RCTs to assess the safety and effi cacy of the CAM products, natural variability of herbal products, diff erences in production methods/contamination issues and, sometimes, the addition of obscure ingredients in unknown amounts (Kaplowitz, 1997 ; Stedman, 2002 ). Herbal mixtures are not required to be standardized, and although they are expected to adhere to regulations of the Dietary Supplement and Health Education Act of 1994, they do not always conform to good manufacturing practices. Public education about how to read the labels of herbal products and understand the ingredients may reduce bad outcomes. It is recommended that the individual look for well-known manufacturers of herbal products and to look for the USP (United States Pharmacopeia) or NF (National Formulary) symbol on the label. Eisenberg et al. reported that 72% of patients using unconventional therapies failed to inform their physicians that they were doing so (Eisenberg, Davis et al., 1998 ). Th is has been a consistent problem noted in most CAM surveys. Most “conventional medicine” physicians are not trained in CAM and they are not aware of ingredients used in herbal remedies. A high index of suspicion is needed to diagnose CAM side eff ects (Strader, Bacon et al., 2002 ). Herbal products are 576 INTEGRATIVE GASTROENTEROLOGY

Table 47.2. Herbal Hepatotoxicity

Herb Type of Liver Injury

Crotalaria Sinusoidal obstruction syndrome (veno-occlusive disease) Heliotropium Senecio longilobus Symphytum offi cinale (Pyrrolizidine alkaloids)

Chaparral leaf, germander Zone 3 necrosis, cirrhosis, cholestasis, chronic hepatitis

Pennyroyal (squamit) oil Zone 3 necrosis, microvesicular steatosis, fulminant liver failure

Jin Bu Huan Acute and chronic cholestatic hepatitis, microvesicular steatosis, fi brosis

Mistletoe Chronic hepatitis

Margosa oil Microvesicular steatosis, Reye syndrome, hepatic necrosis

Usnic acid Fulminant liver failure

Atractylis gummifera Acute hepatitis, fulminant liver failure

Callilepis laureola Acute hepatitis, fulminant liver failure

Impila Acute hepatitis, fulminant liver failure

Camphor Necrolytic hepatitis

Cascara sagrada Cholestatic hepatitis

TJ-8, Dai saiko-toi Autoimmune hepatitis

TJ-9, Sho-saiko-to Acute and chronic hepatitis

Paeonia spp. Acute hepatitis, fulminant liver failure

Greater celandine Chronic hepatitis, cholestasis, fi brosis

Germander Acute and chronic hepatitis, fulminant liver failure

Isabgol Giant cell hepatitis

Kava Acute and chronic hepatitis, fulminant liver failure

Ma Huang Acute hepatitis, autoimmune hepatitis

Oil of cloves Hepatic necrosis

Sassafras Hepatocarcinogen

Saw palmetto Mild hepatitis

Shou-wu-pian Acute hepatitis

Valerian Mild hepatitis Liver Disease 577 capable of producing both intrinsic (or predictable) hepatotoxicity and idio- syncratic (unpredictable) hepatotoxicity (Chitturi & Farrell, 2000 ; Seeff , 2007 ). A prospective study supported by the National Institute of Diabetes and Digestive and Kidney Diseases, referred to as the Drug-Induced Liver Injury Network Study is currently underway. It is a multicenter study and patients with Tylenol hepatotoxicity are excluded. Initial results have shown that CAM is responsible for 6% of enrolled patients. Hepatocellular injury was seen in 53 % of cases as compared to cholestatic (22 %) and mixed pattern of injury (25 % ). A survey of the National Poison Information Service for the years 1991– 1995 documented 785 cases of possible or confi rmed adverse reactions to herbal drugs, among which hepatotoxicity was the most frequent adverse reaction (Shaw, Leon et al., 1997 ). Table 47.2 sets forth examples of CAM-related h e p a t o t o x i c i t y . CAM agents can interact adversely with traditional medications. An example is the potential interaction of St. John’s wort with cyclosporine and indinavir (Ruschitzka, Meier et al., 2000 ). Th is interaction was highlighted when cardiac transplant patients underwent rejection shortly aft er starting St. John’s wort, presumably because of the induction of cytochrome P450 3A4 by the St. John’s wort (Piscitelli, Burstein et al., 2000 ). It is important to instruct all transplant patients (and other patients on immunosuppressive therapy) to inform their physician before starting any CAM agent, and not to use St. John’s wort. MEDwatch is an FDA-sponsored program available for physicians to report adverse events associated with FDA-monitored products, including special nutritional supplements (telephone: 1-800-FDA-1088). Patients can make similar reports through the FDA offi ce of Consumer Aff airs (1-800-532-4400) (Verma & Th u l u v a t h , 2 0 0 7 ) .

Various web sites to consult for hepatotoxicity: http://www.fda.gov/medwatch http://.alhmed.od.nih.gov http://nccam.nih.gov http://www.herbmed.org http://vm.cfsam.fda.org

Conclusion

CAM agents are widely used by people with liver disease (similar to the general population), and this use is frequently not reported to the patient’s physician. Silymarin, or milk thistle, is the most widely used CAM agent for liver disease. 578 INTEGRATIVE GASTROENTEROLOGY

It has an excellent safety profi le, but data are confl icting concerning effi cacy. It would not be unreasonable to use it as supportive therapy during Amanita phalloides mushroom poisoning, and also in alcoholic liver disease and Child’s A cirrhosis. We frequently use zinc supplementation as an anti-infl ammatory and anti-fi brotic agent in multiple types of liver disease, and we utilize zinc and magnesium to treat muscle cramps complicating cirrhosis. It is important to be aware that hepatotoxicity is a major complication of CAM therapy. Moreover, CAM agents may interfere with the metabolism/disposition of traditional medications. Th us, healthcare workers and patients need to beware of both the potential benefi ts and risks of CAM agents.

ACKNOWLEDGMENT

Funding support: Research support was provided by the National Institutes of Health (McClain/Cave) and the Veterans Administration (McClain/Cave).

48 Integrative Approaches to Diseases of the Pancreas and Gallbladder

VINAY CHANDRASEKHARA AND ANTHONY N. KALLOO

key concepts

■ Patients should seek immediate conventional medical treatment for suspected acute pancreatitis, as this is a serious medical condition with a signifi cant risk of morbidity and mortality. ■ Patients with severe acute pancreatitis should be given nutrition early during the course of disease, preferably with enteral feedings if possible. ■ Antioxidant supplements, including polyphenols, have been shown to reduce oxidative stress in animal models, but need to be further studied before they can be recommended for treatment in humans. ■ Gallstone disease is widely prevalent, particularly in Western countries. ■ Cholecystectomy (surgical resection of the gallbladder) is the treatment of choice in the United States for symptomatic gallstone disease. ■ Maintaining appropriate weight and participating in a regular exercise program can reduce the risk of developing gallstone disease. ■ Reducing dietary fat may actually increase the risk of gallstone disease; however, substituting saturated fats with fi sh oil and polyunsaturated fats can lower the risk of gallstone formation. ■ A h i g h - fi ber diet that is low in refi ned carbohydrates and simple sugars may reduce the risk of gallstone disease. ■

579 Pancreas

nfl ammatory disease of the pancreas may occur as an acute or chronic process. Th e incidence of acute pancreatitis in the United States is approx- I imately 5,000 new cases each year, with a mortality rate of 10 % (Kasper, 2 0 0 5 ) . Th e most common causes of acute pancreatitis are summarized in Table 48.1 . Th e classic presentation of acute pancreatitis is epigastric abdominal pain radiating to the back, associated with nausea and vomiting, and it is relieved with sitting or leaning forward. Biochemical and radiographic evaluation usually aid the diagnosis of pancreatitis. Serum amylase is the most widely ordered test, although it is not very specifi c for pancreatitis. Amylase typically rises within 6 to 12 hours of onset, and has a short half-life of 10 hours. In acute uncomplicated attacks, serum amylase remains elevated for three to fi ve days. Serum lipase has a sensitivity

Table 48.1. Causes of Acute Pancreatitis

Gallstone disease (including microlithiasis)

Alcohol

Hypertriglyceridemia

Post-ERCP or biliary manipulation

Trauma

Medications (azathioprine, 6-mercaptopurine, estrogen, tetracycline, sulphonamides, valproic acid, didanosine, pentamidine, metronidazole, furosemide, thiazides, sulfasalazine, 5-ASA)

Sphincter of Oddi dysfunction

Cystic fi brosis

Pancreas divisum

Hereditary pancreatitis

Vasculitis

Renal failure

Infectious causes (mumps, cytomegalovirus, varicella-zoster, coxsackie, HIV, herpes simplex virus)

Pancreatic cancer Integrative Approaches to Diseases of the Pancreas and Gallbladder 581 of 85 % to 100 % and is more specifi c than amylase for acute pancreatitis. Th e various radiographic studies used to evaluate the pancreas are outlined in Table 48.2 . Multiple scoring systems, including the Ranson scoring system and Apache II, have been developed to help predict those patients with higher rates of morbidity and mortality associated with acute pancreatitis. Th ese scoring systems are cumbersome to use and have not been widely incorporated as a patient assessment tool by clinicians. Risk factors that have been shown to aff ect survival in acute pancreatitis include organ failure, pancreatic necrosis, obesity, age above 70, hemoconcentration, and elevated C-reactive protein (Kasper, 2005 ). Treatment of acute pancreatitis typically consists of supportive measures, including resting the bowel by fasting the patient and administering intravenous (IV) fl uids for hydration along with IV pain medications. If the patient is expected to remain fasting for an extended period of time, parenteral or postpyloric tube feedings have been traditionally used, although recent data show that prepyloric feedings do not worsen morbidity or mortality and do not exacerbate symptoms of pancreatitis (Petrov, Correia, & Windsor, 2008 ). IV antibiotics should be administered for acute necrotizing pancreatitis. In addition, surgery may be required for pancreatic debridement. Further treatment is based on the underlying etiology of the pancreatitis (procedures to remove gallstones, removing the off ending medication or alcohol rehabilitation, etc.).

Table 48.2. Diagnostic Studies for Evaluating the Pancreas in Acute and Chronic Pancreatitis

Diagnostic Test Comment

Abdominal Simple, noninvasive but not sensitive X-ray

Abdominal Simple, noninvasive, can provide information on pancreatic Ultrasound pseudocysts, mass lesions, and calcifi cations

CT Scan Useful for the diagnosis of pancreatic calcifi cations, pancreatic ducts and mass lesions in the pancreas

MRCP Noninvasive, good for imaging the pancreatic duct, especially in patients who are at high risk for ERCP

ERCP Invasive, but allows for diagnostic and therapeutic maneuvers for the pancreatic duct and sphincter of Oddi

EUS Allows for excellent imaging of the head of the pancreas and for biopsies and aspiration of masses and cysts within the pancreas 582 INTEGRATIVE GASTROENTEROLOGY

Chronic pancreatitis is a condition with infl ammatory changes of the pancreas that results in permanent structural damage to the organ, leading to impairment of endocrine and exocrine function. Chronic pancreatitis usually manifests as chronic abdominal pain with features similar to that of acute pancreatitis, as well as pancreatic insuffi ciency with steatorrhea and malabsorption of fat-soluble vitamins (Vitamins A, D, E, K) and vitamin B12. Severe cases of chronic pancreatitis can lead to glucose intolerance and diabetes mellitus. Biochemical testing is oft en less helpful in chronic pancreatitis, as serum amylase and lipase levels may be normal due to pancreatic fi brosis. Radiographic imaging may be useful, especially if pancreatic calcifi cations are noted in the organ with beading of the main pancreatic duct (Table 48.2 ). Treatment for chronic pancreatitis usually involves supplementation with pancreatic enzymes, pain management, and avoidance of potential triggering factors, including alcohol and fatty meals. It is important for patients to seek conventional medical treatment for acute attacks of pancreatitis, as they carry a high risk of morbidity and mortality if not treated. An integrative approach may be useful for the prevention and treatment of recurrent attacks of acute pancreatitis and chronic pancreatitis.

Nutrition

Patients with severe acute pancreatitis should be fed early via the enteral route during the course of disease (McClave, Chag, Dhaliwal, & Heyland, 2006 ). Th e use of prepyloric feedings versus postpyloric feeds is debatable; however, enteral nutrition is preferred to parenteral feedings because such therapy modulates reduces oxidative stress, promotes more rapid resolution of the disease process, and is more cost eff ective (McClave et al., 2006 ). Patients who have had at least one episode of pancreatitis should avoid alcohol consumption to prevent further attacks. In cases of hypertriglyceridemia-associated pancreatitis, treatment includes weight loss to the ideal weight, lipid-restricted diet, and control of serum glucose levels in those with diabetes mellitus. Enterally administered n-3 polyunsaturated fats (including fi sh oil) in patients with acute pancreatitis have been shown to decrease length of hospitalization and length of requirement for jejunal feedings (Lasztity et al., 2005 ). For patients with chronic pancreatitis, the ideal diet should be moderate in fat, with restriction of long-chain triglycerides and increase in foods that contain medium-chain fatty acids that do not require lipase for digestion (Kasper, 2 0 0 5 ) . Integrative Approaches to Diseases of the Pancreas and Gallbladder 583

Supplements

Several studies have investigated the role of free radicals in the pathogenesis of acute pancreatitis, which has led to the use of antioxidants for the treatment of acute and chronic pancreatitis (Sanfey, Bulkley, & Cameron, 1984 ; Schoenberg et al., 1990 ). Additionally, people with acute pancreatitis have been found to have lower levels of antioxidants including vitamin A, glutathione, selenium, beta-carotene, and vitamin E compared to healthy controls (Uden et al., 1992 ). One small double-blind, placebo-controlled study demonstrated that oral micronutrient antioxidant therapy with vitamin C, vitamin E, beta-carotene, selenium, and methionine, during the active treatment phase of patients with recurrent acute pancreatitis, was associated with amelioration of oxidative stress (Uden et al., 1992 ). Some practitioners have been using intravenous antioxidant therapy for severe acute pancreatitis based on equivocal data. A recent randomized, double-blind, placebo-controlled trial of intravenous antioxidant therapy with n-acetylcysteine, selenium, and vitamin C, with 43 patients, showed that although relative serum levels of antioxidants rose and markers of oxidative stress fell, treatment with antioxidants did not result in a statistical diff erence in organ dysfunction or patient outcome (Siriwardena et al., 2007 ). It should be noted that the treatment arm had a higher rate of death due to multiorgan failure from severe pancreatitis. For chronic pancreatitis, a randomized, double-blind, placebo- controlled crossover trial of 36 patients with chronic pancreatitis demonstrated that oral antioxidant supplementation was associated with improvements in quality of life in terms of pain, physical and social functioning, and general health perception, as assessed by the SF-36 questionnaire (Kirk et al., 2006 ). Probiotics have also been considered in the treatment of acute pancreatitis, with the intent of preventing infectious complications. A multicenter, randomized, double-blind, placebo-controlled trial with 298 patients demonstrated that probiotic supplementation did not reduce the risk of infectious complications, and was associated with an increased risk of mortality due to ischemic bowel (Besselink et al., 2008 ). At this time, probiotic prophylaxis should not be administered to patients with severe acute pancreatitis.

Herbal Medications

Polyphenols are plant-derived phytochemicals that have anti-infl ammatory and vasculoprotective properties. Resveratrol, epigallocatechin gallate, and 584 INTEGRATIVE GASTROENTEROLOGY curcumin are polyphenols that have been shown to attenuate acute pancreatitis in rodent models (Shapiro, Singer, Halpern, & Bruck, 2007 ). If given early in the course of acute pancreatitis, polyphenols may prevent the development of multiorgan dysfunction and septic shock. Prophylactic administration of polyphenols attenuates ischemia-reperfusion injury to the bowel, kidneys, liver, and heart. Polyphenols have also been shown to improve survival rates in animal models of endotoxemia (Shapiro et al., 2007 ). Other herbs that have been used to prevent acute pancreatitis include Indian gooseberry (Emblica offi cinalis see Th orat et al., 1995 ), grape seed extract ( Vinis vinifera), and Pycnogenol (Pinus pinaster). Traditional Chinese medicine may also be useful for preventing and treating pancreatitis, but has not been validated with prospective placebo-controlled studies. Herbs that are commonly used in traditional Chinese medicine include licorice root (Glycyrrhiza glabra ), ginger root ( Zingiber offi cinale ), Asian ginseng ( Panax ginseng), peony root ( Paeonia offi cinalis), and cinnamon Chinese bark (Cinnamomum verum ) .

Acupuncture

Acupuncture has been used for the treatment of pain due to pancreatic disease; however, formal studies have shown mixed results. Electro-acupuncture stimulation, which uses electrical current on acupuncture needles, is a popular traditional therapy that has been demonstrated to have a protective eff ect in animal models of acute pancreatitis. (An et al., 2007 )

Gallbladder

Gallstones are widely prevalent in Western countries, particularly in the United States, where autopsy series have demonstrated the presence of gallstones in more than 20 % of women and 8% of men over the age of 40 (Kasper, 2005 ). Approximately 1 million new cases of gallstone disease (cholelithiasis) develop each year, resulting in more than 500,000 cholecystectomies being performed annually in the United States (Moga, 2003 ). Th ere are two major types of gallstones: cholesterol stones account for 80% of cholelithiasis, with pigment stones accounting for the remaining 20 %. Cholesterol stones contain more than 50 % cholesterol, whereas pigment stones are primarily composed of calcium bilirubinate (Browning & Sreenarasimhaiah, 2006 ). Th e risk of gallstone formation is increased with supersaturation of bile with cholesterol, decreased secretion of bile acids, and stasis of bile fl ow (Table 48.3 ). Integrative Approaches to Diseases of the Pancreas and Gallbladder 585

Table 48.3. Predisposing Factors for Gallstone Formation

Demographic/ Cholesterol stones – North American Indians, Northern Europe Genetic Factors and North America Pigment stones – Asia

Increased Obesity cholesterol Weight loss saturation of bile Estrogen Increasing age High cholesterol diet Oral contraceptive medications Fibric acid medications (clofi brinate)

Decreased bile Increasing age acid secretion Low fi ber diet Diseases/resection of the ileum resulting in chronic loss of bile salts

Biliary stasis Gallbladder hypomotility Prolonged parenteral nutrition Fasting Pregnancy Inactivity Low fat diets

Th e most characteristic symptom caused by cholelithiasis is biliary colic, which presents as postprandial right upper quadrant pain lasting 30 minutes to 5 hours. Oft en, the patient will complain of worse pain with heavy fatty meals, or eating aft er a period of prolonged fasting. Nausea and vomiting are frequent symptoms that accompany the abdominal pain. Complications of cholelithiasis include acute cholecystitis, biliary obstruction, cholangitis, and pancreatitis. Th e diagnosis of cholelithiasis is confi rmed with one of several diff erent imaging studies listed in Table 48.4 . Th e treatment of choice in the United States for symptomatic cholelithiasis is a laparoscopic cholecystectomy. Although complications from surgery are infrequent (3% to 6 %), they can be signifi cant, resulting in bile duct and liver injury. Additionally, 10% to 15% of patients experience post-cholecystectomy syndrome, in which they continue to have symptoms that were thought to be caused by the gallbladder, or develop new symptoms normally attributed to the gallbladder. Ursodeoxycholic acid and extracorporeal shockwave litho- tripsy have also been used to help dissolve gallstones in patients who are poor surgical candidates. An integrative approach to the treatment of cholelithiasis 586 INTEGRATIVE GASTROENTEROLOGY

Table 48.4. Diagnostic Evaluation of the Gallbladder and Bile Ducts

Diagnostic Test Comment

Abdominal X-ray Rapid, low cost, low yield Pathognomonic fi ndings in calcifi ed gallstones, porcelain gallbladder, emphysematous cholecystitis

Right upper quadrant Rapid, accurate (> 95% accuracy for gallstones) with real ultrasound time imaging Procedure of choice for gallstones

HIDA scan Accurate for cystic duct obstruction or confi rmation of acute cholecystitis Useful with CCK to assess gallbladder emptying

CT scan Useful for evaluating dilated bile ducts, particularly for hepatic or pancreatic masses

Magnetic resonance Excellent sensitivity for bile duct dilatation and cholangiopancreatography intraductal abnormalities (MRCP)

Endoscopic retrograde Best visualization of the distal biliary tract, endoscopic cholangiopancreatogram sphincterotomy and treatment is a possibility (ERCP)

Endoscopic Ultrasound Most sensitive method for detecting ampullary stones

not only focuses on the symptoms of gallstones, but can help dissolve gallstones and reduce the risk of gallstone formation.

Lifestyle Modiﬁ cation

Obesity is an independent risk factor for the development of gallstones. Slow, gradual weight loss can reduce the risk of gallstone formation by reducing the amount of cholesterol secreted into bile; however, weight loss of more than 1.5 kg (3.3 lbs.) per week can trigger gallstone formation (Weinsier, Wilson, & Lee, 1995 ). Ursodeoxycholic acid can prevent gallstone formation during rapid weight loss by increasing the solubility of cholesterol in bile (Worobetz, Inglis, & Shaff er 1993 ). Exercise has been shown to be inversely related to the risk of undergoing cholecystectomy. According to the Nurses Health Study, exercising 2 to 3 hours per week was found to reduce the risk for cholecystectomy by 20% in women (Leitzmann et al., 1999 ). A similar study conducted in male healthcare professionals found that 34% of symptomatic gallstone disease Integrative Approaches to Diseases of the Pancreas and Gallbladder 587 could be prevented by exercising 30 minutes a day with endurance-type training at least fi ve times per week (Leitzmann et al., 1998 ). In both studies, the benefi cial eff ects of exercise were independent of weight reduction. It has been postulated that exercise decreases late-phase postprandial gallbladder volume and increases late-phase gallbladder motility via neural or hormonal mechanisms (Sari, Balci, & Balci, 2005 ).

Dietary Fat

Lowering total dietary fat is not an eff ective treatment for gallbladder disease, but a change in the type of dietary fat ingested can improve the composition of bile and reduce the risk of gallstone formation. Low-fat diets fail to stimulate gallbladder contraction and result in biliary stasis, which actually increases the risk of gallstone formation. Substituting saturated fats with fi sh oil and polyunsaturated fats that are rich in anti-infl ammatory omega-3 fatty acids can reduce the formation of gallstones by enhancing bile fl ow and stabilizing the phospholipid-cholesterol vesicles (Berr et al., 1992 ). Patients should be instructed to reduce their intake of fried foods, red meat, and dairy products to reduce the amount of saturated fat in their diet, and replace this with diets rich in omega-3 fatty acids including coldwater fi sh, walnuts, and fl axseed (Rakel, 2007 ). Omega-3 fatty acids have also been shown to stabilize the cholesterol saturation index and nucleation time (time to cholesterol deposition) in obese patients who are rapidly losing weight, and may possibly prevent the formation of cholesterol gallstones (Méndez-Sánchez et al., 2001 ).

A low fat diet may actually increase the risk of gallstone disease. Substituting saturated fats with ﬁ sh oil and polyunsaturated fats can lower the risk of gallstone formation.

Fiber Intake

It has been shown that vegetarians have a lower risk of cholelithiasis (Nair & Mayberry, 1994 ). Th is has been attributed to a diet low in saturated fat, but also to a high-fi ber diet. Fiber reduces the absorption of deoxycholic acid (DCA), which at high concentrations can act as an irritant to the gallbladder epithelium (Moga, 2003 ). DCA is a microbial product formed from bile acids by intestinal bacteria, which lowers the solubility of cholesterol in bile. Foods that contain water-soluble fi ber have the greatest affi nity for binding DCA and may 588 INTEGRATIVE GASTROENTEROLOGY be helpful for preventing and reversing gallstones (Rakel, 2007 ). A Western diet low in fi ber and high in fat has been associated reduced concentrations of bile acids leading to the formation of gallstones (Moerman. Smeets, & Kromhout, 1994 ). Fruits, vegetables, oat bran, and ground fl axseed are good sources of fi ber. Although legumes are rich in fi ber, they have been shown to signifi cantly raise the concentration of cholesterol in bile.

Simple Sugars and Insulin Resistance

Plasma insulin levels have been found to be elevated in nondiabetic patients with gallstone disease, despite normal serum glucose. (Misciagna et al., 2000 ) Hyperinsulinemia has been shown to decrease cholesterol 7-hydroxylase activity (Subbiah & Yunker, 1984 ), the hepatic enzyme that converts cholesterol to primary bile acids (Apstein & Carey, 1996 ). Additionally, diets that consist of simple sugars increase the DCA content, raise the cholesterol saturation index, and reduce the concentration of the benefi cial cholic acid (Th ornton, Emmett, & Heaton, 1983 ). A higher intake of dietary glycemic load and glycemic index has been shown to increase the risk of cholecystectomy in women (Tsai, Leitzmann, Willett, & Giovannucci, 2005 ). Nutritional strategies to improve insulin sensitivity and glucose tolerance may also have benefi cial eff ects on gallstones. Th ese include substituting saturated fats with mono- or polyunsaturated fats, decreasing trans fatty acids, increasing consumption of omega-3 fatty acids, and replacing refi ned carbohydrates (simple sugars) with unrefi ned carbohydrates found in fruits and vegetables (Lichtenstein & Schwab, 2000 ).

Food Allergy

Some practitioners believe that food allergies may be common triggers for symptoms attributed to gallbladder attacks, based on early studies. (Breneman, 1968 ) It has been hypothesized that this allergic response is mediated by histamine release from mast cells present in gallbladder mucosa (Hemming et al., 2000 ). In one study, a food elimination diet improved all symptoms in 69 patients with gallstones or postcholecystectomy syndrome within 5 days of treatment (Breneman, 1968 ). Foods that were most likely to induce gallbladder symptoms included eggs, pork, onion, fowl, milk, coff ee, citrus, corn, beans, nuts, apples, and tomatoes. Treatment with antihistamines resulted in faster resolution of symptoms, suggesting that the underlying mechanism was food allergy and not food intolerance; however, this has not been validated with placebo-controlled trials. Integrative Approaches to Diseases of the Pancreas and Gallbladder 589

Coffee

In a prospective cohort study that included 46,008 men, and used a 131-item food frequency questionnaire, coff ee consumption was associated with a lower risk of symptomatic gallbladder disease (Leitzmann et al., 1999 ). Th is association was not found with decaff einated coff ee, leading some to believe that the benefi ts were attributable to caff eine. Although there was a positive association with caff einated soft drinks and lower risk of gallbladder symptoms, the correlation was not statistically signifi cant. Coff ee stimulates cholecystokinin release and enhances gallbladder contractility (Douglas, 1999 ). Caff eine is secreted in bile (Holstege, Kurz, Weinbeck, & Gerok, 1993 ), and may decrease bile cholesterol saturation by increasing bile fl ow (Knodell, 1978 ). In animal models, caff eine has been shown to prevent cholesterol crystallization (Lillemoe et al., 1989 ).

Ursodeoxycholic Acid

Ursodeoxycholic acid (UDCA) has been used by some practitioners for dissolution of cholesterol gallstones, although the success of laparoscopic cholcecystectomy has reduced this option to patients who wish to avoid surgery, or are poor surgical candidates. UDCA decreases the saturation of cholesterol in bile, and may also retard cholesterol crystal nucleation (Kasper, 2 0 0 5 ) . Th e best success for complete dissolution is with small (<5 mm) radio- lucent cholesterol gallstones. Gallstone recurrence occurs 30 % to 50 % over 3 to 5 years aft er successful treatment with UDCA. UDCA has also been shown to prevent gallstone formation during rapid weight loss, particularly in those who have undergone bariatric surgery (Uy et al., 2008 ).

Ursodeoxycholic acid (UDCA) can prevent gallstone formation in patients undergoing rapid weight loss (greater than 1.5 kg or 3.3 lbs per week).

Supplements

A lack of dietary ascorbic acid (vitamin C) has been linked to gallstone disease in animal models (Jenkins, 1978 ). Vitamin C aff ects the rate-limiting step in catabolism of cholesterol to bile acids. In humans, vitamin C supplementation 590 INTEGRATIVE GASTROENTEROLOGY has been associated with a decreased risk of gallstones, and a lower need for cholecystectomy, in postmenopausal women who consume alcohol (Simon et al., 1998 ). Th is relationship was not statistically signifi cant in nondrinkers. Follow-up studies have confi rmed this correlation in women, but this same correlation was not seen in males (Simon & Hudes, 2000 ). Vitamin E has been thought to be benefi cial in the prevention of gallstone formation, particularly in patients who are unable to modify their lifestyle or dietary habits. In one animal study, a high-fat diet did not result in a higher rate of gallstone formation if the animals were given vitamin E supplementation (Christensen, Dam, & Prange 1953 ). Calcium has also been shown to have a benefi cial eff ect on the risk of cholesterol gallstones by binding secondary bile acids, including DCA, and reducing the solubility of cholesterol in bile. In middle-aged men, the risk gallstone formation has been inversely correlated with calcium intake (Moerman et al., 1994 ). Lecithin and phosphatidylcholine reduce the saturation of cholesterol in bile. Studies on the supplementation of lecithin have shown higher concentrations in bile. Clinically, this has not had a signifi cant eff ect on dissolving gallstones, but may be benefi cial in gallstone prevention (Rakel, 2007 ).

Gallbladder/Liver Flush

Some alternative practitioners may prescribe gallbladder fl ushes that typically include olive oil and lemon juice. Th e belief is that the monounsaturated fat in olive oil may stimulate gallbladder contraction and improve bile fl ow; however, this has not been clinically validated by prospective studies (Rakel, 2007 ). In fact, these preparations may actually trigger attacks of gallbladder pain, or even acute cholecystitis, and are therefore not currently recommended for patients with gallstone disease.

Herbal Medications

Herbal medications have been used to treat multiple small stones and sludge in patients with infrequent symptoms. Herbs are found in many diff erent preparations, but they are most commonly prepared as dry extracts used to make tea. Choleretic herbs stimulate bile fl ow and reduce the amount of cholesterol in bile (Table 48.5 ). Choleretic herbs are oft en used with peppermint oil, which contains a large amount of menthol and has been used to dissolve g a l l s t o n e s . Integrative Approaches to Diseases of the Pancreas and Gallbladder 591

Table 48.5. Choleretic Herbs Used in the Treatment of Gallstones

Herb Precautions

Milk Th istle (Silybum Laxative eff ect, allergic reaction in persons with allergies to marianum ) ragweed, daisies, marigolds

Dandelion root Gastric hyperacidity, contact dermatitis (if used topically), ( Taraxecum offi cinalis ) allergic reaction in persons with allergies to ragweed, daisies, marigolds

Artichoke ( Cynara Contact dermatitis (if used topically) scolymus )

Turmeric ( Curcuma Rarely causes dyspepsia in high doses longa )

Greater celandine Dyspepsia, contact dermatitis (if used topically), hepatitis ( Chelidonium majus ) (rare)

Oregon grape Should not be used during pregnancy or breastfeeding, as it ( Mehonia aquifolium ) may worsen jaundice in infants

Acupuncture

Some practitioners feel that acupuncture aids in the expulsion of gallstones (Moga, 2003 ); however, the greatest benefi t of acupuncture is relief of abdominal pain through the release of endorphins. Multiple diff erent points have been identifi ed for relief of symptoms attributed to gallbladder disease. In a golden hamster model of cholelithiasis, acupuncture was associated with decreased biliary cholesterol content, and increased benefi cial cholic acid. (Moga, 2003 )

49 An Integrative Approach to Gender-Speciﬁ c Digestive Health Issues

LAURA K. TURNBULL , GERARD E. MULLIN , AND SHARON DUDLEY-BROWN

key concepts

■ Wo m e n a r e a ffl icted with functional bowel disorders, microscopic colitis, collagenous colitis, autoimmune liver disease, proximal colon cancers, and gallstone disease far more than men. ■ Th e purported mechanisms for women to develop the irritable bowel syndrome include: emotional life experiences, abuse, sensitivity to pain, serotonin receptor expression, hormones, and menstrual cycle, among others. ■ Women are more inclined to utilize modalities of complementary and alternative medicine (CAM) than men. ■ CAM modalities have been shown to be eff ective for functional bowel disorders, including functional dyspepsia and the irritable bowel syndrome. ■ Men are predisposed to develop Barrett’s esophagus, achalasia, and autoimmune pancreatitis, for unknown reasons. ■

Introduction

n a healthcare system that is predominantly based upon a male experience of disease, the gender variations in both the symptomology and psychoso- I cial consequences of specifi c disease states unique to women are oft en overlooked. As new research focusing on sex and gender diff erences in GI

592 An Integrative Approach to Gender-Speciﬁ c Digestive Health Issues 593

illness emerges, it is becoming apparent that there are clear diff erences in how such illnesses manifest themselves physiologically, as well as how these diseases aff ect the emotional well-being of those aff ected. In order to adequately diagnose, treat, and support patients affl icted with GI illness, it is imperative to understand the variations between genders in the clinical manifestations, psychosocial experiences, and trends of healthcare-seeking behaviors.

Gender-Speciﬁ c Digestive Conditions

Th ere are a number of GI illnesses with skewed gender-specifi c prevalences (Table 49.1 .). Autoimmune liver disease, celiac disease, collagenous colitis, functional bowel disorders, gallstones, microscopic colitis, primary biliary cirrhosis, and proximal colorectal cancer affl ict women more than men (Lee, Mayer, Schmulson, Chang, Naliboff , 2001 ).On the other hand, achalasia, autoimmune pancreatitis, Barrett’s esophagus, and all digestive cancers (e.g., pancreatic cancer) are seen in men more oft e n t h a n w o m e n ( S i l v e r m a n , 2 0 0 7 ) .

Colorectal Cancer

Th e American Cancer Society estimates that about 108,070 new cases of colon cancer (53,760 in men and 54,310 in women) and 40,740 new cases of rectal cancer (23,490 in men and 17,250 in women) was diagnosed in 2008. Colorectal cancer is expected to cause about 49,960 deaths (24,260 men and 25, 700 women) in 2008. In the United States the incidence of colorectal cancer overall is higher in men than in women. However, when colorectal cancer is subdivided into the region of the colon aff ected, recent evidence suggests that women are more frequently diagnosed with cancer proximal to the splenic fl exure, while men are more frequently diagnosed with cancers in the distal region (Jacobs, Th ompson, & Martinez, 2007 ). Th is diff erence in pathology may explain the apparent variations in response to dietary infl uences between men and women. For instance, while further investigation is required, recent research suggests that obesity, energy intake, selenium, and fi ber have more signifi cant protective eff ects in men than women (Jacobs, Th ompson, & Martinez, 2007 ; Duffi eld-Lillico et al., 2002 ).Additionally, dietary intake of red and processed meat in men has been epidemiologically tied to their predilection of distal colorectal cancers (Chao et al., 2005 ). Conversely, women may experience greater protective eff ects from higher vitamin D levels than men (Jacobs, Th ompson, & Martinez, 2007 ). Dietary and supplemental calcium have been shown to decrease the risk of developing Table 49.1. Gender-Speciﬁ c Conditions: Prevalence, Pathogenesis and Treatment

GI Illness/ U. S. Prevalence, Gender Pathogenesis Integrative Condition (M:F ratio) Treatment

Achalasia (1:100,000) M> > > F Progressive loss of nitrergic neurons (inhibitory; Symptomatic: dilation of LES, surgery, dietary relaxation) with the relative preservation of modifi cations, peppermint oil to relax LES. cholinergic neurons (excitatory; contraction)in the lower esophageal sphincter (LES). Autoimmune 1 in 31 or 3.13% or 8.5 Autoimmune infl ammatory attack on liver Corticosteroids, immunosuppressives, Liver Disease million parenchymal cells ∗ polyphenol biofl avonoids (curcumin, green tea F> > M extract, quercetin, boswellia, ginger), fi sh oils, anti-infl ammatory diet. Autoimmune USA unknown; 0.82 per Autoimmune-infl ammatory attack on pancreas Corticosteroids, immunosuppressives, Pancreatitis 100 000 individuals in Japan ∗ polyphenol biofl avonoids (curcumin, M> > F EGCG–green tea extract, quercetin, boswellia, ginger), fi sh oils, anti-infl ammatory diet Barrett’s 66 2.3% (with refl ux Prolonged exposure of the esophagus to acid Western: acid blockade –proton pump Esophagus symptoms) refl ux causing a pre-malignant transformation inhibition. Integrative options: licorice root, 1.2% (without refl ux of the esophageal lining aloe vera, slippery elm (cytoprotective), symptoms) Swedish bitters, ginger, D-limonene M> > F (promotility) ∗ ∗ Celiac Disease 1:100 Autoimmune disease –gluten initiates Gluten withdrawal from the diet. F> M 2:1 proinfl ammatory attack on small bowel Collagenous Unknown Autoimmune, 67 Bismuth subsalicylate Colitis F> > M collagen deposition in subepithelial basement Boswellia serrata membrane of colonic lining Budesonide Mesalamine Mesalamine + cholestyramine Probiotics Functional 10-15% US of population Motility, hormonal, visceral hypersensitivity, Symptomatic Bowel Disorders F> M others Herbal (all) Hypnosis Cognitive Behavioral Th erapy

Gallstones 8.5 million estrogen and progesterone multiparity increase Dietary F> M risk Surgical Astringent herbals

Microscopic Unknown F > M Autoimmune-collagen deposition in Avoid NSAIDs Colitis subepithelial basement membrane Trial of lactose elimination) Anti-diarrhea agents or tannins Bismuth subsalicylate 5-ASA (mesalamine ) compounds

Primary Biliary 200,000 Autoimmune attack of infl ammatory cells on Immunosuppressives Cirrhosis F> > M the medium-sized intrahepatic bile ducts of the Bezafi brate Ursodeoxycholic acid liver Interferon-a Liv-52 68-70 Sho-saiko-to71-73

Proximal Colon ∗ ∗ ∗ 41,667 Diet, vitamind D levels, calcium intake, Exercise74 Cancer F> M multifactorial vitamin D and calcium protective in women9-14

∗ see Chapter 46: Liver Disease ∗ ∗ See Chapter 39: Upper Gastrointestinal Disorders: Dyspepsia, Heartburn, Peptic Ulcer Disease, and H. Pylori ∗ ∗ ∗ 28% of colorectal cancers are proximal (Rim, Seeff , Ahmed, King, & Coughlin, 2009 )75 596 INTEGRATIVE GASTROENTEROLOGY colorectal cancer and precancerous adenomas (Baron et al., 1999 ).In this study, higher serum 25-hydroxyl-vitamin D levels were associated with a protective eff ect from developing colorectal cancer. Several other investigators support these fi ndings (Martinez, Marshall, Sampliner, Wilkinson, & Alberts, 2002 ; Wu, Willett, Fuchs, Colditz, & Giovannucci, 2002 ; Kampman, Slattery, Caan, & Potter, 2000 ; Marcus & Newcomb, 1998 ). 9–14 However, Martinez and Willett ( 1998 ) reviewed the epidemiological data pertaining to calcium and concluded that it is not associated with a “substantial” risk reduction from developing colorectal cancer and precancerous adenomas.15 Th e Women’s Health Initiative (WHI) was performed with 36,282 women who received either placebo or the combination of 500 mg of elemental calcium carbonate with 200 IU of vitamin D (Wactawski-Wende et al., 2006 ).16 Th e women who received the intervention (calcium, vitamin D) were not protected from developing colorectal cancer. Based upon epidemiological studies, these doses appear to be suboptimal for adequate chemoprevention of colorectal neoplasia (Wu, Willett, Fuchs, Colditz, & Giovannucci, 2002 ). 12

Gallstone Disease

In the United States, gallstone disease affl icts 20 to 25 million adults, with more than 700,000 cholecystectomies performed annually costing $6.5 billion (Sandler et al., 2002 ; Shaff er, 2006 ). 17, 18 Th us, gallstone disease is among the most costly digestive disorders. Gallstone disease has a clear gender-specifi c prevalence, with women before the age of 50 being affl icted two to three times more oft en than men (Shaff er, 2006 ; Rome Group, 1988 ). 18–20 In the United States it is estimated that 6.3 million men and 14.2 million women between the ages of 20 and 74 are aff ected (Everhart, Khare, Hill, & Maurer, 1999 ). 21 Women are at greater risk of both developing gallstone disease and requiring subsequent cholecystectomy (Shaff er, 2006 ). 18 It is thought that hormonal factors are the major contributors to this gender diff erence, with pregnancy and estrogen therapy being signifi - cantly implicated in the development of gallstones (Cirillo et al., 2005 ; Park et al., 2009 ).22, 23 While there is a clear diff erence with regard to gender, the increased incidence is only apparent in younger populations, with women of childbearing age aff ected most greatly (Jensen & Jorgensen, 1991 ). 24 Th is phenomenon suggests the implication of both pregnancy and hormones on the formation of gallstones; specifi cally, the increased levels of estrogen and progesterone along with multiparity (Date, Kaushal, & Ramesh, 2008 ). 25 Furthermore, men who have been placed on estrogen replacement therapy, An Integrative Approach to Gender-Speciﬁ c Digestive Health Issues 597 and women receiving hormone replacement therapy, are at an increased risk for gallstone formation (Novacek, 2006). 26

Autoimmune Gastrointestinal and Liver Disease

Women overall are predisposed to autoimmune disease (Zandman-Goddard, Peeva, & Shoenfeld, 2007 ). 27 However, autoimmune conditions of the gut in general are not more prevalent in women than in men for unclear reasons. For example, the prevalence of infl ammatory bowel disease is not diff erent in males than females. On the other hand, Celiac disease has twice the disease prevalence in women when compared to men, and is associated with other autoimmune conditions that are more common in women (Megiorni et al., 2008 ). 28 Th yroiditis, scleroderma, Sjörgen’s syndrome, collagenous colitis, microscopic colitis, primary biliary cirrhosis, autoimmune gastritis, and autoimmune hepatitis are far more common in women than men (Table 49.2 ; see also Talley, 2008a , 2008b ). 29, 30 Many of these conditions are associated with high titers of autoantibodies, such as antinuclear (ANA), antimitochondrial (AMA), antimicrosomal, anti-SCL-70, anti-smooth muscle antibodies, etc. Th e presentation of a middle-aged female with high titers of any of these autoimmune antibodies, or presence of any of the aforementioned conditions, should raise suspicion for underlying celiac disease.

Achalasia

Achalasia is an uncommon (1:100,000) condition of the esophagus characterized by a progressive loss of nitrergic neurons (inhibitory; relaxation) with the relative preservation of cholinergic neurons (excitatory; contraction) early in the disease process (Kraichely & Farrugia, 2006 ). 31 Th is resulting imbalance of neurotransmitters causes the lower esophageal junction to become tonically contracted and fail to relax during swallowing. Achalasia is equally distributed between men and women; however, chest pain is a female-predominant presentation of the disease (Mikaeli, Farrokhi, Bishehsari, Mahdavinia,& Malekzadeh, 2006 ). 32 Th us, in a female who presents with progressive dysphagia along with chest pain, in the absence of gastroesophageal refl ux disease, achalasia should be considered. On the fl ip side, there is a form of achalasia that is associated with antineuronal autoimmune antibody formation (anti-GAD-65) in the setting of a male gender bias (Kraichely & Farrugia, 2006 ). 31 Th ese data 598 INTEGRATIVE GASTROENTEROLOGY

Table 49.2. Autoimmune Diseases Associated with Celiac Disease

Gastrointestinal-Liver

• Microscopic colitis

• C o l l a g e n o u s c o l i t i s

• A u t o i m m u n e h e p a t i t i s

• Primary biliary cirrhosis

Endocrine

• Autoimmune diabetes mellitus

• A d d i s o n ’ s d i s e a s e

• Autoimmune thyroid disease

Rheumatological

• S j ö g r e n ’ s s y n d r o m e

• S y s t e m i c l u p u s e r y t h e m a t o s u s

Dermatological

• V i t i l i g o

• D e r m a t i t i s h e r p e t i f o r m i s

• P s o r i a s i s

• A l o p e c i a a r e a t a

( adapted from Barker & Liu, 2008 ) suggest that gender-specifi c variants of achalasia exist and require further exploration.

Barrett’s Esophagus

Barrett’s esophagus is a premalignant condition of the esophagus, whereby the squamous mucosa bordering the squamous-columnar junction of the esophagus is replaced by intestinal-type columnar mucosa (Wood & Yang, 2008 ). 33 Th is “specialized” intestinal type of columnar mucosa, which forms as a meta- plastic reaction to chronic acid and bile refl ux from the stomach, has an overall 5 % chance to develop into adenocarcinoma of the esophageal cancer, also a male-predominant disease (Bresalier, 2008 ). 34 Th e classic risk factors for developing Barrett’s esophagus include being male, aged 50, smoking cigarettes, and An Integrative Approach to Gender-Speciﬁ c Digestive Health Issues 599 having a history of gastroesophageal refl ux disease (GERD). Any middle-aged male with chronic GERD presenting with diffi culty swallowing requires an urgent endoscopy in order to rule out esophageal cancer or a stricture arising in the setting of Barrett’s esophagus. Esophageal adenocarcinoma is the fastest rising cancer of the digestive tract (Wood & Yang, 2008 ; Haghdoost et al., 2008 ). 33–35

Autoimmune Pancreatitis

Autoimmune pancreatitis (AIP) is the pancreatic manifestation of a fi broin- fl ammatory systemic disorder aff ecting the kidney, bile ducts, retroperito- neum, lymph nodes, parotid, and lacrimal glands (Gardner & Chari, 2008 ).36 Th e aforementioned organs are populated by an IgG4-dense lymphocytoplas- mic infi ltrate (Chari et al., 2006 ). 37 Th e prevalence of AIP in Japan is 0.82:1000, analogous to achalasia in the United States. AIP in Japan accounts for 5% to 6 % of patients with pancreatitis. Males are twice as likely as females to develop AIP, and the disease typically presents in the fi ft h decade, though more than 85% present older than 50 years of age (Nishimori, Tamakoshi, & Otsuki, 2 0 0 7 ) . 38 AIP is a condition that most commonly presents as painless jaundice, alerting an evaluation for pancreatic malignancy. Since the disease is steroid responsive, IgG4 levels should be evaluated in males presenting with painless jaundice. Supplements and diet aimed at suppressing infl ammation should be considered for this condition, given its steroid responsiveness (see Chapter 31).

Non-Ulcer Dyspepsia

Non-ulcer dyspepsia (NUD) is not clearly linked to gender predisposition. Th ere are several studies showing a higher prevalence of symptoms in females (Richter, 1991 ; Johnsen et al., 1991 ; Agreus, 1993 ; Kay, Jorgensen, Schultz- Larsen, & Davidsen, 1996 ; Meineche-Schmidt & Krag, 1998 ; Stanghellini, 1999 )39-44 , whereas others show either male predominance (Johnsen, Straume, & Forde, 1988 )45 or no gender bias (Drossman et al., 1993 ; Talley, Zinsmeister, Schleck, & Melton 3rd, 1992 ; Bernersen et al., 1990 ; Jones et al., 1990 ; Kay & Jorgensen, 1994 ) 46–50 . One possible explanation for the wide variation in the gender-specifi c prevalence of individuals with non-ulcer dyspepsia, could be from the male gender being more susceptible to dyspepsia from Helicobacter pylori infection (Sasidharan, Uyub, & Azlan, 2008 ). 51 Another possibility is that those aforementioned studies on the prevalence of sex-specifi c dyspepsia only performed descriptive demographics, rather than specifi c gender analyses. 600 INTEGRATIVE GASTROENTEROLOGY

Welen and colleagues reported that functional dyspepsia adversely aff ects women more than men in daily life (Welen, Faresjo, & Faresjo, 2008 ). 52 Overall, it appears that men and women with dyspepsia appear to diff er with respect to symptom patterning and pain processing. Well-designed population studies are needed to investigate the prevalence of dyspeptic symptoms.

Gastroparesis

Gastroparesis is a chronic disorder caused by stomach pump failure, and is characterized by profound nausea, vomiting, and epigastric pain. Most oft en, the cause is unapparent and, of the known associations, diabetes is the most common. Idiopathic gastroparesis is a functional bowel disorder that is more prevalent in females than males (Stanghellini et al., 2003 ). 53 Th e mean age of onset of idiopathic gastroparesis is 34 years, and the female to male ratio has been reported to be 4:1 (Patrick & Epstein, 2008 ). 54 Th e reason for the sex ratio imbalance remains unknown, but Soykan et al. (1998 ) reported that 62 % of patients with idiopathic gastroparesis revealed past history of physical or sexual abuse. 55 Th ere is also evidence of a gender diff erence in solid and liquid emptying between men and women, with female gastric emptying slower than men (Datz, Christian, & Moore, 1987 ).56

Causes of Gastroparesis: • Idiopathic • Diabetes • Gastrointestinal surgery • Gastroesophageal reﬂ ux disease • Viral infection • Scleroderma • Myotonic dystrophies • Iatrogenic (medications)

The Irritable Bowel Syndrome and Functional Bowel Disorders

Irritable bowel syndrome (IBS) is a chronic functional GI disorder characterized by abdominal pain associated with alterations in defecation or stool An Integrative Approach to Gender-Speciﬁ c Digestive Health Issues 601

frequency and consistency (Mearin, 2007 ).57 Th e prevalence of IBS in Western countries is reported to be 10 % to 15 % with a female to male ratio of 2:1 (Ringel, Williams, Kalilani, & Cook, 2009 ). 58 Abdominal bloating is common in patients with IBS, and its prevalence and relative severity diff er on the basis of sex (Lu, Chang, Lang, Chen, Luo, & Lee, 2005 ). 59 Of all digestive diseases, the functional bowel disorders such as IBS have been well described as to the underlying pathophysiology of their gender predilection ( Tables 49.3 and 49.4). Along these lines, recent interest in gender diff erences in IBS has been fueled, in part, by studies suggesting that new pharmacological therapies for this syndrome are more eff ective in female than in male IBS patients (Chang, Heitkemper, 2002 ). 60 Th e epidemiology, pathophysiology, and integrative approach to IBS are discussed by in Chapter 42 by Pickett-Blakely, Davison, and Mullin.

Table 49.3. Gender-Speciﬁ c Differences in IBS

Pathophysiology

• Autonomic nervous system dysregulation

• A ff erent sensory pathway

• P o s t i n fl ammatory/infection

Psychological status:

• Greater prevalence of depression, anxiety, psychological perceived stress and somatization in women

• V i s c e r a l p e r c e p t i o n t o s t r e s s

Response to medication

Hormones

Pain modulation

Visceral hypersensitivity

Motility

Extracolonic manifestations

(adapted from Ouyang and Wrzos, 2006 ) 602 INTEGRATIVE GASTROENTEROLOGY

Table 49.4. Summary of Key Gender-Speciﬁ c Differences in IBS

Epidemiology • F> M 2:1 in the community • F> M 3-4:1 in healthcare-seeking population Clinical Symptoms • Constipation: F> M • D i a r r h e a : M> F • Worsened IBS with extracolonic features f: F > M • Overlap pain syndromes: F> M • Timing with menstrual cycle: 50 % of females Pathophysiology • GI motility: GI transit M > F • V i s c e r a l h y p e r s e n s i t i v i t y : F> M • A b u s e : F> M • Postinfectious: F> M • Psychological perpetuators: F> M • History of hysterectomy: 33% of F • Sexual dysfunction: F > M • Hormonal and menstrual irregularities: F > M • Chronic Stress-HPA axis dysregulation: F> M • Altered serotonin signaling of serotonin reuptake transporter (SERT)gene expression in F Response to Treatment • P h a r m a c o l o g i c a l : F> M for serotonergic drugs • Hypnotherapy: F> M • Melatonin: F> M

(adapted from Ouyang & Wrzos, 2006 )

Bloating symptoms are more prevalent in women than men, and are associated with a decrease in the quality of life and increases in healthcare utilization and use of medications (Cain et al., 2008 ). An Integrative Approach to Gender-Speciﬁ c Digestive Health Issues 603

Issues of extracolonic pain syndromes (e.g., fi bromyalgia), gynecological problems (e.g., dyspareunia) and hormonal imbalances (e.g., estrogen) are well described in this book in Chapter 7, Chapter 9, and Chapter 10.

Extracolonic Conditions Associated with IBS (F> M) • Interstitial cystitis • Dyspareunia • Chronic pelvic pain • Migraine headache • Temporomandibular joint disorder • Fibromyalgia • Depression or anxiety∗ • Dysmenorrhea∗ • Premenstrual syndrome∗

∗ worse in women with IBS> those without IBS ( Lee et al., 2001 ; Mayer et al., 1999 )

Patients with a functional disease were more likely to seek alternative medical care than those with organic disease (33 % vs. 7% ; p<0.0001; see Verhoef, Sutherland, & Brkich, 1990 ).61 Kearney and Brown-Chang ( 2008 ) reported that 21% to 51% of individuals with IBS use CAM practices.62 Overall, mind– body treatments (cognitive-behavioral therapy, hypnotherapy), peppermint oil, traditional Chinese medicine, and Western-based herbs (STW 5) have been shown to be benefi cial for IBS (Mullin, Pickett-Blakely, & Clarke, 2008 ). 63 Additional modalities available to individuals with IBS are discussed in detail in in Chapter 42. Table 49.5 summarizes the type and annual cost of the most commonly utilized modalities in the United States. It is interesting to note that factors associated with CAM use in IBS have been well characterized (van Tilburg et al., 2008 ). 64 Women are more likely than men to utilize integrative approaches to manage their IBS symptoms (van Tilburg et al., 2008 ). 64 Koloski et al. ( 2003 ) reported that approximately one half (n=103, 49.8 %) of patients with IBS or functional dyspepsia had sought conventional care, while only a fraction (n=43, 20.8 %) used CAM. Furthermore, being female independently predicted CAM use. 4 Smart and colleagues ( 1986 ) confi rmed that in IBS subjects, younger females were predictors for CAM utilization. 65 Th e factors associated with CAM use in IBS are shown in Table 49.6 . Th e overall results of CAM utilization in IBS is shown in Table 49.7 . 604 INTEGRATIVE GASTROENTEROLOGY

Table 49.5. Complementary and Alternative Medicine Modalities Used in IBS with Annual Costs in U.S. Dollars

Modality Mean Annual Cost (USD) % Use

Ginger root tea 40 14.8

Massage therapy 400 12.6

Yoga 80 10.0

Psychotherapy 280 8.1

Aromatherapy 40 7.2

Homeopathy 120 8.1

Acupuncture 180 3.3

Biofeedback 40 1.4

Hypnosis 80 1.4

All CAM 240 38.4

(adapted from van Tilburg et al, 2008 )

Table 49.6. Factors Associated with CAM use in IBS

• Yo u n g e r a g e

• C o l l e g e g r a d u a t e

• H i g h e r s e v e r i t y o f s y m p t o m s

• Bloating-distention

• D e p r e s s i o n

• A n x i e t y

• S o m a t i z a t i o n

• Lower quality of life

(adapted from Koloski et al., 2003 ) An Integrative Approach to Gender-Speciﬁ c Digestive Health Issues 605

Table 49.7. Complementary and Alternative Medicine (CAM) in IBS: Overall Results

Herbs Mind–Body: best results

• Peppermint oil (p-IBS), 8 studies, benefi t • P s y c h o l o g i c a l

• TCM (d-IBS), STW-5, benefi t • Cognitive-behavioral therapies

Diet • Yo g a

• Elimination diet (15 % –71% response, • R e fl exology nonsustained) • H y p n o s i s

Supplements • G u i d e d i m a g e r y

• Melatonin (1 study, benefi t) • M e d i t a t i o n

• Probiotics (8 RCTs, 7 benefi t) • B i o f e e d b a c k

Energy Medicine • M u l t i c o m p o n e n t

• Acupuncture (2 controlled sham studies, benefi t)

(adapted from Mullin, Pickett-Blakely, & Clarke, 2008 )

Conclusion

Th ere are several digestive disorders that have a gender-specifi c basis for pathophysiology, symptomology, and response to therapy. Clinicians should be aware of the proclivity of these digestive disorders as it relates to gender, to raise suspicion of underlying disease and enhance early diagnosis and treatment. Research and widespread reporting of the gender disparities of digestive disease will ultimately lead to improved patient care and physician satisfaction. Given that females utilize CAM more than males, clinicians should become familiar with the eff ectiveness of CAM modalities for the functional bowel disorders and consider off ering alternative options, given the high satisfaction rate among patients and the results derived from clinical trials.

50 Gastrointestinal Disorders and Eating Disorders

CAROLYN COKER ROSS

key concepts

■ Gastrointestinal disorders oft en co-occur with eating disorders. ■ It is important for the clinician to be aware of the signs and symptoms of eating disorders, to avoid missing the diagnosis in patients who present with GI problems. ■ It is important for the clinician to distinguish between gastrointestinal disorders related to disordered eating, as many of these will be resolved with refeeding. ■ Th e use of dietary supplements can reduce symptoms of functional bowel disorders. ■ Integrative medicine approaches to the treatment of GI disorders off er the clinician eff ective alternatives to conventional therapies. ■

astrointestinal (GI) complaints are present in 50% of individuals diagnosed with eating disorders. It is oft en diffi cult to distinguish G true GI diseases from complaints related to eating disorders (McClain et al., 1993 ), the majority of which resolve with refeeding. As well, certain GI diseases can present a picture that is similar to eating disorders, or can represent the inciting event that contributes to the development of an eating disorder in vulnerable individuals. In a survey of individuals with functional bowel disorders (FBDs), complementary and alternative medicine (CAM) therapies were used by 35 % of patients in an HMO. Th erapies included the use of ginger, massage therapy, and yoga. Th e use of CAM was not related to dissatisfaction with conventional therapies (van Tilburg et al., 2008 ). Th erefore, it is important

606 Gastrointestinal Disorders and Eating Disorders 607 for gastroenterologists to be able to use the presentation of GI disorders as a means to identify eating disorders in their practice. As well, an understanding of CAM therapies may be helpful in treating these patients.

Incidence/Prevalence

Eating disorders represent a spectrum of conditions including anorexia nervosa (AN), bulimia nervosa (BN) and eating disorder not otherwise specifi ed (ED-NOS). Binge eating disorder (BED) is a new category under consideration for inclusion in the Diagnostic and Statistical Manual but is currently included under ED-NOS.

The lifetime prevalence of eating disorders as reported in a large-scale national study for AN, BN, and BED was 0.9% , 1.5% , and 3.5 % for women and 0.3 % , 0.5% , and 2.0 % for men (Hudson, 2007 ).

Anorexia

Anorexia has the highest mortality of any of the psychiatric diagnoses (Palmer, 2003 ) and is the leading cause of death in young women (15 to 24 years old). Th e mortality rate among those with anorexia is estimated to be 0.56 % per year, 12 times higher than the annual all-cause mortality rate for females 15 to 24 years old in the general population (Sullivan, 1995 ). Anorexics experience an intense fear of gaining weight, and for those who are female and postme- narchal, loss of three consecutive menstrual cycles is required to meet the diagnostic criteria.

The hallmark of AN is the refusal or inability to maintain a healthy body weight, and body image distortion— individuals see themselves as being much larger in size than they are.

Anorexia has been diagnosed in children as young as seven, but is most common in adolescents and young adults. Th ere are also many individuals who are diagnosed in midlife, either with a relapse of an eating disorder diagnosed earlier, or a new eating disorder. 608 INTEGRATIVE GASTROENTEROLOGY

There are two types of AN: the restricting type, in which the individual severely limits food intake, and the binge–purge type, in which restricting alternates with some form of purging including the use of self-induced vomiting, laxative or diuretic abuse, and compulsive exercise.

Bulimia Nervosa

Behaviors associated with bulimia include recurrent bingeing, defined as eating a large quantity of food in a short period of time, followed usually by compensatory purging by self-induced vomiting, laxative, or diuretic abuse. Individuals with BN are usually normal weight or slightly overweight. Th e onset of bulimia parallels that of anorexia, but its prevalence is much higher than that of AN by the early adult years. Comorbid substance use disorders are also higher in BN than in AN, reaching a lifetime prevalence of up to 40% (Lilenfeld et al., 1997 ). Over a 7-year period, approximately one-half of those with restricting anorexia will develop binge–purge type anorexia; one-third will develop bulimia (Eddy et al., 2008 ).

Binge Eating Disorder (BED) and Eating Disorder not Otherwise Speciﬁ ed (ED-NOS)

ED-NOS is the diagnosis used for individuals who do not meet the strict criteria for AN or BN. Binge eating disorder is the most well defi ned of the disorders included under ED-NOS. BED is characterized by the consumption of large quantities of food within a short period of time without a compensatory purging mechanism. Th ose with BED experience a lack of control over their eating behavior, eat beyond the point of fullness, and oft en eat very rapidly. Up to 25% of overweight or obese individuals seeking weight loss treatment have BED (Pull, 2004 ). In fact, most individuals with BED are overweight or obese. Compared with individuals with obesity who do not have BED, persons with BED have more extreme fl uctuations in their weight, higher levels of body dissatisfaction (Marcus et al., 1992 ), and a higher incidence of psychopathology ( Ya n o v s k i , 1 9 9 3 ) . Gastrointestinal Disorders and Eating Disorders 609

Medical Complications (de Zwaan & Mitchell, 1993 )

Th e medical complications associated with anorexia, bulimia, and binge eating disorder can be serious and life-threatening. Th e symptoms associated with these complications, if recognized, can be used as a way to screen patients and enable them to obtain help not just for their GI symptoms but for the underlying eating disorder. For the purposes of this book, the major complications will be summarized, with more extensive focus being placed on the gastrointestinal system. Pulmonary complications : Patients who vomit regularly are at risk for aspiration pneumonia; if vigorous, vomiting can result in pneumomediasti- num, pneumothorax, or subcutaneous emphysema and rib fractures. Cardiac complications : Abnormalities on the electrocardiogram (EKG) in those with AN and BN are common and include nonspecifi c ST-T wave changes, prolongation of the QT interval (which can indicate higher risk for sudden death syndrome), and severe bradycardia (with rates from 25 to 40 beats per minute). Other abnormalities include hypotension, orthostatic blood pressure changes (which are adaptations to starvation and should not be mistaken as secondary to physical conditioning (Palla & Litt, 1988 ), peripheral edema, hypoproteinemia, cardiomyopathy, and mitral valve prolapse. Skin and teeth : Anorexics develop fi ne baby hair (lanugo) on the face and forearms as an adaptation of starvation. Individuals with bulimia can experience loss of dental enamel due to purging. Metabolic consequences : Diabetics with an eating disorder can manipulate their use of insulin to increase glucosuria and loss of calories in the urine. Other fi ndings include hypoglycemia secondary to restricting, hyperlipidemia in AN, BN, and BED, and loss of bone mineral density (BMD) in those with a history of anorexia and extended periods of amenorrhea. Th ere is a sevenfold increase in fracture risk in eating disorder patients with low BMD (Rigotti et al., 1991 ). Th yroid function testing may show the “sick euthyroid syndrome”

(normal TSH, decreased T 3 and increased reverse T 3), which is an adaptation to starvation and returns to normal with refeeding. Patients with BED may have metabolic syndrome. Hematologic system : In AN, leukopenia, thrombocytopenia, and in cases of extreme starvation, bone marrow atrophy (Howard et al., 1992 ) may occur. Electrolytes abnormalities : Hypokalemia can result from dehydration, vomiting, and laxative and diuretic abuse, and is the cause of some of the mortality in eating disorder patients. Hypophosphatemia may be exacerbated with 610 INTEGRATIVE GASTROENTEROLOGY refeeding, increasing the risk for myocardial dysfunction and seizures (Wda et al., 1992 ). Gastrointestinal system : Th e most common complaints by patients with any eating disorder when they begin to refeed are gastrointestinal, and include early satiety, bloating, gas, abdominal pain, diarrhea, and constipation.

The prevalence of functional GI disorders in a study of patients with AN, BN, and ED-NOS reported 98% had a GI disorder, including 52% with irritable bowel syndrome, 51% with heartburn, 23 % with dysphagia, and 22% with functional anorectal pain disorder; 52% had three or more coexisting disorders (Boyd et al, 2005 ).

Underweight, restricting individuals with anorexia can develop delayed gastric emptying (Dubois et al., 1979 ), which improves with refeeding and is thought to be secondary to food-restricting behaviors (Szmukler et al., 1990 ). In eating disorder patients who binge, more serious complications can include ulcers of the stomach and duodenum, gastrointestinal bleeding including rectal bleeding, which is associated with laxative abuse, gastric dilatation, and rupture due to binging or as a side eff ect of overly aggressive refeeding in those with anorexia nervosa. Individuals with BED experience signifi cant bloating, acid regurgitation, heartburn, dysphagia, and upper abdominal pain. BED is also associated with diarrhea, urgency, constipation, and feeling of anal blockage (Cremonini et al., 2009 ). Superior mesenteric artery syndrome is a less common consequence in AN, and is due to the loss of fat around the superior mesenteric bundle (Sours & Vorhaus, 1981 ). Th is can cause abdominal pain and is usually alleviated by weight restoration. Th ose patients with eating disorders who purge or chronically vomit can develop gastroesophageal refl ux disease, and hiatal hernia. Pancreatitis can be a result of pancreatic stimulation during bingeing or during refeeding. A small study of women with anorexia and chronic constipation reported 66 % with slow colonic transit time and 41% with pelvic fl oor dysfunction. Colonic transit time normalized with refeeding (Chiarioni et al., 2000 ). Severe liver dysfunction has been reported as a consequence of malnutrition in AN (Furuta et al., 1999 ). GI diseases can coexist with eating disorders. A case report of 10 patients with celiac disease and eating disorders highlights the diffi culty in diagnosing and treating individuals with both illnesses (Leffl er et al., 2007 ). Gastrointestinal Disorders and Eating Disorders 611

Treatment

Integrative medicine therapies for eating disorders include a wide array of approaches that are founded on the principle that the body has its own self-healing capacity. Th erapies used in integrative medicine can include conventional therapies, nutritional supplements, mind–body therapies, and complementary and alternative therapies such as acupuncture. Th ere is a paucity of research that specifi cally examines therapies for treating GI complications in patients with eating disorders. Studies cited in this chapter will discuss results using complementary and alternative therapies for the GI symptoms common in eating disorder patients. As the studies cited show, many of the medical complications associated with eating disorders are alleviated by refeeding. Refeeding applies to AN, BN, and BED, as patients with an eating disorder— even those who binge eat— are oft en undernourished and may be defi cient in vitamins and minerals, or may be restricting certain macronutrients such as fat or carbohydrates.

The most important ﬁ rst therapy for all the eating disorders should be nutritional in the form of food, and also nutritional or dietary supplements.

NUTRITIONAL SUPPLEMENTS

Th e use of nutritional supplements and herbs off ers an alternative to, and may reduce side eff ects from, prescription medications.

DIGESTIVE SUPPLEMENTS

Eating disorder patients commonly suff er from digestive complaints, which may increase when they resume more normal patterns of eating. Th ese symptoms can create challenges during the refeeding process and become distrac- tions in the treatment process. Symptoms may include constipation, diarrhea, bloating, and abdominal cramping or pain. Integrative therapies work to restore normal bowel function and can prevent the need for stimulant or bulk laxatives, upon which patients can become dependent. 612 INTEGRATIVE GASTROENTEROLOGY

Probiotics

Probiotics are products that contain the benefi cial bacteria and yeast that are used to replace or enhance gut fl ora. Levels of probiotics can be decreased by the use of antibiotics, alcohol and drugs, stress, and chronic constipation. Th e most well studied probiotics are Lactobacillus rhamnosus GG and Bifi dobacterium lactis , which have been eff ective in treating antibiotic-associated diarrhea, rotavirus diarrhea, and ectopic conditions. A preliminary study on the eff ects of fermented milk in individuals with anorexia and children with diarrhea (two malnourished populations) demonstrated an increase in interferon-gamma, thought to be a marker demonstrating the eff ect of probiotics on the immune response (Solis et al., 2002 ). A meta-analysis of 10 randomized controlled trials (RCTs) demonstrated good evidence to support the use of probiotics in treating irritable bowel syndrome, although it was unclear which strain was most eff ective (Moayyedi et al., 2008 ). Probiotics may be useful in decreasing constipation associated with low fi ber and low caloric intake (during dieting) in overweight individuals (Amenta et al., 2006 ). An RCT in irritable bowel syndrome patients demonstrated that a probiotic mixture can reduce abdominal pain, distension, borborygmi, and fl atulence (Kajander et al., 2005 ). Probiotics may also reduce the severity of constipation in individuals with chronic constipation (Koebnick et al., 2003 ).

Use of a preparation that has a double-walled capsule will increase the likelihood that the probiotics are not destroyed in the stomach acidity.

Digestive Enzymes

Pancreatic enzymes have been used in conventional medicine for conditions related to pancreatic insuffi ciency and malabsorption. Th e use of pancreatic digestive enzymes may also be useful in other conditions associated with poor digestion, including eating disorders. Digestive enzymes help break down carbohydrates, fat, and protein. A small study done in an inpatient eating disorder unit, of patients on a combination of a plant-based pancreatic enzyme product and probiotics, resulted in a decrease in reports of GI complaints (from 15 % to 5 % ), and a decrease in the use of conventional medications (from 15% to 2% ) to treat GI complaints. Th e treatment group was compared to a similar group Gastrointestinal Disorders and Eating Disorders 613 of inpatients at the same facility prior to the institution of the supplement regimen (Ross et al., 2008 ). Digestive enzymes are traditionally from porcine or bovine sources; however, plant-based or microbe-derived enzymes are currently available and off er the same effi cacy at a much lower dose. Animal-based and plant-derived or microbe-derived enzymes may be used alone or in combination for treating malabsorption and lactose intolerance (Roxas, 2008 ).

Flaxseed

Flaxseed taken orally or in baked goods has been used for the treatment of constipation, colon damage secondary to laxative abuse, and irritable bowel syndrome. Flaxseed is a good source of soluble fi ber and has the additional benefi t of providing a rich source of alpha linolenic acid and omega-3 fatty acids. A study in healthy adults who were given 50 grams of fl axseed per day for one month showed an increase in bowel movements per week by 30 % (Cunnane et al., 1995 ).

Melatonin

Melatonin is a hormone made by the pineal gland that has been used as a sleep remedy. Th ere is an association between irritable bowel syndrome and insomnia. In one study using melatonin (3 milligrams), insomnia improved and abdominal pain associated with irritable bowel syndrome decreased. Th ere was no eff ect on other symptoms of irritable bowel syndrome. However, in another study using the same dosage of melatonin for a longer period of time, patients with irritable bowel syndrome had less pain and bloating, and had improvements in bowel habits as well as decreases in headache, heartburn, and n a u s e a ( S a h a e t a l . , 2 0 0 7 ) .

ACUPUNCTURE

Acupuncture is one of the treatments used in traditional Chinese medicine (TCM) and is widely practiced in the United States. TCM is based on the principle that disease is caused by imbalances in the fl ow of “qi” (pronounced “chee”), which is the vital life energy that fl ows throughout the body in a complex system of meridians, or channels. A meta-analysis of studies on acupuncture for GI diseases found a number of RCTs demonstrating an improvement 614 INTEGRATIVE GASTROENTEROLOGY

Table 50.1. Supplement doses, Food Sources and Side Effects

Food Source Dosage Side Effects/Drug Interactions

Probiotics Fermented Dose varies by product. No known interactions foods, kefi r, Typical doses for children: with medications. Side yogurt 5–10 billion; adults: eff ects: gas and bloating. 10–20 billion

Digestive Bromelain: Dose varies by product. Allergic reactions can Enzymes pineapple A typical OTC plant/microbial occur. Papain: product may contain: Side eff ects: GI upset papaya Cellulase: 185 GD units when taken in high doses Amylase: 20,000 SKB units Protease: 40,000 HUT units Lipase: 9,000 Lipase units Lactase: 1400 FCC units

Flaxseed Flaxseed 40–50 grams/day Flaxseed may interact with antidiabetic drugs (lowers blood glucose) and anticoagulants (may theoretically increase bleeding times)

Melatonin NONE 3–5 milligrams/day Melatonin may interact with antidiabetic drugs (impair glucose utilization) and anticoagulants (may theoretically increase bleeding times. Caff eine decreases melatonin levels.

in health-related quality of life (although sham acupuncture was as eff ective here as actual acupuncture) for irritable bowel syndrome and infl ammatory bowel disease. Real acupuncture was superior to sham in studies on Crohn’s disease and colitis (Schneider et al., 2007 ). A Cochrane review of acupuncture for irritable bowel syndrome did not fi nd conclusive evidence for its effi cacy for IBS (Lim et al., 2006 ). Gastrointestinal Disorders and Eating Disorders 615

Conclusion

Th ere are few studies that focus specifi cally on the treatment of GI diseases in individuals with eating disorders. Studies cited in this chapter may be useful for extrapolation to this population who suff er with signifi cant GI symptoms. CAM therapies can oft en reduce the risk of side eff ects of conventional therapies. Complementary and alternative therapies in general off er safe, possibly eff ective options that can be used with and in place of the usual conventional therapies.

51 Ethical Issues in Integrative Gastroenterology

JULIE STONE

key concepts

■ Ethical issues are at the heart of therapeutic relationships. ■ Conventional and complementary therapists need an adequate understanding of each other’s therapeutic modalities in order to communicate, refer appropriately, and work in an integrated manner. ■ Acting ethically involves benefi ting and not harming patients, encouraging patients to make choices for themselves by providing adequate information, and treating patients fairly and without discrimination. ■ While legal requirements vary slightly across jurisdictions, the need to obtain consent is a major ethical requirement. ■ All practitioners must work within the limits of their competence and make appropriate referrals where necessary. ■ Th erapists should recognize that all interventions carry risks and that sometimes things go wrong. Th erapists should respond to complaints constructively, putting in place mechanisms to learn from errors and near misses. ■

616 Introduction

gainst a backdrop of high levels of digestive diseases in the West, high numbers of patients access a range of CAM (complementary and A alternative medicine) therapies for treatment of a variety of gastroenterological conditions. Some of these patients will have received a conventional medical diagnosis, whereas other patients will self-refer to CAM therapists without having fi rst been diagnosed by a physician. Th is chapter will explore some of the ethical issues associated with integrative gastroenterology, including the areas of respect for patient autonomy, the competence of CAM practitioners and the need to practice within limits of competence, the duty of any healthcare practitioner not to harm patients, and ethical responsibilities in relation to justice, including the need to ensure appropriate redress in the event of a mishap. Despite some variety in the underlying philosophical bases of diff erent codes of ethics, there is a signifi cant degree of commonality in what is expected of a practitioner. (Stone, 2002 ) Core ethical responsibilities include:

• Being suffi ciently skilled in whatever therapies are provided and only working within the limits of competence, making referrals where necessary • Being aware of any specifi c contraindications to treatment and having additional skills for working with vulnerable groups, including children and mentally incapacitated patients • Keeping up to date by undertaking continuing professional development (CPD), and receiving appropriate supervision to ensure professional support and avoid burn-out • Recognizing when it is appropriate to refer the patient to another therapist, either within the same modality, or to another CAM therapist, or to a conventional physician • Ensuring the quality and safety of healthcare products prescribed, and maintaining equipment and premises to ensure that patients are not harmed • Creating and maintaining eff ective professional boundaries • Providing suffi cient information about treatment and its side eff ects to ensure that patients understand what is proposed and are in a position to consent to or refuse treatment • Maintaining confi dentiality and ensuring compliance with relevant data protection legislation 618 INTEGRATIVE GASTROENTEROLOGY

• Responding appropriately and eff ectively to complaints • Acting on concerns about other practitioners

What Do We Mean by “Ethics”?

Professional ethics is about how practitioners ought to act, and the right thing to do in a contentious situation, where opinions and rights may be in confl ict. Healthcare relationships are not like ordinary contractual relationships between consensual adults, and patients’ capacity to enter into voluntary arrangements may be compromised by a variety of factors, including the obvious factor of being disadvantaged by ill health. Ethics are especially important because of the disequilibrium inherent in professional relationships. Th is disequilibrium is based largely on the relative disparity in knowledge between the therapist and the patient. Th e practitioner has a wealth of technical knowledge about his or her therapy, whereas the patient may know very little about what the therapy involves and what outcomes may be realistic. Th is information gap may be exacerbated by the use of technical jargon or unfamiliar language by the practitioner during consultations (Stone, 2000 ). Ethics and law are now routinely incorporated into professional education curricula, in part refl ecting an increased interest in consumer and patient rights, and in part driven by an increasingly litigious culture and the desire on the part of practitioners not to be sued. Like legal duties, ethics concerns rights and responsibilities. Th ese may be set out in professional codes, statute and case law and organizational protocols. Th e regulatory framework governing conventional medicine, which incorporates many ethical obligations, also translates to CAM practice. (Cohen 1998 ) Th at said, healthcare professionals must familiarize themselves with the precise regulations that apply in a given work situation, and should seek professional legal and ethical advice if they are unsure about their responsibilities. In the past, practitioners in the United States were sanctioned for using or referring patients to CAM practitioners (irrespective of whether the referral caused harm). However, medical freedom statutes instituted in various states have removed this threat, and state boards have adopted regulations that acknowledge the growth of integrative approaches to treatment that combine conventional medicine and CAM. (Cohen, 2005 )

Ethics requires practitioners to be accountable for their actions and act in accordance with professional and societal rules. Ethical Issues in Integrative Gastroenterology 619

Nonetheless, professionals remain accountable for their actions and may need to justify departure from accepted custom and practice in a situation where the practitioner has acted outside professional norms, and in ways that no responsible body of medical opinion would advocate.

Arriving at Ethically Justiﬁ able Decisions

Because practitioners and patients may hold diverse cultural values, it is important to have a shared process for determining how to arrive at ethically justifi able decisions. Th is ensures a level of consistency within healthcare, so that choices are not made according to the whim of individual practitioners. Th is section will explore some of the main traditions of ethical thinking in healthcare.

DUTY-BASED THEORIES

Duty-based theories suggest that the right course of action is that which com- plies with relevant rules. Professional rules, set out in formal codes of practice, have the benefi t of being draft ed with profession-wide consensus, increasingly with signifi cant input from patients and other key stakeholders. An advantage of duty-based approaches is that they provide a degree of consistency, so that professionals know what to do in diffi cult situations. While this is desirable for practitioners and patients, the nature of professional codes is such that they can only ever cover “headline” issues, and cannot provide suffi cient detail to act as a blueprint for how professionals ought to act in every given situation. (Stone, 2002 ) Rather, ethical codes tend to set out a series of imperatives from which other rules in the code are derived. Table 51.1 sets out the key principles which underpin the U.K. General Medical Council’s core ethical guidance.

Ethical decisions are the best possible, in all the circumstances, taking relevant considerations into account.

Acting ethically means trying to decide the best way to act in a given situation. It is about what a practitioner ought to do. To clarify how the GMC expects doctors to work within the code, it defi nes what it means by the terms “ m u s t ” a n d “ s h o u l d .” 620 INTEGRATIVE GASTROENTEROLOGY

Table 51.1. Good Medical Practice (2006)

Th e duties of a doctor registered with the General Medical Council

Patients must be able to trust doctors with their lives and health. To justify that trust, you must show respect for human life and you must:

• Make the care of your patient your fi rst concern

• Protect and promote the health of patients and the public

• Provide a good standard of practice and care

• Keep your professional knowledge and skills up to date

• Recognize and work within the limits of your competence

• Work with colleagues in the ways that best serve patients’ interests

• Treat patients as individuals and respect their dignity

• Treat patients politely and considerately

• Respect patients’ right to confi dentiality

• Work in partnership with patients

• Listen to patients and respond to their concerns and preferences

• Give patients the information they want or need in a way they can understand

• Respect patients’ right to reach decisions with you about their treatment and care

• Support patients in caring for themselves to improve and maintain their health

• Be honest and open and act with integrity

• Act without delay if you have good reason to believe that you or a colleague may be putting patients at risk

• Never discriminate unfairly against patients or colleagues

• Never abuse your patients’ trust in you or the public’s trust in the profession

You are personally accountable for your professional practice and must always be prepared to justify your decisions and actions.

Source: http://www.gmc-uk.org/guidance/good_medical_practice/GMC_GMP.pdf

In Good Medical Practice, the terms “you must” and “you should” are used in the following ways: • “You must” is used for an overriding duty or principle. • “You should” is used when we are providing an explanation of how you will meet the overriding duty. Ethical Issues in Integrative Gastroenterology 621

• “You should” is also used where the duty or principle will not apply in all situations or circumstances, or where there are factors outside your control that affect whether or how you can comply with the guidance.

Source: http://www.gmc-uk.org/guidance/good_medical_practice/how_gmp_ applies_to_you.asp

Practitioners may have to weigh conﬂ icting ethical principles to resolve an ethical dilemma.

Professional codes establish a broad framework, but they do not remove the professional’s own autonomy to make whatever decision seems to be the most ethically sensitive and sensible on the basis of all available information. Neither can codes help practitioners resolve dilemmas where duties appear to confl ict with each other (for example, where maintaining confi dentiality would cause harm to the patient or to another person). Weighing confl icting moral obligations remains the professional’s responsibility. Arguably, to remove this autonomy would turn professionals into mere technocrats, and would remove the artistry and humanity that complement the scientifi c basis of the therapeutic relationship.

Outcome-Based Theories

Th e other main group of ethical theories includes outcome-based or consequence-based theories. Th ese theories subscribe to the notion that the right course of action is the one that is likely to promote the best outcome or consequences. Here, the aim of any action or decision is to choose the option that is likely to promote the best outcome (for the greatest number) or, turned on its head, the option that produces the least harm (for the fewest people). Appeals to this sort of decision-making are helpful in deciding how to allocate scarce resources (for example, use cheaper treatments rather than more expensive treatments if the outcome is thought to be equal). In individual practitioner–patient relationships, the theory would mandate choosing treatments where the side eff ects are less severe, all other factors being equal. From a theoretical perspective, outcome-based decisions are fl awed in that they base the rightness or wrongness of an action on likely outcomes, which may not 622 INTEGRATIVE GASTROENTEROLOGY materialize. In individual treatment decisions, it is impossible to predict with certainty what the outcome will be in advance.

Principle-Based Ethics

Principle-based ethics distill many of the ethical imperatives outlined previously. First pioneered by Beauchamp and Childress ( 2001 ) in the United States, and Gillon ( 1994 ) in the United Kingdom, the principle-based approach involves considering ethical principles in light of the available evidence, and weighing these to arrive at an ethically defensible position. Th e key principles are:

• Respect for autonomy • Th e duty to benefi t and not harm • Respect for principles of justice and fairness

Western ethics place a high value on individual autonomy and the freedom of rights of competent individuals to make their own decisions, rather than have others make decisions for them on the basis of what is perceived to be in their interests. Callahan (2003 ) notes that the principle of respect for autonomy is given a place of honor, “because the thrust of individualism, whether from the egalitarian left or the market-oriented right, is to give people maxi- mum liberty in devising their own lives and values.” Th e emphasis on respect for autonomy is a relatively recent phenomenon. Previously, healthcare in the West was more paternalistic, with many patients trusting their practitioners to make decisions for them. In some Eastern traditions, practitioners still place a high value on preserving a patient’s hope, and bad news may be imparted to family members but withheld from patients. It is arguable whether this respect for autonomy is, indeed, the overriding ethical principle in CAM therapies that originate in non-Western cultures. (Stone, 2002 ) In culturally diverse populations, diff erent weight will be given to each of these principles. Similarly, individual patients will give diff erent weight to how they prioritize these principles. Subject to legal requirements that provide a baseline to ensure that each of these principles meets a given standard, practitioners and patients must negotiate an ethical basis for the relationship. Negotiating a contract of mutual expectations is an important way of minimizing misunderstandings and complaints.

Virtue- or Values-Based Theory

An alternative trend in ethical teaching involves the cultivation of core values or virtues. Virtues may be described as desirable behaviors which, if practiced Ethical Issues in Integrative Gastroenterology 623 habitually, become embedded in a person’s character and incline an individual toward making “good” ethical decisions. Values for healthcare professionals might include trustworthiness, empathy, courage, and integrity. Th is approach concentrates on the practitioner rather than the decision, drawing on the role of practical reasoning, emotion, and the practitioner’s motivation in making moral decisions.

Applying Ethical Frameworks

Th ere is little consensus as to how the ethical frameworks or traditions should be applied in practice. Although healthcare training increasingly emphasizes the importance of refl ective practice, the process of making ethical decisions is rarely explicit and, in practice, a practitioner is likely to draw on a number of the theories and rules just discussed. Ethical implications of treatment or research do sometimes need to be consciously articulated and adjudicated; for example, when a practitioner is making an application to a research ethics committee, or when regulatory bodies are draft ing guidance in an ethically contested area. In practice, however, a healthcare practitioner’s day-to-day decisions are only likely to be externally reviewed retrospectively, should they become the subject of complaint or disagreement. Accordingly, the bulk of this chapter will concentrate on the components or aspects of practice where practitioners may experience ethical uncertainty, and which may give rise to complaint.

Competence and the Duty to Beneﬁ t Patients

A desire to heal is the universal ethical basis of healthcare. Th e overarching ethical principle of any professional relationship is that the intervention will, on balance, produce a net benefi t over harm. Th is recognizes the fact that any therapeutic endeavor will have a risk of side eff ects, whether in conventional treatment or complementary therapies. Within conventional medicine, the scope of healing a patient tends to be narrowly defi ned as alleviating symptoms. Th is is in line with a mechanistic approach to health and human suff ering. Of course, doctors are not a homogenous group, and individual practitioners and specialties will vary to the extent that they embrace a more biopsychosocial or holistic approach to health and healing. A holistic understanding of what healing involves might include the following:

• hearing what a patient is really saying, and understanding the meaning of the illness episode to the patient (including its emotional and spiritual impact) 624 INTEGRATIVE GASTROENTEROLOGY

• understanding what sort of relief the patient is looking to gain out of the treatment; for example, gaining greater control over a long-term condition • minimizing symptoms as much as is possible • being realistic about how much the treatment is likely to benefi t the patient, and not distorting the patient’s expectations by overstating the anticipated eff e c t s o f t r e a t m e n t

Competent Practice Based on Appropriate Pre- and Post-Registration Training

Th erapeutic relationships depend on patient trust, specifi cally, the ability of the patient to trust that the practitioner is suitably skilled in his or her fi eld and has the requisite professional competencies to treat. Ordinarily, this will mean that the practitioner has undertaken a suitable training at an appropriate level, and has obtained the relevant qualifi cations to state that he or she possesses certain skills. Levels of training and expertise vary widely across the complementary and alternative sector. Any professional who is considering making a referral to a nonconventional practitioner should take steps to ensure that the person to whom they are referring the patient is suitably qualifi ed. Failure to do so could result in legal or professional sanction.

Competent practice should be underpinned by evidence that a therapy provides more beneﬁ t than harm.

Qualifi cations should provide a minimum guarantee that the practitioner has the requisite entry-level skills to join a profession, but practitioners should also commit themselves to lifelong learning to keep them up to date and to make sure that they continue to develop as professionals. Most licensing bodies now require professionals to demonstrate that they undertake regular continuing professional development (CPD). CPD is increasingly outcome- based, and practitioners are increasingly expected to demonstrate what they have learned from courses, and encouraged to refl ect upon how this will improve their practice. Practitioners should try to ensure that their post- registration education and training involves learning with others, including opportunities to discuss ethical dilemmas and how these have been resolved in practice. Ethical Issues in Integrative Gastroenterology 625

Evidence-Based CAM and Patient Choice

One of the biggest ethical debates surrounds the extent to which any particular CAM therapy is able to deliver benefi t to the patient. While this is linked, in part, to promoting research/evidence-based practice, there is a more basic question, which is related to the scope of a holistic approach. Th e nature of holism implies that a practitioner is able to treat all aspects of a patient’s condition (looking at the patient as a whole person, paying attention to emotion and spiritual needs and not purely physical symptoms). Arguably, every holistic therapist will consider himself or herself legitimately equipped to accept a patient for treatment, as there will invariably be some aspect of the therapeutic relationship that can off er some level of comfort to a patient. Th is exposes a fundamental tension in balancing the freedoms of individuals to accept treatment of their own choice, with a desire to ensure that patients are not exposed to risks of therapies that may be less eff ective than others. Th is is not solely an issue for CAM practitioners. One of the features of gastric symptoms is that they may be caused by many disease processes, including psychosomatic problems. A patient may resort to complementary and alternative medicine aft er having exhausted a range of conventional specialties. Nonetheless, the holistic nature of nonconventional practice means that practitioners need to be realistic with themselves and their patients as to whether their modality is likely to benefi t the patient. Th is requires an awareness and familiarization on the part of CAM practitioners and doctors with other approaches that might better benefi t a patient. It is not wholly possible to legislate this aspect of practice. Off ers to treat should be based on a realistic assessment of the evidence, and reviewed aft er a few sessions to see if the therapy is delivering benefi t. Th e same principle applies to practitioners who off er not just one form of treatment, but a variety of alternative therapeutic modalities. Not only must such practitioners be adequately trained in each therapy they off er, but they should also be transparent about what treatment they are off ering the patient, and on what evidential basis, so that the patient can make an informed choice. A practitioner should not switch from one modality to another when symptoms are not improving, without being very explicit. All CAM practitioners should be familiar with the contraindications to their particular therapy, and the additional caution to be exercised in applying certain treatment to special groups of patients. CAM therapists should recognize the point at which they should make a referral to a physician for a conventional diagnosis. 626 INTEGRATIVE GASTROENTEROLOGY

Patient Autonomy

Th e surge in usage of CAM in itself refl ects a desire on the part of patients to opt for a treatment modality of their choice. Patients suff ering from gastric conditions may choose from an array of licensed and unlicensed practitioners, with high levels of usage of acupuncture and other energy-based techniques, Ayurvedic and Western herbal remedies, homeopathy, and touch-based therapies, including osteopathy and massage. Patients have a right to choose from a diverse array of practitioners, practicing, for the main part, outside state-funded healthcare. Th e principle of respect for patient autonomy has a number of implications, for both CAM practitioners and mainstream physicians. Autonomy connotes the rights of individuals to make their own choices, in accordance with their own values and principles, free from coercion and interference. Patients need to be given adequate information to be able to make choices about the form of healthcare they are to receive, and to decide whether to accept or reject the treatment off ered. Professional practice refl ects this obligation in the duty of practitioners to make sure that they obtain patient consent. While the legal requirements for obtaining a valid consent may vary between jurisdictions, the underlying ethical premise is based on respecting autonomy, and refl ects the centrality of the principle of bodily integrity and freedom from interference. Th is denotes the rights of individuals not to be touched by anyone unless they have expressly consented to it (other than limited exceptions, including medical emergencies). Th erapists sometimes assume, incorrectly, that the principle of implied consent means that they do not require actual permission to touch or treat a patient. Th is is incorrect. While it is true that a patient has chosen to attend an appointment, a therapist still needs to explain the following aspects of treatment, in a way that the patient can understand:

• What is involved in the therapy • How many sessions are likely to be necessary • What the treatment will involve • Th e anticipated benefi ts of treatment, and when benefi t might be expected • How long the benefi ts of treatment might be expected to last • Possible side eff ects and what the patient should do in response. Patients should be told about small but common risks, and also about less likely risks that carry a risk of signifi cant harm Ethical Issues in Integrative Gastroenterology 627

• Alternatives to what is proposed (both complementary and conventional treatments)

A therapist should also provide an opportunity for a patient to ask questions and should respond fully to any additional questions or concerns that the patient may have. In determining precisely which risks should be disclosed, practitioners should work within their professional code of ethics and any relevant case law. Certain procedures require additional caution. Where an invasive diagnostic or therapeutic procedure is required, for example, therapists should communicate fully why this is necessary, what will happen, and explain that the patient can ask the practitioner to stop at any point. Th erapists should also make sure the patient knows that they can have a chaperone present. In most situations where an invasive procedure is required, therapists should seek consent in advance; e.g., provide the information in a fi rst session, and undertake the procedure at the next.

Respecting autonomy can be enhanced through creating speciﬁ c therapeutic contracts.

Th is will allow patients time to refl ect on what is proposed, and give them a “cooling off ” period if they do not want to go ahead. Where this is not possible because the practitioner feels that the procedure is necessary in a hurry, the patient must nonetheless be told they can ask the practitioner to stop at any p o i n t .

Contracting with Patients

Some therapists fi nd value in creating explicit “contracts” with patients. Th is can be particularly helpful in the private sector, where practitioners work outside organizational frameworks. Drawing up a therapeutic (as distinct from a legal) contract can be a helpful way of both respecting the patient’s autonomy and protecting practitioners from subsequent complaints, by highlighting each party’s responsibilities. While specifi c terms of a therapeutic arrangement may vary from patient to patient, the basic framework provided in Table 51.2 may provide a potential model for nonconventional t h e r a p i s t s . 628 INTEGRATIVE GASTROENTEROLOGY

Table 51.2.

Practitioner’s Responsibilities • Telling the patient about their background and experience and areas of expertise and qualifi cations • Explaining what is involved in the therapy (e.g., providing a leafl et) • Explaining what the patient can expect of each session, including any likely physical or emotional aft er-eff ects • Agreeing on fees and the position regarding missed appointments • Setting a number of sessions aft er which the patient’s progress will be reviewed, together with an indication of how long therapy is likely to be needed to bring about a level of improvement • Supplying the patient with a copy of notes or a résumé of treatment given at the end of therapy, so they can use this when pursuing therapies in the future Patients’ Responsibilities • To attend appointments • To be full and frank in notifying practitioners what treatments they are currently using (so as to minimize the risks of treatment and drug interactions) • To provide information honestly and in suffi cient detail to allow the practitioner to make a diagnosis and provide the appropriate treatment • To follow reasonable advice given by the practitioner • To display courtesy and respect for the practitioner as an individual • To pay promptly for all sessions (including canceled sessions, subject to agreement)

Contracts should set out practitioner and patient responsibilities.

Practitioners must actively avoid directly or indirectly harming patients.

Not Harming Patients

All ethical theories highlight the centrality of not harming patients. For the purposes of integrative therapy, harm, as described by the U.S. Federation of State Medical Boards (FSMB) has been described as conveying three discrete notions:

• Economic harm that results in monetary loss but presents no health hazard; • Indirect harm that results in a delay of appropriate treatment, or in unreasonable expectations that discourage patients and their families from accepting and dealing eff ectively with their medical conditions; • Direct harm that results in adverse patient outcome.

Practitioners have an ethical and legal imperative to refrain from causing harm and, in some jurisdictions, such as the United States, potential liability Ethical Issues in Integrative Gastroenterology 629 can arise if a practitioner indirectly harms a patient, e.g., by delaying access to more appropriate treatment. While Stone and Matthews ( 1996 ) challenge the notion of use of CAM constituting indirect harm per se, all practitioners should ensure that patients are given adequate information to direct them to the most effi cacious treatments available (CAM or conventional). Th is requires knowledge about the benefi ts and risks of conventional and nonconventional treatments.

What Factors State Boards Will Consider in Determining Appropriateness of Treatment

In consideration of these potential harms, the FSMB urges state medical boards to evaluate whether or not a physician is practicing “appropriate medicine” by considering the following practice criteria, namely whether the physician is using a treatment that is:

• eff ective and safe (having adequate scientifi c evidence of effi cacy and/or safety, or greater safety than other established treatment models for the same condition) • eff ective, but with some real or potential danger (having evidence of effi cacy, but also of adverse side eff ects) • inadequately studied, but safe (having insuffi cient evidence of clinical effi cacy, but reasonable evidence to suggest relative safety) • ineff ective and dangerous (proven to be ineff ective or unsafe through controlled trials or documented evidence, or as measured by a risk/ benefi t assessment)

As part of his discussion of the use of CAM in children, Cohen (2005 ) notes that although the FSMB has clarifi ed that using CAM therapies in itself does not constitute grounds for discipline, those guidelines nonetheless require a strong therapeutic rationale, including that the selected CAM therapies are likely to provide “a favorable risk/benefi t ratio compared with other treatments for the same condition,” be “based on a reasonable expectation that it will result in a favorable patient outcome, including preventive practices,” and “be based on the expectation that a greater benefi t will be achieved than that which c a n b e e x p e c t e d w i t h n o t r e a t m e n t .”

Practitioners must refrain from intentionally causing harm, and should not continue treatment longer than is necessary and in the patient’s interests. 630 INTEGRATIVE GASTROENTEROLOGY

Intentionally Causing Harm

Th e requirement not to cause harm goes beyond recognition of the risks inherent in therapy, and requires practitioners to refrain from intentional actions or behaviors that will cause harm to a patient, since this is anathema to the basis of healing relationships. Most professional codes include rules prohibiting practitioners from exploiting professional relationships for their own benefi t. Th is might include:

• prolonging the duration of the professional relationship for the fi nancial benefi t of the practitioner, where there is no longer an ongoing therapeutic basis for seeing the patient • allowing the patient to continue attending and paying for therapy because the patient has formed an emotional dependence on the therapist • carrying out untried or untested approaches to satisfy professional curiosity outside the confi n e s o f r e g u l a t e d r e s e a r c h

Maintaining Appropriate Professional Boundaries

Practitioners must maintain appropriate personal and professional boundaries, including emotional, sexual, and fi nancial boundaries.

Part of the duty to avoid harming patients requires CAM and conventional practitioners to set and maintain appropriate professional boundaries with patients, and to refrain from acting sexually, or in other ways that blur the distinction between professional and social relationships. Evidence shows that boundary violations occur across all healthcare and social care professions, and there are reported incidences of abuse by doctors as well CAM practitioners (Halter et al. 2007 ). It is always the professional’s responsibility to set and maintain clear boundaries (CHRE, 2008). Th e consequences for patients when practitioners breach acceptable boundaries can be very serious, and in the most serious cases, abuse can lead to post-traumatic stress disorder, depression, suicidal tendencies, and emotional distrust, failure to access health services when needed, and use and misuse of prescription and other drugs and alcohol. A proven allegation by a patient of boundary violation can also end a practitioner’s career. Whereas a minority of practitioners deliberately set out to abuse patients, other practitioners may fi nd themselves on the receiving end of a complaint Ethical Issues in Integrative Gastroenterology 631 because they lack self-awareness of how they are perceived by patients, or because they fail, for example, to act appropriately in the light of a patient’s sexual attraction or dependence. Practitioners need to learn how to diff erentiate between caring, empathetic relationships, including the appropriate and safe use of touch, and acting in ways that expose themselves and patients to harm. For example, some alternative therapists may be more physically demon- strative than conventional doctors, and may think it is appropriate to hug a patient. Use of touch is highly potent, and may or may not be appropriate and safe according to context. Practitioners should be particularly sensitive to the use of touch in patients who may have a history of being sexually abused, and in patients with mental health problems. (Stone, 2007 )

Practitioners should be aware of the particular boundary issues working in CAM may pose.

In order to minimize risk, practitioners should also be aware of the vulner- abilities of working from their own homes, or treating patients in the patient’s home with no chaperone. Th ey should also recognize some of the early warning signs that might highlight the blurring of boundaries and should, for example, be wary about giving or receiving gift s from patients, accepting or off ering social invitations, and disclosing too much information about themselves, in situations where self-disclosure is more for the practitioner’s benefi t than the patient’s.

Supervision

A practitioner who has concerns about a particular patient should raise these in supervision. Regular supervision helps to ensure that practitioners maintain high standards of ethical practice. Unethical practice is rarely deliberate, and substandard practice is more likely to originate from inadequate training, reinforced by working in isolation from peers over a period of time. Constructive supervision may provide a necessary outlet for therapists in which technical and ethical diffi culties can be discussed openly and in a supportive and non-judgmental environment.

Upholding Principles of Justice and Fairness

Principles of equality, justice, and fairness should underpin therapists’ deal- ings with patients. Oft en these principles may be enshrined in statutes and 632 INTEGRATIVE GASTROENTEROLOGY professional codes, with laws and regulations ensuring that practitioners treat all patients equally irrespective of gender, disability, sexual orientation, or age (save to the extent that diff erential treatment is therapeutically indicated). Th e principle of respect for justice is oft en taken to include fair distribution of resources. Th is is ethically problematic in the case of CAM therapy— most of which, in the West, is delivered predominantly in the private sector to relatively affl uent clients who can aff ord to pay for treatments that are not provided as part of state-funded healthcare or reimbursed by third-party payers. While inequitable, this position is unlikely to change until there is a stronger evidence base demonstrating clinical and cost eff ectiveness of nonconventional techniques. (Ernst et al., 2004 )

Practitioners should respond appropriately and not defensively to complaints, and take action on concerns about professional colleagues.

Respect for the principle of justice requires practitioners to anticipate that mistakes do happen (even to the most competent practitioners), and to make adequate provision for this eventuality. Most codes require practitioners to hold adequate indemnity insurance so that they can respond appropriately if complained against. Poor communication is at the heart of most patients’ complaints, and practitioners could minimize many complaints from escalating by responding appropriately to patients’ dissatisfactions. A good therapeutic relationship should allow patients to air concerns while still feeling supported, and practitioners should encourage honest feedback from patients as a means of improving their practice. Rather than feeling defensive, practitioners should regard complaints and adverse events as an opportunity to learn from their own mistakes. Where appropriate, practitioners should apologize when something has gone wrong. Th is is not the same as admitting liability; rather it is an acknowledgment of the patient’s sense of grievance and a demonstration of empathy and compassion. Justice considerations also require practitioners to speak out if they encounter poor practice on the part of professional colleagues, whether from their own discipline or practicing within a diff erent modality. In this regard, practitioners have an advocacy role and duty to facilitate the appropriate highlighting of poor practice, recognizing that the role of regulation is public protection and that membership of a profession confers individual as well as collective responsibilities. Where necessary, therapists should signpost how, and to whom, patients can complain, and should report poor practice or criminal Ethical Issues in Integrative Gastroenterology 633 activity, such as suspected child abuse, to the relevant professional body or authorities.

Specifi c ethical issues include failure to diagnose.

Issues specifi c to integrative gastroenterology: As well as the generic ethical issues outlined above, the practice of integrative gastroenterology gives rise to some specifi c ethical issues, whether treatment is off ered by CAM practitioners or conventional physicians trained in CAM modalities.

Failure to Diagnose

Th ere is a risk that CAM therapists treating patients with gastroenterological conditions may fail to spot an underlying pathology that requires urgent medical treatment; e.g., failing to diagnose gastric or bowel cancer. Th is raises the debate around the extent to which CAM practitioners are competent and trained to make a medical diagnosis, and the point at which they should make a referral to a conventional physician. Patients are free to refuse such a referral, but the practitioner’s autonomy means that she or he can equally refuse to treat any patient felt to be in need of urgent medical attention. Th e issue of diagnosis becomes more vexed when the patient is consulting a therapist whose diagnosis is based on a fundamentally alternative system; e.g., a traditional Chinese medicine practitioner, in that the diagnosis would be in energetic terms and would not correspond to a conventional medical diagnosis. Nonetheless, all CAM practitioners must recognize contraindications to treatment and be aware of their potential liability if they fail to make an appropriate referral in such circumstances. Conventional practitioners should also be aware of their potential liability for malpractice if they make a referral to a CAM practitioner that delays access to treatment, resulting in a patient suff ering harm. In order to minimize potential liability, practitioners should record in the notes any recommendation to seek urgent medical care that the patient has chosen to ignore. Practitioners may decide, in such circumstances, that they cannot continue to treat, in which case they should make arrangements to hand over the case appropriately.

Delivering Evidence-Based Treatments

As far as possible, therapists should use evidence-based treatments. While the nature of what constitutes good evidence, or good enough evidence, is highly 634 INTEGRATIVE GASTROENTEROLOGY contested, many therapies do have an emerging evidence base, and practitioners should keep up to date in their fi eld and specialty to be able to treat in accordance with researched treatments. Th erapists also have a collective and individual responsibility to audit their own practice and to promote a research- based culture to the extent that this will benefi t current and future patients.

Practitioners should encourage open communication with the primary care physician to ensure patient safety.

Encouraging Patients to Disclose what Treatments they are Receiving

Unless patients feel confi dent to disclose what treatments they are receiving, there is a real risk of them suff ering side eff ects from drug interactions. All practitioners should strive to be nonjudgmental about a patient’s treatment choices, and equip themselves with enough information to know the likely impact of diff erent modalities. For the purposes of eff ective communication, and also gaining consent, conventional and CAM practitioners need to understand the basics of the diff erent approaches to integrative gastroenterology treatments.

Do as I say, not as I do…

An interesting ethical question is how far practitioners should act as role models, or motivational lifestyle gurus, particularly in integrative gastroenterology, if the therapist suspects that lifestyle issues may be responsible for some or all of the patient’s symptoms. In making recommendations about lifestyle changes, practitioners must be realistic about how much change is appropriate, realistic, or safe. For example, nutritional therapists should be cautious about “prescribing” dramatic purging or highly restrictive dietary regimes, which may be dangerous for some patients and can be particularly damaging for patients with emotional issues— for example, patients with previous histories of eating disorders.

Practitioners should avoid exerting undue inﬂ uence or imposing their own views on patients. Ethical Issues in Integrative Gastroenterology 635

Practitioners should be aware of the potentially disproportionate infl uence they may be exerting on their patient’s life. In order to promote autonomy, practitioners should work toward fostering patients’ self-reliance and inde- pendence, rather than dependence on the practitioner. Th is includes reviewing how long therapy should continue, and a realistic assessment of when therapy should be terminated.

Ensuring that any Products Recommended or Sold to Patients Are in Their Best Therapeutic Interests

Over-the-counter remedies are among the CAM treatments that patients pursue for gastroenterological problems (e.g., peppermint oil for irritable bowel syndrome). Some practitioners have their own range of products and remedies, and may off er these to patients as part of their treatment. Practitioners should never push their own products onto patients to the extent that patients feel compelled to purchase these as a condition of treatment. Not only must any practitioner ensure that their range of products comply with appropriate licensing and regulatory requirements, but practitioners must also ensure that any product that is prescribed is done so on the basis of the practitioner’s assessment of the patient’s interests, and is not motivated by fi n a n c i a l r e a s o n s .

Promoting patients’ best interests underpins all ethical interventions.

Conclusion

All therapeutic relationships give rise to ethical issues, and practitioners must ensure that treatments are underpinned by the patient’s best interests, and backed up by evidence, as much as possible. When a practitioner deviates from accepted professional practice, he or she should be prepared to justify this departure to a licensing board or, potentially, a court of law. While patients have a right to choose and seek out CAM approaches to treatment, professionals have a responsibility to safeguard the welfare and well-being of the patients through the use of safe and effi cacious treatments. In integrative gastroenterology, where the cause of the patient’s problems may be hard to ascertain and treat, practitioners should work constructively and collaboratively with colleagues, working toward an improved evidence base in this challenging clinical area.

52 There Is No Alternative to Evidence

RONALD L. KORETZ

“Th ere cannot be two kinds of medicine — conventional and alternative. Th ere is only medicine that has been adequately tested and medicine that has not, medicine that works and medicine that may or may not work. Once a treatment has been tested rigorously it no longer matters whether it was considered alternative at the outset.” (Angell & Kassirer, 1998 )

key concepts

■ Evidence-based medicine drives our clinical decision making, and should be practiced by all healthcare practitioners. ■ Clinical trials have disparities in methodologies, reporting, and interpretation, which has potential bias. ■ In evaluating the evidence, clinical decision-makers should understand the diff erences between expert opinion, case series, case-controlled studies, cohort studies, randomized clinical trials and systematic reviews. ■ Lack of blinding, failure to conceal allocation, inadequate randomization scheme, lack of intent to treat analysis, involvement of vested interest (confl ict of interest), early stopping, selective outcome reporting, and unequal treatment of control groups are all examples of methods that lead to bias in clinical trials. ■ A Type I error is the term applied to the phenomenon of fi nding what appears to be a signifi cant diff erence when one does not truly exist. A Type II error is the failure to see a diff erence that truly exists. ■ Complementary and alternative medicine is frequently fraught with blinding bias because many studies are subjective and report symptoms as the primary endpoint. ■

636 Introduction

he intent of this chapter is to provide a perspective on evidence-based medicine, in particular evidence regarding therapeutic interventions. T As is to be appreciated from the quote by Angell and Kassirer, the rules are no diff erent for evidence collected to assess the effi cacy of interventions in complementary and alternative medicine than they are for allopathic medicine. Th e main issue that will be considered is the use of data from the literature to assist the clinician in making therapeutic decisions. Th at clinician wants to make decisions that will benefi t his or her patients. Th is is the juncture where an understanding of evidence becomes critical. More and more, clinicians are utilizing the paradigm of evidence-based medicine (Evidence-Based Medicine Working Group, 1992 ), a process that has been defi ned as “integrating individual clinical expertise with the best available external clinical evidence from systematic research” (Sackett et al., 1996 ). In this regard, there is a hierarchy of evidence that extends from the least to the most reliable. Th is hierarchy is based on how much infl uence bias has had in the gathering and/or interpretation of the data. “Bias” is not a pejorative term, but a statistical concept regarding the extent to which external forces infl uence observations. Table 52.1 details this hierarchy.

Table 52.1. Hierarchy of Evidence Regarding Interventional Decisions

Ranking of Evidence Source of Evidence 1

Experience (lowest level) Personal

Local expert

National expert (textbook chapter, narrative review article)

Publication of clinical Uncontrolled experience observations

Nonrandomized controls

Randomized controls

Eff ort to fi nd all data (highest Systematic review of randomized trials level)

1 Reliability of evidence increases as one moves down the table. 638 INTEGRATIVE GASTROENTEROLOGY

Types of Evidence

EXPERT OPINION

From a practical perspective, when one is confronted with a question to which he or she does not know the answer, the easiest path to take is to ask somebody who is believed to be an expert. Th is can be accomplished through a personal contact, or by seeking the answer in a textbook chapter or narrative review article. However, if the answer is not accompanied by the reason(s) that underlie it, that response becomes simple dogma. Even in our enlightened evidence-based era, dogmatic teaching pervades medicine. Like dogma everywhere else, it may or may not be based on valid information. Consider the story of the young girl who, every Christmas, watched her mother prepare a ham dinner. Th e mother fi rst cut off about a quarter of the meat, threw it away, and then cooked the remainder. When the girl asked her mother why she did it that way, the mother told her that that was the way her mother did it. Th e young girl asked her grandmother why, and she received the same answer, namely that it was the way her mother taught her. When the young girl asked her great-grandmother why a quarter of the ham was wasted, the great-grandmother laughed. She said that she had no idea why her daughter or her granddaughter did it, but she did it because her pan was too small to hold the entire ham. Th us, at the time that a new dogmatic principle is introduced, it may be a rational approach. However, with the passage of time and the introduction of n e w k n o w l e d g e , i t c a n b e c o m e o u t d a t e d .

Expert opinion becomes more reliable if the available data still support it. Unfortunately, this is often not the case (Antman et al., 1992).

Uncontrolled Experiences

CASE REPORTS/CASE SERIES

In these studies, the investigators provide a description of one (or a few) patients because the case(s) represent unusual or thought-provoking features. Th is is typically how rare diseases, unusual presentations of more common diseases, and even new therapies fi rst come to light. Ideally, the authors of the There Is No Alternative to Evidence 639 paper will put their new observation into the perspective of what information is already available. Th ese reports of one or a few patients do not provide any insight into the frequency or overall impact of the observation, because there is no denominator (the total population of patients from which the one[s] in the report arose).

The case report simply memorializes the observation. Occasionally, case reports become historically important, such as the ﬁ rst description of AIDS (Gottlieb et al., 1981 ). If the observation refers to a treatment, it can become the rationale for a subsequent interventional trial.

COHORT STUDIES (RETROSPECTIVE OR PROSPECTIVE)

Th ese studies usually document the natural history of a particular condition. While such studies can be conducted aft er the construction of a protocol (patients are followed into the future), they are more oft en retrospective (all of the events have already happened). Typically, all eligible patients are identifi ed from previous diagnoses and their records are reviewed. Such studies are likely to emanate from medical centers where records of patients are systematically stored. In these cases, an entire (albeit selected) population is defi ned, so there is a denominator available to make an estimate of the frequency of a particular outcome (e.g., death).

Retrospective cohort studies are relatively easy to do; the investigator reviews a number of records. There are potential biases in these reports, including ascertainment (a more vigorous effort to ﬁ nd the disease in centers with interests in it) and referral (a type of selection bias).

An example of potential bias is that individuals with chronic hepatitis C who are being followed in tertiary liver clinics develop decompensated cirrhosis at a rate that is 5 to 10 times higher (Tong et al., 1995 ) than that observed in entire cohorts of patients who were identifi ed at the time of infection (Seeff et al., 2001 ). Th is likely refl ects the fact that tertiary centers attract sicker patients. Some investigators have employed this methodology to justify various treatment modalities. In other words, they describe the natural history of patients with a particular disease who are exposed to a particular intervention. However, this does produce a variety of interpretative problems because of the 640 INTEGRATIVE GASTROENTEROLOGY introduction of several kinds of biases. It is usually unknown why these patients (but not others) received the therapy. Treatment in a center of excellence may not be reproducible elsewhere (“guru bias”). No blinding of therapy occurred, allowing the personal biases of both the patient and the healthcare worker to infl uence the apparent outcome. Finally, the absence of a control group prevents any comparison to a group who did not receive the therapy. (Reports that include controls will be considered in the next sections).

CASE-CONTROL STUDIES

Th is methodology was developed by epidemiologists to identify etiologies of disease. Patients with a particular disease are identifi ed and matched to controls who do not have that disease. Exposures that are being hypothesized as being important in the etiology of the disease are then sought in the records of both groups. If the exposure occurs more oft en in the disease group, it is considered as a potential cause; if it is more common in the controls, it is a potential protector.

Case-control studies are retrospective and can only establish associations between the exposure and the disease. Association does not prove causation.

An example of association-causation is: A and B may be associated because A causes B (a true causative association). However, if some other factor (C) causes both A and B, a noncausative association can exist between A and B. For example, malnourished patients have poorer clinical outcomes than do nourished ones (association). However, interventions that improve parameters of malnutrition do not improve clinical outcomes (Koretz, 2005 ), suggesting that the malnutrition does not cause the poorer outcome. Case-control studies are not well suited to make inferences about the effi cacy of therapeutic interventions. Consider the inability of case-control studies to predict therapeutic effi cacy with regard to hormone replacement therapy and cardiac disease. While the case-control (and other observational) studies indicated that replacement therapy would be helpful, a large randomized trial found that the treatment actually caused harm (Anderson et al., 2004 ).

CONTROLLED TRIALS

A controlled trial is the classic methodology to assess the impact of an intervention on a disease state. In such a study, the outcomes in a group of patients There Is No Alternative to Evidence 641 that received an intervention are compared to the same outcomes in a group that did not receive the intervention. Th e control group is important because it provides insight into how the intervention altered the natural history of the disease. Th ere are times when the outcome in a particular patient is absolutely predictable and unfavorable. In such cases, if an intervention favorably alters that prediction, effi cacy is established. We do not need controlled trials to justify cardiopulmonary resuscitation for cardiac arrest or hemodialysis in end-stage renal disease. However, most clinical conditions are not so predictable. Controls can be identifi ed in several ways. Th e important distinction is to know whether or not the controls were selected by a process of randomization. Nonrandomized controls can be historical (retrospectively identifi ed from records) or be concurrent patients who, for some reason, were not treated. Since the purpose of the control is to be an individual who diff ers from the treated patient solely on the basis of not having received the treatment, randomization is paramount. If only the treatment variable were to be changed, any subsequent diff erence in outcome could be attributed to the intervention (establishing a causative relationship between the intervention and the outcome).

In a randomized trial, a homogeneous group of patients is identiﬁ ed and then, by chance, each one of them is either given or not given the treatment. In a randomized trial, unless the randomization scheme breaks down, only one variable is changed.

Diff erent demographic features (gender, age, etc.) are as likely to be randomized into one arm as into the other. (Typically, reports of these studies contain a table that compares the demographic features of both groups in order to prove that a balanced distribution did occur.) Regardless of how a nonrandomized control patient is selected, such an individual must diff er from the treated subject in at least two ways. Th e fi rst is the non-receipt of the therapy. Th e second is the reason(s) why the treatment was not provided. Th us, there are now at least two variables that diff erentiate the two groups, so an observed diff erence in outcome between the groups cannot simply be ascribed to the treatment. Any such diff erence can be considered to be one that is associated with the treatment, but a causative relationship cannot be inferred. (Th e data can be used to create the hypothesis that the treatment may be eff ective, but a randomized trial is still necessary to prove it.) Baseline diff erences between the treated and control groups are known as confounders; randomization eliminates this confounding bias. Trials employing 642 INTEGRATIVE GASTROENTEROLOGY nonrandomized controls usually overestimate the observed effi cacy of the intervention (Ioannidis et al., 2001 ; Sacks et al., 1982 ).

SYSTEMATIC REVIEWS

Most clinicians are used to reading narrative review articles, ones that arise when editors ask “experts” to write articles that provide the reader with the most current information. Narrative reviews appear to suff er from at least the potential infl uence of bias (McAlister et al., 1999 ; Mulrow, 1987 ). In distinction, systematic reviews of interventions provide a more objective assessment of the available evidence. A systematic review begins with a protocol that defi nes a strategy to fi nd all of the relevant randomized trials (in order to avoid “cherry-picking” references that happen to agree with a preconceived bias), and a description of the methodology that will be used to formulate the conclusion. Th e data drive the conclusions. For interventional questions, a well-done systematic review of randomized trials is now considered to be the “gold standard” for establishing effi cacy (Cook et al., 1997 ).

Systematic reviews are often referred to as “meta-analyses,” but the two are not the same. Systematic reviewing is the process of locating and considering all of the available evidence; meta-analysis refers to the process of combining data from different trials. Any meta-analysis should be preceded by a systematic review, but systematic reviews do not necessarily have to combine the data quantitatively.

Data combination, whether by simply adding the numerators and denomi- nators together or by fi rst weighing each study for its statistical reliability and then adding the weighted numbers together (meta-analysis), is done to increase the power of seeing an eff ect or, if an eff ect is present, more precisely defi ning it. Th e downside of combination is the fact that disparate studies are being combined. Obviously, if the trials are too diff erent (too heterogeneous), it makes little sense to combine them.) Th e process of systematic reviewing and meta-analysis has been criticized in the past because the result does not always agree with what has been observed in single large randomized trials (LeLorier et al., 1997 ). At least some of this criticism is more apparent than real; if one looks at the actual data in the paper by LeLorier et al., one can see that the meta-analysis almost always agreed with the outcome from the large trial with regard to the direction of the There Is No Alternative to Evidence 643 eff ect; the issue was that one, but not the other, claimed that the diff erence was statistically signifi cant. “Pre-fi ltered” collections of references that contain only randomized trials and/or systematic reviews are available. Th e best known of these are Th e Cochrane Library, Best Evidence and UpToDate .

BIASES IN RANDOMIZED TRIALS

Th e purpose of randomization is to eliminate biases introduced by confounding factors. However, other biases, enumerated in Table 52.2 , can still occur. Th ese biases are not just intellectual curiosities. If eff orts are not taken to eliminate them, a larger treatment eff ect is usually observed (Kjaergard et al., 2001 ; Moher et al., 1998 ; Schulz et al., 1995 ). Th is enhanced eff ect in the less methodologically

Table 52.2. Biases that Arise in Randomized Trials

Lack of blinding Th e outcome is assessed by individuals who know into which arm the patient was assigned.

Failure to conceal Th e investigator (or the patient) is aware of what the arm allocation assignment will be prior to entering the study.

Poor randomization Th e randomization scheme results in an unbalanced assignment. technique

Lack of intent to Patients are lost aft er the randomization and not accounted for in treat analysis the analysis.

Subgroup analysis Only a portion of the total study group is analyzed.

Surrogate outcome Th e outcome is a lab test or other measure of physiologic function.

Treatment of Th e control group receives some intervention that the study controls group did not receive.

Selective outcome Not all outcomes that were observed were presented. reporting

Breakdown of In spite of randomization process, confounding factors are still randomization present.

Early stopping Study stopped before the original protocol called for completion.

Involvement of Individuals or groups with vested interest(s) in the outcome are vested interests involved in the conduct of the study. 644 INTEGRATIVE GASTROENTEROLOGY rigorous trials is attributed to the presence of bias. Th us, randomized trials can be graded by the degree to which the methodology avoided bias; trials that are more rigorously designed and executed are referred to as being of “high quality” or being at “low risk of bias.”

LACK OF BLINDING

Th is is an easy concept to understand when the outcome is a subjective one (e.g., pain). Of course, even quantitative outcomes (e.g., duration of hospitalization, the presence or absence of infection) can be subjective judgments. While trials of surgical interventions are diffi cult to blind, dramatic placebo eff ects have been observed (Cobb et al., 1959 ; Dimond et al., 1960 ). In general, non-blinded trials produce larger treatment estimates (Kjaergard et al., 2001 ).

FAILURE TO CONCEAL ALLOCATION

Neither the investigator nor the patient should know into which arm the patient will be assigned until the patient actually enters the trial. This concealment of allocation is not the same thing as blinding, which refers to being unaware of the treatment during the course of the trial.

If the patient knows what he or she will be receiving, that knowledge can infl uence his or her decision to participate. If the investigator knows into which arm the patient will be assigned, preferential screening can occur. (For example, a patient who looks particularly sick might have a more intense evaluation looking for the presence of an exclusion criterion if assignment was to be to the treatment arm.) Failure to conceal allocation does result in larger estimates of treatment eff ect (Kjaergard et al., 2001 ; Moher et al., 1998 ; Schulz et al., 1995 ).

INADEQUATE RANDOMIZATION SCHEME

Even if the investigator does not know the allocation, a poor randomization scheme can cause problems. For example, suppose the randomization is based on the fi rst letter of the last name; any trial in Scotland will have a disproportionate number of patients named MacDonald in one of the arms (and some of the MacDonalds may share genetic similarities). There Is No Alternative to Evidence 645

Usually, randomization is done using tables of random numbers or computers; even coin ﬂ ips or card draws are adequate. Quasi-randomization schemes (allocating patients based on a record number or day of the week) are not satisfactory. In such schemes, the investigator and/or the patient will know what treatment will be provided, so concealment of allocation is lost.

LACK OF INTENT-TO-TREAT ANALYSIS

Th e only time when the randomization is known to be intact is at the beginning of the trial. Th us, all of the randomized patients should be accounted for. If patients drop out of one arm for some systematic reason, the randomization will no longer be intact. Consider a trial that compared two types of enteral nutrition (Bower et al., 1995 ) and used length of stay in the intensive care unit as the primary outcome. Th e investigators were not sure how to include data from the patients who died. Th ey did not fi nd a signifi cant diff erence in the mortality rate between the two arms, so they calculated the durations of stay only for the survivors. However, there were twice as many deaths in one arm as in the other; the “not statistically signifi cant” p value was 0.06. Th e shorter length of stay in the arm with the higher mortality rate probably refl ected the fact that there were a larger number of sicker patients who survived in the other arm.

SUBGROUP ANALYSES

Oft en investigators will undertake a comparison between only some of the patients in each arm, namely those who share a common factor. Subgroup analyses are only valid if the randomization is still intact within that subgroup. In reality, it is diffi cult to be sure that this is the case. Subgroup analyses can be used to generate hypotheses, but these analyses cannot prove them.

SURROGATE OUTCOMES

Surrogate (sometimes referred to as intermediate) outcomes are typically lab tests or other measures of function that do not directly refl ect clinical symptoms. In order to qualify as a valid surrogate, it must be shown (1) that the 646 INTEGRATIVE GASTROENTEROLOGY surrogate outcome correlates with the clinical one and (2) that interventions that change the surrogate outcome also change the clinical one in the same direction (Bucher et al., 1999 ). In most cases, surrogate outcomes do not meet this latter criterion. A classic example of this was a randomized trial of anti- arrhythmic therapy for use as prophylaxis aft er myocardial infarction; while there were fewer arrhythmias (surrogate outcome) in the treated group, that group also had a higher mortality (Cardiac Arrhythmia Suppression Trial [CAST] Investigators, 1989).

TREATMENT OF CONTROL GROUPS

Whenever randomized trials are interpreted as testing the effi cacy of a particular intervention, it is easy to assume that the control group was an untreated one. However, oft en two diff erent treatment regimens are compared. In such instances, any diff erence in outcome only refl ects the relative eff ect of one treatment over another, and cannot refl ect the absolute value of either one. Th is creates a problem when the absolute eff ect of either is not k n o w n .

SELECTIVE OUTCOME REPORTING

Th ere are examples of reports of trials in which the outcomes that were originally planned to be observed were not reported (Chan et al., 2004 ). By comparing the original protocols to the fi nal paper, Chan et al. concluded that half of the effi cacy and two-thirds of the harm outcomes were incompletely r e p o r t e d .

BREAKDOWN OF RANDOMIZATION

Sometimes, in spite of all good intentions, a randomization breaks down, resulting in confounding factors being introduced. For example, a randomized trial that compared two diff erent types of enteral nutrition formulations in intensive care unit patients was confounded by the fact that signifi cantly more patients in one group received the infusions into the stomach rather than the small intestine (Brown et al., 1994 ). Gastric, compared to small intestinal, infusions appear to increase the risk of complications (Critical Care Clinical Practice Guidelines Committee, 2009 ). There Is No Alternative to Evidence 647

EARLY STOPPING

Randomized trials are oft en stopped early because of apparent benefi ts. However, there is concern about such decisions, especially when the original protocol did not specify explicit and rigorous criteria for such early stopping. When this issue was examined in depth (Montori et al., 2005 ), some typical characteristics of such trials were identifi ed. Th ey were oft en industry- sponsored drug trials in cardiology, cancer, and AIDS patients. On average, only about 60 % to 65% of the intended patient population had been enrolled at the time of stopping. Th e trial protocol (or methods section of the paper) usually did not contain the appropriate statistical analysis to justify the early cessation.

Involvement of Vested Interest

Industry (and probably other vested interests) does exert subtle (and sometimes not so subtle) inﬂ uence. The problem can arise in the conducting of the trial (Bell et al., 2006 ; Hill et al., 2008 ; Miners et al., 2005 ). More often, the bias appears during the interpretative stage, namely how the data are presented (or “spun”; see Als-Nielsen et al., 2003 ; Turner et al., 2008 ; Yank et al., 2007 ).

STATISTICAL CONSIDERATIONS

Outcome Reporting Statistics

Dichotomous outcomes are those that either do, or do not, happen (e.g., the incidence of death or complications). Th ese outcomes are usually reported as absolute risk diff erences (for benefi cial outcomes, absolute risk reductions) or relative risks (again, for benefi cial outcomes, relative risk reductions).

An absolute risk reduction is the difference in the incidence of the outcome between the treated arm and the control arm. The relative risk reduction is the incidence in the treated arm divided by the incidence in the control arm. While both are reported as percentages, the relative risk is a higher number than the absolute risk reduction (even though the actual effect is the same). 648 INTEGRATIVE GASTROENTEROLOGY

As an example, consider a treatment that reduces a complication rate from 10% to 5 % . Th e absolute risk reduction is 5% (10 % – 5 % ). Th e relative risk reduction is 50% (5 % /10% ). Th e intervention is then marketed with the claim that it reduces the complication rate by 50 %; while this is true of the rate, it only reduced the incidence of the complication by 5% . A helpful way to put all of this into perspective is to calculate the “number needed to treat.” Th is is simply done by dividing 100 % by the absolute risk reduction; in the above example, 20 patients would have to be treated to prevent one complication.

P Values

Th e p value represents the probability that an outcome occurred by chance. Traditionally, great credence is given to a probability that is less than 5 out of 100 (“< 0.05”). However, this is an arbitrary distinction. Aft er all, why believe that a p value of 0.049 means that a diff erence is true, but a value of 0.051 means that there was no diff erence? It is more appropriate to view the p value as an expression of the probability of something happening by chance rather than as a demonstration of truth.

9 5% Conﬁ dence Interval

A trial only produces an estimate of an actual eff ect, not the precise truth. Th us, if the same experiment is conducted many times, a range of estimates would be obtained. Th e 95% confi dence interval represents the range over which these observations would occur 95 % of the time. While this is not the same thing as the probability that an observation was due to chance (the p value), the confi dence interval can be used to defi ne a “signifi cant fi nding.” Th is is commonly employed in meta-analysis. Dichotomous outcomes in meta-analyses are reported as absolute risk differences, relative risks, or odds ratios (the likelihood of the outcome in the treated arm divided by the likelihood of the outcome in the control arm). If the intervention made no diff erence, the outcomes would be equivalent. Th us, the point of equivalence for absolute risk diff erences is 0.00 and that for relative risks or odds ratios is 1.00. Any 95 % confi dence interval that does not cross the point of equivalence is considered to be signifi c a n t . There Is No Alternative to Evidence 649

Type I Error

A Type I error is the term applied to the phenomenon of fi nding what appears to be a signifi cant difference when one does not truly exist. Type I errors can arise when a large number of analyses are done without correcting for the possibility of fi nding chance differences.

An example of a Type I error is that if 25 comparisons are made between interventions that are not truly diff erent, there is a 62% chance of fi nding at least one p value of 0.04. Th e Type I error was even a subject of an article in the Wall Street Journal (Beck, 2009 ). Type I errors can also result from publication bias (Dickersin et al., 1992 ; Easterbrook et al., 1991 ; Shaheen et al., 2000 ; Simes, 1986 ). Publication bias is the term that is applied to the phenomenon of preferentially reporting dramatic diff erences and failing to report outcomes that were less favorable. Such a practice results in chance fi ndings appearing in the medical literature. Furthermore, it is diffi cult for the reader to protect himself or herself from this problem, as no other published information is available. In general, one should be wary of small trials that demonstrate dramatic diff erences; if something seems too good to be true, it probably isn’t.

Type II Error

A Type II error is the failure to see a difference that truly exists.

Type II errors usually occur because inadequate numbers of patients were included in a trial. It is usually incorrect to label a small trial that failed to show an eff ect as “negative”; rather, it should be considered to contain inadequate numbers to demonstrate an eff ect (Freiman et al., 1978 ; Moher et al., 1994 ). One way to try to avoid this problem is to perform an a priori sample size calculation to estimate the number of patients that will be needed in order to see a diff erence of a certain magnitude. 650 INTEGRATIVE GASTROENTEROLOGY

Equivalence/Non-inferiority

Most trials are designed to show that an intervention is better than no treatment (superiority trials). At times, a new intervention is compared to a standard treatment that is known to be eff ective, and the intent is to show that the former is the same (equivalence trial), or at least not worse (non-inferiority trial). Such trials require larger numbers of patients than do superiority trials (Tinmouth et al., 2004 ). When trials are underpowered to establish equivalence, interpretive problems with Type II errors can arise. For example, early small trials did not fi nd any statistically signifi cant diff erences when patients with active Crohn’s disease were treated with steroids or with elemental diets, leading to the claim that the two treatments were equivalent. Larger trials and a meta-analysis (Griffi ths et al., 1995 ) showed that steroid therapy was superior.

SPECIFIC COMMENTS ABOUT EVIDENCE IN THE COMPLEMENTARY AND ALTERNATIVE MEDICINE LITERATURE

Up until now, the topic of evidence-based medicine has not been confi ned to complementary and alternative medicine. However, there are some issues that are specifi c to this literature.

Complementary and alternative medicine largely deals with the treatment of symptoms, often without any regard to the actual underlying diagnosis. Since the symptoms are usually subjective, blinding becomes particularly important as a component of the methodology.

Th ere are literally thousands of randomized trials in complementary and alternative medicine. Th e risk of bias of these trials, in spite of the need for blinding, is comparable to the risk of bias in the allopathic literature (Bloom et al., 2000 ). Unfortunately, the actual risk of bias in both fi elds is usually high, refl ecting a lack of rigorous methodology in clinical science in general. Many of the randomized trials in this fi eld come from Asia, and China in particular. In this regard, two observations should be noted about the Chinese biomedical literature. Th e fi rst is that positive results appear to be far more common than in the Western world (Vickers et al., 1998 ). Secondly, two There Is No Alternative to Evidence 651

investigations into the question about methods used for randomization have concluded that this term is used diff erently in China than in the Western world (suggesting that allegedly randomized trials are not randomized in the traditional way; see Liu et al., 2002 ; Taixiang et al., 2008 ).

Conclusion

Since evidence-based medicine is now widely accepted, it behooves all healthcare workers to be familiar with its methodology. Critical reading of the literature is an important skill to develop. One way to become facile with these techniques is to read original research in a diff erent way. Instead of looking fi rst at the Abstract, and perhaps at the Discussion section, one should start with the Introduction in order to gain insight into what the question is. One then goes to the Methods section and decides if the methodology is capable of addressing the question. If the answer to that question is no, there is no point in reading further. If the answer is yes, one should then read the Results section and decide what the answer is. Aft er that, one is free to read the Abstract and Discussion to see if the author agreed. Another technique to employ is to attend regular journal clubs that focus on methodology. In this model, all of the participants read the paper before the meeting and formulate their own thoughts (along the lines discussed in the preceding paragraph). Th e journal club then allows a collegial interaction and learning. Th ese exercises and activities are going to be cumbersome at fi rst. However, with practice, the process becomes easier. In fact, one can learn to read papers just as quickly this way and, in the process, make the experience much more intellectually engaging.

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A placebo treatment, 374t , 375t AAD. See antibiotic-associated diarrhea predictors, 359–60 ABCB1, 274t probiotics and, 372–73, 374 t abdominal fat deposition, 529 reassurance for, 370 abdominal massage, 191 regulation of treatment, 363–65 abdominal pain, 354–76 TENS for, 369 acupuncture for, 129t , 367–68 treatment options, 357 biofeedback for, 371 abdominal ultrasound, 581 t biologically-based therapies, 371–73 abdominal wall hernia CBT for, 370 costs of, 17t coordination of care, 373–76 prevalence of, 15 t defi ned, 355 abdominal X-ray, 581t , 586t discussion, 362 absorption evidence-guided care, 365–66 Ayurvedic herbs for, 136 family involvement, 362–63 evaluation of, 30–32, 53 t fi ber and, 372 malabsorption, 34, 383, 401 guided imagery for, 371 physiology of, 207–8 hypnosis for, 370–71 zinc, 507 IBS and, 356 AB-yogurt, 425–26 impact of, 356 acacia, 487 knowledge base, 361–62 acanthosis nigricans, 107 NP/CAM use for, 357–59 achalasia, 594 t , 597–98 patient education, 363 achlorhydria, 56 patient in, 361 SIBO and, 85t peppermint for, 373, 375 t acid secretion-suppressing drugs, physical therapies for, 368–69 209–10, 211

653 654 INDEX

acrodermatitis enteropathica, 104 adenovirus, 395 acrokeratosis paraneoplastica. See Bazex’s adrenocorticotropic hormone (ACTH), 195 syndrome Adriamycin, 323 ACTH. See adrenocorticotropic hormone Advasana, 353 acupuncture, 94, 123–30, 158t AGA. See American Gastroenterology for abdominal pain, 129t , 367–68 Association acceptance of, 360t agni , 132, 138 augmentation of immunity theory, 126t AHA. See autoimmune hemolytic anemia circulatory theory, 126 t alanine aminotransferase (ALT), 289 clinical studies, 423–24 alcohol, 488 complications, 424 sensitivity to, 451 contraindications, 130t alcoholic liver disease, 565–66 conventional medical care and, 127 alkaline refl ux, 405 for duodenal motility, 129 t allergies. See food allergies; hypersensitivity for eating disorders, 613–14 reactions electro, 124, 422–24 allium vegetables, 318 endorphin theory, 126t allocation, 644 function of, 125–26 aloe, 90, 134, 217, 324 for gallbladder, 591 for IBD, 521–22 for gastric motility, 129t Alosetron, 468 for gastric secretion, 128t , 129t ALT. See alanine aminotransferase gate control theory, 126 t altered barrier function, 33–34 history of, 123, 127–28 alternating IBS, 481–82 for IBD, 128t ama , 132, 138 for IBS, 128t , 129t pacifying, 139–40 mechanisms of action, 126t amalaki, 135, 139 minor adverse events, 126–27 for upper GI disorders, 414 for nausea, 128t , 129t Amanita, 322 needles in, 124 Amanita phalloides , 311, 571, 577 neurotransmitter theory, 126t America Association of Poison Control for pancreatitis, 584 Centers, 365t precautions, 130t American Cancer Society, 544 risks, 126 American diet, infl ammation and, 288–90 safety, 126 American Digestive Disease Epidemic serious injury, 127 (ADDE), 22 technique, 128–30 American Gastroenterology Association for upper gastrointestinal disorders, (AGA), 13, 21, 220, 345 422–24 American Psychological Association, 175 usefulness of, 124–25 American School of Osteopathy, 142 acute febrile neutrophilic dermatosis. See 5-aminosalicylic acid, 277t Sweet’s syndrome amphetamines, 540 acute myocardial infarction, 397 amygdala, 117 acute pancreatitis, 580t anaerobic bacteria, 62 adaptive immune system, 36, 37 angelica root, 418, 471t , 518 ADDE. See American Digestive Angostura bitters, 320 Disease Epidemic animal models, 121 INDEX 655

Anisette, 320 arginine, 280 annamaya kosha , 132 aromatherapy, peppermint, 411 anorexia nervosa, 404, 607–8 Arthus reaction, 454 diagnosis of, 607 artichoke, 320, 321, 591 t ANS. See autonomic nervous system artichoke leaf extract, 417 Antabuse, 403 articulations, visceral manipulation, 253 t antacids, 378, 388–89 artifi cially-sweetened beverages, 486 nutrient depletions from, 389 asafetida, 136 side eff ects, 388 asana, 349, 351 anthraquinones, 311 ashwagandha, 316, 416 antibiotic-associated diarrhea (AAD), asparagus, 489 probiotics for, 263–64 Asparagus racemosus . See shatavari antibiotics, 31 aspartame, 451 diarrhea and, 263–64 aspirin, 311, 412, 548 t pro-motility therapy, 89–91 Crohn’s disease and, 496 RLS for, 93–94 asthma, 449, 451 antibody-dependent cell-mediated astragalus, 284 cytotoxicity, 453, 459 ATG16L1, 274t antiemetics, herbal, 314–15 Atractylis gummifera, 576t anti-endomysial antibodies, 441 Atractylodis lanceae rhizoma , 419–20 antigens augmentation of immunity theory, 126t apical periodontitis from, 397–98 Aurantii nobilis pericarpium , 420 dental biomaterials, 399–400 autoimmune disease, 33, 253 environmental, 33 gastrointestinal, 597 from marginal periodontitis, 395–97 liver, 594t , 597 antigliadin antibodies, 441 Autoimmune Epidemic (Nakazawa), 236 anti-infl ammatory diet, 489 autoimmune hemolytic anemia anti-infl ammatory therapy, 113 (AHA), 453 herbal, 315–16 autoimmune pancreatitis, 594t , 599 antimicrobial agents, 31 autonomic nervous system (ANS), 40, 152 herbal, 90, 317–18 chiropractic and, 149–51 antimony, 400 in visceral manipulation, 253 t antireticulin, 441 autonomy, 626–27 antispasmodics, herbal, 318–19 awareness, 132–33 anxiety, 165 Ayurvedic medicine, 6, 29, 157 apical periodontitis, 397–98 for absorption enhancement, 136 antigens from, 397–98 for appetite enhancement, 134 infections from, 397–98 for digestion enhancement, 134 treatment of, 398 for digestive fi re quieting, 134–36 apoptosis, 497 for elimination encouragement, appendectomy, 498 136–37 appetite enhancement, Ayurvedic herbs general principles of, 131–32 for, 134 herbs in, 133–38, 137t apple, 487 azathioprine, 276 t arabinogalactans, 91 azoreductase, 49 arachidonic acid, 289, 510 azulenes, 315 656 INDEX

B berberine, 31, 317 Bacon, Francis, 189 beryllium, 399 bacteria beta-carotene, 495 anaerobic, 62 betaine, 568 enterobacteria, 44 Bhagavad Gita, 349 gram-negative, 62, 396 bias, 642 gram-positive facultative, 44 in randomized trials, 643–44 lactic acid, 91 bibhitaki, 136 bacterial gastroenteritis, PPIs bicarbonate, 145 and, 383–85 bidirectional signaling, 40–41 bacterial nucleic acids, 46 Bifantis , 489 bacterial overgrowth, 80, 382. See also small Bifi dobacteria , 68, 74, 91 intestinal bacterial overgrowth Bifi dobacteria infantis , 263 intestinal permeability and, 80 Bifi dobacterium , 263, 297, 299, 513t , 572 urinary markers of, 63–64 Bifi dobacterium breve , 265, 472 bacterial signal transduction, 47 Bifi dobacterium infantis, 265 Bacteroides , 44, 68, 76 evidence-based review of, 472 Bacteroides thetaiotamicron , 46 Bifi dobacterium lactis , 113 baking soda, 405 Bifi dobacterium longum , 265 balsalazide, 514 bile acids, 49, 54t , 584 bamboo shoots, 487 evaluation of, 53 t banana powder. See plantains biliary dyskinesia, 191, 422 barley, 489, 500t biliary stasis, 585t germinated, 516–17 binge eating, 531, 608 Barrett’s esophagus, 384, 594t , 598–99 Bing Gan, 573t barrier function, 32–37 biofeedback, 329, 340, 344, 428 altered, 33–34 for abdominal pain, 371 basil, 136 success of, 331–31 BAT. See body awareness therapy biofi eld, 156 bay, 136 biofi lm layer, 32, 35–36 Bazex’s syndrome, 106–7 biotin, 49 beans, 90, 485, 486, 499, 552 α -bisabolol, 315 Beauchamp, 151 bisacodyl, 390 Beaumont, William, 165 bismuth subsalicylate, 263 behavior modifi cations. See also cognitive bisphenol-A (BPA), 399 behavioral therapy bitter candytuft plant. See clown’s mustard for IBS, 480 bitter orange peel, 320 for long-term results, 490–92 black pepper, 134, 138, 304–5 for practitioners, 492 Bland, Jeff rey, 9 Behçet, Hulusi, 392 Blastocystis hominis , 76 Behçet’s disease, 103 blinding, 644 soft tissue oral lesions and, 392–93 bloating, 602 belladonna, 314 BMI. See body mass index bell peppers, 485 body awareness therapy (BAT), 476 Benson, Herbert, 160 Body Intelligence Techniques, 133, 138 bentiromide, 57 body mass index (BMI), 528, 539 INDEX 657 bogbean, 318 H2 receptor antagonists and, 387 bone broths, 301–2 PPIs and, 385 bone disease, 439–40 supplements, 484, 507, 590 bone status Callilepis laureola, 576 t calcium and, 507 caloric defi cits, 538 vitamin D and, 506 calprotectin, 278, 279 vitamin K and, 506–7 CAM. See complementary and alternative Boswellia serrata , 281 medicine for IBD, 521 Camellia sinensis, 568 boswellic acids, 315 camphor, 576 t botanicals. See herbal medicine Campylobacter, 383 botulinum injections, 94 cancer. See also colorectal cancer; bovine colostrum, 517–18 specifi c types bowel-associated dermatosis arthritis of digestive system, 15t syndrome, 103 esophageal, 446 bowel bypass syndrome, 103 fear of, 328 bowel movements, normative, 29–30 MBSR and, 198–99 BPA. See bisphenol-A metastatic breast, 245 Brahmi, 416 pancreatic, 18t Breaking the Vicious Cycle (Gottschall), Candibactin AR, 90 291, 499 Candibactin BR, 90 breast, 113 Candida albicans , 74 breast-feeding, 436, 496 Candida spp., 74 breath hydrogen and methane test, 63 capsaicin, 413, 414 broccoli, 485 caraway seed oil, 319, 418, 471 t Brodmann’s area, 246 science behind, 410–11 broth, 487 CARD15/NOD2, 274t , 280 bone, 301–2 cardamom, 136, 138 budesonide, 276t cardiac disease bulimia nervosa, 608 eating disorders and, 609 preventative measures, 406–7 MBSR and, 201 Burkitt, Dennis, 299 social support and, 243 cardiovascular events, 381 C Carethers, John M., 384 cabbage juice, 217, 302–3, 409 carminatives, 320 cactus, 487 Carnegie Foundation, 143 n 1 CAD. See coronary artery disease Cartesian principle, 7 caff eine, 480, 487, 488 cascara, 421 sensitivity to, 451 cascara sagrada, 324, 576 t calcitriol, 506 case-control studies, 640 calcium, 279 t , 503t , 548 t case reports, 638–39 bone status and, 507 castor oil, 390 colorectal cancer and, 549–51 catarrh, 301 dental disease and, 401 catechins, 520 foods rich in, 483–84 catecholamines, 246 gastric motility and, 483 caulifl ower, 485 658 INDEX

causative homeopathy, 186 central nervous system (CNS), 38, 81, 253 cayenne, 134 bidirectional signaling, 40–41 CBC. See complete blood count enteric fl ora and, 39–40 CBT. See cognitive behavioral therapy gut changes and, 39–41 celecoxib, 548, 548t mucosal immunity and, 39–40 celery, 487 neuroendocrine immune signaling, 41 celiac disease, 81, 213, 433–48, 594 t parasympathetic tone and, 39 adult-onset, 437 sympathetic nervous system and, 39–40 autoimmune diseases associated CF. See cystic fi brosis with, 598t CFU. See colony-forming units bone disease and, 439–40 CH-100, 573t clinical manifestations, 436–37 chamomile, 134, 136, 315, 318, 320, 418, 471 t complications, 445–47 chaparral leaf, 576t dermatologic manifestations of, 437–38 Chapman’s Refl exes, 144 diagnosis, 440–44 Chavan Prash , 135 disorders associated with, 438 t chelidonium, 422 endocrine disorders, 440 Chelidonium majus . See greater celandine environmental factors, 436 chemical compounds, 487–88 epidemiology, 433–34 chemoprevention, 547, 548 t extraintestinal manifestations of, 437–40 of colorectal cancer, 550t genetic factors, 434 chewing, 491 gluten in, 434–35 Cheyney, Garnett, 303 hematologic manifestations of, 437 chi, 6 hepatic manifestations of, 439 chia seeds, 487 histological assessment, 442–43 chicory root, 489 IBS and, 436 chili powder infertility and, 440 human studies, 414 malignancy and, 445–46 science behind, 413–14 mucosal immune responses, 435–36 for upper GI disorders, 413–14 neurologic manifestations of, 439 chiropractic, 146–55 osteoporosis in, 445 ANS and, 149–51 pathogenesis, 434–36 history of, 147–48 prevalence of, 15 t , 22 integration of, 148 refractory, 447 medicine and disease, 151–53 restless leg syndrome and, 94–95 Chiropractic Leadership Alliance, 150 serological testing for, 441–42, 442 t chitin, 541 as silent epidemic, 20 chitosan, 541 soft tissue oral lesions and, 394 chocolate, 488 treatment, 444–45 cholecystectomy, 585 upper endoscopy, 442–43 cholecystokinin, 41, 56 Celiac Disease: A Hidden Epidemic choleretics, herbal, 321 (Green), 20 cholestyramine, 277 t Center for Disease Control and chromium, 400, 541 Prevention, 450 IBD for, 508–9 Centor, Robert, 9 chronic fatigue syndrome, 84 central iron defi ciency, 92 SIBO and, 91–92 INDEX 659 chronic infl ammatory periodontal disease abdominal pain, 370 (CIPD), 396, 397 evidence-based review of, 477 chronic liver disease in IBS, 331 prevalence of, 15 t limitations, 334–35 research expenditures, 18 t Cohn, Erich, 301 chronic pancreatitis (CP), 213, 581 t cohort studies, 639–40 chronic renal failure, SIBO and, 85 t prospective, 639–40 chronic symptoms, 488–90 retrospective, 639–40 chyme, 56 Colitis Foundation of America, 242 chymotrypsin, 57 collagen, 562 cimetidine, 386 collagenous colitis, 594 t Cinnamomi cortex , 420 colon cinnamon, 136, 138 assessment diffi culties, 66 CIPD. See chronic infl ammatory conventional assessment of, 66–67 periodontal disease evaluation of, 54 t ciprofl oxacin, 264 microbe assessment in, 65–67 circulatory theory, 126 t new technologies for cirrhosis, 59, 572 assessment, 67 prevalence of, 15 t colonic adenomas, 15t primary biliary, 595 t colony-forming units (CFU), 44 research expenditures, 18 t colorectal cancer, 20, 23–24 cisapride, 410, 411, 468 calcium and, 549–51 cisplatin, 315, 323 chemoprevention, 550t Citrucel, 486 curcumin and, 553–54 citrus, 488, 502 diet and, 23–24, 555–57 clinical trials exercise and, 555–57, 558 on EFAs, 510–11 fi ber and, 23–24 licorice, 412–13 folate and, 552 pharmaceutical, 344 gender-specifi c, 593–96 turmeric, 413 glucosinolates and, 554–55 for ulcerative colitis, 510–11 prevalence of, 23–24 clopidogrel, 381 prevention of, 547 Clostridia , 76 rates of, 545–46 Clostridium diffi cile , 48, 50 t , 120, 264, 572 research expenditures, 18 t PPIs for, 380 risk factors, 546, 558 prevalence of, 15 t selenium and, 552–53 clove oil, 576t vitamin D and, 551–52 clown’s mustard, 319, 418, 471t colorectal health, 544–58 CNS. See central nervous system colostrum, 91 cobalamin, 402 bovine, 517–18 cobalt, 400 commensal fl ora, 27, 28–29, 37, 258 Cochrane Library, 469 drug discovery and, 50t , 51t coenzyme Q10, 89 community-acquired pneumonia, PPIs coff ee, 589 and, 381 cognitive behavioral therapy (CBT), 200, community connection, 244 329, 330–31 comorbid disorders, 329 660 INDEX

compassion, 10, 351 copper, 402 in doctor-patient relationship, 237–38 coriander, 136, 138 competence, 623–24 corn, 488 complementary and alternative medicine coronary artery disease (CAD), 243, 395 (CAM), 4 coronary atherosclerosis, 397 for abdominal pain, 357–59 corticosteroids, 276t , 277t , 455, 465 clinician concerns in, 468 adverse events, 523 defi ned, 468 corticotropin-releasing factor (CRF), 40 doctor openness to, 239–40 corticotropin-releasing hormone (CRH), effi cacy, 468 195, 475 evidence-based review of, 467–78, 625 cortisol, 61, 246 hepatotoxicity, 575–77 corydalis, 315 for IBS, 604t –605 t Cowden syndrome, 108–9 patient autonomy and, 626–27 COX-2. See cyclooxygenase 2 patient-doctor relationship in, 361 CP. See chronic pancreatitis placebo eff ect and, 468 CPI. See Consumer Price Index predictors of, 359–60 C-reactive protein, 581t surveys on, 362 CRF. See corticotropin-releasing factor for upper GI disorders, 409–10 CRH. See corticotropin-releasing complete blood count (CBC), 545t hormone complex homeopathy, 185 Crohn’s and Colitis Foundation of complex lesions, 406–7 America, 248 comprehensive stool analyses (CSA), 463 Crohn’s disease, 35, 58–59, 81, 120 computed tomography (CT), 581t , 586t aspirin and, 496 confi dence intervals, 648 exclusion diets and, 501 congestive heart failure, 201–2 fi sh oils and, 511–12 Congress, 19 FODMAPS and, 499–501 constipation functional clinical tests, 278–79 causes of, 480 immune response in, 494 costs of, 17 t lymphocytes in, 494 economic impact of, 21 malnutrition in, 279t fi ber and, 480 pharmaceutical management, 276t homeopathic remedies for, 186 probiotics for, 266 idiopathic, 86 remission, 500 iron and, 484 research expenditures, 18 t magnesium and, 481 restless leg syndrome and, 94–95 medication for, 390–91 risk factors, 271–72 prevalence of, 15 t soft tissue oral lesions and, 392 constitutional remedies, 184 Crotalaria , 576t Consumer Price Index (CPI), 21 cruciferous vegetables, 554 contact dermatitis, 399 cryoglobulinemia, 103 peppermint and, 412 mixed, 105 contraceptives, oral, 498 crypt hyperplasia, 443, 445 contracting, 627–28 CSA. See comprehensive stool analyses control groups, 646 CT. See computed tomography controlled trials, 640–41 cucumber, 487 INDEX 661 cultured foods, 298 bulimia nervosa, 404 cumin, 136, 138 calcium and, 401 Curcuma amada , 413 clinical nutritional considerations, Curcuma domestica Val , 422 400–401 Curcuma longa , 211 complex lesions, 406–7 curcumin, 281, 315, 316–17, 548 t . See also copper and, 402 turmeric eating disorders and, 609 administration of, 520 folic acid and, 402 colorectal cancer and, 553–54 GERD and, 405 for IBD, 520–21 hard tissue lesions management, 405–7 cyclooxygenase 2 (COX-2), 372, 510, 547 iron and, 401 cyclosporine, 577 magnesium and, 401 cystic fi brosis (CF), 213 malabsorption and, 401 cytochrome P450, 553, 577 systemic management of cytokines, 84 immunodysfunction, 394–95 infl ammatory, 289 vitamin A and, 402 vitamin B12 and, 402 D vitamin C and, 402 DA. See d -arabinitol vitamin D and, 402 dACC. See dorsal anterior cingulate cortex vitamin K and, 402 dairy, 483–84, 488, 499 zinc and, 402 Dandasana, 352 depletions, 391 dandelion, 134 depression, 200 dandelion root, 320, 591t obesity and, 531 DANS. See descending antinociceptive social support and, 243 system dermatitis herpetiformis (DH), 104, 437 d -arabinitol (DA), 65 Descartes, Rene, 7 Davison, Kathryn P., 249 descending antinociceptive system DCs. See dendritic cells (DANS), 118 deamidation, 435 detoxifi cation, 114–15 death rates, 243 devil’s claw, 518 de Chauliac, Guy, 189 DGL. See deglycyrrhizinated licorice defense factors, 458–59 DH. See dermatitis herpetiformis deglycyrrhizinated licorice (DGL), 211, 412 dharana, 349 dehydration, 485 DHEA. See dehydroepiandrosterone dehydroepiandrosterone (DHEA), 61, 517 Dhunurasana, 351 delayed food allergies dhyana, 349 symptoms, 460 diabetes mellitus, 49, 213, 396, 440 testing, 460–61 type 1, 29 delayed hypersensitivity reactions, 455t type 2, 201 Demodex folliculorum , 96 diagnostic considerations, 29–30 demulcent foods, 301, 487 diaphragm, 351 herbal, 321–22 diarrhea, 464 dendritic cells (DCs), 36, 46 antibiotic-associated, 263–64 dental biomaterials, 399–400 causes of, 481 dental disease, 392–407 diet and, 481 662 INDEX diarrhea, (continued ) silent epidemics, 20 homeopathic remedies for, 186 support groups, 248 infectious, 16t Western-based, 25 traveler’s, 263 digestive enzymes, 458, 614t diet, 270. See also elimination diet eating disorders and, 612–13 American, 288–90 digoxin, 49, 311 anti-infl ammatory, 489 dill, 136 assessment, 535–36 disease susceptibility, 243 change, 360t disulfi ram, 403 colorectal cancer and, 23–24, 555–57 diuretics, 540 diarrhea and, 481 diverticular disease eucaloric, 538 costs of, 17t exclusion, 501–3 fi ber and, 23 gluten-free, 444t , 446t prevalence of, 15 t , 22–23 IBD and, 496, 498–503 diverticulosis, 23 IBS and, 480 prevalence of, 15 t low sulfur, 501 d -lactic acid, 64 obesity and, 534–36 DLG5, 274t types of, 538–39 DNA analysis, 67 very-low-caloric, 539 doctor-patient relationship, 9–11, 236–40, Westernization of, 22–23 327–30 yeast elimination, 502–3 behaviors aff ecting, 341 t Dietary Supplement and Non-Prescription of CAM users, 361 Drug Consumer Protection establishment of, 340 Act, 364 hope in, 240 Dietary Supplement Health and Education knowledge in, 238–39 Act (DSHEA), 364 openness to CAM in, 239–40 digestifs, 320 product recommendations, 635 digestion professional boundaries, 630–31 Ayurvedic herbs for, 134 treatment disclosure, 634–35 evaluation of, 30–32 in Western medicine, 9 Indian spices and, 306t docusate, 391 maldigestion, 31–32 don tien, 6 mind-body interactions in, 132–33 dopamine, 49 physiology of, 207 dorsal anterior cingulate cortex yoga and, 350–51 (dACC), 246 digestive disease double-blind challenge test, 457 in American households, 19 Drossman, Douglas, 338, 343, 346 battle against, 20–22 drug-induced interstitial nephritis, 381 burden of, 15t –18 t drug-induced nutrient defi ciency, 277t costs of, 20–21 drug interactions epidemic, 5 antacids, 389 facts, 13–14 H2 receptor antagonists, 387 growth of, 19–20 herbal medicine and, 313 prevalence of, 14–19, 19–20 laxatives, 391 research expenditures, 18 t drug resistance genes, 74–75 INDEX 663

DSHEA. See Dietary Supplement Health edge-to-edge attrition, 407 and Education Act Edison, Th omas, 11 Duke, W.W., 449 EED. See erythema elevatum diutinum duloxetine, 118, 122 EFA. See essential fatty acids duodenal motility, 129t egg allergies, 450, 502 duty-based theories, 619–20 elastase, 32 dynamic qi gong, 222 elderly, pneumonia in, 382 dysbiocide, 90 electro-acupuncture, 124 dysbiosis, 62, 77, 92 clinical studies, 423–24 fermentation, 302 complications, 424 management, 489 for upper GI disorders, 422–24 probiotics for, 489 electrolyte abnormalities, 609–10 dyspepsia electromyography, 150 functional, 179–81, 208, 464 elimination diet, 90, 462 non-ulcer, 599–600 case studies, 292t –295t visceral manipulation for, 255 implementing, 290–91 research on, 291 E yeast, 502–3 E. Coli , 48, 62, 82, 259, 318, 513t ELISA. See enzyme-linked immunoassays EAACI. See European Academy of Allergy EMBASE, 469 and Clinical Immunology Emblica offi cinalis , 414 earth, 28 emotional factors East Anglia Multicenter Controlled FMS and, 118 Trial, 501–2 IBS and, 111–12 eating disorders, 606–15. See also specifi c emotional motor system (EMS), 39, 478 disorders empathy, 9 acupuncture for, 613–14 EMS. See emotional motor system cardiac complications, 609 enamel demineralization, 404 digestive enzymes and, 612–13 Enbrel, 276t electrolytes in, 609–10 endometrium, 113 fl ax seeds for, 613 endomysium, 435 incidence of, 607 endorphin theory, 126t medical complications, 609–10 endoscopic retrograde melatonin for, 613 cholangiopancreatogram metabolic consequences, 609 (ERCP), 586t not otherwise specifi ed, 608 endoscopic sampling, 56 probiotics for, 612 endoscopy, upper, 442–43 pulmonary complications, 609 energy fl ow. See qi skin and teeth in, 609 energy manipulation, 474 supplements for, 611 energy medicine, 156–63 treatment, 611–13 anatomy and, 159–60 eating mechanics, 491 defi nition of, 156–59 ECF-A, 453t evidence for, 161–62 ecosystem diversity, 77 healing and, 159–60 ECs. See enterochromaffi n cells illness development and, 159–60 eczema, 451 prevalence of, 156–59 664 INDEX energy medicine, (continued ) ulcerative colitis and, 510–11 research evidence for, 160–61 essential nutrients, 289 side eff ects, 162–63 estrogen, 113–14, 548t systematic reviews of, 161 ethanol consumption, 58 techniques, 158 ethics, 616–35 Entamoeba histolytica , 317, 318 competence and, 623–24 enteric fl ora, 39–40 decision making, 619–20 enteric infections defi ning, 618–19 costs of, 17t duty-based theories, 619–20 intestinal permeability and, 80 frameworks, 623 enteric nerve terminals (ENTs), 38 law v., 618 enteric nervous system, 27, 38–39, 253 outcome-based theories, 621–22 gut homeostasis and, 38 principle-based, 622 gut microbiota and, 38–39 responsibilities, 617–18 enteritis, 17 t virtue-based, 622–23 Enterobacter , 572 eucaloric diet, 538 enterobacteria, 44 European Academy of Allergy and Clinical enterochromaffi n cells (ECs), 38, 41, 228 Immunology (EAACI), 461 Enterococcus , 572 evidence, 636–51 ENTs. See enteric nerve terminals hierarchy of, 637 t environmental antigens, 33 in literature, 650–51 enzyme immunoassays, 75 types of, 638 enzyme-linked immunoassays (ELISA), vested interest, 647–49 457, 460–61, 464 evidence-based review scientifi c validity of, 461 of abdominal pain, 365–66 ephedra, 540 of BAT, 476 epigallocatechin, 281, 583–84 of Bifi dobacterium infantis , 472 epinephrine, intramuscular, 465 of CAM, 467–78, 625 Epstein, Ronald, 9 of CBT, 477 equivalence, 650–51 of energy manipulation, 474 ERCP. See endoscopic retrograde of herbal medicine, 469–71 cholangiopancreatogram of hypnosis, 476–77 erythema elevatum diutinum (EED), 101 of meditation, 475 erythema nodosum, 103–4 methods, 469 Esomeprazole, 18 t of mind-body interventions, 475–78 esophageal adenocarcinoma, 384 of probiotics, 472–74 esophageal cancer, 446 study selection criteria, 469 esophageal disorders, 426–27 of support groups, 477–78 essential fatty acids (EFA), 91. See also of yoga, 475–76 omega-3 fatty acids; omega-6 evidence-based treatments, 633–34 fatty acids exclusion diets, 501–3 clinical trials on, 510–11 Crohn’s disease and, 501 enteric-coated, 511 exercise, 219–20 IBD and, 509–12 assessment, 536–37 physiology, 509–10 benefi ts of, 220, 536 supplementation, 509–12 colorectal cancer and, 555–57, 558 INDEX 665

regimen, 536 fermented foods, 298, 489 sessions, 536 soy, 489 exocrine pancreatic insuffi ciency, 212–14 FGID. See functional gastrointestinal causes, 213–14 disorder diagnosis, 213 FIAF. See fasting-induced adipocyte factor intervention, 214 fi ber, 540–41 expert opinion, 638 abdominal pain and, 372 expressive writing. See self-care journaling chart, 300 t extraintestinal disorders, 48–49 colorectal cancer and, 23–24 constipation and, 480 F dehydration and, 485 Faecalibacterium prausnitzii , 48 diverticular disease and, 23 failure to diagnose, 633 foods rich in, 486 fairness, 631–33 gallstones and, 587–88 familial adenomatous polyposis (FAP), GI function and, 299 548 t , 553–54 increasing, 481 family involvement, 362–63 insoluble, 299 famotidine, 386 intake basics, 485 FAP. See familial adenomatous polyposis motility and, 485–86 Fasano, Alessio, 33 soluble, 299 fast food, 25, 289–90 supplements, 486 IBD and, 496 Fiber Choice, 486 fasting-induced adipocyte factor fi bromyalgia, 84 (FIAF), 49 symptoms, 117 fasting plasma amino acids, 53t true, 117 fat bugs, 76 fi bromyalgia syndrome (FMS), 116–22 FC Cidal, 90 diagnosis of, 118 FDA. See Food and Drug Administration emotional disorders and, 118 fecal chymotrypsin, 53t , 57 IBS and, 119–20 fecal fats, 57 mood disorders and, 118 evaluation of, 53 t PTSD and, 120 fecal fi bers, 58 SIBO and, 120–21 fecal pancreatic elastase, 57 symptoms, 117 fecal pH, 68 fi re, 28 fecal sampling, 66 FISH. See fl uorescence in situ hybridization fecal short-chain fatty acids, 69 fi sh oils, 282, 587 fecapentaenes, 69–70 Crohn’s disease and, 511–12 Federal State Medical Boards ulcerative colitis and, 511 t (FSMB), 628 5-HT, 314 Federal Trade Commission (FTC), 365t fl agellin, 46 fennel, 136, 320 fl ax seeds, 323, 486, 487, 489, 614t fenugreek, 518 for eating disorders, 613 Fermentable Oligo-,Di- and Mono Flexner Report, 143n 1 Saccharides and Polyols. See fl ora. See commensal fl ora; enteric fl ora; FODMAPS gut fl ora fermentation dysbiosis, 302 Floradix, 320 666 INDEX

fl ow cytometry, 45–46 long-term management, 465–66 fl uorescence in situ hybridization migraine and, 452 t (FISH), 45 milk, 450 FMS. See fi bromyalgia syndrome organ systems involved in, 450–51 FODMAPS (Fermentable Oligo-,Di- and peanut, 450 Mono Saccharides and Polyols), short-term management, 465 Crohn’s disease and, 499–501 symptoms, 460 folate, 49, 279 t , 503t , 548 t testing, 460–61 colorectal cancer and, 552 Food and Drug Administration (FDA), defi ciency, 566, 567–68 312, 365t IBD and, 504t foodborne illness, 18t folic acid food challenge testing, 457–58 dental disease and, 402 food reactions, 449–66 prolonged use of, 524 history of, 449–50 supplements, 503–4 Foot-Yangming meridian, 423 foods. See also diet; nutrition strategies; formula feeding, IBD and, 496–97 specifi c foods 4R GI Restoration Program, 281–82 calcium in, 483–84 Four “R” Program, 59t cultured, 298 free radical injury, 281 demulcent, 301, 321–22, 487 Friedman, Gerald, 296, 489 fast, 25, 289–90, 496 fructans, 90, 297 fermented, 298, 489 fructooligosaccharides, 297, 516, 574 fi ber in, 486 fructose, 90 magnesium in, 484 FSMB. See Federal State Medical Boards medical, 90, 296 FTC. See Federal Trade Commission migraines and, 452 t functional bowel disorders, 595 t minerals in, 483–84 Functional Brain-Gut Research Group, 346 portion sizes, 536 functional dyspepsia, 208, 464 prebiotics in, 296–98, 489 hypnosis and, 179–81 preferences, 536 functional foods, 287–308 probiotics in, 296–98, 489 functional gastrointestinal disorder water based, 487 (FGID), 20, 338 food allergies, 216, 290. See also categories for, 356t hypersensitivity reactions; management of, 342t specifi c foods functional MRI, 166, 196, 344 classifi cation of, 452–55 clinical presentation of, 450–51 G common, 451t Galen, 449 costs of, 450 gallbladder, 579–93 delayed, 460–61 acupuncture for, 591 egg, 450, 502 coff ee and, 589 epidemiology of, 450 diagnostic evaluation of, 586 gallstones and, 588 evaluation of, 53 t, 56–58 GALT in, 459 fl ush, 590 IgG and, 459–60 herbal medications, 590 interstitial cystitis and, 95 homeopathy for, 187 INDEX 667

research expenditures, 18 t diagnostic considerations, 29–30 supplements for, 589–90 fi ber and, 299 ursodeoxycholic acid and, 589 healthy, 270–71 gallstones, 539, 584, 595 t immune system in, 35, 459 costs of, 17t laboratory evaluations, 53t dietary fat and, 587 restoration program, 281–84 disease, 596–97 stress and, 195 factors in formation of, 585 in TCM, 28–30 fi ber and, 587–88 gastroparesis, 600 food allergies and, 588 gate control theory, 126 t lifestyle modifi cation and, 586–87 GBF. See germinated barley foodstuff prevalence of, 15 t , 24 GDH. See gut-directed hypnotherapy GALT. See gut-associated lymphoid tissue GDV. See gas discharge visualization gamma-interferon (γ -IFN), 494 GE junction. See gastroesophageal junction Gardner’s syndrome, 107–8 gelatin, 301–2 garlic, 318 gender-specifi c issues, 592–605 gas, intestinal, 86–87 colorectal cancer, 593–96 gas discharge visualization (GDV), 159 IBS, 600–605 gas production, 50 Genesis Today 4 Fiber, 486 gastric acid gentian, 134, 320, 421 evaluation of, 53 t Gentiana lutea . See gentian suppression of, 30–31 GERD. See gastroesophageal gastric bypass, 541 refl ux disease gastric emptying, enhancement of, 421 t germander, 576 t gastric motility. See motility germinated barley foodstuff (GBF), 516–17 gastric secretion, acupuncture for, 128 t , 129t Giardia lamblia , 75, 317, 318 gastrin, 384 ginger, 134, 138, 303–4, 548 t gastritis peppermint and, 421 costs of, 17t science behind, 417 prevalence of, 15 t tea, 139 gastroduodenal disorders, 427 for upper GI disorders, 417 Gastroenterology (magazine), 346, 384 Gingko biloba , 518 gastroesophageal (GE) junction, 30 Ginseng radix , 420 gastroesophageal refl ux disease (GERD), gliadin, 435, 448 13, 29, 359 GLP-1. See glucagon-like peptide-1 costs of, 17t glucagon-like peptide-1 (GLP-1), 574 dental management, 405 glucagonoma syndrome, 104, 106 evaluation of, 30–31 glucose, 86t hard tissue lesions and, 402–3 glucosinolates, 548t PPIs for, 379–86 colorectal cancer and, 554–55 prevalence of, 15 t , 25 β -glucuronidase, 67–68 structural causes of, 256t glucuronidation, 115 visceral manipulation for, 255–56 glutamine, 90, 217, 280 gastrointestinal malignancy, 17 t IBD and, 512 gastrointestinal motility, SIBO and, 84–85 supplementation, 512 gastrointestinal tract glutathione, 217, 399, 508, 567 668 INDEX

gluten gut-associated lymphoid tissue celiac disease and, 434–35 (GALT), 37, 216 intolerance, 290 food allergies and, 459 introduction of, 436 gut-directed hypnotherapy (GDH), 476 gluten-free diet, 444t gut fl ora, 34–35, 216, 494 poor response to, 446t pathological alterations in, 573 glycocalyx, 458 gut-gynecological axis, 114 glycosides, 68 gut homeostasis, enteric nervous system Glycyrrhizae radix , 420 and, 38 Glycyrrhiza glabra , 422 gut immunology, 36–37 glycyrrhizin, 315–16, 571 gut microbiota, 38 GnRH. See gonadotropin-releasing assessment techniques, 72–73 hormone dysbiosis, 77 goldthread, 317 ecosystem diversity, 77 gonadotropin-releasing hormone infl uence of, on health, 71–78 (GnRH), 195 insulin resistance and, 76–77 Goodheart, George J., 153 obesity and, 76–77 Good Medical Practice, 620 t specimen integrity, 73–74 Goodpasture’s syndrome, 454 transport issues, 73–74 Gordon, James S., 247 gynecological health Gorei-san, 420 IBS and, 113 Gottschall, Elaine, 291, 499 nutritional interventions for, 113–14 gram-negative bacteria, 62, 396 gram-positive facultative bacteria, 44 H greater celandine, 319, 418, 471t , 576t , 591t H2 receptor antagonists, 378, 386–88, 405 clinical studies, 417 calcium and, 387 science behind, 416 drug interactions, 387 for upper gastrointestinal disorders, 416 iron and, 387 Green, Peter, 20 nutrient depletions, 387 green bananas, 301 side eff ects, 386 green beans, 485 vitamin B12 and, 387 green tea, liver and, 568–69 zinc and, 387 guided imagery, 164–73, 332–33 Haas, Sydney Valentine, 499 for abdominal pain, 365–66, 371 Hahnemann, Samuel, 183 applications of, 166, 168–69 halitosis, 403–4 contraindications to, 172 t Helicobacter pylori and, 403 defi ning, 166 Hange-koboku-to, 420 function of, 167–68 hard tissue lesions hypnosis v., 167 dental systemic management of, 405–7 for IBS, 165 GERD and, 402–3 questions, 171t haritaki, 136–37, 139 research studies, 166 Hashimoto’s thyroiditis, 29 risks, 171–72 Hawkins, David, 153 sessions, 169t –171 t HBD-2, 274t use of, 169–71 HBD-3, 274t Guillain-Barré syndrome, 82, 237, 240 HBD-4, 274t INDEX 669

HCl supplementation, 212 drug interactions, 313 healing touch, 158 t , 162 evidence-based review of, 469–71 health-related quality of life (HRQOL), 120 for gallbladder, 590 Healthy Aging (Weil), 489 hepatics, 322–23 heartburn, 31 for IBD, 518 PPIs for, 379 for IBS, 471t Heidelberg capsule, 54t introduction to, 309–10 test, 55–56 laxatives, 323–24 Helicobacter pylori , 44, 106, 210, 304, 317 for obesity, 540–41 discovery of, 409 for pancreatitis, 583–84 halitosis and, 403 quality of, 312 mastic and, 415 randomized trials, 470 peppermint and, 411 safety of, 312–13 prevalence of, 15 t for upper GI disorders, 410–18 rosacea and, 96–97 Hering, Constantine, 183 Heliotropium , 576t Hering’s Law of Cure, 183 HEMA. See hydroxy methylmethacrylate hernia hematocrit, 160 abdominal wall, 15 t, 17 t hemoglobin, 160 hiatal, 31 hemorrhoids herpes simplex, 395 costs of, 17t Herter, C.A., 301–2 prevalence of, 16t hex, 163 henbane, 314 hiatal hernia, 31 hepatics, herbal, 322–23 HIDA scan, 586t hepatitis A, 16t hing, 136 hepatitis B, 16t hip fracture, 382–83 hepatitis C, 105, 248, 322, 560 hippocampus, 117 milk thistle for, 560 Hippocrates, 7, 10–11, 157, 165, 183, 449 prevalence of, 16t histamine, 453t research expenditures, 18 t histocompatibility antigen (HLA), 394, 395 as silent epidemic, 20 HIV, 202 hepatitis D, 16t HLA. See histocompatibility antigen herbal medicine, 309–25, 570–72. See also HLA-DQ2, 444, 445 specifi c herbs HLA-DQ8, 444, 445 actions of, 314–24 Hoelen , 420 adverse eff ects, 313 homeopathy, 158t , 182–88 antiemetic, 314–15 acceptance of, 360t anti-infl ammatory, 315–16 causative, 186 antimicrobial, 90, 317–18 clinical studies, 185 antispasmodics, 318–19 complex, 185 in Ayurvedic medicine, 133–38 for constipation, 186 bitters, 211, 320 for diarrhea, 186 choleretics, 321 for gallbladder disorders, 187 combinations, 418–22 history of, 183 demulcents, 321–22 mechanism of action, 184–85 digestifs, 320 for nausea and vomiting, 187 670 INDEX homeopathy, (continued ) defi nition of, 175 remedy samples, 186–87 evidence-based review of, 476–77 scientifi c confi rmation, 185 follow-ups, 177 for upper GI disorders, 428–29 fourteen day diary symptom scores, 178 t homocysteine, 566 functional dyspnea and, 179–81 honey, 304 guided imagery v., 167 raw, 489 gut-directed, 476 Hoodia gordonii, 541 for IBD, 181 hope, 240 for IBS, 176–79 hops, 318, 320 mechanisms of, 175–76 hormone replacement therapy (HRT), 498 patient response, 177 t hormones. See also specifi c hormones physiological parameters, 179t gut and health of, 114 randomized controlled trials on, 333 IBS and, 112 reviews, 178–79 host-microbe communication, 47–48 hypoalbuminemia, 83–84 HPA axis. See hypothalamic-pituitary- hypochlorhydria, 55–56, 58, 209–12 adrenal axis causes, 209–10 HRQOL. See health-related quality of life diagnosis, 209 HRT. See hormone replacement therapy iatrogenic, 30–31 Human Genome Project, 269 intervention, 210–12 human lactoferrin (Lf), 60 hypothalamic-pituitary-adrenal (HPA) Humira, 276t axis, 81, 91, 117, 122 hunger, 534 hypothalamus, 117 hydrogen, 31 hypothyroidism, 531 hydrogen-methane breath test, 54t hydroxy methylmethacrylate (HEMA), 399 I 5-hydroxytryptamine (5-HT), 314 I3C. See indole-3-carbinol hyperadrenalism, 531 IAT. See Integrative Assessment Technique hypercalcemia, 506 iatrogenic hypochlorhydria, 30–31 hyperhomocysteinemia, 505 IBD. See infl ammatory bowel disease hyperparathyroidism, 401 Iberogast, 319 hyperpermeability, 58, 458–59 IBS. See irritable bowel syndrome hypersensitivity reactions, 290. See also IC. See idiopathic constipation; interstitial food allergies cystitis delayed, 455t ICAM-1. See intercellular adhesion pharmacologic mediators of, 453t molecule 1 type I, 452 iceberg lettuce, 487 type II, 453 ICU. See intensive care unit type III, 454 ICV. See ileocecal valve type IV, 454–55 idiopathic constipation (IC), 86 hyperthyroidism, 401 IFFGD. See International Foundation of hypertriglyceridemia, 582 Functional Gastrointestinal Disorders hypnosis. See hypnotherapy γ -IFN. See gamma-interferon hypnotherapy, 91, 165, 329, 332–33, 427 IgA. See immunoglobulin A abdominal pain, 370–71 IgE. See immunoglobulin E acceptance of, 360t IgG. See immunoglobulin G INDEX 671

IgM. See immunoglobulin M infectious diarrhea, 16 t ileocecal valve (ICV), 192 infertility, 440 immune barrier, evaluation of, 54t infl ammation, 95–96 immune enhancers, 91 American diet and, 288–90 immune-infl ammatory connection, 272–73 anti-infl ammatory diet, 489 immune system anti-infl ammatory therapy, 113, 315–16 adaptive, 36, 37 causes of, 489 in digestive tract, 35, 459 in IBD, 495 maturation, 51 t in IBS, 112–13 ImmunoCAP, 457 intestinal permeability, 80–81 immunodysfunction, systemic dental management, 489–90 management of, 394–95 metastatic, 396 immunoglobulin A (IgA) mucosal, 60–61 defi ciency, 441 in premenstrual IBS, 112–13 secretory, test, 61 infl ammatory bowel disease (IBD), 29, 48, serologic tests, 441, 442t 214, 261, 493–525 immunoglobulin E (IgE), 54 t, 291 acupuncture for, 128 t long-term management, 465–66 adverse events, 523 quantifi cation of, 457 aloe for, 521–22 short-term management, 465 alternative therapies, 498–509 testing, 452, 464 Boswellia serrata for , 521 immunoglobulin G (IgG), 54 t , 91, 291, 400 bovine colostrum and, 517–18 food allergies and, 459–60 calcium supplementation, 507 in IBS, 462 catechins for, 520 protective roles for, 466t chromium supplementation, 508–9 testing for, 461–62 costs of, 17t immunoglobulin M (IgM), 105, 400 curcumin for, 520–21 immunology, gut, 36–37 current medical management, 276–77 immunosuppressants, 276t dietary associations and, 496 inadequate randomization scheme, 644–45 ecosystem diversity in, 77 increased intestinal permeability, 80, EFAs and, 509–12 214–18 fast food and, 496 causes, 215 folate and, 504 t diagnosis, 215 folic acid supplements, 503–4 IBD and, 497 formula feeding and, 496–97 Indian spices, 305 gene variants in, 273–75 digestive stimulation from, 306 t glutamine and, 512 indinavir, 577 herbal medicine for, 518 indole, 63–64 hypnosis and, 181 indole-3-carbinol (I3C), 554–55 infl ammation in, 495 infections intestinal permeability and, 497 apical periodontitis from, 397–98 iron supplementation, 509 enteric, 17 t , 80 isotretinoin and, 498 from marginal periodontitis, 395–97 Lactobacillus rhamnosus and , 515 respiratory, 396 magnesium supplementation, 508 systemic illness and, 81–82 malnutrition and, 495, 503t 672 INDEX infl ammatory bowel disease (IBD), principles of, 4–5 (continued ) Western medicine v., 8 t melatonin and, 518 Integrative Medicine , 229 mind-body medicine for, 522–23 intensive care unit (ICU), 380–81 NAG and, 513 intentional harm, 630 nutritional genomics and, 271–72 intent-to-treat analysis, 645 nutritional infl uences in, 279–81 intercellular adhesion molecule 1 pathogenesis, 275 (ICAM-1), 372 polyphenols for, 519 interkingdom signaling, 40 prebiotics and, 516–17 interleukin-2, 494 precursors, 498 interleukin-4, 273 prevalence of, 16t , 24 interleukin-6, 246 preventive prescription, 524–25 interleukin-8, 246, 425 probiotics for, 264–65, 513–16 interleukin-12, 273 remission, 523 interleukin-13, 181 resveratrol for, 519–19 internal transcribed spacer (ITS) regions, 73 reversible symptoms, 495 International Foundation of Functional Saccharomyces boulardii Gastrointestinal Disorders (IFFGD), and, 515 13, 14, 21, 345 selenium supplementation, 508 interstitial cystitis (IC) self-management, 522 food allergies and, 95 smoking and, 498 SIBO and, 95 special diets for, 498–503 intestinal gas, 86–87 stress and, 522 intestinal hyperpermeability, 58, 458–59 supplements, 503–9 intestinal microbiota, 43–51 susceptibility genes, 274t absence of, 46 treatment considerations, 254 t assessment, 65–67 visceral manipulation for, 254 assessment diffi culties, 66 vitamin A supplementation, 505 conventional assessment of, 66–67 vitamin B6 supplementation, 505 development of, 258–59 vitamin B12 supplementation, 504 as disease contributor, 48 vitamin C supplementation, 505 drug discovery and, 50 vitamin D3 and, 497–98 environmental modifi ers, 45 vitamin E supplementation, 505 evaluation of, 54 VSL-3, 514–15 extraintestinal disorders and, 48–49 zinc supplementation, 507 as health asset, 48 infl ammatory cytokine pathways, 33, 289 host-microbe communication, 47–48 Insight Subluxation Station, 150 lifestyle modifi ers, 45 insoluble fi ber, 299 metabolic activity of, 49–50 insulin, 409, 556 new technologies for assessment, 67 resistance, 76–77, 588 population assessment, 61–62 Integrative Assessment Technique (IAT), studying, 45–46 146, 153–55 transduction of bacterial signals, 47 integrative gastroenterology, roots of, 5 intestinal permeability, 33–34, 41 integrative medicine bacterial overgrowth and, 80 goals in, 10 decreased, 34 INDEX 673

diagnoses of, 33t nutrition strategies for, 479–92 enteric infections and, 80 pathophysiological mechanisms, 343 genetics and, 80–81 peppermint for, 470 t increased, 80, 214–18, 497 personalization for, 491 infl ammation and, 80–81 postinfectious, 82t , 262 intramuscular epinephrine, 465 premenstrual exacerbation of, 110–15 inulins, 297, 500 t prevalence of, 16t , 24–25 iron, 279t , 503t probiotics for, 262–63 constipation and, 484 research expenditures, 18 t defi ciency, 92 Rome III diagnostic criteria for, 468t dental disease and, 401 SIBO and, 86t H2 receptor antagonists and, 387 stress and, 111 motility and, 484 Symptom Severity Score, 368 supplements, 484, 509 types, 480–81 irritable bowel syndrome (IBS), 13, 14, visceral manipulation for, 254–55 29, 60 isabgol, 576t abdominal pain and, 356 isotretinoin, 498 acceptable treatments, 360t ITS regions. See internal transcribed acupuncture for, 128 t , 129t spacer regions alternating, 481–82 awareness, 491 J behavior modifi cations and, 480 Janssen Clinical Investigator CAM modalities for, 604 t–605 t Awards, 345 CBT in, 331 Janu Sirsasana, 352 celiac disease and, 436 jejunoileal bypass, 541 chronic symptom management, 488–90 Jerusalem artichoke, 489 costs of, 17t , 21 jimson weed, 314 defi nition, 480 Jin Bu Huan, 576t diagnosis of, 208 jiva, 349 diet and, 480 JNK. See Jun-N-terminal kinase economic impact of, 368 Johns Hopkins, 10, 338 emotional factors, 111–12 Joh Rei, 158t evidence-based review of, 467–78 Journal of General Internal Medicine , 9 extracolonic conditions associated Jun-N-terminal kinase (JNK), 574 with, 603 justice, 631–33 FMS and, 119–20 gastric motility and, 482–88 K gender-specifi c diff erences, 600–605 kale, 485, 509 guided imagery for, 165 Kampo, 157 gynecological manifestations of, 113 kapha, 140 t , 350 herbal medicine for, 471t katuka, 322 hormones and, 112 kava, 576 t hypnosis and, 176–79 kefi r, 489 IgG in, 462 kelp, 487 infl ammation and, 112–13 keratinized gingiva, 394 menstrual exacerbation of, 110–15 kimchi, 489 674 INDEX

kininogenase, 453t lectins, 290 knowledge, 238–39 Leishmania donovani , 317 Konsyl, 486 lemon balm, 318, 319, 320, 418, 471 t Koop, C. Everett, 232 lemon juice, 485 Kupff er cells, 573 lemon verbena, 136 Leptospermum scoparium, 304 L Leptospirosis, 186

LAB. See lactic acid bacteria leukotriene B4 , 453t

laboratory evaluation, 53t leukotriene C4, D4 , 453t Lack, Gideon, 451 levofl oxacin, 263 lactic acid bacteria (LAB), 91 Lewis, Pearl, 247–48 Lactobacillus , 64, 76, 211 Lf. See human lactoferrin trials, 425 l -glutamine, 34, 282 Lactobacillus acidophilus , 31, 64, 265 LHBT. See lactulose hydrogen breath Lactobacillus bulgaricus , 425 testing Lactobacillus casei , 31, 265 licorice, 135–36, 139, 284, 315, 316, 388, Lactobacillus delbrueckii , 265 471 t , 518 Lactobacillus gasseri , 425 clinical trials, 412–13 Lactobacillus paracasei , 263 deglycyrrhizinated, 211, 412 Lactobacillus plantarum , 113, 265, 574 for liver disease, 571–72 Lactobacillus reuteri , 425 science behind, 412 Lactobacillus rhamnosus , 425, 472, 612 for upper GI disorders, 412–13 IBD and, 515 Lillard, Harvey, 147 trials, 473t limbic structures, 117 Lactobacillus salivarius , trials, 473 t Lin, Henry, 261 lactose intolerance lipase, 49 prevalence of, 16t evaluation of, 53 t probiotics for, 260–61 lipopolysaccharide (LPS), 46, 372, 396 lactulose, 31, 33 t, 86t lipoteichoic, 50t lactulose hydrogen breath testing (LHBT), Liu-Jun-Zi-Tang, 419–20 120–21 Liv 52, 573 t lactulose-mannitol challenge, 53 t , 54t , liver, 559–78 58–59 alcoholic disease, 565–66 lamina propria, 41 autoimmune disease, 594t , 597 l -amino acid decarboxylase, 64 CAM toxicity, 575–77 Lansoprazole, 18 t celiac disease and, 439 law, ethics v., 618 chronic disease, 15t , 18t law of totality, 183 detoxifi cation pathways, 296 laxatives, 323–24, 379, 389–90 disease costs, 17 t drug interactions, 391 disease research expenditures, 18t nutrient depletions, 391 evaluation of, 53 t osmotic, 391 fl ush, 590 l -dopa, 49 green tea and, 568–69 leafy greens, 484, 552 licorice for, 571–72 leaky guy, 32 magnesium for, 562–63 lecithin, 590 minerals and vitamins for, 561–66 INDEX 675

nonalcoholic fatty, disease, 16 t, 20 in Crohn’s disease, 279 t prebiotics and, 572–75 IBD and, 495, 503 t probiotics and, 572–75 MALT. See mucosa-associated resveratrol and, 569–70 lymphoreticular system silymarin for, 570–71 managed care, 7 vitamin E for, 563–66 mannitol, 33t , 59 zinc for, 561–62 MAP. See Mycobacterium avium subspec long pepper, 134, 136, 138 paratuberculosis lower esophageal incompetence, 405 marginal periodontitis low sulfur diet, 501 antigens from, 395–97 LPS. See lipopolysaccharide infections from, 395–97 lubricants, motility and, 487 margosa oil, 576t lymphatic system, 145 Marichyasana, 352 lymphocytes Marjariasana, 351 in Crohn’s disease, 494 Marks, Loren, 153 in ulcerative colitis, 494 marshmallow, 321 lymphokines, 455 massage, 189–93 abdominal, 191 M benefi ts, 190 macronutrient balance, 490–91 contraindications, 193 magnesium, 323, 495 digestive tract technique, 191–92 constipation and, 481 eff ects of, 190 defi ciency, 563 gastric motility and, 191 dental disease and, 401 history, 189–90 food sources of, 484 thermovibromassage, 191 gastric motility and, 483 mastic for liver, 562–63 clinical studies, 415 PPIs and, 385 H. pylori and , 415 supplements, 484, 508, 562–63 science behind, 415 magnetic resonance for upper GI disorders, 415 cholangiopancreatography MAT. See methionine adenosyltransferase (MRCP), 586t Mayo Clinic, 223 magnetic resonance imaging (MRI), 150 MBSR. See mindfulness-based stress functional, 166, 196, 344 reduction magnetism, 157 McDonald’s, 25 Ma Huang, 576t mechanical dialogue, 252 major histocompatibility complex Medicaid, 21 (MHC), 274 t medical foods, 90, 296 malabsorption, 34 meditation dental disease and, 401 brain changes in, 196 PPIs and, 383 evidence-based review, 475 malaise, 396 mindfulness, 196 maldigestion, 31–32 relaxation response, 475 malignancy-associated disorders, 106–9 Mediterranean diet, 557 malignant melanoma, 245 MEDLINE, 469 malnutrition medroxyprogesterone acetate, 548 t 676 INDEX

MedScape, 250 milnacipran, 118, 122 MEDwatch, 577 mind-body interactions megalovirus, 395 dietary recommendations for, 139t –140 t melanoma, 446 in digestion, 132–33 melatonin, 614t evidence-based review of, 475–78 for eating disorders, 613 prescription for, 138–39 IBD and, 518 mind-body medicine, 326–36, 337–48 Mendelian traits, 273 for abdominal pain, 369–71 menstrual IBS, 110–15 for IBD, 522–23 Mentha piperita L . See peppermint limitations, 334–35 6-mercaptopurine, 276 t practicing, 328 mercury, 399 mindfulness-based stress reduction meridian, 159 (MBSR), 195–96, 475. See also stress small intestine, 36 benefi ts of, 197, 199 meridians, 6 cancer and, 198–99 mesalamine, 18t , 276t , 513t congestive heart failure and, 201–2 meta-analyses, 642 healthcare utilization, 202 metabolic syndrome, 48, 556 in healthy adults, 197–98 metal, 28 heart disease and, 201 metastasis, 396–97 HIV and, 202 metastatic breast cancer, 245 limitations of, 203 metastatic infl ammation, 396 pain and, 198 methionine adenosyltransferase in practice, 196–97 (MAT), 566 psychiatric conditions and, 199–201 methionine metabolism, 566–68 transplant patients and, 201 methionine synthase (MS), 566 type 2 diabetes and, 201 methotrexate, 276t , 318, 509 mindfulness meditation, 196 metoclopramide, 419 mineral defi ciencies, 31 metronidazole, 264, 277t mineralocorticoid excess syndromes, 412 MGUS. See monoclonal gammopathy of mineral oil, 391 undetermined signifi cance minerals. See also specifi c types MHC. See major histocompatibility clinical studies, 429–30 complex foods rich in, 483–84 miasmatic remedies, 184 for liver, 561–66 microbial metabolic markers, 67–70 motility and, 482–85 microbiota. See gut microbiota; intestinal science behind, 429 microbiota supplements, 484 microscopic colitis, 595t for upper GI disorders, 429 migraine, 451 mistletoe, 576 t foods linked to, 452 t mixed cryoglobulinemia, 105 Military Appropriations Act, 143 monoclonal gammopathy of undetermined milk, 409, 449, 502 signifi cance (MGUS), 101 allergies, 450 monosodium glutamate, 451 skim, 535 Monotoux test, 455 milk thistle, 311, 322, 418, 471 t, 591t mood disorders, FMS and, 118 for hepatitis C, 560 morbid obesity, 539 INDEX 677 morphine, 311 National Center for Complementary and motilin, 423 Alternative Medicine (NCCAM), 157, motility 160, 357 acupuncture for, 128 t , 129t National Institutes of Digestive Diseases, calcium and, 483 Diabetes and Kidney Diseases chemical compounds and, 487–88 (NIDDK), 14 disruption of, 482 National Institutes of Health (NIH), 14, duodenal, 129t 19, 565 fi ber and, 485–86 National Poison Information IBS and, 482–88 Service, 577 iron and, 484 natto, 487 lubricants and, 487 naturopathic medicine, 205–18 magnesium and, 483 nausea, 128 t , 129t , 187 massage and, 191 NCCAM. See National Center for minerals and, 482–85 Complementary and Alternative optimizing, 482–88 Medicine potassium and, 484 NCV. See nerve conduction velocity SIBO and, 84–85 necrotizing enterocolitis, 261 sodium and, 484 needles, acupuncture, 124 vitamin C and, 485 negative nitrogen balance, 279 t , 503t water and, 486–87 Neiguan point, 129 mouth guards, 405, 406 neomycin, 121 MRCP. See magnetic resonance nerve conduction velocity (NCV), 150 cholangiopancreatography nerve impingement syndrome, 149 MRI. See magnetic resonance imaging neuroendocrine immune signaling, 41 MS. See methionine synthase neuroendocrine system, 117 mucosa-associated lymphoreticular system neurotransmitter theory, 126t (MALT), 273, 459 neutrophilic dermatoses, 100–103 mucosal immunity, 39–40 Newton, Isaac, 7 mucosal infl ammation, 60–61 nickel, 399, 400 Mullin, Gerard, 247 nicotine, 487 must, 620, 621 NIDDK. See National Institutes of musta, 139 Digestive Diseases, Diabetes and myasthenia gravis, 238 Kidney Diseases Mycobacterium avium subspec NIH. See National Institutes of Health paratuberculosis (MAP), 48 95  confi dence interval, 648 myelodysplastic syndrome, 101–2 niyama, 349 myeloma, 101–2 nizatidine, 386 myocardial infarction, 395 non-alcoholic fatty liver disease acute, 397 (NAFLD) prevalence of, 16t N as silent epidemic, 20 N-acetylglucosamine (NAG), 513 non-alcoholic steatohepatitis, 29, 215, 560, NAFLD. See non-alcoholic fatty liver 563, 564–65 disease non-Hodgkin’s lymphoma, 446 NAG. See N-acetylglucosamine non-inferiority, 650–51 678 INDEX

nonsteroidal anti-infl ammatory drugs sarcopenic, 528 (NSAIDs), 58, 215, 271, 548 t surgery for, 540–41 colorectal cancer and, 547–49 treatment for, 529–30 non-ulcer dyspepsia, 599–600 treatment maintenance, 542 nonverbal behaviors, 341 t treatment success, 543 Novartis Pharmaceuticals Corporation, 21 obstetric complications, 396 NSAIDs. See nonsteroidal anti- okra, 487 infl ammatory drugs olive oil, 487, 557 nuclear factor κ B, 47, 517 omega-3 fatty acids, 217, 496, 587 nutmeg, 136, 139 omega-6 fatty acids, 509 nutraceuticals, 296 Omeprazole, 18 t, 384 nutrient depletions, 389 Omnivore’s Dilemma (Pollan), 288 nutrient supply, 490 Ondansetron, 315 nutritional genomics, 9, 268–86 onions, 489 functional clinical tests, 278–79 online support groups, 249–50 infl ammatory bowel disease and, 271–72 opioid pathway, 423 management, 277 opportunistic overgrowth, 62 nutrition strategies. See also diet; foods oral contraceptives, 498 chronic symptoms, 488–90 oral desensitization, 466 for gynecological health, 114–15 oral signs, 401–2 for IBS, 479–92 oral tolerance, 27, 36 motility, 482–88 mechanics of, 458 in pancreatitis, 582 orange, 485 orange peel, 134 O oregano, 136 oats, 489 Oregon grape root, 317, 591 t oat bran, 486, 487, 500 t orlistat, 540 obesity, 48, 526–43 Ornish program, 245 behavioral assessment, 532–35 orthobiosis, 62 behavioral factors, 533–34 Osler, William, 10–11 depression and, 531 osmotic laxatives, 391 dietary assessment, 535–36 osteopathic medicine, 141–45 dietary modifi cation for, 534 application of, 144–45 drugs for, 540–41 history of, 142–43 epidemic of, 527 introduction to, 142–44 exercise assessment, 536–37 osteoporosis, 506 genetic factors, 529 in celiac, 445 gut microbiota and, 76–77 outcome-based theories, 621–22 health risks of, 528 outcome reporting statistics, 647–48 herbal medications for, 540–41 over-the-counter remedies, 377–91 integrative assessment, 531–32 oxalate, 49 laboratory examination, 532 oxidative stress, 495 medical assessment, 530–32 morbid, 539 P mortality and, 527 PABA index, 53t physical examination, 532 Padhastasana, 351 INDEX 679

Paeonia , 576t pattern-recognition receptors (PRR), 27, pain. See also abdominal pain 36–37 MBSR for, 198 Pauling, Linus, 9, 269 pelvic, 95–96 Pawanmuktasana, 351 palladium, 399 PCR. See polymerase chain reaction Palmer, B.J., 147–48 peanut allergies, 450 Palmer, D.D., 147 pectin, 409 palmoplantar keratoderma, 107 Peginterferon alfa-2a, 18 t PAM. See pathogen-associated molecular pelvic fl oor dyssynergia (PFD), 331, 371 patterns pelvic pain, 95–96 pancreas, 579–93 PEMF. See pulsed electromagnetic fi eld evaluation of, 53 t , 56–58, 581t pemphigus, 453 pancreatic cancer, 18 t pennyroyal oil, 576 t pancreatic insuffi ciency, 31–32 peppermint, 136, 305, 319, 418, 471t pancreatic panniculitis, 104–5 for abdominal pain, 373, 375t pancreatitis, 58–59 aromatherapy, 411 acupuncture for, 584 clinical data on, 411–12 acute, 580 t contact dermatitis and, 412 autoimmune, 594 t, 599 ginger and, 421 chronic, 213, 581t for IBS, 470t herbal medicine for, 583–84 science behind, 410–11 nutrition in, 582 trials, 411 prevalence of, 16t for upper GI disorders, 410–11 probiotics for, 583 pepsin, 53t supplements for, 583 Pepticare, 422 Pantoprazole, 18 t peptic ulcer disease, 409 papillomatosis, 109 costs of, 17 t Paracelsus, 183 prevalence of, 16t parasitology, 75–76 research expenditures, 18 t parasympathetic tone, 39 peptidoglycans, 46 Pare, Ambroise, 189 peripheral edema, 83–84 Parkinson’s syndrome, 92 peristalsis, 44 parsley, 485 peroxisome proliferator-activated Paschimottanasana, 351, 352 receptor-γ (PPAR-γ ), 47 Pasteur, Louis, 151, 318 personalization, 491 pathogen-associated molecular patterns PET. See positron emission tomography (PAM), 37 Peumus boldus , 421 patient. See also doctor-patient Peutz-Jeghers syndrome, 108 relationship Peyer’s patches, 33, 37 in abdominal pain, 361 PFD. See pelvic fl oor dyssynergia autonomy, 626–27 PG. See pyoderma gangrenosum education, 363 pH, fecal, 68 harm, 628–30 pharbitis seed, 315 hypnotherapy, 177t pharmaceutical trials, 344 in self-care journaling, 230 t phase I detoxifi cation, 114–15 transplant, 201 phase II detoxifi cation, 114–15 680 INDEX

phenolic fl avonoids, 451 post-traumatic stress disorder (PTSD), 229 phenylalanine, 451 FMS and, 120 philosophy, Western, 7 potassium, 279t , 503t phosphatidylcholine, 590 motility and, 484 p-hydroxyphenylacetic aciduria, 64 potatoes, 289, 499 physical abuse, 329 pouchitis, 264 physical barrier, 54 t Power Vs. Force (Hawkins), 153 physical therapy, 368–69 PPAR- γ . See peroxisome proliferator- physiological systems approach, 207–8 activated receptor-γ function restoration, 208–9 PPIs. See proton-pump inhibitors pineapple, 485 pranayama, 349, 351 Pinelliae tuber , 420 pratyahara, 349 pioglitazone, 565 prebiotics piperine, 304 characteristics of, 297 Piper longum , 422 defi nition of, 259, 516–17 pitta, 139t , 350 food sources, 296–98, 489 pituitary extract, 409 IBD and, 516–17 placebo response, 9–10, 161 liver and, 572–75 in abdominal pain, 374t , 375t in ulcerative colitis, 500 t CAM and, 468 prednisolone, 502 plantago ovata seed, 500 t prednisone, 276t plantains, 301 preeclampsia, 563 clinical studies, 415 prematurity, 498 science behind, 415 premenstrual IBS, 110–15 for upper GI disorders, 415 emotional factors, 111–12 plasma fatty acids, 53t hormones and, 112 PMN-e. See polymorphonuclear infl ammation and, 112–13 neutrophil-elastase premenstrual syndrome (PMS), 111 PMS. See premenstrual syndrome pressures, 253t pneumonia Prevotella , 76 community-acquired, 381 Prilosec, 379 in elderly, 382 primary biliary cirrhosis, 595t polarity therapy, 158 t principle-based ethics, 622 Pollan, Michael, 288 ProAdjuster, 150 polymerase chain reaction (PCR), probiotics, 34, 257–67, 614 t . See also specifi c 45, 73, 121 probiotics advantages of, 78 t abdominal pain and, 372–73, 374t polymorphonuclear neutrophil-elastase clinical applications of, 260 (PMN-e), 60 clinical studies, 425 polyphenols, 299–301, 568–70, 583–84 for Crohn’s disease, 266 IBD and, 519 defi nition of, 259 Polyporus , 420 drug discovery and, 50t , 51t polysaccharides, 302 for dysbiosis, 489 portion sizes, 536 for eating disorders, 612 positron emission tomography (PET), evidence-based review of, 472–74 176, 344 food sources, 296–98, 489 INDEX 681

for IBD, 264–65, 513–16 psychiatric conditions, MBSR for, 199–201 for IBS, 262–63 psychological treatments, 340 immunoregulatory roles of, 514 rationale behind, 426 for lactose intolerance, 260–61 for upper GI disorders, 426–28 liver and, 572–75 psyllium, 136, 486 mechanism of action, 259–60 PTSD. See post-traumatic stress disorder for necrotizing enterocolitis, 261 pulsed electromagnetic fi eld (PEMF), 159 for pancreatitis, 583 p values, 648 randomized trials on, 473 t pyoderma gangrenosum (PG), 101–2 regimen construction, 472 pyostomatitis vegetans, 392 safety of, 266 pyrexia, 396 science behind, 424–25 SIBO and, 89–90 Q strains, 472 qi, 124 for ulcerative colitis, 265 qi gong, 158t , 221–22 upper gastrointestinal disorders for, dynamic, 222 424–26 QOL. See quality of life product recommendations, 635 quality of life (QOL), 464, 467 professional boundaries, 630–31 quercetin, 217, 281, 553–54 promotility antibiotic therapy, 89–91 quinine, 311 Propionibacterium freudenreichii , 472 quorum-sensing, 36, 40–41 trials, 473t Pro Solutions, 150 R prospective cohort studies, 639–40 Rabeprazole, 18 t prostaglandins D2 , 453t radioallergosorbent test (RAST), 452, 457 protease, 53t Raji cell test, 454 protease inhibitors, 301 Rakel, David, 229 protein-calorie malnutrition, 395 randomized trials, 640 proton-pump inhibitors (PPIs), 209–10, biases in, 643–44 378, 405 breakdown of, 646 calcium defi ciency and, 385 controlled, 640–41 cardiovascular events and, 381 of herbal therapy, 470 Clostridium diffi cile , 380 on hypnosis, 333 community-acquired pneumonia Lactobacillus , 425 and, 381 Lactobacillus rhamnosus , 473t complications of, 380–85 Lactobacillus salivarius , 473t for frequent heartburn, 379–80 peppermint, 411 for GERD, 379–86 on probiotics, 473 t hip fracture and, 382–83 Propionibacterium freudenreichii , 473t magnesium defi ciency and, 385 Shermanii , 473t malabsorption and, 383 TCM, 470 nutrient depletion and, 385–86 Ranitidine, 18 t , 386, 416 side eff ects, 380 RAST. See radioallergosorbent test protozoa, 72 raw honey, 489 proximal colon cancer, 595t Raynaud’s arthralgia, 401 PRR. See pattern-recognition receptors rDNA. See ribosomal DNA 682 INDEX

reassurance, 370 Rome II criteria, 291 reductionism, 7–8 Rome III criteria, 468t refl exology, 474 root canal, 397–98 refractory celiac disease, 447 rosacea, 96 regulatory T cells, 36 H. pylori and , 96–97 reiki, 158 t , 160, 162, 225–26 SIBO and, 97 benefi ts of, 225 RRM. See relaxation response meditation history of, 226 relaxation, 165 S for esophageal disorders, 426–27 Saccharomyces boulardii , 91, 259, 265, stress and, 475 266, 513t training, 168, 333–34 IBD and, 515 relaxation response meditation (RRM), 475 Saccharomyces cerevisiae , 502 Remicade, 276t S-adenosylhomocysteine (SAH), 566 reproducibility, 461 S-adenosyl methionine (SAMe), 357, respiratory infections, 396 566, 567 restless leg syndrome (RLS) SAH. See S-adenosylhomocysteine alternative therapies for, 94 Salmonella, 82 antibiotics, 93–94 Salmonella , 318, 383 celiac and, 94–95 Samadhi, 349 Crohn’s disease and, 94–95 SAMe. See S-adenosyl methionine medical therapy for, 93t Samhita, Sushruta, 5, 6, 7 secondary, 92–93 Sandler, Robert S., 13 SIBO, 92 sarcopenic obesity, 528 resveratrol, 281, 315, 583–84 sassafras, 576 t for IBD, 519–19 saturated fat, 23–24 liver and, 569–70 sauerkraut, 489 retrospective cohort studies, 639–40 Savasana, 352 rhabdomyolysis, 385 saw palmetto, 576 t Rhamnus purshiana . See cascara SCFAs. See short-chain fatty acids Rheum . See rhubarb Schilling test, 53t rheumatoid arthritis, 202 Schweitzer, Albert, 318 SIBO and, 85t scleroderma, SIBO and, 85t rhinitis, 451 scopolamine, 314 rhubarb, 421 secondary restless leg syndrome, 92–93 ribavirin, 18t , 565 secretin, 56 ribofl avin, 296 selective outcome reporting, 646 ribosomal DNA (rDNA), 67 selenium, 495, 548t rice bran, 486 colorectal cancer and, 552–53 rifaximin, 121, 263 supplementation, 508 for SIBO, 87–89 selenoproteins, 552 studies, 88 t self-care journaling, 227–31 right upper quadrant ultrasound, 586 t clinical practice, 229 RLS. See restless leg syndrome medical literature on, 228–29 Rome Foundation Research patient handout, 230t Committee, 345 self-help groups, 249 INDEX 683

Senecio longilobus , 576t achlorhydria, 85 t senna, 324, 390 animal models, 121 serotonin, 41, 122 chronic fatigue syndrome and, 91–92 serotonin and norepinephrine reuptake chronic renal failure and, 85 t inhibitors (SNRIs), 118 common causes, 85t sesame oil, 487 gastrointestinal motility and, 84–85 sesame seeds, 485 IBS and, 86t sexual abuse, 329 interstitial cystitis and, 95 Shandong Provincial Hospital, 464 intestinal gas and, 86–87 Shanka bhasma , 422 lesser known causes, 85t Shashankasana, 351 probiotics and, 89–90 shatavari, 134–35, 139 protection against, 83 for upper GI disorders, 416 restless leg syndrome and, 92–93 Shenxiahewining, 420 rheumatoid arthritis and, 85t Shermanii , 472 rifaximin for, 87–89 trials, 473t rosacea and, 97 Shigella, 82 scleroderma and, 85 t shogaols, 315 systemic consequences of, 91–95 short-chain fatty acids (SCFAs), 258 therapy, 87 fecal, 69 small intestine evaluation, 53t , 58–60 should, 620, 621 small intestine meridian, 36 Shou-wu-pian, 576 t small ribosomal subunit RNA, 45 SIBO. See small intestinal bacterial SmartPill GI Monitoring System, 56 overgrowth smoking, 480, 527 Sigma Instruments, 150 IBD and, 498 silent epidemics, 20 perinatal exposure to, 498 silibinin, 322 Sneddon-Wilkinson syndrome, 102 silymarin, 315, 323 SNMC. See Stronger Neo-Minophagen C for liver disease, 570–71 SNRIs. See serotonin and norepinephrine safety of, 571 reuptake inhibitors simple sugars, 588 SNS. See sympathetic nervous system Singh, Gurkirpal, 21 social isolation, 241 single nucleotide polymorphisms, 269, 270 sodium, motility and, 484 skepticism, 361 sodium nitrate, 451 skim milk, 535 soft palate, 394 skin, 99–109 soft tissue oral lesions in eating disorders, 609 Behçet’s disease and, 392–93 prick testing, 456–57 celiac disease and, 394 SLC22A4, 274t , 275 Crohn’s disease and, 392 SLE. See systemic lupus erythematosus diseases producing, 392 sleep apnea, 539 soluble fi ber, 299 slippery elm, 321, 518 somatostatin, 41 small bowel adenocarcinoma, 446 sound therapy, 158 t small bowel aspirate, 121 sourdough, 298 small intestinal bacterial overgrowth soy, fermented, 489 (SIBO), 31, 83–84, 261 Specifi c Carbohydrate Diet, 291, 498–99 684 INDEX

specimen integrity, 73–74 tolerability of, 419 specimen transport, 73–74 for upper GI disorders, 418–19 spinal manipulative therapy, 152 subcutaneous immunotherapy, 465 spirituality, 232–35 subgroup analyses, 645 care, 233–35 subtle body, 156 importance of, 234 sucrose, 499 SQUID. See superconducting quantum sugar, 488 interference devices sulfasalazine, 49, 277, 277 t St. John’s wort, 577 sulforaphane, 548 t , 554–55 Staphylococcus aureus , 74 sulfur, 501 statistics, 647–49 sulindac, 548 t outcome reporting, 647–48 sunshine, 548t , 551 type I error, 649 superconducting quantum interference type II error, 649–50 devices (SQUID), 159 steatorrhea, 57 superior mesenteric artery syndrome, 610 Still, Andrew Taylor, 142 Supersize Me (fi lm), 289 stomach, 53 t , 55 supervision, 631 stool supplements assessment diffi culties, 66 calcium, 484, 590 comprehensive analyses, 463 for eating disorders, 611 conventional assessment of, 66–67 EFA, 509–12 fecal pH, 68 fi ber, 486 fecapentaenes in, 69–70 folic acid, 503–4 β -glucuronidase in, 67–68 for gallbladder, 589–90 microbe assessment in, 65–67 glutamine, 512 microbial metabolic markers, 67–70 HCl, 212 new technologies for assessment, 67 iron, 484, 509 short-chain fatty acids in, 69 lecithin, 590 wetting agents, 391 magnesium, 484, 508, 562–63 strawberries, 485 minerals, 484 Streptococcus thermophilus , 263, 265 for pancreatitis, 583 Streptomyces, 259 phosphatidylcholine, 590 stress. See also mindfulness-based stress selenium, 508 reduction vitamin A, 505 defi nition of, 194–95 vitamin B6, 505 GI disease and, 195 vitamin B12, 504 IBD and, 522 vitamin C, 505, 589–90 IBS and, 111 vitamin D3, 506 oxidative, 495 vitamin E, 505, 563–66, 590 post-traumatic, 120, 229 vitamin K, 506–7 reduction, 168, 194–204, 219–20 zinc, 507, 561–62 relaxation and, 475 support groups, 241–50 Stronger Neo-Minophagen C (SNMC), 572 benefi ts of, 244 STW 5, 471t cardiac disease and, 243 clinical studies of, 419 community connection, 244 science behind, 418 death rates and, 243 INDEX 685

depression and, 243 atypical type, 494 digestive disease, 248 therapeutic touch, 158 t , 160 disease susceptibility and, 243 thermovibromassage, 191 evidence-based review of, 477–78 thrombocytopenia, 386 online, 249–50 thyme, 136 surrogate outcomes, 645–46 thyroid disease, 440 Surya Nadi, 351 Hashimoto’s thyroiditis, 29 susceptibility genes, 274t hyperthyroidism, 401 Sweet’s syndrome, 102–3 hypothyroidism, 531 sympathetic chain, 144t thyroid-stimulating hormone (TSH), 532 sympathetic nervous system (SNS), 39–40 tienchi ginseng, 284 Symphytum offi cinale , 576t titanium, 399 symptom monitoring control, 477–78 TJ-8, 576t synbiotics, 573 TJ-9, 573t , 576t defi nition of, 259 TJ-108, 573t systematic reviews, 642–43 TNF- α . See tumor necrosis factor alpha systemic illness, infections triggering, α -tocopherol, 505 81–82 toll-like receptors, 27, 37, 46, 274 t systemic lupus erythematosus (SLE), 454 tomatoes, 487, 502 systemic signs, 79–98 toothbrush, 404 traditional Chinese medicine (TCM), 6–7, T 28, 123–24, 157. See also herbal Tack, Jan, 384 medicine Tai Chi, 158t gastrointestinal tract in, 28–30 components of, 221–24 gut immunology in, 36–37 form, 223 trials, 470 health improvement from, 223 transcription factor, 47 tangweikang, 418 transcutaneous electrical nerve stimulation Taylor, Charles, 189 (TENS), 369 Taylor, George, 189 transforming growth factor β 1 (TGF-β 1), 564 T-cell lymphoma, 447 transglutaminase (TTG), 435 TCM. See traditional Chinese medicine transitional gut, 62–63 T eff ector responses, 37 transplantation, 201 Tegaserod, 18t , 468 traveler’s diarrhea, 263 TENS. See transcutaneous electrical nerve trials. See clinical trials; randomized trials stimulation Trichomonas vaginalis , 317 terminalia, 417–18 triggers, 488 Terminalia arjuna , 417–18 Trikonasana, 351 Terminalia chebula , 417–18, 422 triphala, 136, 324 TGF- β 1. See transforming growth factor β 1 tryptase, 453t thalassemia, 307 tryptophan, 63 T-helper 1, 424 TSH. See thyroid-stimulating hormone atypical type, 494 TTG. See transglutaminase proinfl ammatory activity, 272–73 tumor necrosis factor alpha (TNF- α ), 84, T-helper 2, 424 96, 246, 372, 399, 494, 502, 567 anti-infl ammatory activity, 272–73 turkey rhubarb, 324 686 INDEX

turmeric, 305–6, 315, 316, 422, 591t . upper gastrointestinal disorders, 408–31. See also curcumin See also specifi c disorders clinical trials, 413 acupuncture for, 422–24 eff ects of, 306 amalaki for, 414 science behind, 413 artichoke leaf extract, 417 for upper GI disorders, 413 ashwagandha for, 416 type 2 diabetes, MBSR for, 201 Brahmi for, 416 tyramine, 64, 290 CAM for, 409–10 sensitivity to, 451 electro-acupuncture for, 422–24 tyrosine, 64 ginger for, 417 Gorei-san for, 420 U greater celandine for, 416 UC. See ulcerative colitis Hange-koboku-to for, 420 ulcerative colitis (UC), 35, 60, 494 herbal combinations for, 418–22 clinical trials, 510–11 herbal medicine, 410–18 EFAs and, 510–11 historical perspective, 409 fi sh oils and, 511t homeopathy for, 428–29 low sulfur diet, 501 licorice for, 412–13 lymphocytes in, 494 Liu-Jun-Zi-Tang for, 419–20 prebiotics in, 500 t mastic, 415 probiotics for, 265 minerals for, 429–30 remission, 500 peppermint for, 410–11 research expenditures, 18 t plantains for, 415 risk factors, 271–72 preventative strategies, 430–31 ulcerative proctitis, 500 probiotics for, 424–26 ultrasound psychological therapies, 426–28 abdominal, 581t shatavari for, 416 right upper quadrant, 586 t Shenxiahewining for, 420 umeboshi plums, 307 STW 5 for, 418–19 UNC Center for Functional tangweikang, 418 GI and Motility Disorders, turmeric for, 413 337–38 vitamin C for, 430 academic training, 346–47 vitamin E for, 430 clinical program, 340–41 zinc and, 429 international activities, 346 urinary d -lactate, 64 mentored learning, 347 urinary indican, 63–64 public education, 346–47, 347 urinary markers, 63–64 research infrastructure, 345–46 of bacterial overgrowth, 63–64 research program, 343–44 of yeast overgrowth, 65 research team, 344–45 urinary metabolic markers, 54 t structure of, 339 urinary phenolic compounds, 64 training seminars, 347 ursodeoxycholic acid, 548 t , 585 uncontrolled experiences, 638–39 gallbladder and, 589 unidirectional signaling, 39 Ushtrasana, 351 Unity, 349 usnic acid, 576t upper endoscopy, 442–43 Usui, Mikao, 226 INDEX 687

V IBD and, 497–98 Vajrasana, 351 supplementation, 506 valerian, 318–19, 576t vitamin E varicella zoster virus, 395 for liver, 563–66 vascular disease, 401 plasma levels, 495 vata, 139t , 350 supplementation, 505, 563–66, 590 verbal behaviors, 341 t for upper GI disorders, 430 Vermont, 143 vitamin K, 49, 524 very-low-caloric diet (VLCD), 539 bone status and, 506–7 vested interest, 647–49 dental disease and, 402 villous atrophy, 443 t supplementation, 506–7 Viparta Karani, 352 VLCD. See very-low-caloric diet viral hepatitis, 16t vomiting, 404 virtue-based ethics, 622–23 homeopathic remedies for, 187 visceral hypersensitivity, 119 VSL-3, in IBD, 514–15 visceral manipulation, 251–56 ANS in, 253t W articulations in, 253 t water, 28 clinical relevance, 254–56 beverages, 487 for dyspepsia, 255 dehydration, 485 for GERD, 255 foods based in, 487 goals of, 253 t motility and, 486–87 for IBD, 254 taste of, 486 for IBS, 254–55 watermelon, 487 mobility in, 252, 253t weight control programs, 530 t parameters, 252 Weil, Andrew, 4, 9, 489 pressure sin, 253t wellness care, 150–51 viscerosomatic refl ex, 144 Wells, H.G., 458 vitalism, 157 Westernization of diet, 22–23 vitamin A, 279t , 495, 503 t Western medicine, 7 dental disease and, 402 doctor-patient relationship in, 9 supplementation, 505 integrative medicine v., 8t vitamin B6, 505 Western philosophy, 7 vitamin B12 defi ciency, 209–10, 279t , 503t wheat, 488, 502 dental disease and, 402 wheat bran, 485 H2 receptor antagonists and, 387 wheatgrass juice, 307–8 supplementation for, 504 Wheatley, Margaret, 234 vitamin C, 403 Whipple’s disease, 103, 401 dental disease and, 402 Whitehead, William, 338, 345, 346 motility and, 485 WHO. See World Health supplementation, 505, 589–90 Organization for upper GI disorders, 430 wild celery seeds, 134, 136, 138 vitamin D3, 279t , 503t , 524, 548 t Williams, Roger, 269 bone status and, 506 Wolinella , 397 colorectal cancer and, 551–52 Women’s Health Initiative, 597 dental disease and, 402 wood, 28 688 INDEX

World Health Organization yogurt, 425–26, 489 (WHO), 124 yuj, 349 World War I, 143 Z X Zelnorm, 21 xerostomia, 405 zero balancing, 158 t , 162 zinc, 90, 279t , 495, 503 t Y absorption, 507 yama, 349 defi ciency, 561 Yang & Li, 464 dental disease and, 402 yeast elimination diet, 502–3 H2 receptor antagonists and, 387 yeast overgrowth, 65 for liver, 561–62 Yersinia, 82 supplementation, 507 yoga, 158 t , 349–53 upper GI disorders and, 429 acceptance of, 360t zinc carnosine, 34, 282 digestive health and, 350–51 Zingiberis rhizoma , 420 evidence-based review of, 475–76 Zizyphi fructus , 420 postures, 351–53 Zusanli point, 129