Primer to First Edition of

Multi-Dimensional Clinical Profile (MDCP) For Functional Gastrointestinal Disorders

A Rome Foundation Publication 2 | Primer to the Multi-Dimensional Clinical Profile Editor MAX J. SCHMULSON, MD DOUGLAS A. DROSSMAN, MD Professor of Medicine President, Rome Foundation Facultad de Medicina-Universidad Nacional Autónoma de Professor Emeritus of Medicine and , University México (UNAM) of North Carolina Laboratorio de Hígado, Páncreas y Motilidad (HIPAM)- Co-Director Emeritus, UNC Center for Functional GI and Departamento de Medicina Experimental Motility Disorders Hospital General de México President, Center for Education and Practice of Mexico City, Mexico Biopsychosocial Patient Care Drossman Gastroenterology PLLC MAGNUS SIMRÉN, MD, PhD Chapel Hill, NC, USA Professor of Gastroenterology Consultant, Department of Internal Medicine and Clinical Contributors Nutrition FERNANDO AZPIROZ, MD, PhD Institute of Medicine Chief, Department of Digestive Diseases Sahlgrenska Academy Professor of Medicine University of Gothenburg University Hospital Vall d’Hebron Gothenburg, Sweden Universitat Autonoma de Barcelona Barcelona, Spain ROBIN SPILLER, MD Professor of Gastroenterology LIN CHANG, MD Co-Director, Nottingham Digestive Diseases Biomedical Professor of Medicine Research Unit Oppenheimer Family Center for Neurobiology of Nottingham Digestive Diseases Centre Division of Digestive Diseases University of Nottingham David Geffen School of Medicine at University of Queens Medical Centre California at Los Angeles Nottingham, UK Los Angeles, CA, USA Jan Tack, MD, PhD WILLIAM D. CHEY, MD, AGAF, FACP, FACG Professor of Medicine, University of Leuven Professor of Medicine Head, Department of Clinical and Experimental Medicine, Director, Gastroenterology Physiology Laboratory University of Leuven Co-Director, Michigan Bowel Control Program Head of Clinic Division of Gastroenterology Department of Gastroenterology University of Michigan University Hospital Ann Arbor, MI, USA K. U. Leuven TARGID (Translational Research Center for DOUGLAS A. DROSSMAN, MD Gastrointestinal Disorders) President, Rome Foundation Leuven, Belgium Professor Emeritus of Medicine and Psychiatry, University of North Carolina WILLIAM E. WHITEHEAD, PhD Co-Director Emeritus, UNC Center for Functional GI and Professor, Medicine & OBGYN Motility Disorders Director, UNC Center for Functional GI & Motility President, Center for Education and Practice of Disorders Biopsychosocial Patient Care University of North Carolina at Chapel Hill Drossman Gastroenterology PLLC Chapel Hill, NC, USA Chapel Hill, NC, USA

JOHN E. KELLOW, MB BS, MD, FRACP Associate Professor Head of the Discipline of Medicine Sydney Medical School - Northern University of Sydney Sydney, Australia Copyright © 2015 by the Rome Foundation Contents A Rome Foundation Educational Product All rights reserved. No part of this book may be reproduced Editor’s Note 4 in any form or by electronic, online or mechanical means, including information storage and retrieval systems, Aim, Objectives and Rationale 4 Guidelines for Use of the MDCP 5 without permission in writing from the publisher, except Learning from the Case Reports 8 by a reviewer who may quote brief passages in a review. Use in Primary Care 8

Project Management, Book Design and Public Functional GI Disorders 8 Relations Functional Gastroduodenal Disorders 8 Ceciel Rooker Functional Dyspepsia (Postprandial Distress Publishing Consultant Syndrome); Moderate 8 Lynne Herndon Functional Bowel Disorders 10 Copy Editor Irritable Bowel Syndrome; Moderate 10 Jackie Mollenauer Functional Anorectal Disorders 12 Copy Assistants Functional Fecal Incontinence; Moderate 12 Kaylie Gibson, Tyler Westall Rome IV 14 Logo Design and Illustrations Jerry Schoendorf The Rome Foundation 15 Board of Directors 15 Educational Products 15 Sponsors 15

The Rome Foundation PO Box 6524 Raleigh, NC 27628 Phone − (919)787-5859 Fax − (919)900-7646 www.theromefoundation.org

The Mission of the Rome Foundation To improve the lives of people with Functional GI Disorders

The goals of the Rome Foundation are to: • Promote clinical recognition and legitimization of the functional GI disorders • Develop a scientific understanding of their pathophysiological mechanisms • Optimize clinical management for patients with FGIDs

Rome Foundation Staff: Executive Director, Wink Hilliard Jr. Public Relations Director, Ceciel Rooker Public Relations Assistant, Tyler Westall Administrators, Michele Pickard, Claudia Rojas Medical Illustrator, Jerry Schoendorf Copy Editor, Jackie Mollenauer Website/Newsletter Design, Ceara Owre Trade Show Manager, Jamie DuMont

Primer to the Multi-Dimensional Clinical Profile | 3 4 | Primer to the Multi-Dimensional Clinical Profile Aim, Objectives and Rationale Editor’s Note The Multi-Dimensional Clinical Profile This primer provides an introduction to the (MDCP) for Functional Gastrointestinal concept of the Multi-Dimensional Clinical Profile (GI) Disorders was developed to capture the (MDCP). It describes the MDCP, the criteria for wide range of clinical features of patients with FGIDs and to present the information the subcategories and a template for its use by in a manner that is patient specific and including three illustrative cases. After reviewing consistent with the thinking of experts in the field. this document, the reader will understand how to use the MDCP to develop clinical profiles for patients Aim: To develop a multi-component assessment system for that will permit more targeted treatment. FGIDs that can be used to characterize the full dimensionality of the patient’s illness state, and which will be applied in With publication of the MDCP book, we are beginning treatment planning and research. There are five dimensions: a new endeavor, one that will redefine the ways in A. The categorical Rome diagnosis (Category A); which clinicians can help patients having even the B. Additional information that subclassifies the diagnosis most complex functional GI disorders. Discerning leading to more specific treatments, e.g., IBS-D or clinicians are well aware that making a diagnosis of IBS-C; sphincter of Oddi dysfunction (SOD) I or II; IBS, functional dyspepsia, or functional abdominal functional dyspepsia EPS; or PDS (Category B); pain is not sufficient to determine treatment. Not all C. The personal impact of the disorder on the patient (Category C); patients with a diagnosis are the same. For example, D. Psychosocial influences (Category D); and a patient with IBS-D having mild and occasional E. Physiological abnormalities or biomarkers (Category E). symptoms of abdominal discomfort and loose stools and functioning without impairment would be treated Objectives: quite differently than a patient with the same diagnosis 1. To be useful in making valid treatment decisions within having continuous severe and disabling pain, and co- a variety of clinical settings morbid with fears of incontinence 2. To have reliable categories when leaving the house. 3. To be accepted internationally by clinicians and investigators of various theoretical orientations The MDCP identifies and classifies these components 4. To be useful for educating trainees and health into a highly specific plan placed within a framework professionals that is targeted to the needs of the individual. The five 5. To maintain compatibility with and be accepted and/ components of this framework include the categorical or endorsed by ICD-10 and third-party payers (to be Rome diagnosis (Category A), additional information established) that subclassifies the diagnosis leading to more specific 6. To provide terminology, including psychiatric terms treatments (e.g., IBS-D or IBS-C, SOD I or SOD II, that are readily understood and obtained by non-mental- EPS or PDS), the personal impact of the disorder on health professionals the patient (Category C), psychosocial influences 7. To make efforts to reach consensus on the meaning of (Category D), and physiological abnormalities or the terms that previously have been used inconsistently and to avoid terms that have outlived their usefulness biomarkers (Category E). This framework is intuitively 8. When possible, to use information that has been clear and the organizational approach is both pragmatic obtained from research studies in order to provide a and useful. level of validation 9. To permit identification of subjects for use in research The MDCP book containing 32 patient cases is studies available for purchase at $29.95 USD or €20.00 EUR 10. To permit responsiveness to change over time based on online at http://www.romecriteria.org/shop.cfm, or by scientific evidence visiting the Rome Foundation booth in the exhibitor 11. To be amenable to future investigation and validation area at various medical conferences. Rationale: The diagnosis of FGIDs is based on a categorical Douglas A. Drossman, MD system that uses the Rome criteria. These criteria relate to President, Rome Foundation patient symptoms and (for some disorders) physiological On behalf of the Rome Foundation Board of Directors findings that occur around a pre-specified time frame. This categorical assessment system is helpful for selecting patients for clinical studies and treatment trials. However, there are limitations for using solely the criteria in clinical practice since this assessment system is not able to address: • Certain clinically meaningful subsets of these diagnoses, – Fatigue • Physiological contributions or degrees of impairment, – Sleep disturbance • Psychosocial co-morbidities which impact on severity, – Any other medical diagnosis or relevant symptom disability and centrally targeted treatment options, contributing to the illness condition • Future categorizations (e.g., biomarkers), and • Globus • Overall severity and disability which affects the extent – With of diagnostic evaluation and the nature of treatment – With transit dysphagia choices. • Rumination Syndrome The MDCP enriches our understanding of the patient – Reswallows or spits out by adding these missing dimensions to the categorical – With diagnosis, and this optimizes the treatment. • Aerophagia – With excessive belching Guidelines for Use of the • Functional Dysphagia Multi-Dimensional Clinical – Frequent vs. sporadic – Continuous vs. episodic Profile – Solid, liquid or both – With impaction The MDCP provides a comprehensive, – With weight loss individualized, clinical understanding of the patient that incorporates the biopsychosocial – With chest pain aspects of the individual’s illness experience. It contains the • Functional Heartburn information every clinician would want to know to more – Frequent vs. sporadic precisely target clinical management decisions for his/her – Continuous vs. episodic patient. This information can also be conveyed to clinicians, – Daytime vs. nighttime investigators, industry and regulatory organizations and – Postprandial or not may be used by third-party payers. The categories as noted • Functional or Non-cardiac Chest Pain below cover the range of information clinicians would use – Frequent vs. sporadic for diagnosis, treatment and ongoing care of their patients. – Continuous vs. episodic – Postprandial Category A. Categorical Diagnosis – Relieved by belching or not This is the standard Rome categorical criteria currently – Related to physical effort using Rome III, which will in the future be modified for – Related to eating Rome IV. It usually is symptom based but may include the – Daytime or nighttime or both presence of physiological criteria (e.g., fecal incontinence). • Functional Dyspepsia – PDS, EPS or both Category A provides the “specific” diagnostic criteria used in – Subsyndromic PDS or EPS (i.e., does not meet clinical trials and office practice. The additional categories criteria) below (B, C, D, and E) are available optimizing clinical care – Postinfectious and in specific research situations. – Acute-onset – Weight loss Category B. Clinical Modifiers – Co-existing , bloating, belching or The clinical modifiers areadditional symptoms or subtypes, – historical information, physical signs, laboratory or physiological studies that subcategorize the diagnosis in • Chronic Idiopathic Nausea ways that would potentially affect treatment planning. – Postprandial While not required for a diagnosis (i.e., Category A), its – Continuous vs. episodic presence may help in the pathophysiological understanding – Weight loss of the patient’s diagnosis or help direct treatment. Unlike • Functional Vomiting the other categories, the clinical modifiers are not yet based – Frequent vs. sporadic on full scientific evidence. However, it follows clinical – Continuous vs. episodic wisdom and provides the option for validation or the use – Weight loss of treatments targeted to the specific subcategory. The • Cyclic Vomiting Syndrome following modifiers were determined by the contributing – Frequent vs. sporadic authors and may be modified in the future as needed: – With pain • General Modifiers – With reflux – Functional Somatic Syndromes - Fibromyalgia, – Weight loss Chronic Fatigue, etc. • Functional Sphincter of Oddi Disorder – Narcotic Bowel Syndrome – Subtypes I, II, III Primer to the Multi-Dimensional Clinical Profile | 5 6 | Primer to the Multi-Dimensional Clinical Profile – Post-Cholecystectomy composite of patient reported gastrointestinal and extra- – Functional Pancreatic Sphincter Disorder intestinal symptoms, degree of disability and illness – Symptoms sporadic vs. frequent related perceptions and behaviors” in which both visceral • Functional Abdominal Pain Syndrome and central factors will contribute. Impact must be based – Narcotic bowel syndrome on the patient’s perception, including clinical judgment. Therefore, the degree of severity will be assessed by asking – Opioid induced constipation the patient the following question: “Overall, how much do • Irritable Bowel Syndrome the symptoms currently interfere with life (work, school, – Post-infectious social activities, self-care, concentration and performance) – Postprandial symptoms – none/mild/moderate/severe”. In the cases that follow, – FODMAP sensitive efforts are made to correlate the patient’s report with the – Stool pattern ‒ IBS-D, -C, -M or -U evident data. However, it is recognized that the patient’s – With urgency report may differ from the clinician’s observations and in – With fecal incontinence those cases the clinician must reconcile these differences – With pain-predominance when planning treatment. – Frequent vs. sporadic – With bloating Category D. Psychosocial Modifiers – IBD-IBS This category identifies psychological and psychosocial • Functional Bloating modifiers and co-morbidities that influence the patient’s – Postprandial experience of the illness and behaviors that will affect – FODMAP sensitive treatment decisions. It can include categorical evidence • Constipation (e.g., Diagnostic and Statistical Manual of Mental Disorders – Slow transit, normal transit [DSM-5] psychiatric diagnosis), quantitative measures – Opioid induced constipation (e.g., anxiety by HADS ‒ Hospital Anxiety and – Infrequent vs. very infrequent BM (<1/week) Scale) as a continuous score or categorical diagnosis based – Absence of call-to-stool on cutoffs, or patient report (e.g., abuse) that is judged – Straining by the clinician to be relevant to the person’s functional – Splinting gastrointestinal disorder, the illness behaviors associated – Manual manoeuvers with it or its impact on daily functioning. Care must be taken to permit identification by non- professionals. – With dyssynergic defecation, obstructive This information would be obtained from known records defecation (e.g., DSM or HADS diagnosis), clinical observation • Functional (e.g., reported history of abuse), clinical evidence for – Postprandial symptoms depression that is observed or stated stressful life events – Bile salt malabsorption such as recent death of a pet (if interpreted as meaningful – Severe urgency as a trigger or perpetuating factor for FGID symptoms). In – With fecal incontinence addition, inclusion of any item listed below that does not – Nocturnal or daytime only have a severity category (e.g., traumatic life events) must – Stool volume estimate be judged as a significant contributor to the development or • Functional Defecation Disorder (or Dyssynergic exacerbation of the current FGID disorder or its severity. Defecation) • Psychological/Psychiatric Symptoms/Syndromes – Dyssynergic defecation – Axis I or Axis II diagnosis from DSM IV or DSM- – Inadequate defecatory propulsion 5 diagnoses (e.g., – Splinting - 300.82), based on criteria or mental health • Chronic Proctalgia professional diagnosis. – Levator syndrome • Current – Proctalgia fugax • Previous • Fecal Incontinence – Current symptoms of depression, anxiety, anticipatory – Passive vs. urge anxiety, post-traumatic stress disorder (PTSD), – Diarrhea excessive worry about symptoms, obsessive- – Overflow constipation compulsive behaviors (expressed by patient and/ or interpreted by clinician) or psychometric scale Category C. Impact on Daily Activities (none, mild, rated as clinically significant. The clinician may moderate, severe) also use psychosocial flags (see next page). This category designates and quantifies the overall • Major Stressors effect on patient illness perceptions, behaviors and daily – Traumatic life events – Emotional, sexual or functioning that influences treatment. It is understood physical abuse history, war trauma, major work (using the Rome Severity definition) as: “a biopsychosocial disruption, major loss that is either recent (i.e., grief process within the past year) or longstanding • Movement of contents: Cine swallow but unresolved. • Sensitivity: Oropharyngeal sensitivity • Mild – no clear psychological residua or life • Evidence of inflammation:None disruption* • Other analytical techniques (disease specific): Brain • Moderate – some psychological residua or life imaging disruption* • Severe – known adverse events with psychological residua and life disruption* • Wall structure and activity: Manometry, Luminal (e.g., rape/penetration, multiple experiences, ultrasound life threat) • Movement of contents: Impedance Scintigraphy – Other major stressor judged by the clinician to be • Sensitivity: Barostat, Thermal, Chemical considered relevant (e.g., loss of job, divorce) • Evidence of inflammation:Biopsy • Other analytical techniques (disease specific): 24h pH • Rome Psychosocial Flags (9 items) – Would indicate profile consideration of a referral to a mental health professional) and may be used for current symptoms category & duodenum – Anxiety – Tense or wound up most of the time – Depression – Downhearted or low most of the time • Wall structure and activity: Manometry, MRI, SPECT – Suicidal Ideation – Often or occasionally felt like imaging hurting or killing oneself (responding “often” • Movement of contents: Scintigraphy, MRI, Ultrasound requires a referral) • Sensitivity: Nutrient drink test, Barostat, Chemical – Abuse and trauma history – Having been • Evidence of inflammation: Histology emotionally, physically or sexually victimized and • Other analytical techniques (disease specific): HP it is causing distress testing – Partner abuse – Having been afraid for personal safety in one’s intimate relationship (requires a referral) Biliary dysfunction – Pain severity – Having had severe bodily pain in • Wall structure and activity: SO Manometry last four weeks • Movement of contents: HIDA scan – Somatic symptoms associated with distress • Sensitivity: None and health concerns – Worried about physical • Evidence of inflammation:None symptoms for last 6 months that the clinician • Other analytical techniques (disease specific): Liver believes are serious function test – Impairment/disability – Pain or other symptoms interfere over past 4 weeks with normal activities Small intestine quite a bit or extremely • Wall structure and activity: Manometry, Capsule for – Drug/Alcohol abuse – Having used alcohol (5+ motility, MRI drinks for men, 4+ drinks for women), prescription • Movement of contents: Scintigraphy, Smart Pill, MRI drugs for non-medical reasons and/or illegal drugs • Sensitivity: Barostat, Chemical for past year daily or weekly (responding “daily” • Evidence of inflammation: Histology, Calprotectin, requires mental health referral) Perfusion *(e.g., psychological residua include constant/intrusive thoughts and behaviors, , anniversary • Other analytical techniques (disease specific):Glucose reactions, etc.) breath test for SIBO, Aspiration / breath tests, Lactose breath or tolerance test for lactose intolerance Category E. Physiological Modifiers of Function and Biomarkers (type/severity) Colon This category provides the dimensionality for physiological • Wall structure and activity: Manometry, MRI or biochemical parameters that may have clinical • Movement of contents: Radio-opaque markers, relevance and which may enhance the understanding of Scintigraphy, Smart Pill, MRI the diagnosis or have treatment implications. There must • Sensitivity: Barostat be sufficient external evidence for an item to be endorsed • Evidence of inflammation:Histology, Calprotectin, (e.g., by manometry or radionuclide report, or biochemical Perfusion/diffusion, Cytokines, mRNA, Histology sampling). The list below provides the measures that may • Other analytical techniques (disease specific): be used by physiological domain for each anatomic region. Permeability, Fecal tryptase, Microbiota (HITChip)

EXAMPLES OF TESTS: Anorectum Oropharynx • Wall structure and activity: Manometry, Defecography, • Wall structure and activity: Manometry Ultrasound, MRI, Digital exam Primer to the Multi-Dimensional Clinical Profile | 7 8 | Primer to the Multi-Dimensional Clinical Profile • Movement of contents: Balloon expulsion, Case 1: Functional Dyspepsia Defecography (PDS) (Moderate) • Sensitivity: Barostat/ balloon, Electrical • Evidence of inflammation:Histology, Calprotectin A 30 year old male accountant sees • Other analytical techniques (disease specific):None a gastroenterologist due to upper abdominal bloating and fullness with Learning from the Case Reports early satiety occurring after meals most every This monograph is designed to use clinical cases for self- day with 4 kg weight loss. Symptoms began 8 learning: months ago after having a severe gastroenteritis Title. The reader is aware of the diagnosis with vomiting and diarrhea. Currently there are from the start since the categorical Rome no bowel symptoms. He reports the symptoms as III diagnosis is placed in the title. moderate: they limit his ability to travel and he Case History. The case history contains avoids eating at work, and this has been associated all the information that is needed to use the with 4 kg weight loss. He saw a psychiatrist and MDCP. is taking an SSRI for generalized anxiety disorder. MDCP Categories. These are based on the case report. Upper endoscopy with H. Pylori testing and The specific items used are drawn from the preceding abdominal ultrasound are negative. Proton pump information and tables and the full Rome III Diagnostic inhibitors are not helpful. criteria (Category A) is in Appendix A. Explanation of MDCP Categories. For each category, a MDCP Categories brief description of the rationale is provided along with A. Categorical Diagnosis: Functional Dyspepsia references. B. Clinical Modifier:Postinfectious postprandial distress Overall Assessment. This is a brief summary of the case syndrome (PDS) report. C. Impact on Daily Activities: Moderate Treatment. The treatment section is a major component D. Psychosocial Modifier:Moderate generalized anxiety of the MDCP. Using the categories, the reader is able disorder to construct a treatment plan that is highly specific to E. Physiological Features and Biomarkers: None the case. Citations are used to support the treatment known decisions. Reference List. Key references are provided with each Explanation of MDCP Categories case. A. Categorical Diagnosis: Functional Dyspepsia was fulfilled by meeting Rome III criteria and having We encourage the reader to review the case report and symptoms most every day for 8 months. See inset box consider ways to characterize this particular patient in terms for diagnostic criteria. of clinical features and treatment. Following this, the reader B. Clinical Modifier: A postinfectious diagnosis relates can systematically review the information provided and to the onset after a gastroenteritis with vomiting and reconcile the differences. diarrhea1. Postprandial distress (PDS) relates to meeting criteria based on symptoms occurring after Use in Primary Care meals and associated with early satiety, and fullness2. We recognize that patients seen in primary This is presumed due to incomplete receptive relaxation care may not have as complex histories of the fundus with hypersensitivity to distension after a as represented here and the primary meal3. care physician may not have access to C. Impact on Daily Activities: This is moderate based psychosocial or physiological investigation, on the patient’s self-report, weight loss, and his need to nor may it be necessary. Therefore, we restrict travel and not eat at work due to development suggest that Categories A, B and C be used of symptoms. The patient endorsed Moderate to the for patients seen in primary care, and at times Categories question: ‘Overall how much do your symptoms D and E would be applied at the discretion of the clinician. currently interfere with life (work, school, social activities, self care, concentration and performance)?’ D. Psychosocial Modifier: Generalized anxiety disorder is based on a diagnosis made by a psychiatrist who prescribed medication for this diagnosis. There is evidence from brain imaging and gut-brain signaling studies that anxiety and depression are linked to the clinical expression of functional dyspepsia4. anxiety agent which can also augment the effect of the B. Functional Gastroduodenal Disorders SSRI on treating psychological symptoms6. In Japan, B1. FUNCTIONAL DYSPEPSIA tandospirone, another 5-HT1A agonist used in the Diagnostic criteria* Must include: treatment of anxiety, was found superior to placebo in 1. One or more of the following: alleviating dyspeptic symptoms in a controlled trial7. a. Bothersome postprandial fullness 2. Mirtazepine – Dyspeptic symptoms can be associated b. Early satiation with weight loss due to voluntary dietary restriction to c. Epigastric pain prevent dyspeptic symptoms. In one controlled study d. Epigastric burning of patients with functional dyspepsia and about 10% AND weight loss, mirtazepine had significantly improved 2. No evidence of structural disease (including at symptoms of early satiety and was associated with upper endoscopy) that is likely to explain the weight gain and better caloric intake during a nutrient symptoms challenge test8. * Criteria fulfilled for the last 3 months with 3. Continue with psychologist for anxiety management symptom onset at least 6 months prior to – This patient is currently under treatment with a diagnosis psychologist, and there is value in continuing this activity to help reduce his ongoing symptom-associated B1a. Postprandial Distress Syndrome anxiety which behaviorally is related to sitophobia Diagnostic criteria* Must include one or both of the (reduction of eating to avoid symptoms) and travel following: restriction. 1. Bothersome postprandial fullness, occurring after ordinary-sized meals, at least several Reference List times per week 1. Spiller R, Lam C. An update on post-infectious Irritable Bowel 2. Early satiation that prevents finishing a regular Syndrome: Role of genetics, immune activation, serotonin meal, at least several times per week and altered microbiome. J Neurogastroenterol Motil 2012 * Criteria fulfilled for the last 3 months with Jul;18(3):258-68. symptom onset at least 6 months prior to 2. Tack J, Talley NJ. Functional dyspepsia-symptoms, definitions diagnosis and validity of the Rome III criteria. Nat Rev Gastroenterol Hepatol 2013 Feb 12;10(3):134-41. Supportive criteria 3. Farre R, Vanheel H, Vanuytsel T, Masaoka T, Tornblom H, Simren M, Van Oudenhove, Tack JF. In functional dyspepsia, 1. Upper abdominal bloating or postprandial hypersensitivity to postprandial distention correlates nausea or excessive belching can be present with meal-related symptom severity. Gastroenterol 2013 2. Epigastric pain syndrome may coexist Sep;145(3):566-73. 4. Van Oudenhove L., Aziz Q. The role of psychosocial factors E. Physiological Features and Biomarkers: None and psychiatric disorders in functional dyspepsia. Nat Rev known. There is no record of physiological testing or Gastroenterol Hepatol 2013 Jan 29;10(3):158-67. history of such tests. 5. Tack J, Janssen P, Masaoka T, Farre R, Van OL. Efficacy of buspirone, a fundus-relaxing drug, in patients with functional dyspepsia. Clin Gastroenterol Hepatol 2012 Jul 17. Overall Assessment 6. Trivedi MH, Fava M, Wisniewski SR, Thase ME, Quitkin This young man has moderately severe Postprandial F, Warden D, Ritz L, Nierenberg AA, Lebowitz BD, Biggs Distress Syndrome associated with weight loss. In addition MM, Luther JF, Shores-Wilson K, Rush AJ, STAR*D Study he is being treated for generalized anxiety disorder. Team. Medication augmentation after the failure of SSRIs for depression. N Engl J Med 2006 Mar 23;354(12):1243-52. Treatment 7. Miwa H, Nagahara A, Tominaga K, Yokoyama T, Sawada 1. Buspirone (5HT1 receptor agonist) – Given the Y, Inoue K, Ashida K, Fukuchi T, Hojo M, Yamashita H, presumed pathophysiology of PDS, therapeutic efforts Tomita T, Hori K, Oshima T. Efficacy of the 5-HT1A agonist are directed toward enhancing postprandial fundic tandospirone citrate in improving symptoms of patients with functional dyspepsia: a randomized controlled trial.. Am J relaxation. Buspirone is a 5HT1 receptor agonist that Gastroenterol. 2009 Nov;104(11):2779-87. relaxes the proximal stomach. In one study, patients with 8. Ly HG, Carbone F, Holvoet L, Bisschops R, Caenepeel P, Arts functional dyspepsia (mostly PDS) were given 30 mg. J, Boeckxstaens GE, Van Oudenhove L, Tack JF. Mirtazapine buspirone or placebo for 4 weeks. The buspirone had improves early satiation, nutrient intake, weight recovery, significant improvement in dyspeptic symptoms (early and quality of life in functional dyspepsia with weight loss: satiety, fullness, bloating), and this was associated with a doubleblind, randomized, placebo-controlled pilot study. increased gastric accommodation to a meal. There was Gastroentrology 2013;144(Supp 1):S-37. no effect on gastric emptying5. In addition, buspirone is used in psychiatry as a non-benzodiazepine anti- Primer to the Multi-Dimensional Clinical Profile | 9 10 | Primer to the Multi-Dimensional Clinical Profile

Case 2: Irritable Bowel Syndrome C. Functional Bowel Disorders (Moderate) C1. Irritable Bowel Syndrome Diagnostic criterion* A 25 year old female who recently took up Recurrent abdominal pain or discomfort** at least a post as employment arbitrator which 3 days/month in the last 3 months associated with has involved working shifts with change in two or more of the following: eating pattern and exercise. She complains 1. Improvement with defecation of 2 years of worsening left upper quadrant 2. Onset associated with a change in frequency discomfort associated with bloating and of stool frequent loose stools occurring about 5 days per 3. Onset associated with a change in form week. There is some relief from defecation. She (appearance) of stool often feels a sense of incomplete evacuation. Her * Criterion fulfilled for the last 3 months with diet is high in fruit, vegetables and whole meal symptom onset at least 6 months prior to bread. There is no past psychiatric history. She is diagnosis finding the discomfort is interfering with her work ** “Discomfort” means an uncomfortable and has missed 2 days of work per month recently. sensation not described as pain. A local physician prescribed a low FODMAP In pathophysiology research and clinical trials, a diet. She responds well to this, but finds it rather pain/discomfort frequency of at least 2 days a week restrictive socially. during screening evaluation is recommended for subject. MDCP Categories A. Categorical Diagnosis: Irritable Bowel Syndrome Rome III IBS Subtypes B. Clinical Modifier:IBS-D, FODMAP intolerance 100 C. Impact on Daily Activities: Moderate D. Psychosocial Modifier:None known E. Physiological Features and Biomarkers: None 75 25% of BM is the threshold known % BM for classification hard or 50 Explanation of MDCP Categories lumpy IBS C Types 1,2 A. Categorical Diagnosis: Irritable Bowel Syndrome IBS-M The patient meets Rome III IBS criteria of abdominal 25 IBS-U IBS-D discomfort with relief from defecation and association Types 6, 7 with loose stools for >1 day per week, with symptoms 0 1 lasting > 6 months . See inset box for diagnostic criteria 0 25 50 75 100 and refer to Figure 1 for IBS subtypes. % BM loose or watery B. Clinical Modifier: IBS-D, FODMAP intolerance. Figure 1. Rome III categorization of IBS-subtypes. IBS FODMAPs (Fermentable, Oligo-, Di- and Mono- can be categorized as IBS-C where patients 25% of the time saccharides and Polyols) are poorly absorbed dietary or more have hard or lumpy stools and less than 25% of carbohydrates which if taken in sufficient quantity can the time have loose or watery stools. IBS-D is the reverse: cause symptoms of bloating, flatulence and abdominal loose or watery stools 25% or more and hard or lumpy stools discomfort, as confirmed in a placebo controlled double- less than 25% of the time. IBS-mixed (IBS-M) shows both blind trial2. A recent placebo-controlled, randomized types of stool equal or more than 25% of the time and IBS-U shows no predominant stool pattern. Subtyping has important controlled trial (RCT) confirmed the benefit of a low implications for selecting treatments for this disorder. FODMAP diet3, and comparisons with historical controls suggest that the response is significantly better in relieving symptoms than is current standard advice 4. Overall Assessment C. Impact on Daily Activities: Moderate; the patient This young female has adopted a diet high in fruit, endorsed Moderate to the question: ‘Overall how much vegetables and whole meal bread, which has resulted in do your symptoms currently interfere with life (work, IBS symptoms of discomfort and bloating with loose stools. school, social activities, self care, concentration and These symptoms respond well to dietary exclusion. performance)?’ Patient is losing 2 days of work per month. Treatment D. Psychosocial Modifier:None known 1. Selective exclusion of specific fruits / vegetables E. Physiological Features and Biomarkers: None identified during reintroduction phase of low-FODMAP known diet Rationale: FODMAPs (Fermentable, Oligo-, Di- and reported non-celiac gluten sensitivity after dietary reduction Mono-saccharides and Polyols) have been shown to of fermentable, poorly absorbed, short-chain carbohydrates. induce IBS symptoms of pain, wind, flatulence, bloating Gastroenterology 2013; 145(2):320-328. in double-blind RCT2. There is evidence in trials with 6. Staudacher HM, Whelan K, Irving PM, Lomer MC. Comparison of symptom response following advice for a weaker design (open label and hence subject to placebo 5 diet low in fermentable carbohydrates (FODMAPs) versus effect) that low FODMAP diets improve symptoms standard dietary advice in patients with irritable bowel 6 when compared with either low residue diets or no diet syndrome. J Hum Nutr Diet 2011; 24(5):487-495. change7. FODMAPs increase colonic gas and increase 7. Staudacher HM, Lomer MC, Anderson JL, Barrett JS, colonic diameter8. IBS patients appear specifically Muir JG, Irving PM, Whelan K. Fermentable carbohydrate sensitive to this distension since in healthy volunteers restriction reduces luminal bifidobacteria and gastrointestinal substantial colonic distension can be observed with symptoms in patients with irritable bowel syndrome. J Nutr minimal symptoms. Lactose is a common FODMAP, 2012; 142(8):1510-1518. and recent studies in Chinese subjects, 93% of whom 8. Murray K, Wilkinson-Smith V, Hoad C, Costigan C, Cox E, Lam C, Marciani L, Gowland P, Spiller RC. Differential Effects have lactose malabsorption, show clearly that anxiety of FODMAPs (Fermentable Oligo-, Di-, Mono-Saccharides is a good predictor of symptoms after lactose ingestion, and Polyols) on Small and Large Intestinal Contents in 9 which causes few symptoms in healthy Chinese adults . Healthy Subjects Shown by MRI. Am J Gastroenterol 2013. 2. Loperamide may be used in addition to the diet and 9. Yang J, Fox M, Cong Y, Chu H, Zheng X, Long Y, Fried taken as required, e.g., before travelling or an event M, Dai N. Lactose intolerance in irritable bowel syndrome when defecation would be problematic patients with diarrhoea: the roles of anxiety, activation of Rationale: Several small old studies show benefit the innate mucosal immune system and visceral sensitivity. with improvement in diarrhea but not pain10;11. Again, Aliment Pharmacol Ther 2014; 39(3):302-311. consensus statements support this use12;13. 10. Cann PA, Read NW, Holdsworth CD, Barends D. Role of loperamide and placebo in management of irritable bowel 3. If neither of the above regimes helps, then consider using syndrome (IBS). Dig Dis Sci 1984; 29(3):239-247. 5HT3 receptor antagonists as available (ramosetron, 11. Efskind PS, Bernklev T, Vatn MH. A double-blind placebo- alosetron, ondansetron) controlled trial with loperamide in irritable bowel syndrome. Rationale: Meta-analysis shows benefit with NNT of 7 Scand J Gastroenterol 1996; 31(5):463-468. using alosetron 1mg b.d.14. The dose of 1mg b.d. may 12. Spiller R, Aziz Q, Creed F, Emmanuel A, Houghton L, be excessive since 25% suffer from constipation and Hungin P, Jones R, Kumar D, Rubin G, Trudgill N, Whorwell 0.1% ischemic colitis, but a recent study with 0.5 mg P,Clinical Services Committee of The British Society o.d. shows lower incidence of constipation to be 9% of Gastroenterology. Guidelines on the irritable bowel but still 1/177 with ischemic colitis15. Ramosetron used syndrome: mechanisms and practical management. Gut 2007; 56(12):1770-1798. at very low dose shows benefit with lower incidence 16 13. Brandt LJCW, Foxx-Orensetin AE, Moayyedi P, Quigley of constipation . Recent evidence shows ondansetron EMM, Schiller ER, Schoenfeld PS, Chey WD, Spiegel BM, titrated starting at 4mg daily and either increasing to Talley NJ. An Evidence-Based Review of the Management 4mg t.d.s. or decreasing to 4mg alternate days provides of Irritable Bowel Syndrome: American College of satisfactory relief in 69% compared with 17% on Gastroenterology IBS Task Force. American Journal of placebo giving an NNT of 2.017. Constipation rate was Gastroenterology 2009; 104:S1-S34. 9% and all responded to dose reduction. 14. Cremonini F, Delgado-Aros S, Camilleri M. Efficacy of alosetron in irritable bowel syndrome: a meta-analysis of Reference List randomized controlled trials. Neurogastroenterol Motil 2003; 1. Longstreth GF, Thompson WG, Chey WD, Houghton 15(1):79-86. LA, Mearin F, Spiller RC. Functional bowel disorders. 15. Cremonini F, Nicandro JP, Atkinson V, Shringarpure R, Gastroenterology 2006; 130(5):1480-1491. Chuang E, Lembo A. Randomised clinical trial: alosetron 2. Shepherd SJ, Parker FC, Muir JG, Gibson PR. Dietary improves quality of life and reduces restriction of daily triggers of abdominal symptoms in patients with irritable activities in women with severe diarrhoea-predominant IBS. bowel syndrome: randomized placebo-controlled evidence. Aliment Pharmacol Ther 2012; 36(5):437-448. Clin Gastroenterol Hepatol 2008; 6(7):765-771. 16. Matsueda K, Harasawa S, Hongo M, Hiwatashi N, Sasaki D. 3. Halmos EP, Power VA, Shepherd SJ, Gibson PR, Muir JG. A A randomized, double-blind, placebo-controlled clinical trial diet low in FODMAPs reduces symptoms of irritable bowel of the effectiveness of the novel serotonin type 3 receptor syndrome. Gastroenterology 2014; 146(1):67-75. antagonist ramosetron in both male and female Japanese 4. Staudacher HM, Whelan K, Irving PM, Lomer MC. patients with diarrhea-predominant irritable bowel syndrome. Comparison of symptom response following advice for a Scand J Gastroenterol 2008; 43(10):1202-1211. diet low in fermentable carbohydrates (FODMAPs) versus 17. Garsed K, Chernova J, Hastings M, Lam C, Marciani L, Singh standard dietary advice in patients with irritable bowel G, Henry A, Hall I, Whorwell P, Spiller R. A randomized trial syndrome. J Hum Nutr Diet 2011; 24(5):487-495. of Ondansetron for the treatment of irritable bowel syndrome 5. Biesiekierski JR, Peters SL, Newnham ED, Rosella O, Muir with diarrhea. Gut 2013; online. JG, Gibson PR. No effects of gluten in patients with self-

Primer to the Multi-Dimensional Clinical Profile | 11 12 | Primer to the Multi-Dimensional Clinical Profile Case 3: Functional Fecal F. Functional Anorectal Disorders Incontinence (Moderate) F1. Functional Fecal Incontinence Diagnostic criteria* A 68 year old male reports 1. Recurrent uncontrolled passage of fecal urgency, constant fear of soiling, material in an individual with a developmental and fecal incontinence at least age of at least 4 years and one or more of the once a week. He has 12-15 semi- following: formed BMs per day and wears protective pads. a. Abnormal functioning of normally Onset was one year previously following low innervated and structurally intact muscles anterior resection for rectal cancer and a recovery b. Minor abnormalities of sphincter structure complicated by an anastamotic leak with abscess and/or innervation and a revision. Anorectal manometry shows slightly c. Normal or disordered bowel habits, (i.e., weak squeeze pressure, reduced rectal compliance fecal retention or diarrhea) and threshold for urge to defecate, and reduced d. Psychological causes maximum tolerable volume. The patient responds AND to the question on impact as Moderate. 2. Exclusion of all the following: a. Abnormal innervation caused by lesion(s) MDCP Categories within the brain (e.g., ), spinal A. Categorical Diagnosis: Fecal Incontinence cord, or sacral nerve roots, or mixed B. Clinical Modifier:Diarrhea , urge incontinence lesions (e.g., multiple sclerosis), or as part C. Impact on Daily Activities: Moderate of a generalized peripheral or autonomic D. Psychosocial Modifier: Fear of incontinence neuropathy (e.g., due to diabetes) (anticipatory anxiety) b. Anal sphincter abnormalities associated E. Physiological Features and Biomarkers: Reduced with a multisystem disease (e.g., rectal compliance, mild weakness of external anal scleroderma) sphincter c. Structural or neurogenic abnormalities believed to be the major or primary cause Explanation of MDCP Categories of fecal incontinence A. Categorical Diagnosis: Fecal Incontinence * Criteria fulfilled for the last 3 months The patient meets Category A criteria for Fecal Incontinence. See inset box for diagnostic criteria. A C. Impact on Daily Activities: Moderate diagnosis of fecal incontinence is based on a patient Moderate impact is shown by the patient’s report of reporting accidental loss of solid or liquid stool; no a constant fear of incontinence. The condition is not diagnostic tests are required to make the diagnosis, defined as severe because the patient is not home although tests such as anorectal manometry and bound and is able to socialize and to work. The patient imaging of pelvic floor structures using endoanal endorsed Moderate to the question: ‘Overall how much ultrasound or MRI help to characterize the etiology and do your symptoms currently interfere with life (work, select treatment 1,2. school, social activities, self-care, concentration and B. Clinical Modifier:Diarrhea, urge incontinence performance)’? Chronic or recurrent diarrhea (i.e., loose or watery D. Psychosocial Modifier: Fear of incontinence stools) is the most consistently reported risk factor for (anticipatory anxiety) fecal incontinence in population-based studies3. It is The patient reports a constant fear of fecal incontinence important to recognize the association with diarrhea which interferes with his quality of life by causing him because this directs treatment towards the diagnosis to have to seek out all the toilets in any location he of treatable causes of diarrhea and/or the management expects to be in, to take a change of clothes with him, of idiopathic diarrhea with fiber supplements or and to avoid eating in public restaurants. This modifier antidiarrheal medications2,4. A report of strong has implications for specific treatments referred to as sensations of urgency preceding fecal incontinence urge resistance training. is another risk factor identified in population-based E. Physiological Features and Biomarkers: Reduced epidemiological studies; it is an independent risk rectal compliance, mild weakness of external anal factor from diarrhea although it may be associated with sphincter diarrhea5. This patient fits the profile of a patient with The most significant physiological finding is reduced a hypersensitive rectum, also called urge incontinence6 rectal compliance (i.e., reduced maximum tolerable or “low anterior resection syndrome”7. volume of rectal distention). This is consistent with the patient’s history of onset following surgical resection of part of his rectum for treatment of rectal cancer; one 5. An alternative, evidence-based treatment for moderate would expect reduced compliance in this setting. The to severe fecal incontinence is sacral nerve stimulation significance of external anal sphincter squeeze showing (which is also called neuromodulation)10. This involves only mild weakness is to rule out sphincter weakness implanting wire electrodes into the sacral nerve at a as the primary cause of his fecal incontinence and to location that triggers external anal sphincter contractions underscore the importance of reduced rectal compliance when stimulated electrically. These electrodes are as a cause of incontinence. connected to a battery-operated stimulator which is implanted beneath the skin. Overall Assessment 6. Injecting beads of an inert bulking agent (dextranomer) This man reports frequent bowel movements with into the submucosal space surrounding the anal rectal urgency and fecal incontinence after low anterior canal is also an evidence-based treatment for fecal resection for rectal cancer. The incontinence is causing incontinence11. moderate disability and psychological symptoms (fear of incontinence). Reference List 1. Wald A, Bharucha AE, Enck P, Rao SSC. Functional anorectal Treatment disorders. In: Drossman DA, Corazziari E, Delvaux M, et al., 1. Conservative management should be tried first; it eds. Rome III: The Functional Gastrointestinal Disorders. McLean, Virginia: Degnon Associates; 2006:639-85. will include (1) taking a careful history to identify 2. Wald AB, A.; Cosman, B.C.; Whitehead, W.E. ACG Clinical dietary or other treatable causes of diarrhea, (2) adding Guidelines: Management of Benign Anorectal Disorders. Am fiber supplements to bind water in stools, and (3) J Gastroenterol. 2014;In press. antidiarrheal medication such as loperamide if still 3. Whitehead WE, Borrud L, Goode PS, Meikle S, Mueller ER, needed to normalize stool consistency. Tuteja A, Weidner A, Weinstein M, Ye W; Fecal incontinence 2. If the response to conservative treatment is inadequate in US adults: epidemiology and risk factors. Gastroenterology in patient’s or physician’s view, try biofeedback 2009;137:512-7. treatment. Type of biofeedback training will be guided 4. Whitehead WE, Wald A, Norton NJ. Treatment options by patient having moderately severe urge incontinence for fecal incontinence. Diseases of the Colon & Rectum 2001;44:131-42. with anticipatory anxiety and weak sphincter: 5. Bharucha AE, Zinsmeister AR, Locke GR, Seide BM, 3. Biofeedback to improve sphincter strength McKeon K, Schleck CD, Melton LJ 3rd.; Risk factors for Although this patient’s most significant physiological fecal incontinence: a population-based study in women. Am J deficit is reduced compliance of the rectum with Gastroenterol. 2006;101:1305-12. associated strong urge sensations, he also presents with 6. Siproudhis L, El AM, El AM, Juguet F, Bretagne JF. Low decreased sphincter squeeze pressures. The availability rectal volumes in patients suffering from fecal incontinence: of physical therapists and other providers who can what does it mean? Aliment Pharmacol Ther. 2005;22:989- assist the patient to strengthen the pelvic floor muscles 96. through a combination of biofeedback and pelvic floor 7. Ziv Y, Zbar A, Bar-Shavit Y, Igov I. Low anterior resection syndrome (LARS): cause and effect and reconstructive exercises is substantially greater than the availability considerations. Tech Coloproctol 2013;17:151-62. of therapists who can provide urge resistance training. 8. Heymen S, Scarlett YV, Jones KR, Ringel Y, Drossman Strength training with biofeedback has been shown to DA, Whitehead WE. Randomized controlled trial shows improve continence by improving the strength of pelvic biofeedback to be superior to pelvic floor exercises for fecal floor muscles8. incontinence. Dis Colon Rectum 2009;52:1730-7. 4. Urge resistance training (a form of biofeedback) 9. Whitehead WEP, Palsson, OS. Behavioral treatment of fecal – Teach deep breathing as a coping skill to counteract incontinence. In: Mostofsky DI, ed. Handbook of Behavioral anticipatory anxiety Medicine. First ed. New York: John Wiley & Sons; 2014:787- – Have patient practice tolerating larger volumes of 806. 10. Wexner SD1, Coller JA, Devroede G, Hull T, McCallum R, rectal balloon distention by using deep breathing to Chan M, Ayscue JM, Shobeiri AS, Margolin D, England M, inhibit urge sensation Kaufman H, Snape WJ, Mutlu E, Chua H, Pettit P, Nagle D, – Encourage patient to practice delaying defecation Madoff RD, Lerew DR, Mellgren A; Sacral nerve stimulation for short periods after experiencing urge sensation for fecal incontinence: Results of a 120-patient prospective at home multicenter study. Ann Surg 2010;251:441-9. Urge resistance training as a treatment for urge- 11. Graf W, Mellgren A, Matzel KE, Hull T, Johansson C, related fecal incontinence has not been frequently Bernstein M, on behalf of the NASHA Dx Study Group. described in the published literature; however, the Efficacy of dextranomer in stabilised hyaluronic acid for rationale, differential diagnosis, and steps to be taken treatment of faecal incontinence: a randomised, sham- controlled trial. Lancet 2011;377:997-1003. in performing this type of training are described in a book chapter9.

Primer to the Multi-Dimensional Clinical Profile | 13 14 | Primer to the Multi-Dimensional Clinical Profile Rome IV As many clinicians’ habits of accessing relevant information have changed in the last decade, Rome IV publication and formats Rome IV will be available in several formats: as Rome IV, The Functional Gastrointestinal an online database which will allow searching Disorders, will be published by The Rome and cross-linking; as a two volume printed book Foundation in May 2016, replacing the previous containing the diagnostic and non-diagnostic edition, Rome III (2006). chapters; as a volume on algorithms; and as the full and updated Multi-Dimensional Clinical In this new edition, the Editors Profile volume (MDCP). Two (Drossman, Chang, Chey, smaller books, one on pediatrics Kellow, Tack and Whitehead) and another on primary care, will and their 160 contributors offer round out the offering. updated guidelines for the diagnosis and management of The Rome IV editorial process functional GI disorders. Through As in previous editions, the a well-established process Editors and their contributors of working in committees of form expert committees to international experts, Rome IV develop a consensus approach to presents definitive consensus the content. Each diagnostic area and evidence-based knowledge has its own committee to decide about the diagnostic criteria for on clinical management and esophageal, gastroduodenal, agree on medical and scientific bowel, biliary, chronic abdominal advances. The non-diagnostic pain, and anorectal disorders in committees are also comprised of addition to two pediatric chapters international and interdisciplinary for neonate/toddler and child experts. The resulting work of adolescents. In addition, eight these committees is peer-reviewed non-diagnostic chapters focus on an overview of and ultimately based on rigorous consensus the field, multicultural aspects of disease, gender, reached after several years of discussion. psychosocial issues, intestinal mircoflora, basic science, physiology, and pharmacokinetics, adding In addition to evidence based information acquired up to full-spectrum and authoritative coverage of through up to date searches, the diagnostic and the subject. non-diagnostic committees get help from two additional sources: the support committees and In Rome IV, the Editors capture a biopsychosocial the working teams. The support committees orientation that helps discard the functional- gather relevant and specific information in organic dichotomy that can stigmatize patients. advance of the other committees’ consensus Functional GI disorders are now understood as meetings, e.g., on questionnaire development and having biological substrates including mucosal validation, systematic reviews and meta-analyses, immune dysfunction-altered microbiota, disrupted primary care and its unique view of FGIDs, and brain-gut signaling and biomarkers that can all development of cases for the Multi-Dimensional play a role in the clinical expression of the illness. Clinical Profile. The working teams also gather Finally, as medicine is truly global, this edition relevant reviews on such topics as brain imaging, reflects a wealth of cross-cultural information intestinal microbiota, the role of diet in FGIDs, from around the world. and cross-cultural and multinational research, among others. Rome Foundation BOARD OF Other Rome Foundation DIRECTORS Educational Products Douglas A. Drossman, MD President The Rome Foundation Diagnostic Algorithms for Chapel Hill, NC USA Common Gastrointestinal Symptoms. American Journal of Gastroenterology. Volume 105, Issue 4 (April Fernando Azpiroz, MD, PhD 2010). Barcelona, Spain The Rome Foundation Computer-Based Learning Giovanni Barbara, MD Program. The Rome Foundation; 2009. Bologna, Italy Understanding the Irritable Gut: The Functional Lin Chang, MD Gastrointestinal Disorders. Thompson WG. McLean, Los Angeles, CA USA Virginia: Degnon Associates, Inc.; 2008.

William Chey, MD Rome III: The Functional Gastrointestinal Disorders. Ann Arbor, MI USA Drossman DA, Corraziari E, Delvaux M, Talley NJ, Spiller RC, Thompson WG, Whitehead WE. McLean, Virginia: Degnon Associates, Inc.; 2006. John Kellow, MD New South Wales, Australia Rome II: The Functional Gastrointestinal Disorders. Drossman DA, Corraziari E, Talley NJ, Thompson WG, Jan Tack, MD, PhD Whitehead WE. McLean, Virginia: Degnon Associates, Leuven, Belgium Inc.; 2000.

Max Schmulson, MD The Functional Gastrointestinal Disorders. Drossman Mexico City, Mexico DA, Richter JE, Talley NJ, Thompson WG, Corraziari E, Whitehead WE. Boston: Little, Brown and Company; Magnus Simrén, MD, PhD 1994. Reprinted McLean, Virginia: Degnon Associates, Gothenburg, Sweden Inc.; 1997.

Ami Sperber, MD Rome Foundation educational products can be ordered Beer-Sheva, Israel online at http://www.romecriteria.org/shop.cfm The Rome Foundation gratefully acknowledges their Robin C. Spiller, MD sponsors for their financial support which allows us Nottingham, England to create our educational materials. Almirall William E. Whitehead, PhD Astellas Pharma Global Development, Inc. Chapel Hill, NC USA AstraZeneca Entera Health, Inc. Former Board Members Ferring Pharmaceuticals Nicholas J. Talley, MD, PhD Forest Laboratories, Inc. Callaghan, Australia Furiex Pharmaceuticals, Inc. 1990-2011 Genova Diagnostics, Inc. Ironwood Pharmaceuticals, Inc. Enrico Corazziari, MD Ono Pharmaceutical Co., Ltd. Rome, Italy Prometheus Laboratories, Inc., 1989-2010 A Nestlé Health Science Company QOL Medical W. Grant Thompson, MD Salix Pharmaceuticals, Inc. Ottawa, Canada Shire Pharmaceuticals 1989-2008 SOFAR S.p.A. Sucampo AG Michel Delvaux, MD, PhD Synergy Pharmaceuticals, Inc. Nancy, France Takeda Pharmaceuticals International, Inc. 1999-2006 Zeria Pharmaceutical Co., Ltd. Primer to the Multi-Dimensional Clinical Profile | 15 The Rome Foundation Proudly Presents the latest educational resources for all health care professionals and patients concerned with functional gastrointestinal disorders (FGIDs)

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