Nutrition for the Primary Care Provider

Supported by an unrestricted educational grant from the World Review of Nutrition and Dietetics

Vol. 111

Series Editor

Berthold Koletzko Munich Nutrition for the Primary Care Provider

Volume Editor

Dennis M. Bier Houston, Tex.

Co-Editors

Jim Mann Dunedin David H. Alpers St. Louis, Mo. H.H. Este Vorster Potchesfstroom Michael J. Gibney Dublin

20 figures, 8 in color and 50 tables, 2015

Basel • Freiburg • Paris • London • New York • Chennai • New Delhi • Bangkok • Beijing • Shanghai • Tokyo • Kuala Lumpur • Singapore • Sydney Dennis M. Bier Jim Mann H.H. Este Vorster USDA/ARS Children’s Nutrition Medicine and Human Nutrition Faculty of Health Sciences Research Center University of Otago Centre of Excellence for Nutrition Baylor College of Medicine PO Box 56 North-West University 1100 Bates Street Dunedin 9054 (New Zealand) Potchefstroom 2531 (South Africa) Houston, TX 77030-2600 (USA) David H. Alpers Michael J. Gibney Washington University School of School of Agriculture and Food Medicine Science 660 S. Euclid Ave. University College Dublin St. Louis, MO 63110 (USA) Science Centre – South Belfield Dublin 4 (Ireland)

Library of Congress Cataloging-in-Publication Data

Nutrition for the primary care provider / volume editor, Dennis M. Bier ; co-editors, Jim Mann, David H. Alpers, H.H. Este Vorster, Michael J. Gibney. p. ; cm. -- (World review of nutrition and dietetics, ISSN 1660-2242 ; vol. 111) Includes bibliographical references and index. ISBN 978-3-318-02666-5 (hard cover : alk. paper) -- ISBN 978-3-318-02667-2 (e-book) I. Bier, Dennis M., editor. II. Mann, Jim, editor. III. Alpers, David H., editor. IV. Vorster, H. H., editor. V. Gibney, Michael J., editor. VI. Series: World review of nutrition and dietetics ; v. 111. 0084-2230 [DNLM: 1. Nutritional Physiological Phenomena. 2. Physicians, Primary Care. 3. Nutrition Policy. 4. Nutrition Therapy. W1 WO898 v.111 2014 / QU 145] RM216 615.8‘54--dc23 2014030004

Bibliographic Indices. This publication is listed in bibliographic services, including Current Contents® and PubMed/MEDLINE. Disclaimer. The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publisher and the editor(s). The appearance of advertisements in the book is not a warranty, endorsement, or approval of the products or services advertised or of their eff ectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements. Drug Dosage. The authors and the publisher have exerted every eff ort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant fl ow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. © Copyright 2015 by S. Karger AG, P.O. Box, CH–4009 Basel (Switzerland) www.karger.com Printed in Germany on acid-free and non-aging paper (ISO 9706) by Kraft Druck, Ettlingen ISSN 1660–2242 e-ISSN 1662–2898 Contents

VII List of Contributors XI Foreword

Nutrition for Health 1 Evidence-Based Approach to Inform Clinical Nutrition Practice Chung, M. (Boston, Mass.); Lau, J. (Providence, R.I.) 7 Nutrient Adequacy Vorster, H.H. (Potchefstroom) 13 Energy Balance and Body Composition Schoeller, D.A. (Madison, Wisc.); Thomas, D. (Montclair, N.J.) 19 Appetite: Measurement and Management Mattes, R.D. (West Lafayette, Ind.) 24 Macronutrients: Requirements and Distribution Mann, J. (Dunedin) 30 Water-Soluble Vitamins Said, H.M. (Long Beach, Calif.) 38 Fat-Soluble Vitamins Johnson, E.J.; Mohn, E.S. (Boston, Mass.) 45 Minerals and Trace Elements Fairweather-Tait, S.J. (Norwich); Cashman, K. (Cork) 53 Vegetarian Diets Barr, S.I. (Vancouver, B.C.) 58 Dietary Supplements Coates, P.M.; Thomas, P.R. (Bethesda, Md.)

Nutrition for Special Circumstances 64 Nutrition in Pregnancy and Lactation Kruger, H.S. (Potchefstroom); Butte, N.F. (Houston, Tex.) 71 Exercise and Sports Maughan, R.J. (Loughborough); Shirreffs, S.M. (Brentford) 76 Food Allergy and Food Intolerance Leung, J. (Boston, Mass.); Crowe, S.E. (San Diego, Calif.) 82 Religion and Culture Vorster, H.H. (Potchefstroom) Nutrition for Disease States 87 Approach to the Patient and Differential Diagnosis Hoffer, L.J. (Montreal, Que.); Bistrian, B.R. (Boston, Mass.) 94 Cardiovascular Disease Risérus, U. (Uppsala) 100 Hypertension McLean, R.M. (Dunedin) 104 Obesity Gibson, A.A.; Sim, K.A.; Caterson, I.D. (Sydney, N.S.W.) 110 Diabetes Mellitus Mann, J. (Dunedin) 116 Obesity, Diabetes and the Asian Phenotype Bhardwaj, S.; Misra, A. (New Delhi) 123 Cancer Prevention and Treatment Key, T. (Oxford) 130 Nutritional Management in HIV/AIDS Infection van Graan, A.E. (Potchefstroom) 136 Osteoporosis Adeel, S.; Tangpricha, V. (Atlanta, Ga.) 141 Nutrition Support in Gastrointestinal Disease Scolapio, J.S.; Smith, D.J. (Jacksonville, Fla.) 146 Liver Diseases Obert, J.; Cave, M.; Marsano, L. (Louisville, Ky.) 151 Neurological Disorders Kumar, N. (Rochester, Minn.) 164 Anemias due to Essential Nutrient Deficiencies Stabler, S.P. (Aurora, Colo.) 169 Anorexia Nervosa Marzola, E. (Turin); Kaye, W.H. (San Diego, Calif.)

Food Policy 174 Global Food Policy and Sustainability Drewnowski, A. (Seattle, Wash.) 179 Undernutrition in the Developing World Vorster, H.H. (Potchefstroom) 186 The Changing Landscape of Malnutrition: Why It Matters Salam, R.A. (Karachi); Bhutta, Z.A. (Karachi/Toronto, Ont.) 193 Food Preparation, Processing, Labeling and Safety Hanekom, S.M. (Potchefstroom) 198 The Food Industry and Consumer Nutrition and Health Barclay, D. (Vevey); Haschke, F. (Salzburg)

205 Author Index 206 Subject Index List of Contributors

Saira Adeel Bruce R. Bistrian Division of Endocrinology, Metabolism and Lipids Clinical Nutrition Department of Medicine Beth Israel Deaconess Medical Center Emory University School of Medicine 1 Deaconess Road 101 Woodruff Circle, NE-WMRB1301 Boston, MA 02215 (USA) Atlanta, GA 30322 (USA) E-Mail [email protected] E-Mail [email protected] Nancy F. Butte Denis Barclay USDA/ARS Children’s Nutrition Research Center Nestec SA Department of Pediatrics Avenue Nestlé 55 Baylor College of Medicine CH–1800 Vevey (Switzerland) 1100 Bates Street E-Mail [email protected] Houston, TX 77030-2600 (USA) E-Mail [email protected] Susan I. Barr Food, Nutrition & Health Kevin D. Cashman The University of British Columbia School of Food and Nutritional Sciences and 2205 East Mall Department of Medicine Vancouver, BC V6T 1Z4 (Canada) Room 242, Food Science Building E-Mail [email protected] Cork (Ireland) E-Mail [email protected] Swati Bhardwaj Nutrition and Fatty Acid Research Ian D. Caterson National Diabetes, Obesity and The Boden Institute of Obesity, Nutrition, Exercise Cholesterol Foundation (N-DOC) and Eating Disorders D 16/8, 2nd Floor, Ardee City, Sector 52 The University of Sydney Gurgaon, Haryana, 122011 (India) Medical Foundation Bldg (K25) E-Mail [email protected] 92–94 Parramatta Road Camperdown, NSW 2050 (Australia) Zulfiqar A. Bhutta E-Mail [email protected] Center of Excellence in Women and Child Health Aga Khan University Matt Cave Stadium Road University of Louisville and Robley Rex VAMC PO Box 3500 505 S. Hancock Street, CTR512 Karachi 74800 (Pakistan ) Louisville, KY 40202 (USA) E-Mail [email protected] E-Mail [email protected] Mei Chung Ferdinand Haschke Nutrition/Infection Unit Department of Pediatrics Department of Public Health and Community Medicine Paracelsus Medical University School of Medicine Müllner Hauptstrasse 48 Tufts University AT–5020 Salzburg (Austria) 136 Harrison Avenue, M&V Wing 1st Floor E-Mail [email protected] Boston, MA 02111 (USA) E-Mail [email protected] L. John Hoffer Lady Davis Institute for Medical Research Sheila E. Crowe Jewish General Hospital Division of Gastroenterology 3755 Cote-Ste.-Catherine Road Department of Medicine Montreal, QC H3T 1E2 (Canada) University of California at San Diego E-Mail [email protected] 9500 Gilman Drive #0063 La Jolla, CA 92093-0063 (USA) Elizabeth J. Johnson E-Mail [email protected] Jean Mayer USDA Human Nutrition Center on Aging Tufts University Paul M. Coates 711 Washington Street Office of Dietary Supplements Boston, MA 02111 (USA) National Institutes of Health E-Mail [email protected] 6100 Executive Boulevard Room 3B01, MSC 7517 Walter H. Kaye Bethesda, MD 20892-7517 (USA) UCSD Eating Disorder Research and Treatment Program E-Mail [email protected] UCSD Department of Psychiatry Chancellor Park Adam Drewnowski 4510 Executive Dr., Suite 315 Center for Public Health Nutrition San Diego, CA 92121 (USA) University of Washington E-Mail [email protected] 355 Raitt Hall #353410 Seattle, WA 98195-3410 (USA) Timothy Key E-Mail [email protected] Cancer Epidemiology Unit Nuffield Department of Population Health Susan J. Fairweather-Tait University of Oxford Norwich Medical School Richard Doll Building, Roosevelt Drive University of East Anglia Oxford OX3 7LF (UK) Bio-Medical Research Centre (BMRC) 0.04 E-Mail [email protected] Norwich NR4 7TJ (UK) E-Mail [email protected] H. Salome Kruger Centre of Excellence for Nutrition Alice A. Gibson North-West University The Boden Institute of Obesity, Nutrition, Exercise PO Box 20333 and Eating Disorders Noordbrug The University of Sydney Esselen Street Medical Foundation Bldg (K25) Potchefstroom 2522 (South Africa) 92–94 Parramatta Road E-Mail [email protected] Camperdown, NSW 2050 (Australia) E-Mail [email protected] Neeraj Kumar Department of Neurology Susanna Magrietha Hanekom Mayo Clinic Center of Excellence for Nutrition E8A, Mayo Building, 200 First St. SW North-West University Rochester, MN 55905 (USA) Private Bag X6001 E-Mail [email protected] Potchefstroom 2520 (South Africa) E-Mail [email protected]

VIII Joseph Lau Rachael McLean Center for Evidence-Based Medicine Departments of Preventive and Social Medicine Public Health Program and Human Nutrition Brown University University of Otago 121 S. Main Street, 8th floor PO Box 56 Providence, RI 02912 (USA) Dunedin 9054 (New Zealand) E-Mail [email protected] E-Mail [email protected]

John Leung Anoop Misra Food Allergy Center at Tufts Medical Center and Fortis C-DOC Center of Excellence for Diabetes, Floating Hospital for Children Metabolic Diseases and Endocrinology Departments of Gastroenterology, Pediatric B16 Chirag Enclave Gastroenterology, and Allergy and Immunology New Delhi 110016 (India) Tufts Medical Center E-Mail [email protected] 800 Washington Street Boston, MA 02111 (USA) Emily S. Mohn E-Mail [email protected] Jean Mayer USDA Human Nutrition Center on Aging Tufts University Luis Marsano 711 Washington Street University of Louisville and Robley Rex VAMC Boston, MA 02111 (USA) 505 S. Hancock Street, CTR512 E-Mail [email protected] Louisville, KY 40202 (USA) E-Mail [email protected] Jonathan Obert University of Louisville and Robley Rex VAMC Jim Mann 505 S. Hancock Street, CTR512 Department of Human Nutrition Louisville, KY 40202 (USA) University of Otago E-Mail [email protected] PO Box 56 Dunedin 9054 (New Zealand) Ulf Risérus Email [email protected] Clinical Nutrition and Metabolism Department of Public Health and Caring Sciences Enrica Marzola Uppsala Science Park Department of Neuroscience SE–75185 Uppsala (Sweden) University of Turin E-Mail [email protected] Via Cherasco 11 IT–10126 Turin (Italy) Hamid M. Said E-Mail [email protected] University of California/VA Medical Program-151 5901 E. 7th St Richard D. Mattes Long Beach, CA 90822 (USA) Department of Nutrition Science E-Mail [email protected] Purdue University 212 Stone Hall, 700 W. State Street Rehana A. Salam West Lafayette, IN 47907-2059 (USA) Division of Women and Child Health E-Mail [email protected] Aga Khan University Stadium Road Ronald J. Maughan PO Box 3500 School of Sport, Exercise and Health Sciences Karachi 74800 (Pakistan) Loughborough University E-Mail [email protected] Ashby Road Loughborough LE11 3TU (UK) E-Mail [email protected]

IX Dale A. Schoeller Vin Tangpricha Nutritional Sciences Division of Endocrinology, Metabolism and Lipids University of Wisconsin Department of Medicine 1415 Linden Dr. Emory University School of Medicine Madison, WI 53706 (USA) 101 Woodruff Circle, NE-WMRB1301 E-Mail [email protected] Atlanta, GA 30322 (USA) E-Mail [email protected] James S. Scolapio Division of Gastroenterology Diana Thomas University of Florida, Jacksonville Campus Mathematical Sciences 4555 Emerson Street, Suite 300 Montclair State University Jacksonville, FL 32207 (USA) Richardson Hall 205 E-Mail [email protected] 1 Normal Ave Montclair, NJ 07043 (USA) Susan M. Shirreffs E-Mail [email protected] New Product Research GlaxoSmithKline Paul R. Thomas 980 Great West Road Office of Dietary Supplements Brentford, TW8 9GS (UK) National Institutes of Health E-Mail [email protected] 6100 Executive Boulevard Room 3B01, MSC 7517 Kyra A. Sim Bethesda, MD 20892-7517 (USA) The Boden Institute of Obesity, Nutrition, Exercise [email protected] and Eating Disorders The University of Sydney Averalda E. van Graan Medical Foundation Bldg (K25) Centre of Excellence for Nutrition 92–94 Parramatta Road North-West University Camperdown, NSW 2050 (Australia) Potchefstroom Campus E-Mail [email protected] Private Bag X6001 Potchefstroom 2520 (South Africa) Donna J. Smith E-Mail [email protected] Division of Gastroenterology University of Florida, Jacksonville Campus H.H. Este Vorster 4555 Emerson Street, Suite 300 Centre of Excellence for Nutrition Jacksonville, FL 32207 (USA) North-West University E-Mail [email protected] Potchefstroom Campus Private Bag X129 Sally P. Stabler Potchefstroom 2520 (South Africa) Division of Hematology E-mail [email protected] School of Medicine University of Colorado 12700 E. 19th Avenue, Room 9122 RC2, Campus Box B170 Aurora, CO 80045 (USA) E-Mail [email protected]

X Foreword

Nutrition takes center stage amongst all the life- Nutrition for the Primary Care Provider is style-related players which contribute to health or aimed at physicians around the world who treat disease. Indeed, nutrition underlies the preven- patients from all walks of life. The first section of tion and management of the most prevalent con- the book is devoted to the basic principles of nu- ditions faced by today’s primary care providers. trition, covering the fundamentals of body com- In developed countries, the erosion of our dietary position, energy balance and appetite as well as habits is a major contributor to conditions such the importance of the different macro- and mi- as type 2 diabetes, cardiovascular diseases and cronutrients. The following section builds on the obesity. A large proportion of the health care bud- principles of the first by focusing on the special get of developed countries is consumed by the needs for specific circumstances including preg- management of these increasingly widespread nancy, exercise, food allergies and religion. The disorders. In addition to these well-known condi- third section, Nutrition for Disease States, pro- tions, physicians also face a plethora of the more vides an overview of our latest understanding of subtle manifestations of inadequate nutrition, various disease states and how they are influ- such as liver disease, neurological disorders or enced by nutrition. The final section on Food anemia. And the problem of nutrition-related Policy takes a bird’s eye view, offering perspec- conditions is not only confined to the borders of tives on global sustainability, the rapidly chang- the developed world. In developing countries, the ing face of malnutrition and the role played by the specter of malnutrition is two-headed: on the one food industry in consumer health. hand, a large percentage of the population is af- We hope that this book will not only serve as flicted by malnutrition, but on the other hand, a practical reference source but also shape the there is a rising trend in the same noncommuni- way physicians use nutrition as a tool to prevent cable diseases that afflict the ‘westernized’ na- and cure disease. tions, such as metabolic conditions, obesity and Karen Yeow, Medical Writer cardiovascular disease.

Nutrition for Health

Bier D, et al. (eds): Nutrition for the Primary Care Provider. World Rev Nutr Diet. Basel, Karger, 2015, vol 111, pp 1–6 DOI: 10.1159/000362289

Evidence-Based Approach to Inform Clinical Nutrition Practice

a b Mei Chung Joseph Lau a Nutrition/Infection Unit, Department of Public Health and Community Medicine, School of Medicine, Tufts University, b Boston, Mass. , and Center for Evidence-Based Medicine, School of Public Health, Brown University, Providence, R.I. , USA

Key Words Introduction Evidence-based practice · Systematic reviews · Nutrition recommendations · Nutrition guidelines · The ultimate goal of evidence-based practice is to Clinical practice improve health outcomes and quality of care by applying valid up-to-date research findings to clinical practice. Although evidence-based prac- Key Messages tice began in medicine, over the past 20 years this • Nutrition is an important factor that underlies many approach for informing clinical decision-making chronic diseases, and dietary modification plays an important role in the management of established has been embraced by other fields, including nu- disease states. There is thus an expectation for nutrition. There is now an appreciable body of evi- trition recommendations and clinical practice dence to suggest that nutrition is an important guidelines to be evidence based. determinant of many chronic diseases and that • The systematic review is a comprehensive synthesis of dietary modification has a role in the manage- available evidence for addressing a specific clinical ment of established disease states. Thus, there is question. Evidence-based clinical practice guidelines an expectation that nutrition recommendations are formulated statements aimed at facilitating clinical decision-making for specific clinical circumstances. and nutrition clinical practice guidelines should • Systematic reviews and evidence-based guidelines be evidence based. The systematic review, an in- are the two best sources of information to assist tegral component of the evidence-based ap- clinical decision-making, and are important tools proach, is a comprehensive synthesis of available for addressing clinical questions. evidence that meets predefined eligibility criteria • The practitioner should be aware of unique nutrition- to address a specific clinical question or range of specific parameters that must be taken into consideration before applying the findings of systematic re- questions. It uses rigorous processes to minimize views or evidence-based guidelines to daily practice. bias [1], and can provide busy primary care pro- • In the clinic, it is necessary to integrate the best viders with a ‘quick and easy way’ to the best syn- available evidence with clinical expertise, patient thesized scientific evidence for informing clinical values and preferences, and cultural beliefs. practice. Evidence-based guidelines are system- © 2015 S. Karger AG, Basel atically developed statements based on scientific Table 1. Example of research questions formulated based on the PI(E)CO components

Clinical nutrition care Example research question structure process Nutrition assessment What is the O accuracy, reliability, or agreement of E calculated energy expenditure (assessment) versus C measured energy expenditure by indirect calorimetry (assessment) among P obese children? Nutrition diagnosis What is the O sensitivity and specificity of E nutrition assessment tools (assessment) to diagnose C vitamin deficiency (nutrition diagnosis by a reference standard) among P adult men and women? Nutrition intervention Among P pregnant or breastfeeding women, what are effects of I maternal dietary supplementation of omega-3 fatty acids versus C placebo or no supplementation on O infant health outcomes? P = Population of interest; I/E = intervention/exposure of interest; C = control or comparator of interest; O = outcome of interest.

evidence to assist practitioner and patient decisions about appropriate health care for specific Ask clinical circumstances. While sharing the same principles with evidence-based medicine, the application of evi- Assess Acquire dence-based methods to nutrition needs to incorporate unique nutrition-related considerations [2]. This chapter focuses on examples of these issues and how they should be considered when evaluating evidence to inform clinical nutrition practice. Apply Appraise

Basic Steps of Evidence-Based Clinical Fig. 1. Basic steps of evidence-based clinical nutrition Nutrition Practice practice.

Basic steps of evidence-based clinical nutrition practice are presented in figure 1 . information, or evidence. One useful way of de- Step 1: Ask a Clinical Question fining a research question is to use the PI(E)CO Important clinical questions may not be directly approach: answerable from the literature. For example, • P opulation or patient: Who is the target popu- ‘Should dietary supplements be recommended to lation? my patients?’ is an important clinical question but • I ntervention or E xposure: What intervention needs to be specifically focused in order to seek or exposure are you interested in? for research evidence. A well-constructed re- • C ontrol or comparison: What are you com- search question will help to identify the correct paring the intervention or exposure with?

2 Chung /Lau

• O utcome: What outcomes are you interested views as part of their methods for analyzing the in measuring? evidence. Other important aspects of guideline The PI(E)CO approach is most suitable for development, such as conflict of interest disclo- formulating a research question on the compara- sure and grading of body of evidence, should also tive efficacy of two alternative clinical nutrition be evaluated. A high quality, trustworthy, evi- interventions, but can also be used to define re- dence-based practice guideline should be based search questions on nutrition assessment or diag- on a systematic review of the existing evidence nosis ( table 1 ). and apply an explicit and transparent process that minimizes distortions, biases, and conflicts of in- Step 2: Acquire the Best Evidence for Informing terest [4] . Clinical Nutrition Decision-Making In everyday clinical nutrition practice, many Searching and Evaluating Systematic Reviews questions arise, such as what nutrition informa- Published systematic reviews can be identified tion or advice should be discussed with patients, through PubMed ® Clinical Queries search for and the benefits and harms of performing a par- ‘Systematic Reviews’. The PI(E)CO components ticular nutritional assessment, diagnosis, inter- of your clinical question can also be used to effec- vention, or monitoring and evaluation [3] . With tively find relevant systematic reviews. For a sys- more than 1,900 new articles being added to Med- tematic review, the PI(E)CO components define line® each day1, clinicians have a daunting task to much of the eligibility criteria for selecting the keep up with the rapidly expanding knowledge studies, and thus define the relevance of the base related to health. An evidence-based ap- systematic reviews to inform clinical practice. proach to clinical decision-making is time-con- Unique nutrition-related considerations [2] for suming and requires considerable skill. System- evaluating the relevance of a systematic review to atic reviews and evidence-based clinical practice inform clinical nutrition practice include: base- guidelines are the two best sources of information line nutrient exposure, nutrient status (e.g. nutri- to assist clinical decision-making. Many orga- ent deficient vs. sufficient, or malnutrition vs. nizations have produced systematic reviews on overnutrition/obesity), bioequivalence of bioac- nutrition-disease relationships or nutritional in- tive compounds, bioavailability, multiple and interventions (table 2 ). Many of these systematic terrelated biological functions, undefined nature reviews have also been used to support evidence- of some nutritional interventions (e.g. food prep- based nutrition guidelines or practice recommen- aration methods and the formulation of dietary dations. supplements), and uncertainties in dietary intake assessment. Searching and Evaluating Evidence-Based Practice Guidelines Step 3: Appraise the Evidence for Its Validity and Evidence-based practice guidelines can be identi- Usefulness fied by searching National Guideline Clearing- Systematic reviews vary in their quality [5] , which house (http://www.guidelines.gov) and limiting can affect their usefulness in clinical nutrition the searches to guidelines that used systematic re- practice [6]. Poor-quality systematic reviews can lead clinicians to the wrong conclusions and ultimately to inappropriate clinical decisions. The In- 1 Over 1,900 indexed per day was based on 724,831 institute of Medicine has published a report that indexed citations added to Medline® in 2011 divided by 365 cluded 21 standards to ensure objective, transpar- days (http://www.nlm.nih.gov/bsd/stats/cit_added.html). ent, and scientifically valid systematic reviews [7] .

Evidence-Based Approach to Inform Clinical Nutrition Practice 3 Table 2. Organizations producing systematic reviews or evidence-based guidelines on nutrition-disease relationships or nutritional interventions

Sources Clinical nutrition topics

3ie International Initiative for Impact 3ie aims to generate new evidence of what works, synthesize and disseminate this Evaluation evidence, build a culture of evidence-based policy-making, and develop a capacity (http://www.3ieimpact.org/) to produce and use impact evaluations. 3ie’s Systematic Review Programme provides a range of research synthesis products and services include a database of systematic reviews of the effectiveness of social and economic interventions in low- and middle-income countries, such as the following topics related to food and nutrition: – Community-based interventions for improving perinatal and neonatal health outcomes in developing countries: a review of the evidence. – Impact of maternal education about complementary feeding and provision of complementary foods on child growth in developing countries. Academy of Nutrition and Dietetics, The Evidence Analysis Library aims to promote evidence-based dietetics practice Evidence Analysis Library through an online library of systematic reviews on important dietetic practice (http://www.adaevidencelibrary.com) questions and evidence-based guidelines and toolkits. Topics are organized according to diseases/health conditions, nutrients, foods, life cycle and nutrition, and the nutrition care process. Topics under the nutrition care process include: – Screening and referral system – Health disparities nutrition assessment – Nutrition assessment – Nutrition diagnosis – Nutrition intervention – Nutrition monitoring and evaluation – Outcomes management system

Agency for Healthcare Research and The Effective Health Care Program develops a wide array of products for researchers Quality and others interested in the systematic study of evidence and research methods. Effective Health Care Program Selected evidence reports on clinical nutrition topics include: (http://www.effectivehealthcare.ahrq.gov/) – Dietary supplements in adults taking cardiovascular drugs – Adjuvant treatment for phenylketonuria – Vitamin D and calcium: a systematic review of health outcomes – Comparative effectiveness of treatments to prevention fractures in men and women with low bone density or osteoporosis Community Preventive Services Task Force The Guide to Community Preventive Services is a free resource to help you choose The Community Guide – Promoting Good programs and policies to improve health and prevent disease in your community. Nutrition Systematic reviews are used to answer these questions: (http://www.thecommunityguide.org/ – School-based programs promoting nutrition and physical activity nutrition/index.html) – Provider-oriented intervention (e.g. education, reminders) – Interventions in community settings (e.g. reducing screening time, technology-based interventions, specific settings) The Cochrane Collaboration The Cochrane Library consists of over 5,000 Cochrane systematic reviews that aim The Cochrane Library to help health care providers, policy-makers, patients, their advocates and carers, (http://www.thecochranelibrary.com) make well-informed decisions about health care. Selected Cochrane reviews on clinical nutrition topics include the following: – Enteral nutritional therapy for induction of remission in Crohn’s disease – Protein restriction for children with chronic kidney disease – Nutrition support for bone marrow transplant patients – Protein and energy supplementation in elderly people at risk of malnutrition

4 Chung /Lau

Table 2 (continued)

Sources Clinical nutrition topics

United Sates Department of Agriculture The Nutrition Evidence Library provides a detailed evidence portfolio for each of Center for Nutrition Policy and Promotion the 2010 Dietary Guidelines Advisory Committee’s systematic reviews, which form Nutrition Evidence Library the bases for the Dietary Guidelines for Americans. Topics are organized into the (http://www.nel.gov/) following categories: Dietary Guidelines for Americans – Alcohol (http://www.cnpp.usda.gov/ – Carbohydrates DietaryGuidelines.htm) – Energy balance and weight management – Fatty acids and cholesterol – Food safety and technology – Nutrient adequacy – Protein – Sodium, potassium, and water World Cancer Research Fund & American The WCRF/AICR Continuous Update Project (CUP) is an ongoing review of cancer Institute for Cancer Research (WCRF/AICR) prevention research that provides up-to-date evidence on how people can reduce Food, Nutrition, Physical Activity, and the their cancer risk through diet and physical activity. Prevention of Cancer: A Global Perspective They provide cancer site systematic reviews, and separate reviews on cancer (http://www.dietandcancerreport.org/) survivorship, the determinants of weight gain, overweight and obesity.

A critical step in evidence synthesis is the assessment methods or nutrient biomarkers) and quality assessment of the primary studies includ- controlling for potential confounding by other ed in the systematic review. Quality assessment lifestyle factors. helps to determine the validity of the study findings and to interpret the effects of methodologi- Steps 4 and 5: Apply the Evidence to Clinical cal and clinical/biological heterogeneity on the Nutrition Practice and Assess the Impacts of the study results. The readers of any systematic re- Evidence-Based Practice view, however, should be aware that there are in- In the clinical decision-making process, it is nec- trinsic subjective components in any quality ap- essary to integrate the best available evidence with praisal tool, and there is no true reference stan- clinical expertise, patient values and preferences, dard for quality. Thus, it is important to have and cultural beliefs. Clinical nutrition practice transparent reporting of quality assessment indi- ideally should be based on high strength of evi- cators in order to minimize subjectivity and er- dence (incorporating quality, quantity, and con- rors in quality appraisal. Quality appraisal is im- sistency of the evidence) and high applicability to portant because the strength of a body of evi- the clinical setting. When applying the evidence to dence that underlies the answers to a particular clinical practice, clinicians should also account for research question is primarily determined by the the constraints of clinical decision-making, such validity of the primary studies relevant to that re- as policies, community standards, time, and research question. Several nutrition-specific issues sources. After the evidence-based practice is ap- may need to be considered as part of quality as- plied, changes to quality of care should be assessed sessment indicators, such as uncertainty in mea- and analyzed to inform future adjustments [8] to suring nutrient exposures (e.g. validity of dietary the evidence-based clinical nutrition practice.

Evidence-Based Approach to Inform Clinical Nutrition Practice 5 Conclusions • Many unique nutrition considerations have been identified and need to be incorporated • Systematic reviews and evidence-based clini- into the clinical nutrition decision-making cal practice guidelines can provide an objec- process. tive summary and critical appraisal of the • Further research on how to integrate and ana- available evidence and can increase transpar- lyze these unique nutrition considerations in ency in the clinical decision-making process. systematic reviews [10] is needed to promote However, they are not free of limitations [9] . and inform evidence-based clinical nutrition • To use these evidence-based resources effec- practice. tively, an understanding of the strengths and limitations of the systematic reviews and clinical practice guidelines is needed.

References

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Med 1997; 126: 376–380. Clin Nutr 2009; 89: 1099–1113. Altman DG (eds): Systematic Reviews in 2 Lichtenstein AH, Yetley EA, Lau J: Ap- 6 Wolfenden L, Wiggers J, Tursan d’Espai- Health Care: Meta-Analysis in Context, plication of systematic review method- gnet E, Bell AC: How useful are system- ed 2. London, BMJ Publishing Group, ology to the field of nutrition. J Nutr atic reviews of child obesity interven- 2008.

2008; 138: 2297–306. tions? Obes Rev 2010; 11: 159–165. 10 Chung M, Balk EM, Ip S, et al: System- 3 Lacey K, Pritchett E: Nutrition Care Pro- 7 Institute of Medicine: Finding What atic review to support the development cess and Model: ADA adopts road map Works in Health Care: Standards for of nutrient reference intake values: chal- to quality care and outcomes manage- Systematic Reviews. Washington, The lenges and solutions. Am J Clin Nutr

ment. J Am Diet Assoc 2003; 103: 1061– National Academies Press, 2011. 2010; 92: 273–276. 1072. 8 Langley GL, Nolan KM, Nolan TW, et al: 4 Institute of Medicine: Clinical Practice The Improvement Guide: A Practical Guidelines We Can Trust. Washington, Approach to Enhancing Organizational The National Academies Press, 2011. Performance, ed 2. San Francisco, Jossey-Bass Publishers, 2009.

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Nutrition for Health

Bier D, et al. (eds): Nutrition for the Primary Care Provider. World Rev Nutr Diet. Basel, Karger, 2015, vol 111, pp 7–12 DOI: 10.1159/000362290

Nutrient Adequacy

H.H. Vorster

Centre of Excellence for Nutrition, North-West University, Potchefstroom Campus, Potchefstroom , South Africa

Key Words Introduction Nutrient adequacy · Nutritional assessment · Nutritional status · Nutrient recommendations · Human growth, development and health through- Nutrient goals · Food-based dietary guidelines out the life course, from preconception until death, are dependent upon adequate nutrition. Nutrient adequacy means being nutrition secure Key Messages through the appropriate consumption of energy • Nutrient adequacy, a result of consumption of and all essential nutrients in sufficient amounts sufficient amounts of all essential nutrients and over time. Nutrient adequacy leads to ‘optimal’ energy to meet individual requirements, is a pre- nutritional status in which both under- and over- requisite for normal growth, development and health. nutrition are avoided. • Two thirds or more of hospital patients suffer from Many ‘apparently’ healthy individuals may malnutrition at initial presentation. suffer from some form of malnutrition, and up to • A variety of standardized methodological tools to two thirds or more of hospitalized patients may assess, restore and maintain nutritional status are be malnourished, often because of the multiple available. effects of disease on the intake, absorption, me- • A holistic approach is advised, including processes tabolism, storage and excretion of nutrients [1] . It of screening for malnutrition, assessing nutritional status, diagnosing specific deficiencies, and design- is therefore important for health professionals ing and implementing an appropriate medical nu- (HPs) to screen patients for risk of nutritional in- trition therapy plan. adequacies [1, 2], to assess nutritional status, and • Health professionals should be aware of and use to implement and evaluate appropriate medical available methodological and interpretive tools to nutrition therapy (MNT) when necessary. These assist them in this important task. processes are complex and need specialized © 2015 S. Karger AG, Basel skills. Table 1. Steps to follow for restoring and maintaining nutrient adequacy

Sequence of steps Measurement and evaluation tools

1. Nutritional screening: To identify those at risk and Routine medical history information when admitted to vulnerable (e.g. children, pregnant women, the elderly, the hospital/clinic. Standardized, simple, brief, generic and flexible poor, and the ill). hospital questionnaires, screening forms and checklists to be used by all HPs. Nutritional scores are available. 2. Nutritional status assessment: To identify those that need Methods include standardized ecological, dietary intake, nutrition support to restore and maintain optimal nutrition anthropometric, biochemical and clinical (physical) status and to design appropriate MNT interventions. examinations. For each type, appropriate tables, charts, growth curves, etc. with recommended values available. 3. Diagnosis: Classification of malnutrition for planning of an Integrate the information obtained in 1 and 2, and design an appropriate MNT plan. appropriate plan to address the specific nutrition problem, either by counselling, diversification of diets, supplementation or specialized medical intervention. 4. Designing and implementation of MNT plan. The MNT plan must define the nutrition problem, therapeutic goals, appropriate intervention, educational needs of patients, including an evaluation plan. After evaluation (by reassessing) and adjustments to care if necessary, the discharge documents of the hospital/clinic should be completed (for follow-up care).

A variety of methodological tools have been Nutritional Status Assessment developed to assist HPs to restore and maintain the nutritional status of individuals, each with A summary of available methods and tools to as- appropriate recommendations, standards, charts sess nutritional status is given in table 2 . In clin- and cut-points indicating ‘normal’ ranges and ical settings, it is often not possible to obtain ac- values for optimal, under- and overnutrition. curate nutrient intakes, and HPs must rely on Comprehensive descriptions of these can be indices calculated from anthropometric mea- found in most nutrition texts, especially those for surements, using standardized tables and charts clinical dietetic and nutrition practice [1] . [1] for evaluation of assessment results. This chapter shows how these processes and Different levels or stages of depletion/reple- tools are interlinked, and highlights some new tion should be considered because they may developments in nutritional assessment method- need different assessment methodologies. Blood ology. values of a micronutrient will not necessarily reflect intakes or status, because the body has well-coordinated, tightly controlled regulatory A Holistic Approach to Achieving and systems to maintain blood levels of nutrients Maintaining Nutrient Adequacy within narrow ranges, as well as different storage mechanisms for different nutrients. The The steps to be taken to achieve nutrient adequa- stages of depletion and repletion and the sug- cy are summarized in table 1 . They often form gested assessment methods are briefly summa- part of established protocols and algorithms in rized in table 3 . hospitals and clinics. The same steps can be followed for patients outside clinical settings.

8 Vorster

Table 2. Summary of general nutritional assessment methods

Nutrition status assessment methods Application and interpretation

Ecological methods: Noninvasive, suitable for all settings, nonspecific. Also used Documentation of all factors known to influence nutrition intakes: for screening purposes. Use standardized hospital forms medical, social, health (e.g. allergies, dental problems), medication and checklists. use, and nutrition history, cultural factors, recent weight changes, etc. Dietary and nutrient intake measurement: Use validated questionnaires; food composition and Use of validated questionnaires, interviews and recording methods nutrient recommendation tables necessary for calculations, to assess dietary patterns, food and nutrient intake over specified interpretation and comparisons. Most noninvasive method. times: 24-hour recalls, weighed food records, diet histories (diaries), Low cost, high throughput. Suitable for all settings. Have qualitative and quantitative food frequency questionnaires, or many limitations: under- and overreporting, impaired short questionnaires. Translate dietary data to nutrients with memory, etc. Verify intakes by using biomarkers: computer programs based on food composition tables. metabolomic finger-printing of the food metabolome, in spot urine samples; may identify new biomarkers. Anthropometry: Noninvasive and reliable. Growth charts, tables with cut- Measurement of physical dimensions and gross body composition; points and standards available in nutrition texts. Low-cost, usually weight and height (for age), body circumferences (head in high throughput. Suitable in all settings, especially to children, waist, hip, mid-arm, etc.) and 7 skin folds (to calculate fat monitor growth of children and assess hospital patients. percent). Several indices and ratios are calculated from these Indicative of past nutritional history. Standardized measurements, including weight-for-age, height-for-age, and equipment should be used. weight-for-height z-scores in children, body mass index (BMI), waist-hip ratio etc. Impedance, dual-energy X-ray absorptiometry and other methods used to determine body fat percentage. Laboratory methods: Provide ‘unbiased’ scientific data. Invasive. Static and functional tests, using capillary blood, dried blood spots, For some nutrients, cut-points and normal ranges are venous blood, serum, plasma, spot urine, 24-hour urine or saliva. available, but may be nonspecific (other contributing and Tests can be behavioral, physiological, biochemical, nutrient confounding factors influence results). May be difficult to challenge tests, or using genomics and/or a metabolomics interpret because of a lack of standards and cut-points. approach to identify dietary intake markers and/or markers of Often expensive equipment and ‘sophisticated‘ expertise nutritional status. needed. Clinical (physical) methods: Suitable for all settings, but HPs must be specially trained Medical history and physical (clinical) examinations looking for to recognize symptoms of specific deficiencies. Use a well-established signs and symptoms of nutrient deficiencies (skin, holistic approach in which observations are integrated with hair, tongue, eyes, etc.), by using systematic inspection, palpitation, other assessment results for correct diagnosis. Specific percussion and auscultation techniques. Handgrip dynamometry texts and illustrations of signs of malnutrition, especially used to assess muscle strength. micronutrients, are available.

Table 3. Measurement of stages of depletion/repletion of nutrient status

Depletion/repletion stage Suggested assessment method

1. Dietary inadequacy Dietary intakes 2. Decreased level in reserve tissue store Biochemical laboratory 3. Decreased level in body fluids Biochemical laboratory 4. Decreased functional level in tissues Anthropometry and/or biochemical 5. Decreased concentration and activity of nutrient-dependent Biochemical and molecular laboratory methods; metabolic enzymes or messenger RNA for relevant protein synthesis and functional challenge tests 6. Functional change Physiological and behavioral assessments 7. Clinical symptoms Clinical: anthropometry (growth), clinical signs 8. Anatomical signs Clinical: anthropometry (growth), clinical signs

Nutrient Adequacy 9 New Developments in Nutrient Assessment ty factor. It is similar to the ‘upper tolerable Tools nutrient intake level’ (UL) used in the USA and Canada, and the ‘upper end of safe intake Nutrient Recommendations range’ used in the UK and Europe. Nutrient recommendations (NRs) are evidence- • Individual nutrient levelx (INLx ): The INL is based recommendations designed by authorita- derived from the ANR where x is a percentile tive bodies, such as the United Nations (WHO, of the mean chosen to guide individual in- FAO) Agencies or the USA Institute of Medicine takes. It is similar to the Recommended Di- [3] for defining adequate nutrient intakes. Al- etary Allowance (RDA) used in the US and though the ranges of optimal intake for specified Canada, the ‘reference nutrient intake’ (RNI) age, sex and activity groups given in different sets used in the UK, and the ‘population reference of NRs are remarkably similar, the terminology intake’ (PRI) used in Europe. An INL 98 would used is varied and confusing. UN agencies recent- be the level that, based on scientific evidence, ly harmonized the terminology and suggest the would meet the need of 98% of individuals in following terms [4] : a particular age and sex group. • Nutrient intake values (NIVs): An umbrella NRs are used for assessment of nutritional sta- term. It includes the average nutrient require- tus (by comparing reported intakes with NRs), for ment (ANR) and upper nutrient level (UNL) the planning of nutrition policies, strategies, pro- and terms derived from these. It is synony- grams and regulatory frameworks, for implement- mous with the term ‘daily reference values’ ing nutrition programs, and also for surveillance (DRVs) or ‘dietary reference intakes’ (DRIs) and for evaluating the outcomes of interventions. used in many countries and ‘nutrient refer- Most nutrition textbooks include tables of NRs, of- ence values’ (NRVs) used by the food industry ten still called the RDAs. They can also be found on to label products. the websites of several UN Agencies (such as the • Average nutrient requirement: The ANR is esti- WHO or FAO) that provide scientific advice for mated based on distributions of nutrient intakes member countries on achieving nutrition security. required to achieve a specific outcome in a specified population. If those intakes are distributed Dietary Goals normally, the population’s mean requirement is Dietary goals, such as those of the WHO [5] , are its ANR. If not normally distributed, data must recommendations from authoritative bodies to be transformed and the resulting median is the lower the risk of overweight, obesity and many ANR. ANRs are established for all essential nu- noncommunicable diseases (NCDs) and often in- trients, but also for those of public health rele- clude recommendations for nutrients and/or vance, such as dietary fiber. The ANR is similar foods that are not essential but of public health to the estimated average requirement (EAR) importance, or that should be limited or avoided used in the USA, Canada and the UK, and the (e.g. added sugars or salt). Planning interventions average requirement (AR) used in Europe. in patients suffering from nutrition-related NCDs • Upper nutrient level: The highest level of ha- will rely on both NRs and dietary goals. Some sci- bitual nutrient intake that is likely to pose no entific and/or professional societies have their risk of adverse health effects in almost all indi- own regularly updated dietary goals [6] . viduals in the general population. It is determined by using the ‘no observed adverse effect Food-Based Dietary Guidelines level’ (NOAEL) and the ‘lowest observed effect A set of food-based dietary guidelines (FBDGs) is level’ (LOAEL) with an appropriate uncertain- a tool to educate individuals and groups on

10 Vorster

Fig. 1. The South African Food Guide: indicating only those groups of foods (with examples from traditional foods) that should be eaten regularly. The size of the circles is in proportion to the amounts that should be eaten. Used with permission from the SA Department of Health, Direc- torate Nutrition, 2013.

healthy eating. FBDGs are based on foods and Growth Standards eating patterns, and consist of short, positive, and An essential tool to evaluate the growth of chil- ‘marketable’ science-based messages that aim to dren is growth reference data. Many nutrition change eating behavior towards more optimal di- texts still give growth charts based on the growth ets. People eat foods and not nutrients. Nutrition of children that have been formula fed. The WHO scientists have therefore ‘translated’ NRs into [9] recently published physical growth curves guidelines that consumers can understand and based on a multicenter study in which the growth relate to [7] . FBDGs should be country specific, of breastfed children was monitored. These charts based on existing eating patterns, traditional provide growth reference data for children of foods and foods and beverages that are available, 0–60 months, and 5–19 years. Their website [9] accessible and affordable. FBDGs are supported also includes application tools for use of these by a food guide (see fig. 1 ) and other relevant ed- charts in assessing growth and nutritional status. ucational materials that may help with targeted implementation. Any set of FBDGs should lead to adequate nutrition, but also to diets that will Conclusions help to protect against development of NCDs. More than 50 countries have developed FBDGs • Nutrient adequacy of individuals can be for their own populations [8]. Most have messag- achieved by following a systematic, integrated es on the basic food groups: cereals and grains, approach of screening, assessment, diagnosis vegetables and fruit, legumes or pulses, milk and and implementation of appropriate MNT dairy, animal-derived foods (meat, fish, chicken plans. and eggs), and fats and oils, to advise that people • HPs should be aware that there are many should eat and enjoy a variety of foods. Some also methodological as well as interpretation, eval- advise on alcohol consumption, food hygiene, uation, and education tools available to assist breastfeeding and physical activity. them in this important task.

Nutrient Adequacy 11 References

1 Mahan LK, Escott-Stump S (eds): Krau- 4 King JC, Vorster HH, Tome DG: Nutri- 7 FAO/WHO: Preparation and use of se’s Food, Nutrition & Diet Therapy, ed ent intake values (NIVs): a recommend- food-based dietary guidelines. Report of 10. Philadelphia, WB Saunders, 2000, ed terminology and framework for the a joint FAO/WHO consultation. WHO p 1194. derivation of values. Food Nutr Bull Technical Support Series No. 880. Ge-

2 Pablo AMR, Izaga MA, Alday LA: As- 2007; 28:S16–S26. neva, WHO, 1998, pp 1–108. sessment of nutritional status on hospi- 5 WHO: Diet, nutrition and the preven- 8 http://www.fao.org/aghumannutrition/ tal admission: nutritional scores. Eur J tion of chronic diseases. Report of a nutritioneducation/49741/en/, updated

Clin Nutr 2003; 57: 824–831. joint FAO/WHO consultation. WHO 2013 (accessed February 2013). 3 Institute of Medicine, Food and Nutri- Technical Support Series No. 916. Ge- 9 http://www.who.int/childgrowth/en/, tion Board, RDA subcommittee on the neva, WHO, 2003. 2006 and 2007 (accessed February tenth edition of the recommended di- 6 Krauss RM, Eckel RH, Howard B, et al: 2013). etary allowances, ed 10. Washington, AHA Dietary Guidelines: Revision 2000. National Academy Press, 1989. A statement for health professionals from the Nutrition Committee of the American Heart Association. Circula-

tion 2000; 102: 2284–2299.

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Nutrition for Health

Bier D, et al. (eds): Nutrition for the Primary Care Provider. World Rev Nutr Diet. Basel, Karger, 2015, vol 111, pp 13–18 DOI: 10.1159/000362291

Energy Balance and Body Composition

a b Dale A. Schoeller Diana Thomas a b Nutritional Sciences, University of Wisconsin, Madison, Wisc. , and Mathematical Sciences, Montclair State University, Montclair, N.J. , USA

Key Words Introduction Adiposity · Body mass index · Body fat · Body composition · Energy balance In the last 30 years, global health concerns have shifted focus from malnutrition to obesity. De- spite the serious health consequences of both di- Key Messages rections of energy imbalance, most physicians do not respond with equal concern with regard to • Changes in weight and height over time are critical parameters for detecting health-related energy im- obesity. Indeed, weight status is frequently not re- balances. corded in a patient’s chart. Yet changes in weight • Current adult adiposity can be evaluated using and height over time are critical statistics for de- body mass index (BMI). The healthy BMI range is be- tecting health-related energy imbalances. Cur- tween 18.5 and 25. Though medically useful, BMI is rent weight status is a summary of energy balance an imperfect measure of excess fat. over time and, when tracked, can indicate the risk • Other clinical methods for assessment of fat percentage (such as skin-fold measurement, bioelectri- of existing or future chronic disease. These trends, cal impedance analysis, or dual X-ray absorptiome- however, can only be identified by frequent re- try) should be used to determine an individual’s cording in the patients’ chart. overall health status. • It is difficult to assess energy intake or energy expenditure with sufficient accuracy to predict an in- Interpreting Weight Status dividual’s weight change. The application of weight change models can be useful for summarizing the components of energy metabolism as they capture Current adult adiposity is easily evaluated using weight-dependent alterations in energy balance. the body mass index (BMI), which is weight (kg)/ • The evolution of an individual’s weight over time height (m) 2 [705 × weight (lbs)/height (in)2 ]. The can indicate potential energy imbalances, high- healthy BMI range falls in between 18.5 and 25. lighting trends towards obesity and increased risk Individuals with BMI below the healthy range are of related illnesses. © 2015 S. Karger AG, Basel classified as underweight and those with BMI ex- 60

30 Body fat (%) 20

Male 10 Female

0 15 20 25 30 35 40 45 50 BMI

Fig. 1. Percent body fat increases with BMI, but is highly variable for a given BMI. At the same BMI, percent body fat is about 10 percentage points greater in women than in men. Values are for adults between 18 and 60 years of age.

ceeding the healthy range are classified as over- or eating disorders. Individuals classified as weight (BMI between 25 and 30) or obese (BMI obese have increased risk for prediabetes, diabe- 30 or greater). Childhood adiposity cannot be as tes, cardiovascular disease, hypertension, stroke, easily classified using BMI, largely because clas- certain cancers, and all-cause mortality. Chil- sification cut-points vary with age. Instead, clas- dren not classified at a healthy weight are also at sification of adiposity in children is based on risk for these comorbidities. The rise in pediat- the percentile of weight-for-height as a function ric obesity from 5 to 20% over the past 35 years of age and sex using the CDC growth charts, or has been followed by a concomitant increase in BMI z-scores (the number of standard deviations chronic disease (e.g. type 2 diabetes), raising con- away from the 50th percentile). Online calcula- cerns regarding excess weight in children. tors have been developed to determine percentile and z-scores for children; these are available on the CDC website (http://www.cdc.gov/healthy- B o d y C o m p o s i t i o n weight/assessing/bmi/childrens_bmi/about_ childrens_bmi.html). BMI is an anthropomorphic indicator of body Adult BMI cut-points were developed from composition and though medically useful, it is an epidemiological evidence that individuals classi- imperfect measure of excess fat [1]. A high BMI fied as underweight are more at risk for contract- can result from either excess body fat or, less fre- ing infectious diseases. Moreover, unintentional quently, elevated muscularity. This is evidenced weight loss is an indicator of limited access to by the high variance in percent fat versus BMI food, gastrointestinal disease, wasting diseases, ( fig. 1 ). Waist circumference provides an addi-

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Table 1. Classification of weight and waist circumference status Children <18 years, weight-for-height percentile <5th percentile for age and sex undernourished ≥5th percentile for age and <85th for sex healthy weight ≥85th percentile for age and <95th for sex overweight ≥95th percentile for age and sex obese Adults, BMI <18.5 undernourished ≥18.5 and <25 healthy weight ≥25 and <30 overweight ≥30 and <35 class I obesity ≥35 and <40 class II obesity ≥40 class III obesity Adults, waist circumference Male >102 cm (>40 in) high metabolic risk Female >88 cm (>35 in) high metabolic risk

tional clinical measurement to distinguish be- fer). While the expense and/or increased burden tween body types (table 1 ). Waist circumference on the patient make other methods of body com- is an excellent indicator of abdominal fat, which position assessment less accessible, some meth- is the fat depot most highly associated with chron- ods such as magnetic resonance imaging (MRI) ic disease [2] . provide highly accurate estimates. Other mea- Numerous methods exist for body composi- surements include ultrasound, isotope dilution tion assessment [3] . The most common body for total body water, and underwater weighing. composition model is the two-compartment MRI, ultrasound, and isotope dilution require model, which divides the body into fat (neutral expensive equipment and trained operators, lipids) and fat-free mass (water, protein, mineral, while underwater weighing also requires patients structural lipid and carbohydrate) and generally to be submerged in a water tank. The recent de- expresses adiposity as a percent of body mass (ta- velopment of air displacement plethysmography, ble 1 ). Clinically feasible methods of determining however, offers a somewhat more practical alter- percent body fat are skin-fold measurement or native to underwater weighing. bioelectrical impedance analysis (BIA), but the Clinical assessment of percent fat can be ap- accuracy varies widely depending on the meth- plied to determine health status. Young and odology and instrument. Additionally, skin-fold middle-aged adult percent fat values of <6% in and BIA-assessed body fat are less accurate espe- males and <12% in females may indicate under- cially among obese populations. The most com- nutrition. Obesity as classified by BMI corre- mon clinically applicable three-compartment as- sponds to body fat percentages above 25% fat in sessment of body composition (fat, nonosseous males and 35% in females (percentages vary fat-free tissue, and bone mineral) is dual X-ray slightly with age and race) [1] . As a total mass, absorptiometry (DXA).The bone mineral mea- body fat in healthy adults averages 12 kg and sure, expressed either as bone mineral mass or provides thermal and mechanical insulation bone mineral density, includes risk assessment of and a valuable energy store. Body fat has an en- osteoporosis, along with body composition esti- ergy density of 9.5 kcal/g (39.7 kJ/g) and can pro- mates of prior energy balance status (DXA mea- vide 114,000 kcal (476 MJ) of energy during surement protocols for these two outcomes dif- starvation. Lipid energy stores can vary, howev-

Energy Metabolism 15 er, from 33,000 kcal (140 MJ) in athletes, to over ages between 1.7 and 1.9 [4] but can vary from 1.4 500,000 kcal (2,010 MJ) in class III obese indi- (very sedentary) to over 2.0 (elite athletes or heavy viduals, compared to a carbohydrate store of manual laborers) [5] . only about 2,000 kcal. Energy balance is rarely achieved on a day to day basis. Daily energy intake varies with a standard deviation of 25%, and TEE varies with a E n e r g y B a l a n c e standard deviation of about 10%. When time av- eraged over a few weeks, however, energy balance Since energy can neither be created nor destroyed, is usually observed in weight-stable individuals. energy intake must equal the summed energy In individuals who are not weight stable, the dis- output and changed body energy stores. Energy crepancy between energy intake and energy ex- intake can be defined as either gross energy (total penditure, referred to as the energy gap, is best chemical energy of foods that can be released by calculated from changes in body composition. combustion), digestible energy (total chemical Because measurement of body composition is energy of foods minus fecal energy loss), or me- complex, body weight is typically used as a proxy tabolizable energy (total chemical energy of foods to compute the energy gap. The average adult minus fecal and urinary energy loss). Metaboliz- gains about 1 kg/year of body weight in the Unit- able energy represents food energy available to ed States, and studies have shown that this weight the body for use in all metabolic processes and gain is largely fat. The fraction of this gain as fat ranges from 93 to 97% of gross energy. Increased varies with BMI, but a 1-kg change in weight cor- fecal loss in response to high fiber diets is factored responds to an increase in energy stores of 7,600 into nutrient databases. However, disease states kcal/year (31 MJ/year), or only 20 kcal/day (90 kJ/ including malabsorptive diseases, ketoses, and day); an imbalance of <1%. Studies indicate, how- uncontrolled diabetes reduce database accuracy. ever, that the estimated energy gap is not a result When an individual is in energy balance, me- of daily imbalance, but rather an accumulation of tabolizable energy intake equals total energy ex- a few larger imbalances occurring on a limited penditure (TEE), and body weight is relatively number of days [6, 7]. Nevertheless, an annual constant over a given time frame. TEE has three gain of 1 kg continued for over 15–20 years will major components: resting metabolic rate (RMR), result in an increased BMI of 5. physical activity energy expenditure (PAEE) and A common misconception based on overly thermic effects of meals (TEM). RMR, the rate of simplified energy balance calculations is that a energy expenditure at rest, after an overnight (12- small (on the order of 20 kcal/day) change in ei- to 15-hour) fast, and in a thermal neutral envi- ther energy intake or expenditure will lead to ronment, is the largest component and comprises obesity or a medically significant weight loss. between 50 and 65% of TEE. PAEE is the most This calculation, however, does not account for variable component both between and within in- the passive energy regulatory system. Energy ex- dividuals and comprises between 25 and 40% of penditure varies with body size (fig. 2 ). While TEE. TEM is the energy associated with the me- continued imbalance will lead to weight gain, tabolism and storage of the macronutrients from greater weight will simultaneously increase en- meals and comprises 6–12% of TEE. Because ergy expenditure. Therefore for continued weight RMR is the most easily measured or formula- gain, energy intake must increase to offset the en- ically predictable component of TEE, TEE is usu- ergy expenditure associated with higher weight. ally expressed as a multiple of RMR. This multi- As such, there are two energy gaps associated plier (TEE/RMR) is referred to as PAL and aver- with the difference between an individual who is

16 Schoeller /Thomas

4,500

4,000 Excess gap

3,500 Maintenance gap 3,000

2,500

2,000

Male Total energy expenditure (kcal/d) expenditure energy Total 1,500 Female

1,000 35 55 75 95 115 135 155 Body mass (kg)

Fig. 2. TEE increases with weight in both men and women. This reflects increases in RMR due to increased fat-free mass and increased costs of physical activity due to the larger mass to be moved [5] . The energetic of a weight during adulthood can be described in terms of two energy gaps. The larger gap is the increase in weight maintenance energy requirement and a smaller positive energy balance over time that leads to energy storage and weight gain [8] .

at healthy weight and one who is overweight usually reflect changes in intestinal contents and (fig. 2 ). The first is the positive energy balance total body water, and detecting weight changes in gap that results in energy deposition and weight, response to systematic energy balance fluctua- and the second is the difference in energy re- tions requires long-term monitoring. quirement between the two different body weights. Online Weight Change Models

Energy Imbalance and Weight Change The use of weight change models can summa- rize the components of energy metabolism as Not surprisingly, individuals cannot measure en- they capture weight-dependent changes in energy intake or energy expenditure with adequate ergy balance. These models [9, 10] are based on accuracy to predict weight change. Even person- the first law of thermodynamics. These are de- alized devices for tracking energy intake and ex- pendent on baseline body composition, age, penditure are not sufficiently accurate for this height, gender, and degree of caloric restriction, task, and tracking changes in weight remains the and result in a curvilinear self-limiting pattern best indicator of systematic energy imbalance. In of weight change over time. These complex doing so, however, it should be remembered that models have been successfully simplified for the day-to-day changes in body mass (range ± 1 kg) physician for clinical application through web-

Energy Metabolism 17 based software (http://pbrc.edu/research-and- Conclusions faculty/calculators/, http://bwsimulator.niddk. nih.gov/). • Energy balance and body composition are in- Specifically, thermodynamically based mod- tricately tied to energy intake and expenditure. els describe changes in energy balance resulting Accurate measurements of body composition, from altering energy intake and/or PAEE by de- energy expenditure components, and intake veloping specific terms for each component of require expensive equipment and contribute the energy balance equation. These models di- to patient burden. vide the rate of energy stored into two compart- • Body weight, which is a much more easily ments, namely changes in energy resulting from measured parameter, provides a summary of changes in fat mass and fat-free mass to account these individual components and can be trans- for energy storage and resulting changes in en- lated to a measure of health status. ergy expenditure. For example, a patient placed • While single weights provide some insight on a 500 kcal/day energy deficit diet for weight into past energy balance and current health loss who loses 3–4 kg in 6 weeks is probably in status, a better measure of health should also compliance with the diet prescription, while one include serial weights tracked over time. who loses less than 1–2 kg is probably not. Such • Time trends in an individual’s weight can in- models can be valuable tools for assessing di- dicate potential energy imbalance, for example etary compliance during physician-assisted indicating a trend toward obesity and in- weight loss. creased risk for related illnesses.

References

1 Gallagher D, Heymsfield SB, Heo M, et 4 Dugas LR, Harders R, Merrill S, et al: 8 Swinburn BA, Sacks G, Lo SK, et al: Esti- al: Healthy percentage body fat ranges: Energy expenditure in adults living in mating the changes in energy flux that an approach for developing guidelines developing compared with industrial- characterize the rise in obesity preva-

based on body mass index. Am J Clin ized countries: a meta-analysis of doubly lence. Am J Clin Nutr 2009; 89: 1723–

Nutr 2000; 72: 694–701. labeled water studies. Am J Clin Nutr 1728.

2 Després JP, Lemieux I, Prud’homme D: 2011; 93: 427–441. 9 Hall KD, Sacks G, Chandramohan D, et Treatment of obesity: need to focus on 5 Institute of Medicine: Dietary Reference al: Quantification of the effect of energy

high risk abdominally obese patients. Intakes for Energy, Carbohydrate, Fiber, imbalance on bodyweight. Lancet 2011;

BMJ 2001; 322: 716–720. Fat, Fatty Acids, Cholesterol, Protein 378: 826–837. 3 Ellis KJ: Human body composition: in and Amino Acids. Washington, Nation- 10 Thomas DM, Schoeller DA, Redman LA,

vivo methods. Physiol Rev 2000; 80: 649– al Academic Press, 2002, pp 154–185. et al: A computational model to deter- 680. 6 Yanovski JA, Yanovski SZ, Sovik KN, et mine energy intake during weight loss.

al: A prospective study of holiday weight Am J Clin Nutr 2010; 92: 1326–1331.

gain. N Engl J Med 2000; 342: 861–867. 7 Casazza K, Fontaine KR, Astrup A, et al: Myths, presumptions, and facts about

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Nutrition for Health

Bier D, et al. (eds): Nutrition for the Primary Care Provider. World Rev Nutr Diet. Basel, Karger, 2015, vol 111, pp 19–23 DOI: 10.1159/000362292

Appetite: Measurement and Management

Richard D. Mattes

Department of Nutrition Science, Purdue University, West Lafayette, Ind. , USA

Key Words Introduction Hunger · Satiation · Satiety · Food intake · Eating pattern Much has been and continues to be debated about the controls or regulation of appetite, food intake, body weight and body composition. Of course, not all these factors can be regulated as some must Key Messages be free to vary to account for the regulation of the • Appetitive sensations and food intake stem from a complex interplay of factors that ultimately influ- other factors. Arguably, the weakest evidence for ence body weight and body composition. active regulation applies to appetitive sensations, • Appetite is a central focus in the management of which are widely viewed as fluctuating in concert several disorders, including undernutrition, eating with energy needs to promote energy balance. disorders (anorexia, bulimia) and obesity. However, Whether this is, in fact, their role and the degree appetitive sensations are not a reliable marker of to which they can drive behavior are controver- food intake. sial. Some evidence indicates the appetitive sys- • Appetite is multidimensional and, in research and clinical practice, is often divided into selected com- tem is biased towards excess energy intake as ponents, including hunger, desire to eat, and full- insurance against future energy deficits. If so, ness. There are no reliable biological markers for advice to better attune ingestive behavior with quantifying appetite. appetite could be counterproductive for weight • Satiety hormones can modulate appetite and/or management. Alternatively, under customary di- food intake, but their functional roles are not clear etary conditions, the signals from the appetitive because their release and activity are influenced by cognitive, physiological, and lifestyle factors. system may be trumped by other systems guiding • Clinicians who wish to modulate appetite in pa- ingestive behavior such as neural reward centers. tients may apply diet or lifestyle interventions, but In this case, appetitive signals would not be suf- only subtle effects should be expected. Pharmaco- ficiently powerful to achieve energy balance in logical agents have varying efficacies and are best environments where food is abundant, accessible used in combination with nonpharmacological ap- and palatable. A better understanding of this bio- proaches. © 2015 S. Karger AG, Basel logical system should inform clinical practice. Role of Appetite and Definitions Specific appetites are special cases where there is a strong motivation to ingest a particular nutri- The high prevalence of dysfunctional eating re- ent (e.g. salt, iron, protein). Animals express these sulting in outcomes ranging from undernutri- appetites (e.g. herbivores’ attraction to salt licks), tion to eating disorders (anorexia, bulimia, etc.) but humans have demonstrated them only under and obesity has prompted considerable interest extreme conditions. Pica, the ingestion of non- in the role of appetite in ingestive behavior. Ap- food items, is often attributed to a nutrient defi- petite is multidimensional and, in research and ciency, but rarely is this substantiated [2] . There clinical practice, is often divided into selected appears to be a stronger sociocultural basis to the components. Hunger comprises those sensations practice. that motivate food seeking and ingestion and is Appetitive sensations are of clinical interest in commonly viewed as stemming from a biological several regards. First, when the sensations are need for energy. The latter differentiates hunger strong, most view them as unpleasant, and they from sensations labeled ‘desire to eat’, which also can compromise the quality of life. This has prompt ingestive behaviors but do so based more prompted considerable research on the develop- on the rewarding properties of foods. Thus, it is ment of products and eating patterns to amelio- possible to have low hunger and a strong desire rate or emphasize sensations without exacerbat- to eat, such as when a highly palatable dessert is ing possible energy balance problems (e.g. weight provided after a large meal. Fullness represents loss or gain). Second, therapeutic dietary regi- the sensations that diminish interest in eating, mens are only effective if followed, and strong ap- and while it appears to be on the opposite pole on petitive sensation may lead to poor compliance. a continuum with hunger, they are controlled by Third, by guiding food choice, appetitive sensa- different mechanisms. Fullness may play out tions directly influence nutrient intake and nu- over different time frames. Within an eating tritional status. event, these sensations terminate intake and are referred to as satiation. Fullness may also delay the onset of the next eating event and is then Measurement Options termed satiety. Thirst is another appetitive sensation and is most closely linked with hydration There is no universally accepted method to quan- status, though beverages now contribute about tify appetite. The most common approach is to 20% of daily energy in the US diet. While these assess the sensations via questionnaires. Partici- biological systems are available to guide ingestive pants are asked to rate their hunger, desire to eat behavior, much eating and drinking occurs in the (generally or for selected qualities such as sweet absence of hunger or thirst and in the presence of or savory foods), fullness, prospective consump- reasonably strong fullness sensations [1] . Fur- tion (how much could you eat right now) and thermore, eating and drinking frequently do not thirst according to category or visual analog scales occur despite high levels of hunger and thirst or with end anchors of ‘not at all’ to ‘extremely’. Pri- low levels of fullness, often due to practical issues mary limitations of this approach are that, gener- of daily living. The purposeful overriding of these ally, there is no control over individual differenc- signals may occur for various reasons such as an- es in understanding of the descriptive terms, lack ticipated future food limitations or maximiza- of training in quantifying them, assumptions that tion of present pleasure. Thus, appetitive sensa- sensations change linearly over time and the act tions are important but not reliable markers of of completing the questionnaires may alter the food intake. underlying sensations themselves (expectation

20 Mattes

Table 1. Selected peptides associated with appetitive sensations

Hormone Appetitive effect Primary site of release Primary nutrient stimuli

Ghrelin hunger (initiates an fundus of stomach total energy, possibly eating event) carbohydrate suppress strongest Cholecystokinin satiation I cells of duodenum protein, fat > carbohydrate Glucagon-like peptide-1 satiation L cells of ilium and colon protein > carbohydrate > fat Glucose-dependent satiation K cells of duodenum carbohydrate, fat insulino-tropic polypeptide Peptide YY satiation L cells of ilium and colon protein > fat > carbohydrate Pancreatic polypeptide satiation F cells in endocrine pancreas neural, individual nutrients weak Apolipoprotein A-IV satiation enterocytes during lipid packaging fat Gastric leptin satiety P cells of fundus and total energy pepsinogen-secreting chief cells Insulin satiety pancreatic β-cell carbohydrate Amylin satiation and satiety pancreatic β-cell carbohydrate Oxyntomodulin satiation L cells of ilium and colon total energy Enterostatin inhibits fat intake pancreas fat, protein (satiation)

effects). Open-ended questionnaires have also mones (see table 1 for common candidates) [4] . been used, but the lack of standardized response Under nonphysiological conditions, each can be options limits their interpretation. shown to modulate appetite and/or intake, but Due to concerns about subjective reports, their role under customary dietary conditions is there has been considerable interest in identify- less clear because they have both neural (including objective biomarkers of appetitive sensations. ing cognitive) and nutrient bases for secretion, Many have been identified, but none substanti- their release is influenced by lifestyle, they are ated. Glucose and/or insulin concentrations have highly interactive, and humans can willfully ig- been proposed and form the basis of the glycemic nore the sensations they reportedly elicit. index or load theory of appetite regulation. It is Time is another proxy measure as it is as- proposed that foods prompting rapid glucose ab- sumed that hunger grows and fullness diminish- sorption elicit a strong insulin response that leads es directly with time since the last eating event. to a rebound hypoglycemic state and augmented However, for most people, the overnight fast is hunger. However, euglycemic clamp studies indi- the longest interval between eating events and cate independent manipulation of either glucose few are most hungry upon awakening. Also, sen- or insulin does not lead to a change of appetite sations adapt to lifestyles and expected meal (noted changes are associative rather than causal) times. The association between meal size and in- [3] . Many peptides secreted from enteroendo- termeal interval is stronger than the effect of time crine cells throughout the GI tract, the pancreas since the last eating event on energy intake at the and adipocytes have been labeled satiety hor- next eating event [5] .

Appetite 21 Table 2. Selected dietary and behavioral approaches to modulate appetite for therapeutic purposes

Food/ingredient/practice Purported satiation/satiety value Dominant suggested mechanism Strength of evidence

Clear beverages weak weak compensatory dietary response strong Sweet foods/beverages weak activation of reward system weak Highly palatable foods weak activation of reward system weak High-fat items weak passive overconsumption moderate High sensory variety weak activation of reward system moderate Timing of eating events weak when occurring at night weak compensation potential weak Nuts high unknown strong Fiber high gastric stretch weak-moderate Protein high gut peptide secretion moderate Soup moderate-high cognitive moderate Fruits/vegetables/high volume moderate-high gastric stretch weak High eating frequency high modulation of appetitive swings weak Low-glycemic-index foods high moderation of glycemia weak Chewing gum moderate neural activation of satiety centers weak Physical activity moderate uncertain moderate

Items or practices that have weak satiety effects may be useful adjuncts to diets intended to increase energy intake.

Gastric load (volume, composition) has been desire to eat and intake in individuals with early proposed as an important determinant of appeti- satiety (e.g. the elderly, patients with selected can- tive sensations. However, the volume of a meal or cers), or the opposite in individuals where energy snack outside the body has little correlation with its restriction is desired (e.g. overweight/obese indi- volume in the stomach due to masticatory degra- viduals). Table 2 contains a list of popularized dation of foods and differential rates of gastric food attributes or eating practices that reportedly emptying. Plus, a given load will have different ef- lend themselves to manipulation of appetite and fects based on gastric volume and tone [6] . It should feeding. In all cases, the entries are generaliza- also be noted that gastrectomized patients experi- tions as subtle differences can alter responses. For ence largely normal appetitive sensations [7] . example, protein has strong satiety value in solid Motivational or behavioral indices may also foods, but less so in beverages. Generally, each be used to quantify appetite, such as how hard an manipulation of diet or lifestyle may be used to individual would be willing to work to obtain move in an intended direction, but in all cases, food. Marked interindividual variability in appe- only subtle effects should be expected. titive sensations has been documented; whether Pharmacological management of appetite has or not they predict ingestive behavior remains to proven especially problematic [9] . Appetite re- be established [8] . flects the contributions of multiple redundant biological systems that subserve core survival functions. As a consequence, pharmacological inter- Modulation of Appetite through Food ventions tend to evoke undesired consequences Properties and Eating Patterns resulting in their failure to reach the market or remain on it. The FDA has recently approved two A number of options are available to the clinician new agents for managing hunger and desire to wishing to modulate appetitive sensations in a eat: Belviq (a serotonin 2C receptor agonist that given patient. The goal may be to increase hunger, promotes satiety) and Qsymia (a combination of

22 Mattes

phentermine, a stimulant, and topiramate, an an- • Appetitive sensations are clinically important ti-seizure agent). Currently approved agents may as they influence food choice, and this influ- be expected to promote about a 5–10% reduction ences nutrient intake, quality of life and adher- of body weight, comparable to dietary interven- ence to and benefit from therapeutic dietary tions. A number of orexigenic agents are avail- regimens. able, also with varying efficacy and often uncer- • There is no single accepted approach to quan- tain mechanisms that are most effective when tify appetitive sensations. combined with nonpharmacological interven- • The properties of foods and lifestyle practices tions [10] . of individuals may be exploited to selectively enhance or inhibit appetite for directed purposes, but the magnitude of effects is generally Conclusions limited. • Pharmacological approaches to appetite man- • Appetite encompasses sensations that may agement are frequently associated with unac- motivate or inhibit feeding behavior, but their ceptable side effects, but have a role in weight influence on energy balance has yet to be clear- management, especially when combined with ly characterized. nonpharmacological approaches.

References

1 McKiernan F, Hollis JH, McGabe G, 4 Karhunen LJ, Juvonen KR, Purhonen 8 McKiernan F, Houchins JA, Mattes RD: Mattes RD: Thirst-drinking, hunger-eat- AK, Herzig KH: Effect of protein, fat, Relationships between human thirst, ing; tight coupling? J Am Diet Assoc carbohydrate and fibre on gastrointesti- hunger, drinking, and feeding. Physiol

2009; 109: 486–490. nal peptide release in humans. Regul Behav 2008; 94: 700–708.

2 MacClancy J, Henry J, Macbeth H (eds): Pept 2008; 149: 70–78. 9 Kabra DG, Karba UD, Tschop MH, Hoff- Consuming the Inedible: Neglected Di- 5 Bernstein IL, Zimmerman JC, Czeisler man S: Pharmacological treatment of mensions of Food Choice. New York, CA, Weitzman ED: Meal patterns in obesity; in Shiromani PJ, Horvath T, Berghahn Books, 2007. ‘free-running’ humans. Physiol Behav Redline S, van Cauter E (eds): Sleep Loss

3 Chapman IM, Goble EA, Wittert GA, et 1981; 27: 621–623. and Obesity: Intersecting Epidemics. al: Effect of intravenous glucose and 6 Delgado-Aros S, Cremonini F, Castillo New York, Springer, 2012, pp 203–225. euglycemic insulin infusions on short- JE, et al: Independent influences of body 10 Nasr SZ, Drury D: Appetite stimulants term appetite and food intake. Am J mass and gastric volumes on satiation in use in cystic fibrosis. Pediatr Pulmonol

Physiol 1998; 274:R596–R603. humans. Gastroenterology 2004; 126: 2008; 43: 209–219. 432–440. 7 Kamiji MM, Troncon LEA, Suen VMM, de Oliveira RB: Gastrointestinal transit, appetite, and energy balance in gastrec-

tomized patients. Am J Clin Nutr 2009;

89: 231–239.

Appetite 23 Nutrition for Health

Bier D, et al. (eds): Nutrition for the Primary Care Provider. World Rev Nutr Diet. Basel, Karger, 2015, vol 111, pp 24–29 DOI: 10.1159/000362293

Macronutrients: Requirements and Distribution

Jim Mann

Department of Human Nutrition, University of Otago, Dunedin , New Zealand

Key Words Introduction Macronutrients · Protein · Fat · Carbohydrate · Dietary fiber Macronutrient requirements and the proportion of total energy which should be provided by carbohydrate, fat and protein are perennial topics for de- Key Messages bate. An underlying principle, often forgotten, is • A wide range of macronutrients is compatible with that a wide range of dietary patterns, and hence satisfactory growth and development, mainte- macronutrient intakes, is compatible with satisfac- nance of good health and longevity. • Intakes within the recommended range are readily tory growth and development, maintenance of achievable regardless of preferred dietary pattern. good health and longevity. For example, in most • Other than in situations of food insecurity, advice to traditional Asian dietary patterns, a high propor- avoid excessive intakes of fat and free sugars, which tion of total energy is provided by carbohydrate, contribute to an increased risk of overweight and and fat intake is relatively low, whereas in most obesity, is of particular importance. ‘Western’ diets fat intake is appreciably higher. • Consumption of even small amounts of meat pro- Yet, both approaches have the potential to achieve tein or a wide variety of plant protein sources generally enables adequate intakes of total protein and the expectations of optimal nutrition, suggesting indispensable amino acids. that total energy intake and nature (quality) of • Advice regarding fat intake relates principally to a macronutrients must be of greater importance reduction of saturated fatty acids and elimination than the precise distribution of intake. Table 1 as far as possible of trans-fatty acids from manufac- shows the range of acceptable intakes recommend- tured foods. Linoleic acid and α-linolenic acid are ed by the World Health Organization (WHO) con- essential fatty acids. A wide range of intakes of cis- monounsaturated fatty acids is acceptable. sidered appropriate for all populations. • Carbohydrates should be derived principally from vegetables, fruits and minimally processed wholegrain cereals. This ensures an adequate intake of Protein dietary fiber which protects against colon cancer, type 2 diabetes and coronary heart disease. Proteins are essential to the structure and func- © 2015 S. Karger AG, Basel tion of all cells and are involved in many essential metabolic functions which are linked to the me- Table 1. Macronutrient intake goals as recommended by Table 2. Dispensable and indispensable amino acids the WHO [1, 2] Indispensable Partially Dispensable Fat amino acids indispensable amino acids

Total 15 – 30 SFA <10 Histidine Arginine Alanine Isoleucine Asparagine Aspartate PUFA 6 – 10 Leucine Glutamine Glutamate n-6 PUFA 5 – 8 Lysine Glycine n-3 PUFA 1 – 2 MUFA by difference1 Methionine Proline TFA <1 Phenylalanine Serine Dietary cholesterol, mg/day 300 Threonine 1 Carbohydrate Tryptophan Cysteine Valine Tyrosine1 Total 50 – 75 Free sugars <10 1 Dietary fiber, g/day >25 Requires essential amino acid precursors methionine and phenylalanine. Protein 10 – 15

Unless otherwise stated, the goals are expressed as percentage total energy. SFA = Saturated fatty acids; Table 3. Amino acid requirements (mg/kg/day) as rec- PUFA = cis-polyunsaturated fatty acids; MUFA = cis-mo- ommended by WHO/FAO UNU Expert Consultation nounsaturated fatty acids; TFA = trans-fatty acids. The (based on stable isotope studies) 2012 Nordic Nutrition Recommendations permit up to 40% total energy from fat but a restriction on the intake Histidine of SFA remains. 10 1 Total fat = SFA + PUFA + TFA. Isoleucine 20 Leucine 39 Lysine 30 Methionine and cysteine 15 tabolism of other nutrients. Protein is the second Phenylalanine and tyrosine 25 Threonine most abundant chemical compound in the body 15 Tryptophan 4 (after water) contributing about 16% (i.e. 11 kg) Valine 26 of the weight of a 70-kg man. Dietary proteins are absorbed, following digestion, as amino acids Total 184 which then contribute to the total amino acid pool, from which the body’s proteins are synthesized. All 20 amino acids are essential for protein ids. The estimated average requirement for total synthesis but some can be synthesized from other protein in order for an individual to remain in metabolic precursors and are described as ‘dis- nitrogen balance is estimated to be about 0.65 g pensable’ amino acids. Nine of the 20 amino acids protein/kg/day, with two standard deviations required for protein synthesis cannot be found in added to define the recommended daily intake, the body and therefore must be obtained from the i.e. 0.83 g/kg/day, with specified amounts of es- diet. These are termed as ‘indispensable’ amino sential amino acids (table 3). Protein require- acids with the remainder being ‘partially dispens- ments may also be considered in terms of nutri- able’, i.e. they have the potential to be synthesized ent density [protein (P):energy (E) ratios] when but not to the extent that fulfils the body’s re- giving advice about types of diet and foods. Be- quirements (table 2 ). cause infants and children have very high energy Requirements for protein are expressed in requirements, their protein needs, at least in most terms of total protein and individual amino ac- societies, are met by diets with a relatively low P:E

Macronutrients: Requirements and Distribution 25 ratio. As energy requirements reduce with age, F a t s the P:E ratio needs to increase and protein dense foods are more important. This applies especially Some people in high-income countries regard fats for the elderly. and most oils as foods to be avoided as far as pos- With even relatively small amounts of meat sible because of their roles in obesity and coronary protein or a wide variety of plant protein sources, heart disease. However, lipids form an essential most populations achieve adequate intakes of to- component of adequate nutrition as sources of en- tal protein and indispensable amino acids. How- ergy and some, which cannot be synthesized by ever, when only a limited range of vegetable the body, are essential nutrients. They are impor- sources of protein are available, lysine and tryp- tant structural components of all membranes and tophan deficiencies may occur. Protein deficien- have roles in cell signaling. They are the only form cy is commonly seen in association with famine, in which the body can store energy for prolonged resulting from natural disasters or conflict and in periods of time and are essential for the provision conditions of extreme poverty. In any society and and absorption of fat-soluble vitamins. in association with any dietary pattern, deficien- Most fatty acids can be made in the body, ex- cy may occur in situations of increased demand cept for two essential fatty acids, linoleic and (e.g. infections or stress), increased losses (e.g. α-linolenic acids. Specific deficiencies are very hemorrhage or burns) or when individuals are rare even when intakes are very low, as is the case living in adverse social and physical conditions. in some African and Asian countries. However, Protein intake from nonmeat sources is re- to ensure adequate intakes, some organizations markably similar throughout the world, around have suggested minimum desirable intakes. For 50 g/day. However, protein from meat sources var- example, the WHO recommends that at least 2% ies enormously from very small amounts in coun- total daily energy be derived from ω6 (n-6) poly- tries such as Nigeria, Zimbabwe and India to aver- unsaturated fatty acids, which includes linoleic age intakes of around 50 g/day or more in affluent acid, and 0.5% total energy from ω3 (n-3) polyun- countries. This equates to intakes of between 10 saturated fatty acids, which includes α-linolenic and 15% total energy. This has traditionally been acid. There are also recommendations for eicosa- considered to be an appropriate range of intake. pentaenoic (EPA) and docosahexaenoic (DHA) Somewhat more controversial has been the re- acids (the WHO recommends 0.25–2.00 g/day of cent discussion as to whether diets containing EPA plus DHA), especially during pregnancy and larger amounts of protein might facilitate weight lactation, to ensure adequate levels for the fetus reduction and maintenance in overweight and and young infant. Infant formulae, especially obese individuals and populations, management those intended for premature infants, should of diabetes and enhanced bone health in the el- contain EPA and DHA in similar proportions to derly. Relatively high-protein, low-carbohydrate those found in breast milk. diets such as the ‘South Beach’ and ‘Zone’ diets While much of the discussion around fat intake provide up to 30% total energy as protein and centers on acceptable upper limits, it is important have been shown in relatively short-term studies to appreciate that dietary fat is essential for ensur- to be more effective than high-carbohydrate diets ing that energy needs are met in addition to pro- in these respects. However, there is no convinc- viding the source of fat-soluble vitamins and es- ing evidence of long-term benefit, and issues of sential fatty acids. It is generally assumed that for cost, sustainability and long-term safety also re- most adults, fat should provide at least 15% of the quire further consideration before such a recom- total energy requirements and 20% for women of mendation can be endorsed. reproductive age. A much higher proportion is

26 Mann

generally assumed to be required by infants and risk indicators, have led to the suggestion that a young children in order to meet energy require- high fat intake (up to 40% or even more) may be ments for growth. Fifty to 60% of the energy con- acceptable or even desirable, especially when tent of breast milk is derived from fat, and during consumed in conjunction with a high protein in- weaning it is necessary to ensure that fat intake is take. It is argued that epidemiological data, most reduced gradually. At least until the age of 2 years, notably the potential health benefits of various fat should provide about 40% total energy. Mediterranean dietary patterns, relatively high The dietary patterns of many Asian countries in mono- and polyunsaturated fat, support such and the traditional diets of some other popula- an approach. A strong counter-argument to lib- tions include fat intakes at these lower limits. eralizing total fat intake in populations prone to Given the low rates of ischemic heart disease, low overweight and obesity is the association between levels of LDL cholesterol and relatively long life higher total fat intakes and excess body weight. expectancy, for example amongst the Japanese, it The only official endorsement, at least in part of has been widely assumed that, regardless of di- this approach is to be found in the 2012 Nordic etary pattern, optimal fat intake should be much nutrition recommendations which permit a total lower than those which characterize the diets of fat intake as high as 40% total energy, though the most Western populations. Diets low in saturated restriction on saturated fat intake to 10% total en- fat and with moderate amounts of cis-unsaturat- ergy remains. ed fatty acids have been shown in dietary inter- A total polyunsaturated fatty acid intake of vention trials to reduce indicators of cardiometa- between 6 and 10% has been recommended, the bolic risk and in a limited number of longer term greater proportion (5–8% total energy) being n-6 trials to reduce clinical ischemic heart disease. cis-polyunsaturated fatty acids and intake of cis- Guidelines have varied from country to country monounsaturated fatty acids being determined and according to whether individuals or popula- by difference, assuming a saturated fat intake of tions are at particularly high risk of ischemic no greater than 10% total energy. These ranges heart disease, but have generally suggested upper permit a wide variety of food choices, compatible limits of total fat intakes ranging between 30 and with most dietary patterns. Trans-fatty acids 35% total energy with intakes even below 30% in from manufactured foods, which increase the those at high risk of ischemic heart disease or risk of ischemic heart disease and some cancers, where a low-fat dietary pattern is preferred. The should be eliminated as far as possible from the recommendations have particularly focused on diet. reductions of saturated fatty acids to around 10% total energy (or less for those at risk of ischemic heart disease), well below that currently con- C a r b o h y d r a t e sumed in many countries with typical ‘Western’ dietary patterns. Carbohydrates are the most important source of More recently, the concern that a high intake food energy in the world. A wide range of cereals of carbohydrate and sugars in particular may be including rice, wheat, maize, barley, rye, oats, a cause of obesity and some of its comorbidities, millet and sorghum are staple foods in many dif- the observation that saturated fatty acids may ferent dietary patterns. Starchy roots, pulses, oth- only adversely affect the nonatherogenic forms of er vegetables, fruit and sugar all contribute to a LDL and the demonstration in relatively short- varying extent to the energy derived from carbo- term studies that high-fat diets may facilitate hydrate, which generally ranges between 40 and weight loss and improve some cardiometabolic 80% of total food energy, depending upon per-

Macronutrients: Requirements and Distribution 27 sonal preference, culture and economic status. ommending a relatively high intake of carbohy- Carbohydrate-containing foods are also impor- drate is the expectation of a reduced risk of isch- tant sources of antioxidants, protein, vitamins, emic heart disease by facilitating a reduction in minerals, phytochemicals and sterols. intake of fat. The FAO/WHO Scientific Update Glucose is essential as an energy source for the on Carbohydrates recommended a range of 50– brain, red blood cells and the renal medulla. The 75% total energy. The European Food Safety Au- body can generate approximately 130 g of the thority suggests that for adults and children in- 180 g glucose required from noncarbohydrate takes should range between 45 and 60% total en- sources via gluconeogenesis. Thus, the recom- ergy, a range more compatible with current mended minimum intake is considered to be European and North American practices. The about 50 g/day. However, utilizing gluconeogen- nature of carbohydrate is arguably more impor- esis is not a particularly efficient means of gener- tant than the quantity. Avoidance of excess in- ating glucose and could necessitate a protein intakes of sugars is recommended, either in the take above usual requirements or, where protein form of food-based guidelines (e.g. in South Af- intakes are marginal, an increase in muscle pro- rica) or in quantitative terms (e.g. WHO recom- tein breakdown. A carbohydrate intake greater mends that free sugars should provide less than than the recommended minimum intake is pref- 10% total energy) to reduce the risk of overweight erable. If sufficient glucose is not available from and obesity and rates of dental caries, now ac- the diet or via gluconeogenesis, these organs knowledged worldwide as an important chronic adapt by using ketones derived from fatty acid disease. Of course, both obesity and dental caries oxidation as an energy source. Ketosis may im- have many causes other than intake of sugar. Rec- pair cognitive function, and other possible long- ommendations regarding dietary fiber have been term effects are unknown. Requirements for glu- complicated by lack of agreement regarding defi- cose are increased during pregnancy and lacta- nitions, but CODEX has now agreed on a definition, and the fetus may be adversely affected by tion which distinguishes between the naturally ketosis, so the minimum recommended intake of occurring fiber in plant-based foods from syn- carbohydrate during these phases of the life cycle thetic and extracted fiber. The WHO has recom- should be around 100 g/day. mended that at least 25 g of dietary fiber (20 g Most dietary patterns provide an appreciably nonstarch polysaccharides) from plant foods higher intake than these minimum require- should be consumed daily. This advice taken in ments. Average intakes range from around 200– conjunction with the recommendation to reduce 250 g in countries where a ‘Western’ dietary pat- sugars represents an attempt to ensure that the tern is the norm (e.g. USA, UK, Australia, The bulk of the carbohydrate intake is derived from Netherlands) to over 400 g in some Asian coun- minimally processed wholegrain cereals, vegeta- tries and elsewhere where indigenous popula- bles, pulses and fruit. Foods rich in dietary fiber tions consume traditional diets (e.g. Papua New are associated with reduced risk of colon cancer, Guinea and many African countries). Epidemio- coronary heart disease and type 2 diabetes. logic observations and dietary intervention stud- The recent argument that high-carbohydrate ies, mostly involving intermediate end points diets promote insulin resistance and increase the (biomarkers or risk indicators) have led many na- risk of obesity and associated diseases, especially tional and international organizations to recom- type 2 diabetes, and conversely that a low carbohy- mend a range of intakes higher than those typi- drate intake is beneficial in these regards has led to cally consumed in Western countries. From a the recommendation by some researchers and health perspective, the major justification for rec- practitioners that reduction of carbohydrate

28 Mann

(sometimes to levels as low as will cause ketosis) Table 4. Dietary guidelines for which there is almost should be followed by all at-risk individuals and complete agreement even populations with high rates of obesity. While Eat a nutritionally adequate diet composed of a variety there has been fairly widespread adoption of such of foods practices, they have not been recommended by of- Eat less fat, particularly saturated fat ficial bodies. Indeed, there is no evidence against Adjust energy balance for body weight control – less the advice that a wide range of carbohydrate in- energy intake, more exercise Eat more wholegrain cereals, vegetables and fruits take is acceptable, provided appropriate carbohy- Reduce intake of salt and foods rich in salt drate-containing foods predominate. A low glyce- Drink alcohol in moderation, if you do drink mic response after eating carbohydrate-containing foods has been suggested as a useful means of identifying such foods. While many ‘low-glycemic-index’ foods do represent appropriate food choices, the approach is not generally accepted as • A wide range of intakes is compatible with sat- being universally applicable. There is considerable isfactory growth and development, mainte- inter- and intraindividual variation in glycemic nance of good health and longevity. responses to the same foods, the composition of • Other than in situations of food insecurity, an many foods is not consistent, and many low-glyce- excessive intake of energy-dense foods high in mic-index foods are high in fat or sugars. total fat and free sugars, which contribute to the global epidemic of obesity and its comorbidities, is arguably the issue relating to mac- Conclusions ronutrients which is of greatest importance to human health. • When adequate food supplies are available, • Globally applicable dietary guidelines (table 4 ) macronutrient requirements are generally can readily translate recommended ranges of readily met regardless of the preferred dietary macronutrient intakes into appropriate food pattern. choices.

References

1 Joint WHO/FAO Expert Consultation: 4 Malhotra A: Saturated fat is not the ma- 7 Moynihan PJ, Kelly SA: Effect on caries

Diet, nutrition and the prevention of jor issue. BMJ 2013; 347:f6340. of restricting sugars intake: systematic chronic diseases. World Health Organ 5 Hooper L, Abdelhamid A, Moore HJ, et al: review to inform WHO guidelines. J

Tech Rep Ser 2003; 916:i-viii, 1–149. Effect of reducing total fat intake on body Dent Res 2014; 93: 8–18. 2 Joint FAO/WHO scientific update on weight: systematic review and meta-anal- 8 Cummings JH, Mann JI, Nishida C, Vor- carbohydrates in human nutrition. Eur J ysis of randomised controlled trials and ster HH: Dietary fibre: an agreed defini-

Clin Nutr 2007; 61(suppl 1):S1–S137. cohort studies. BMJ 2012; 345:e7666. tion. Lancet 2009; 373: 365–366. 3 Joint FAO/WHO/UNU Expert Consulta- 6 Te Morenga L, Mallard S, Mann J: Di- 9 Mensink RP, Zock PL, Kester AD, Katan tion: Protein and amino acid require- etary sugars and body weight: system- MB: Effects of dietary fatty acids and car- ments in human nutrition. World atic review and meta-analyses of ran- bohydrates on the ratio of serum total to

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1–265. studies. BMJ 2013; 346:e7492. apolipoproteins: a meta-analysis of 60

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Macronutrients: Requirements and Distribution 29 Nutrition for Health

Bier D, et al. (eds): Nutrition for the Primary Care Provider. World Rev Nutr Diet. Basel, Karger, 2015, vol 111, pp 30–37 DOI: 10.1159/000362294

Water-Soluble Vitamins

Hamid M. Said

University of California – School of Medicine, Irvine, Calif. , and VA Medical Center, Long Beach, Calif. , USA

Key Words Introduction Ascorbate · Biotin · Cobalamin · Folate · Niacin · Pantothenic acid · Pyridoxine · Riboflavin · Thiamin The water-soluble vitamins are a group of structurally and functionally unrelated compounds that share the characteristics of being essential Key Messages for normal cellular functions, growth and devel- • The two main sources of the water-soluble vitamins opment. Deficiency of these micronutrients leads are dietary intake and the intestinal microflora. to a variety of clinical abnormalities that range • Although structurally unrelated, each of these vita- from anemia to growth retardation and neuro- mins plays key roles in a multitude of cellular and logical disorders; on the other hand, optimizing physiological processes. • Deficiencies can result in various clinical abnormal- their body levels brings about positive health out- ities that range from anemia to growth retardation comes. Humans cannot synthesize water-soluble and neurological disorders. vitamins (with the exception of some synthesis of • Deficiency of a vitamin could be localized (tissue niacin); thus, they must obtain them from exog- specific) as in the case of vitamin B1 deficiency in the enous sources via intestinal absorption. While autosomal recessive disorder thiamin-responsive diet has been considered as the main source of megaloblastic anemia. • This review outlines the main functions of vitamins these micronutrients in humans, there has been a growing appreciation in recent years for the B 1 , B2 , B3 , B5 , B6 , B9 , C, and H, as well as the consequences of deficiencies and overdosage, the main contribution of the normal microflora of the sources, and recommended daily allowances for large intestine towards overall homeostasis of a each of these essential micronutrients. number of these micronutrients [e.g. thiamin, bi- © 2015 S. Karger AG, Basel otin, folate, riboflavin (RF), pyridoxine, pantothenic acid], and especially towards the cellular human thiamin transporter-1, hTHTR-1 (prod- nutrition and health of the local colonocytes [1, uct of the human SLC19A2 gene), which is highly 2]. The aim of this review is to provide a summa- expressed in the affected tissues [4] . Thiamin-re- rized description of the metabolic roles of these sponsive Wernicke’s-like encephalopathy is a ge- micronutrients, conditions associated with their netic disorder that is associated with seizure, oph- deficiency and the clinical consequences of these thalmoplegia, nystagmus, and ataxia and is caused deficiencies, their physiology, occurrence, and by mutations in hTHTR-2 (product of the human the Recommended Daily Allowance (RDA) as SLC19A3 gene) [5] . Both of these genetic disor- well as description of any adverse effect(s) that ders respond favorably to high doses of thiamin. may develop as a result of their overdosing. Thiamin deficiency represents a significant nutritional problem in both developing and developed countries. In developing countries, the Vitamin B 1 (Thiamin) main cause of thiamin deficiency is poor dietary intake of the vitamin (i.e. consumption of thia- Thiamin was the first member of the water-solu- min-deficient or depleted diets). In developed ble family of vitamins to be described. Reference countries, chronic alcoholism is the main cause to beriberi (a thiamin deficiency disease) in the of thiamin deficiency, although the condition Chinese medical literature dates back to as early can also be seen in patients with diabetes melli- as 2700 B.C. Thiamin plays an essential role in tus, inflammatory bowel disease, celiac disease, normal cellular functions via its involvement in a renal diseases, AIDS, cancer, and in those with variety of critical metabolic reactions related to congestive heart failure, as well as in subjects on energy metabolism. It also plays a role in reducing chronic diuretic therapy [for review, see 3 ]. Thia- cellular oxidative stress. Thus, cellular deficiency min deficiency and suboptimal levels have also of thiamin leads to an impairment in energy me- been reported in the elderly despite an average tabolism and to a propensity for oxidative stress; daily intake of the vitamin that exceeds the rec- cellular deficiency also leads to apoptosis. Recent- ommended requirement. ly, additional roles for thiamin (e.g. effect on the Chronic thiamin deficiency leads to two dis- function of membrane chloride channels in nerve tinct types of conditions: beriberi and Wernicke’s cells) have been reported [for review, see 3 ]. Clin- encephalopathy. Beriberi is recognized in three ically, systemic thiamin deficiency in humans different forms: (a) dry beriberi, which is a sym- leads to a variety of abnormalities including neu- metrical ascending peripheral neuritis that usu- rological (neuropathy and/or Wernicke-Korsa- ally affects older individuals and is associated koff syndrome) and cardiovascular (peripheral with wasting; it may also be associated with car- vasodilatation, biventricular myocardial failure, diac involvement; (b) wet (or edematous) beri- edema and potentially acute fulminant cardiovas- beri, which involves the heart and leads to edema cular collapse) disorders. Tissue-specific (i.e. lo- of the lower extremities resulting from the ensu- calized) deficiency of thiamin also occurs, as can ing heart failure, and (c) acute ‘fulminating’ beri- be seen in patients with thiamin-responsive meg- beri (which is also called shoshin beriberi), which aloblastic anemia (TRMA), and in patients with occurs more frequently in infants and is associ- thiamin-responsive Wernicke’s-like encephalop- ated with heart failure and metabolic abnormali- athy [4, 5]. TRMA is an autosomal recessive dis- ties (with little evidence of peripheral neuritis). order that is associated with megaloblastic ane- Thiamin deficiency in the human central ner- mia, sensorineural deafness, and non-type 1 dia- vous system may lead to Wernicke’s encephalopa- betes mellitus, and is caused by mutations in the thy and Korsakoff’s psychosis, conditions that are

Water-Soluble Vitamins 31 associated with chronic alcoholism and manifest tein source in certain part of Africa) contain thi- as the Wernicke-Korsakoff syndrome. Some evi- aminase I and II, thiaminolytic enzymes that de- dence, however, exists to suggest that thiamin de- grade thiamin leading to the generation of thia- ficiency alone is not sufficient to cause Wernicke- min antagonists. Korsakoff syndrome but that alcohol is a neces- The RDA for thiamin is 1.4, 1.1, 1.5, and 1.6 sary factor for the induction of this abnormality. mg/day for adult men, adult women, and during Korsakoff’s psychosis is associated with confusion pregnancy and lactation, respectively. Since the and loss of recent memory, although long-term requirement for thiamin is dependent on total memory may continue to be intact. Wernicke’s en- caloric intake (especially that from carbohy- cephalopathy develops later and is associated with drate), consumption of a calorie-rich diet may af- clear neurological abnormalities (nystagmus, ex- fect these RDA levels. traocular palsy, ataxia, confabulation, coma) and No toxic effects have been reported in humans anatomic lesions (including hemorrhagic lesions as a result of ingestion of high doses of thiamin in the thalamus pontine tegmentum, and mam- (up to 500 mg), or as a result of parenteral admin- millary body with severe damage to astrocytes, istration of the vitamin (single or repeat injec- neuronal dendrites and myelin sheaths). tions), although in very rare cases symptoms re- Two sources of thiamin are available to hu- sembling anaphylactic shock and minor allergy mans, one being the diet (absorbed in the small have been described when the vitamin was given intestine), and the other is the normal microflora via the parenteral route. of the large intestine (absorbed in the colon). While the relative contribution of the bacterial source to total body nutrition of thiamin is not V i t a m i n B2 (Riboflavin) clear, the existence of an efficient carrier-mediated mechanism for thiamin uptake by human RF in its coenzyme forms, riboflavin-5-phos- colonocytes, combined with the considerably phate and flavin adenosine dinucleotide, plays longer transit time in the colon, suggests that this key roles in a variety of reactions involving carbo- source of thiamin contributes to host nutrition, hydrate, amino acid, and lipid metabolism, and in especially towards the cellular nutrition of the lo- the conversion of folic acid and vitamin B 6 into cal colonocytes. Intestinal absorption of thiamin their active coenzyme forms [for review, see 6 ]. and its transport into other cell types is via a spe- Deficiency and suboptimal levels of RF occur in cific, carrier-mediated process that involves both patients with inflammatory bowel disease and in hTHTR-1 and -2 [for review, see 1 ]. subjects with chronic alcohol use; it also occurs in Good dietary sources of thiamin include rice Brown-Vialetto-Van Laere syndrome (BVVL), a bran, dried baker’s yeast, wholegrain cereal, nuts, rare neurodegenerative disorder characterized by and dried legumes. Attention should be paid, pontobulbar palsy, sensorineural hearing loss, however, to diets that contain thiamin antago- and respiratory problems. BVVL is caused by nists or thiaminases. Sulfites (a food preserva- mutations in the RF transporter-2 (see below) tive) and a number of heat-stable polyhydroxy- and responds to RF supplementation [7] . System- phenolic compounds (which exist in certain ic RF deficiency leads to a variety of clinical ab- types of food like ferns, tea leaves, blueberry, red normalities that include degenerative changes in chicory, red beetroot, black currant, red beetroot, the nervous system, endocrine dysfunction, skin Brussels sprouts, and red cabbage) can cleave the disorders, and anemia. In contrast, optimization thiamin molecule. Certain foods (e.g. fern, crab of RF status reduces the risk of esophageal squa- the African silkworm Anaphe spp. which is a pro- mous cell carcinoma.

32 Said

Two sources of RF are available to humans: a cific, carrier-mediated process [for review, see 1 ]. dietary source, which is absorbed in the small in- Good dietary sources for niacin include meat testine, and a bacterial (normal microflora of the products, cereals and brewers’ yeast. The RDA for large intestine) source, which is absorbed in the niacin (i.e. niacin equivalents) is 16, 14, 18, and 17 colon. Transport of RF into human cells occurs mg/day for adult males, adult females, and during via a carrier-mediated process that involves RF pregnancy and lactation, respectively. No adverse transporters-1, -2 and/or -3 (RFT-1, -2 and -3, re- effects have been reported with low doses of nia- spectively). The intestine utilizes RFT-1 and -2 cin. Chronic use of large doses of niacin (3–9 for absorption of the vitamin [for review, see 1 ]. g/day), however, is associated with skin flushing, RF is widely available in many foods, with itching, and gastrointestinal and liver disorders. vegetables, meats, and milk products being particularly rich in the vitamin. The RDA for RF is 1.3, 1.1, 1.4, and 1.6 mg for adult males, adult fe- V i t a m i n B5 (Pantothenic Acid) males, and during pregnancy and lactation, respectively. No adverse effects are known for RF Pantothenic acid is needed for the synthesis of overdosing even at high levels. coenzyme A and acyl carrier protein, which are involved in carbohydrate, fat, and protein metabolism. Due to the ubiquitous distribution of panto- V i t a m i n B3 (Niacin, Nicotinic Acid) thenic acid in foods, no known cases of spontane- ous deficiency of the vitamin have been reported Niacin is a precursor of the coenzymes nicotin- in humans. However, an inherited disorder, pan- amide adenine dinucleotide and nicotinamide ad- tothenate kinase-associated neurodegenerative enine dinucleotide phosphate, both of which are disorder (an autosomal recessive neurodegenera- involved in metabolic reactions (including glycol- tive disease with iron accumulation in the basal ysis and the pentose phosphate shunt) that main- ganglia of the brain; previously called Hallervor- tain the redox state of the cell. At high doses, the den-Spatz syndrome), has been described in hu- vitamin also has a lipid-lowering effect, and thus, mans and is believed to be due to mutations in the has been used in the treatment of hypercholester- gene encoding pantothenate kinase 2 PANK2. olemia and the prevention of atherosclerosis. Nia- Humans obtain pantothenate from dietary cin deficiency leads to pellagra, a disease that is sources and from the colonic microflora. Ab- characterized by inflammation of the mucous sorption of pantothenate from both sources oc- membranes, skin lesions, diarrhea and neurologi- curs via a carrier-mediated process that is shared cal disorders. Deficiency and suboptimal levels with biotin and lipoate and involves the sodium- occur in alcoholics and in patients with Hartnup’s dependent multivitamin transporter [for review, disease. Patients with the latter disease have muta- see 1 ]. tions in the membrane transporter of the amino Rich sources of pantothenic acids include acid tryptophan (which is the precursor of endog- meats (liver and heart in particular), vegetables, enous niacin synthesis). Humans obtain their re- and yeast. The RDA for pantothenic acid is not quirements of niacin from endogenous and exog- well defined; however, adequate intake has been enous sources. The former source is provided via estimated to be between 5 and 7 mg for adults the metabolic conversion of tryptophan to niacin, (including during pregnancy and lactation). No while the latter source is the diet. adverse effects have been reported as a result of Transport of niacin into human cells (includ- consumption of large doses of pantothenic acid of ing its absorption in the intestine) is via a spe- up to 10 g/day.

Water-Soluble Vitamins 33 V i t a m i n B6 (Pyridoxine and Derivatives) and is associated with megaloblastic anemia, neural tube defects, growth retardation, cardiovascu- Vitamin B6 refers to three naturally occurring lar disease and increased risk of certain types of compounds: pyridoxal, pyridoxine, and pyridox- cancer. On the other hand, optimizing folate body amine. The vitamin acts as a cofactor in a number homeostasis leads to a significant reduction in the of metabolic reactions involving carbohydrate, incidence of neural tube defects. A variety of con- protein and lipid metabolism. Pyridoxal 5′ -phos- ditions and factors interfere with the normal phys- phate is the most biologically active form of the iology and metabolism of folate, especially with its vitamin. Deficiency of vitamin B 6 (which leads to intestinal absorption process. This includes con- a variety of clinical abnormalities including neu- genital defects in the absorptive system, i.e. muta- rological disorders and anemia) occurs in chronic tions in the folate transport proton-coupled folate alcoholism, in patients with diabetes mellitus and transporter (PCFT) system, which occurs in pain those with celiac disease; it also occurs in sub- tients with hereditary folate malabsorption syn- jects on long-term therapy with the agents isonia- drome (HFMS) [9] , intestinal diseases (e.g. celiac zid and penicillamine. Suboptimal levels of vita- disease and tropical sprue), as a result of prolonged min B 6 have also been reported in patients with use of certain medications (e.g. sulfasalazine, tri- vitamin B 6-dependent seizure, an autosomal-re- methoprim, pyrimethamine, diphenylhydantoin), cessive disorder believed to be due to impairment and in subjects with chronic alcoholism. in pyridoxine transport into cells [8] . Two sources of folate are available to humans, Humans obtain vitamin B6 from dietary and a dietary source (absorbed in the small intestine) colonic bacterial sources. Absorption of these and a large intestinal bacterial source (absorbed sources of vitamin B6 occurs via a carrier-medi- in the colon). A positive relationship has been ated uptake process [for review, see 1 ]. No infor- demonstrated in humans between fiber intake mation is currently available about the molecular (which translates to flourishing intestinal micro- identity of the transport system(s) involved. flora) and serum folate levels. Good sources of dietary vitamin B6 include Transport of folate into human cells is via a meats, wholegrain products, vegetables, and nuts. specific and saturable process that involves three The RDA for vitamin B6 is 2.0, 1.6, 2.1, and 2.1 systems: the reduced folate carrier, PCFT and the mg/day for adult males, adult females, and during folate receptor systems. In the intestine, the PCFT pregnancy and lactation, respectively. Incidences and reduced folate carrier systems are involved, of adverse effects of overdosing of vitamin B6 are with evidence supporting a predominant role for relatively low, although a few cases of sensory the former system coming from findings in pa- neuronopathy, which is associated with gait and tients with HFMS, where loss-of-function muta- peripheral sensation, have been reported. tions in PCFT have been identified [for review, see 1 ]. HFMS is a rare autosomal recessive disorder that is characterized by anemia, hypoimmuno- Vitamin B9 (Folate) globulinemia (with recurrent infections), diarrhea, and neurological abnormalities. When di- Folate is a generic term for folic acid and its de- agnosed early, the condition can be effectively rivatives, compounds that act as coenzymes for treated with parenteral administration of folate or cellular one-carbon metabolism and consequently with oral administration of high pharmacological for the synthesis of thymidine and purine as well as doses of the vitamin. If treatment of the disease is for the interconversion of amino acids. Folate de- delayed, the neurological disorders could become ficiency is a highly prevalent vitamin deficiency permanent; if untreated, the condition is fatal.

34 Said

Good dietary sources of folate include fruits, Meat and microbes are the main source of Cbl, fortified cereals, vegetables, dairy products and and the vitamin is virtually absent from a vege- liver. The RDA for folate for adults (both males tarian or vegan diet; therefore, such individuals and females) is 400 μg/day; during pregnancy are at risk of developing Cbl deficiency. In addi- and lactation it is 600 and 500 μg/day, respective- tion, an impaired absorption of Cbl is frequently ly. No adverse effects have been reported as a re- observed in elderly people, in whom a poor Cbl sult of large oral doses of folate, although allergic status is believed to have a prevalence of around reaction has been observed in a few cases. 20%. The RDA for Cbl is 2.0, 2.0, 2.6 and 2.8 μg/ day for adult males, adult females, and during pregnancy and lactation, respectively. No major V i t a m i n B12 (Cobalamin) toxicity has been reported in humans even with high doses of vitamin B12 . Cobalamin (Cbl), in its coenzyme forms methyl-Cbl and adenosyl-Cbl, plays critical roles in the metabolism of propionate, amino acids, Vitamin C (Ascorbate, Dehydroascorbate) and in single-carbon exchange reactions. Cbl deficiency in humans occurs in a variety of condi- Dietary ascorbate (vitamin C) exists in the re- tions including intrinsic factor-deficient subjects duced (i.e. ascorbic acid, AA) and oxidized (de- (due to gastric atrophy, inborn lack of the factor, hydro-L -ascorbic acid, DHAA) forms. The vita- total gastrectomy), subjects with inflammatory min acts as a cofactor in a variety of critical meta- bowel disease, vegans, in diabetic patients treated bolic reactions that include the synthesis of with metformin, and in subjects with genetic de- collagen, carnitine, and catecholamine as well as fects in the receptors and proteins responsible for in peptide amidation and tyrosine metabolism; it the intestinal and cellular uptake of vitamin B12 . is also involved in maintaining metal ions (like This deficiency leads to megaloblastic anemia, iron and copper) in their reduced forms, and neurological disorders, and growth retardation. serves as a scavenger for free radicals. A role for The deficiency can be corrected by parenteral ad- AA in the regulation of cystic fibrosis transmem- ministration of the vitamin, or by oral adminis- brane conductance regulator-mediated chloride tration of high pharmacological doses of the vita- secretion in epithelial cells has also been suggest- min. ed. DHAA is structurally different from AA; rath- Cbl is obtained from foods of animal origin. er, it is structurally similar to glucose. DHAA is The vitamin is first liberated from its dietary converted to AA intracellularly via the action of binding proteins and then binds to haptocorrin (a DHAA reductase. Converting DHAA to AA protein that is synthesized by the salivary glands) helps maintain low (nontoxic) levels of the com- to protect it against the effect of low gastric pH pound. Deficiency of this vitamin leads to a vari- [for review, see 8 ]. In the jejunum, haptocorrin is ety of clinical abnormalities that include scurvy, degraded by pancreatic proteases, and the re- poor wound healing, vasomotor instability and leased Cbl then binds to the intrinsic factor connective tissue disorders. (which is produced by parietal cells in the stom- Humans cannot synthesize vitamin C endog- ach). The intrinsic factor-bound Cbl is then rec- enously as they lack the enzyme L-gulonolactone ognized by a specific receptor complex, cubam, oxidase; rather, they obtain the vitamin from di- present on the apical brush border membrane of etary sources via intestinal absorption. Unlike a the intestinal cells in the distal part of ileum [for number of other water-soluble vitamins (e.g. thia- review, see 10 ]. min, biotin, folate), which are also produced by

Water-Soluble Vitamins 35 the normal microflora of the large intestine, there studies have shown that during pregnancy, biotin appears to be no net production of ascorbate by deficiency may lead to congenital malformation these bacteria. Cellular uptake of AA, including and death. Biotin deficiency and suboptimal levels its absorption in the intestine, involves the sodi- occur in subjects with biotinidase deficiency (an um-dependent vitamin C transporter-1 (SVCT-1; autosomal-recessive inherited metabolic disorder product of the SLC23A1 gene), and SVCT-2 (prod- in which the enzyme biotinidase is defective and uct of the SLC23A2 gene) [for review, see 1 ]. Trans- biotin is not recycled; the condition can be treated port of DHAA into cells, including its intestinal with biotin supplementation) [12] , those on long- absorption, also occurs via a carrier-mediated term therapy with anticonvulsant drugs, those on process and involves the glucose transporters long-term parenteral nutrition, after prolonged GLUT1, GLUT3 and GLUT4 [for review, see 1 ]. consumption of raw eggs, in chronic alcoholics, Vitamin C is widely distributed in fruits (e.g. during pregnancy, and in subjects with inflamma- orange, strawberry, cantaloupe, grapefruit, man- tory bowel disease. go) and vegetables (e.g. broccoli, Brussels sprouts, Humans obtain biotin from dietary and colon- cabbage, pepper, cauliflower) occurring mostly ic bacterial sources. Absorption of biotin in the (up to 90%) as AA and the remaining portion as small and large intestine as well as transport into DHAA; this ratio could change with prolonged cells occurs via a carrier-mediated uptake process storage, exposure to air, and in aqueous solution. that is shared with the vitamin pantothenic acid Because the body can reduce DHAA to AA, this and with the metabolically important substrate li- form also has biological activity. The RDA for vi- poate (a potent intracellular and extracellular an- tamin C is 90, 75, 85, and 120 mg/day for adult tioxidant) and involves the sodium-dependent males, adult females, and during pregnancy and multivitamin transporter [for review, see 1 ]. lactation, respectively. Biotin is widely distributed in foodstuff with Toxic effects of vitamin C are few and are de- dairy products, meat (liver), egg yolk, and vegeta- pendent on the level of intake. Oral ingestion of bles representing good sources for the vitamin. large doses of vitamin C (3–5 g) can cause gastro- The RDA for biotin is not well defined; however, intestinal problems (diarrhea and bloating); it adequate intake has been estimated at 30 μg/day may also cause transient hyperuricosuria and an for adult males and females (including pregnant increase in oxalate production and excretion. women) and at 35 μg/day during lactation. No ad- The latter may increase the risk of urinary cal- verse effects have been reported as a result of culi formation. large daily oral (up to 200 mg) or intravenous (20 mg) biotin doses.

Vitamin H (Biotin) Conclusion In mammals, biotin serves as a cofactor for a number of carboxylases that are involved in a variety of Significant progress has been made in recent metabolic reactions including fatty acid biosyn- years with regard to physiology and pathophysi- thesis, gluconeogenesis, and catabolism of certain ology of water-soluble vitamins and their involve- amino acids and fatty acids. The vitamin also plays ment in different and previously unrecognized a role in regulating the expression of oncogenes physiological events. With proper identifications, [for review, see 11 ]. Deficiency of biotin leads to incidences of mutations in the involved transport dermatitis around body orifices, alopecia, con- systems for a number of these micronutrients junctivitis, and neurological disorders. Animal have also been recognized allowing for proper

36 Said

treatment of the resulting clinical conditions in a Acknowledgements timely manner. Also recognized now is the contribution of the intestinal microbiota toward This study was supported by grants from the overall vitamin body homeostasis and nutrition, National Institutes of Health (DK56061 and and especially toward the cellular nutrition and DK58057) and the Department of Veterans Af- health of the local colonocytes. fairs.

References

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Biochem J 2011; 437: 357–372. gene and Wernicke’s-like encephalopa- er and the molecular basis for hereditary

2 Arumugam M, Raes J, Pelletier E, et al: thy. N Engl J Med 2009; 360: 1792–1794. folate malabsorption. Cell 2006; 127: Enterotypes of the human gut microbi- 6 Said HM, Ross C: Riboflavin; in Ross C, 917–928.

ome. Nature 2011; 473: 174–180. Caballero B, Cousins RJ, et al (eds): 10 Quadros EV: Advances in the under- 3 Said HM: Thiamin; in Coats PM, Betz Modern Nutrition in Health and Dis- standing of cobalamin assimilation and

JM, Blackman MR, et al (eds): Encyclo- ease, ed 11. New York, Lippincott Wil- metabolism. Br J Haematol 2010; 148: pedia of Dietary Supplements. New liams and Wilkins, 2012. 195–204. York, Informa Healthcare, 2010, pp 7 Bosch AM, Abeling NG, Ijlst L, et al: 11 Said HM: Biotin: Biochemical, Physi- 752–757. Brown-Vialetto-Van Laere and Fazio ological and Clinical Aspects; in Stanger 4 Neufeld EJ, Fleming JC, Tyartaglini E, Londe syndrome is associated with a O (ed): Water Soluble Vitamins. New Steinkamp MP: Thiamin-responsive riboflavin transporter defect mimicking York, Springer, 2012, pp 2–20. megaloblastic anemia syndrome: a dis- mild MADD: a new inborn error of me- 12 Wolf B, Heard GS, Secor-McVoy JR, order of high-affinity thiamin transport. tabolism with potential treatment. J In- Raetz HM: Biotinidase deficiency: the

Blood Cells Mol Dis 2001; 27: 135–138. herit Metab Dis 2011; 34: 159–164. possible role of biotinidase in the pro- 8 Gospe SM: Pyridoxine-dependent sei- cessing of dietary protein-bound biotin.

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Water-Soluble Vitamins 37 Nutrition for Health

Bier D, et al. (eds): Nutrition for the Primary Care Provider. World Rev Nutr Diet. Basel, Karger, 2015, vol 111, pp 38–44 DOI: 10.1159/000362295

Fat-Soluble Vitamins

Elizabeth J. Johnson Emily S. Mohn

Jean Mayer USDA Human Nutrition Center on Aging, Tufts University, Boston, Mass. , USA

Key Words cholesterol, phospholipids, and fatty acids. This Fat-soluble vitamins · Absorption · Transport · requires bile from the liver and gallbladder as well Storage · Functions · Requirements as pancreatic enzymes. Micelles are absorbed into intestinal enterocytes via passive diffusion or specific transporters. Fat-soluble vitamins are re- organized into chylomicrons and released into Key Messages the lymphatic system. Chylomicrons are broken • The four fat-soluble vitamins are vitamins A, D, E, down by lipoprotein lipase, an enzyme on periph- and K. Due to their fat-soluble properties, they have eral tissue surfaces, releasing fat-soluble vitamins similar absorption, transport, and storage as dietary into the tissue. Chylomicron remnants are taken fat. • Fat-soluble vitamins play essential roles in various up by the liver and broken down. Fat-soluble vi- bodily tissues, including (but not limited to) the ret- tamins can either be stored in the liver or repack- ina, brain, nervous tissue, epithelial linings, immune aged and released into the bloodstream for uptake cells, and bone. into various tissues either for use or storage. Re- • Inadequate intake or absorption of these vitamins quirements for these vitamins are found in ta- can lead to a number of serious clinical complica- ble 2 . Tolerable upper limits have been set for tions at all stages of the human life cycle. © 2015 S. Karger AG, Basel these vitamins, except for vitamin K (table 3 ).

Vitamin A Introduction Dietary Sources The fat-soluble vitamins are vitamins A, D, E, and Vitamin A is found in foods as either fatty acid K (table 1 ). Fat-soluble vitamins follow the same esters of retinol (retinyl esters) or provitamin A absorption mechanism as fat [1] . For fat-soluble carotenoids (β-carotene, α-carotene, β-crypto- vitamins to be absorbed, they must be emulsified xanthin) [2, 3] . These carotenoids are converted and incorporated into mixed micelles containing to retinol with varying degrees of efficiency. Di- Table 1. Fat-soluble vitamins Vitamin Chemical name Structure

A retinol H O

H H H H H H

D cholecalciferol (D3)

H H H

O H

D ergocalciferol (D2) H

H H

H H H

O H E α-tocopherol

E α-tocotrienol

HO H

O H

K menaquinone (MK-7)

O H H H H H H

K phylloquinone O H

Fat-Soluble Vitamins 39 Table 2. RDA for fat-soluble vitamins

Age Vitamin A, Vitamin D, Vitamin E, Vitamin K, μg/day1 μg/day mg/day μg/day2

Males Infants2

0 – 6 months 400 (1,333) 10 (400) 4 (6) 2

7 – 12 months 500 (1,667) 10 (400) 5 (7.5) 2.5 Children

1 – 3 years 300 (1,000 15 (600) 6 (9) 30

4 – 8 years 400 (1,333) 15 (600) 7 (10.5) 55

9 – 13 years 600 (2,000) 15 (600) 11 (16.5) 60

Adolescents (14 – 18 years) 900 (3,000) 15 (600) 15 (22.5) 75 Adults

19 – 70 years 900 (3,000) 15 (600) 15 (22.5) 120 ≥71 years 900 (3,000) 20 (800) 15 (22.5) 120 Females Infants2

0 – 6 months 400 (1,333) 10 (400) 4 (6) 2

7 – 12 months 500 (1,667) 10 (400) 5 (7.5) 2.5 Children

1 – 3 years 300 (1,000) 15 (600) 6 (9) 30

4 – 8 years 400 (1,333) 15 (600) 7 (10.5) 55

9 – 13 years 600 (2,000) 15 (600) 11 (16.5) 60

Adolescents (14 – 18 years) 700 (2,333) 15 (600) 15 (22.5) 75 Adults

19 – 70 years 700 (2,333) 15 (600) 15 (22.5) 90 ≥71 years 700 (2,333) 20 (800) 15 (22.5) 90 Breastfeeding ≤18 years 1,200 (4,000) 15 (600) 19 (28.5) 75 >18 years 1,300 (4,333) 15 (600) 19 (28.5) 90 Pregnancy ≤18 years 750 (2,500) 15 (600) 15 (22.5) 75 >18 years 770 (2,567) 15 (600) 15 (22.5) 90

Figures in parentheses indicate IU. 1 Retinol activity equivalents. 2 Adequate intake.

etary β-carotene is the most efficient (12 μg Absorption and Transport β-carotene = 1 μg of retinol, or 1 retinal activity Retinyl esters and provitamin A carotenoids are equivalent). Dietary α-carotene and β-crypto- often attached to food compounds and are hydro- xanthin are approximately half as efficient. Vita- lyzed and freed for small intestine uptake. The min A is obtained mostly from animal sources, small intestine releases pancreatic enzymes to re- including meats, cheeses, and fortified milk. Pro- lease vitamin A from food to its free form. Brush vitamin A carotenoids are found in fruits and border enzymes on the surface of intestinal cells vegetables. also contribute to the release. A fraction of the

40 Johnson/Mohn

Table 3. Tolerable upper level for fat-soluble vitamins

Age Vitamin A, μg/day Vitamin D, μg/day Vitamin E, mg/day

Infants

0 – 6 months 600 (2,000) 25 (1,000) not established

6 – 12 months 600 (2,000) 37.5 (1,500) not established Children

1 – 3 years 600 (2,000) 62.5 (2,500) 200 (300)

4 – 8 years 900 (3,000) 75 (3,000) 300 (450)

9 – 13 years 1,700 (5,667) 100 (4,000) 600 (900)

Adolescents (14 – 18 years) 2,800 (9,333) 100 (4,000) 800 (1,200) Adults (>18 years) 3,000 (10,000) 100 (4,000) 1,000 (1,500)

Figures in parentheses indicate IU.

provitamin A carotenoids are converted to vita- tissues, red blood cells, and components of the min A in the intestinal lumen prior to absorption eye. Vitamin A also plays an important role in or within intestinal cells. Vitamin A is then re- immune function. It maintains the integrity of packaged into chylomicrons and released into the the epithelium inside and outside the body, which lymphatic system, where it is taken up by periph- serves as a barrier against foreign pathogens. eral tissues until it reaches the liver. The liver is the main storage site of vitamin A. Upon release D e f i c i e n c y from the liver, vitamin A is bound to retinol- Vitamin A deficiency symptoms develop once vi- binding protein (RBP) and travels through the tamin A liver stores are completely or nearly de- bloodstream for uptake by tissues containing pleted. Night blindness occurs when there is not RBP receptors. enough retinal to regenerate rhodopsin in the retina. This leads to the inability to immediately re- Functions cover vision after light flashes, as well as vision loss In the retina, vitamin A is converted to retinal and in dark/dim light. Vitamin A deficiency also plays binds to the protein opsin forming rhodopsin. a role in permanent blindness where, due to inad- When light hits the retina cells, retinal changes equate mucus secretion in the front of the eye, the conformation and detaches from opsin. Opsin corneal cells become dry and hard, and keratin, a also changes shape to generate an electrical im- hard-water-insoluble protein accumulates. pulse in the retina cells, which transfers the signal Vitamin A deficiency can increase suscepti- to nerve cells, and then to the brain. The brain bility to diseases and infection. Severe deficien- interprets the signal as light. Some retinal is lost cies can lead to death. A priority in international during every cycle. Therefore, vitamin A must be nutrition policy is vitamin A supplementation to replenished through diet. developing nations, where vitamin A deficiencies Vitamin A deficiency during pregnancy may are prevalent, to decrease infant morbidity/mor- lead to birth defects and high infant mortality tality. Keratinization can occur in prolonged vi- rates. Retinoic acid, a form of vitamin A is vital tamin A deficiency in external epithelial cells (or for the differentiation of stem cells into epithelial skin cells), leading to dry, red, bumpy skin.

Fat-Soluble Vitamins 41 T o x i c i t y thyroid hormone, which increases the activa- Vitamin A toxicity occurs from either extremely tion of vitamin D via a hydroxylation reaction high doses over a short period of time or chronic in the kidney, forming calcitriol (1,25-dihy- overexposure with high doses. This leads to the droxyvitamin D). Calcitriol increases serum saturation of RBP, and free retinol can damage calcium and phosphorous concentrations by in- cells. Intakes above this limit may cause liver creasing intestinal absorption of calcium and damage, changes in vision, headache, dry/itchy phosphorous. Calcitriol increases the reabsorp- skin, and hair loss. tion of calcium filtered by kidneys and mobi- lizes calcium in bones. This allows for calcium and phosphorous levels to rise to the desired Vitamin D range. Calcitriol has been shown to modulate a vari- Dietary Sources ety of processes through binding to its receptor A significant amount of the vitamin D is synthe- and regulating gene expression, cell proliferation, sized in the skin when exposed to UVB radiation and cell differentiation. Vitamin D status has from sunlight [4] . This form of vitamin D is bio- been linked to the decreased risk for developing logically inactive and must undergo hydroxylation autoimmune diseases. Furthermore, vitamin D reactions in the liver and kidney before it can func- deficiency has been linked to increased inflam- tion within the body. The main form of vitamin D mation. found in food is vitamin D3 . Many sources also contain D2 . D3 is the form synthesized in the skin. D e f i c i e n c y The active form of vitamin D is calcitriol (1,25 di- In children, vitamin D deficiency causes rickets, a hydroxyvitamin D). Vitamin D naturally occurs in disease of inadequate bone mineralization. In few foods, although it is naturally found in wild rickets, weak bones bend under the body weight salmon and swordfish. Most dietary vitamin D is and sometimes there are deformed rib cages. For from fortified sources. Two main fortified sources adults, lack of vitamin D can cause osteomalacia. of vitamin D are milk and ready-to-eat cereals [2] . Long-term vitamin D insufficiency is a factor for increased risk of osteoporosis. Osteoporosis is Absorption, Transport and Activation characterized by low bone density and bone tissue Vitamin D absorption follows the same path as deterioration. dietary fat (see above). Adipose tissue is the main vitamin D storage site. Vitamin D synthesized in Toxicity the skin enters the circulation and is taken up by Vitamin D toxicity occurs due to oversupplemen- the liver. Once there, vitamin D undergoes a hy- tation, not from overexposure to sunlight. Excess droxylation reaction to form calcidiol (25-hy- vitamin D in the body causes high blood calcium droxyvitamin D). This form binds to the vitamin levels above a healthy range leading to inappro- D-binding protein and is released into the circu- priate deposition of calcium in soft tissues. Cal- lation. Calcidiol is the major form of vitamin D in cium deposition in the kidneys can lead to kidney serum and increases with increased vitamin D stone formation. Blood vessels and arteries begin from the diet or sun. to harden with calcification in the heart. Increased vitamin D can also lead to increased bone resorp- Functions tion, leading to bone loss. Vitamin D tolerable up- When serum calcium and phosphorous levels per intake levels have been determined for vari- drop too low, parathyroid glands secrete para- ous age groups (table 3 ).

42 Johnson/Mohn

Vitamin E Toxicity Oversupplementation is the main cause of vita- Dietary Sources min E toxicity. Too much vitamin E can lead to Vitamin E exists in different forms, four of which blood coagulation problems and hemorrhaging. are: α-tocopherol, γ-tocopherol, α-tocotrienol, and γ-tocotrienol [5]. α-Tocopherol is the main form stored and used by the body. The following Vitamin K information will be on this form. Vitamin E is naturally found in oils, such as sunflower and saf- Dietary Sources flower oil, and oily foods, such as nuts [2] . Vitamin K refers to several different molecules that all possess similar structural characteristics Absorption, Transport and Storage [3]. Phylloquinone is the main form of vitamin K Dietary vitamin E is absorbed in the intestine found in foods. Some menaquinones can be found through the same mechanisms as other fat-solu- in food sources. Additionally, menaquinone-4 can ble vitamins. In the liver, the vitamin E forms (ex- be synthesized from phylloquinone in the body. cept α-tocopherol) are metabolized or excreted. Main sources of phylloquinone in the diet include α-Tocopherol is maintained in the liver through green, leafy vegetables and broccoli [2] . Menaqui- its binding to α-tocopherol transfer protein and is nones with long side chains can be synthesized by the only form that the liver releases. Liver release microbiota in the human colon, although its con- of α-tocopherol in lipoproteins is taken up by var- tribution to overall vitamin K status is unknown. ious tissues for use. Absorption and Transport Functions Vitamin K absorption in the intestine follows the The main function of vitamin E is as an antioxi- same mechanism as dietary fat. In the liver, vita- dant. Oxidative stress is caused by environmental min K is used or repackaged and released in tri- factors, such as smoke or alcohol. Oxidants are glyceride-rich lipoproteins. The major site of vi- also formed endogenously through normal pro- tamin K storage is the adipose tissue. Unlike the cesses of energy metabolism. Vitamin E inter- other fat-soluble vitamins, a significant portion of cepts free radicals in lipid membranes to prevent vitamin K is excreted in the bile and urine. the propagation of lipid peroxidation. In this way, vitamin E prevents the oxidation of tissue Functions membranes and circulating lipoproteins. Vita- The main role of vitamin K is the activation of vi- min E must be recycled by other antioxidants to tamin K-dependent coagulation and bone forma- continue to function. Vitamin C is one of the tion proteins. Many observational studies have main antioxidants responsible for vitamin E re- shown that vitamin K intake is associated with a generation. decreased risk of hip fracture. However, other studies have shown no association between vita- Deficiency min K intake and bone mineral density, and ran- Vitamin E deficiency leads to the breakdown domized controlled trials have failed to show an of cell membranes and tissue damage due to effect of vitamin K on bone health. oxidative stress. Hemolysis can occur. Com- mon manifestations of vitamin E deficiency are Deficiency peripheral neuropathy and degeneration of ax- Vitamin K deficiency leads to increased risk for ons. hemorrhaging. Vitamin K deficiency is a problem

Fat-Soluble Vitamins 43 for newborns due to poor vitamin K placental Conclusion transfer. Injections of vitamin K are given to infants at birth to prevent any bleeding issues. Vita- • Fat-soluble vitamins play an important role in min E may play a role in antagonizing vitamin K human health. status; therefore, extremely high doses of vitamin • Main functions of these nutrients are known. E may increase the risk for vitamin K deficiency. • Each fat-soluble vitamin has specific symp- Similarly, anticoagulants have been shown to an- toms of deficiencies and toxicities. tagonize the role of vitamin K. Those on such • New roles for each fat-soluble vitamin are con- medication should monitor vitamin K intake. stantly being discovered.

Toxicity To date, there is no clinical evidence that increased consumption of vitamin K is toxic in healthy individuals.

References

1 Reboul E, Borel P: Proteins involved in 3 Food and Nutrition Board, Institute of 4 Food and Nutrition Board, Institute of uptake, intracellular transport and baso- Medicine: Dietary Reference Intakes for Medicine: Dietary Reference Intakes for lateral secretion of fat-soluble vitamins Vitamin A, Vitamin K, Arsenic, Boron, Calcium, Phosphorus, Magnesium, Vi- and carotenoids by mammalian entero- Chromium, Copper, Iodine, Iron, Man- tamin D, and Fluoride. Washington,

cytes. Prog Lipid Res 2011; 50: 388–402. ganese, Molybdenum, Nickel, Silicon, National Academy Press, 2010. 2 USDA Agricultural Research Service, Vanadium, and Zinc. Washington, Na- 5 Food and Nutrition Board, Institute of National Agricultrual Library: USDA tional Academy Press, 2014. Medicine: Dietary Reference Intakes for National Nutrient Database for Standard Vitamin C, Vitamin E, Selenium and Ca- Reference. ndb.nal.usda.gov/. rotenoids. Washington, National Acad- emy Press, 2000.

44 Johnson/Mohn

Nutrition for Health

Bier D, et al. (eds): Nutrition for the Primary Care Provider. World Rev Nutr Diet. Basel, Karger, 2015, vol 111, pp 45–52 DOI: 10.1159/000362296

Minerals and Trace Elements

a b, c Susan J. Fairweather-Tait Kevin Cashman a b Norwich Medical School, University of East Anglia, Norwich , UK; School of Food and Nutritional Sciences, and c Department of Medicine, University College Cork, Cork , Ireland

Key Words Introduction Minerals · Trace elements · Deficiency · Toxicity Essential minerals and trace elements have well-characterized physiological functions within the body (table 1 ) and must be supplied Key Messages by the diet [for more details, see 1 ]. Dietary Ref- • Inappropriate intakes and/or elevated require- erence Intakes for the various minerals and by ments resulting from a range of conditions, including disease, malabsorption, medications, and ex- life stage groups have been derived by the North cessive losses, eventually lead to a state of deficien- American Institute of Medicine [2] . Inappro- cy or toxicity. priate intakes and/or elevated requirements re- • Disorders that affect the organs can manifest as de- sulting from a range of conditions, including ficiencies in minerals or trace elements. For exam- disease, malabsorption, some medicines, and ple, iron deficiency is common in inflammatory excessive losses, will eventually lead to a state of bowel disease. • Excess levels of certain minerals or elements result deficiency or toxicity with associated patho- in damage to the related organs, as demonstrated physiology. For many minerals, there are no in the kidney where high phosphorus levels are as- simple, sensitive and specific biomarkers of sta- sociated with the parenchymal deposition of calci- tus ( table 2 ), so deficiency or toxicity may not um phosphate precipitates. be diagnosed until fairly well advanced, at • Vulnerable groups or conditions with increased risk which point the patient may present with clini- of mineral deficiency include those with anorexia nervosa, pregnant women, infants and children, cal signs or symptoms (table 3 ). With a poor and patients on parenteral nutrition. diet, it is likely that multiple micronutrient de- • The use of certain drugs and medications can also af- ficiencies will occur, but there are also rare ge- fect the body’s mineral and trace element status. This netic mutations that affect the metabolism of can also be influenced by hereditary disorders such single minerals or trace elements; these are usu- as hereditary hemochromatosis, Wilson’s disease ally unrelated to diet. and Menkes’ syndrome. © 2015 S. Karger AG, Basel Table 1. Major functions of minerals and trace elements

Minerals Calcium Structural (bones, teeth), extracellular cation (neural transmission, muscle contraction, vascular tone) Magnesium >300 enzymatic processes, bone health, maintenance of intracellular levels of K and Ca Phosphorus Structural (bones, teeth, phospholipids), acid-base balance, protein activation via phosphorylation Potassium Intracellular cation (neural transmission, muscle contraction, vascular tone) Sodium Extracellular cation, membrane potential, membrane transport Chloride Extracellular anion, fluid and electrolyte balance, gastric juice Trace elements Copper Metalloenzymes, red blood cell formation, connective tissues Fluoride Not an essential nutrient but present as fluorohydroxyapatite in tooth enamel Iodine Thyroid hormones Iron Heme proteins, flavoproteins, other enzymes Manganese Metalloenzymes, bone formation Selenium Selenoproteins, thyroid hormone, redox status Zinc >100 enzymes, growth, development, gene expression

The Role of Minerals and Trace Elements in Liver the Etiology and Management of Various Deficiencies of minerals occur in patients with Diseases or Disorders liver disease due to steatorrhea (calcium), alcohol abuse and increased levels of aldosterone (potas- The following section will highlight conditions sium) and the use of diuretics (potassium, calci- where the risk of deficiency can be increased and um, magnesium, zinc). Dietary treatment of asci- may warrant detailed investigations of mineral tes requires sodium restriction, depending on the nutritional status (table 2 ). severity, but very low sodium diets are impracti- cal and unpalatable. GI Tract Iron deficiency is frequent in inflammatory bow- Pancreas el disease (IBD) due to blood loss. Zinc deficiency Patients with chronic pancreatitis are generally is also a problem, and low serum zinc concentra- undernourished; selenium appears to be the min- tions have also been reported in Crohn’s disease eral most frequently noted as being deficient, but and in ulcerative colitis. Serum selenium is low in this is thought to be due to malabsorption or in- IBD, and the activity of glutathione peroxidase, creased oxidative stress rather than an inadequate a selenium-dependent enzyme, is decreased in intake. some patients with Crohn’s disease and ulcerative colitis. Celiac disease patients have global malab- Kidney sorption problems, and gluten-free diets may not High phosphorus intakes are associated with the contain an adequate level of some micronutrients parenchymal deposition of calcium phosphate such as magnesium; microcytic anemia (iron de- precipitates, which causes kidney damage; there- ficiency) is very common, and these patients are fore, phosphorus intake should be reduced ac- also at risk of developing low bone mineral den- cording to the glomerular filtration rate (GFR): sity (BMD), where calcium and vitamin D play a • GFR 25–70 ml/min, phosphorus 8–10 g/kg/day key role. • GFR <25 ml/min, phosphorus 5–10 g/kg/day.

46 Fairweather-Tait /Cashman

(1, 2) Maintained 2) within(1, a narrow range T score is the(3) number of standard deviations below the average for a young adult at peak bone density Large(4) assay-dependent differences in values and thus ranges normal in No clear(6) relationship between dietary intake and 24-hour urinary excretion (1) Detects IDA,(1) low specificity and sensitivity Accurate(2) measure of stores but elevated with infection inflammationand Good(3) early indicator of iron deficiency Sensitive(4) measure of erythropoiesis Fasting essential(5) as changes after meals Gold(6) standard but invasive Comment on usefulness of biomarker (1) Accurately reflects(1) intake (24-hour samples best) Useful(2) biomarker of adequacy in children and adults Less sensitive(3) biomarker, not useful in pregnancy Useful(4) in newborn infants Long-term(5) measure of inadequate iodine intake (1) Changes occur in response(1) to pathological conditions Decreases(2) in Wilson’s disease, increases in inflammatory conditions

–

5.0

–

[20]

[19]

(free form) 3.5 [20]

3 [19] 1.65 mg/l);

1.4 mg/l); –

450 mg/l

52.8 mg/l) [10]

–

102 mg/l)102 [10]

[19] 4.4 mg/l4.4

1.9 mg/l)1.9 [10] –

–

1.7 mg/l)1.7 [10]

–

250 mg)/24 h (normal250 mg)/24 diet); 7.5 –

1 –

18 pmol/l,18 T

–

150 mg)/24 h (on low-calcium h (on mg)/24 150 diet) [16]

–

31.3 μmol/l (0.65

22.0 μmol/l (0.7 550 mg/l;550 F 200

175 (mean 157) g/l (mean 157) 175

5.0 mg/l;F 1.9

–

– –

–

1.32 mmol/l (46.4 2.55 mmol/l (86 mmol/l 2.55

300 μg/l

5 mIU/l 24.4 μmol/l (0.8

– –

65 pg/ml65 [15] 20 mmol (100

153 (mean 138) g/l (mean 138) 153

–

30.4 μmol/l (0.5 –

–

40 μl 40

– –

–

(free form) 11 –

– 170 μg/l centile) to 95th (5th 170

4 –

(1) M 11.0 (1) (1) 100 (2) M 16-328 μg/l centile) M 16-328 to 95th (2) (5th (1) 2.15 M 2.2(3) (3) T scored Grade 2) (5) by palpation 1, (0, M 140 (1) F 5 F 12.6 (3) BMD as T scores;(3) normal bone: T score better than –1; osteopenia: T score between and osteoporosis: –2.5; –1 T score less than –2.5 (5) 15 (2) 1.16 (6) 15 22.5 mmol (50 F 9.0 F 123 (2) 4 pmol/l (4) 0.1 (2) M 250 (2) (4) >40(4) μmol/mol heme iron (washed erythrocytes), >80 μmol/mol heme iron (unwashed erythrocytes) indicates deficiencyiron M 11.6 (5) 3 and T 4 Biomarkers for assessing trace element/mineral exposure and status Copper Serum copper(1) ceruloplasmin Serum/plasma (2) Table 2. Biomarkers of exposure or status (body levels) Adult ‘normal range’ Serum(4) thyroid-stimulating hormone (including women during pregnancy and lactation) (5) Goiter Calcium Serum calcium (1) Serum(2) ionized calcium Mineral(3) content of skeletal bone (DXA, CT) Urinary(4) and/or serum bone remodeling biomarkers Serum(5) PTH 24-hour(6) urinary calcium Iron (1) Hemoglobin Ferritin(2) (plasma or serum) Soluble(3) transferrin receptor (plasma or serum) protoporphyrin zinc Erythrocyte (4) Serum(5) iron Bone(6) marrow biopsy Iodine [17, 18] [17, Iodine Urinary iodine(1) (children and adults) Serum(2) thyroglobulin (children and adolescents) Serum(3) T

Minerals and Trace Elements 47 200 mmol/l

–

[14] and NDNS [23]. [14] 5) Large5) assay-dependent differences in values and

–

(1) There are changes(1) in serum magnesium concentration associated with various pathological conditions Insensitive(2) biomarker Used as biomarker(3) of magnesium status primarily in association with magnesium load test (for screening for deficiency)magnesium (2) 24-hour(2) urine reflects intake, and thus varies by population; example opposite from UK National Diet and Nutrition Survey data for to 64-year-olds 19- Comment on usefulness of biomarker hair samples are particularly prone to contamination (2 Zinc deficiency/excess can be detected using serum/ plasma and hair zinc concentrations, but these biomarkers are insensitive and cannot be used to assess statuszinc (1) Lowest recorded value(1) 90 mmol/l, highest recorded 170 values (1) 24-hour urine(1) reflects intake, and thus varies by population; example opposite from UK National Diet and Nutrition Survey data for to 64-year-olds 19- body Total (2) K is a research tool thus in normal ranges normal in thus [21]

127.0) mmol/

274) mmol/24 h 274) –

–

3.29 g/l, range) 95%

26 mg/l)26 [10] 1.5 mg/l)1.5 [10]

–

– –

45 mg/l)45 [10]

231) μg/g 231)

–

1 –

277) μg/g

–

[21]

1.07 mmol/l (16

22.9 μmol/l (0.7

140 mg/24 h 140 143 mmol/l143 (3.08

–

143 μg/l [10]143 All useful measures; GPx mainly used to detect deficiency;

– –

1.45 mmol/l (25 –

[21] –

(1) 10.7 (1) 0.66 (2) M 180 (SD 25; 138 25; (SD M 180 (2) (1) 46 (2) M 1.95 (SD 0.19) mmol/l, 47.5 (SD 4.5) (SD mmol/l, mg/l 47.5 0.19) (SD M 1.95 (2) mol/l, 5.2) (SD mg/lF 2.03 49.4 0.21) (SD (3) 120 (2) 127 (2.5th to 97.5th percentile (2.5th 53 to 97.5th 127 (2) (1) 134 (1) M 76.7 (2.5th to 97.5th percentile 24.3 to 152.1) percentile (2.5th 24.3 M 76.7 to 97.5th to 152.1) (1) h mmol/24 F 195 (SD 23; 154 23; (SD F 195 F 65.2 (2.5th to 97.5th percentileF 65.2 22.4 (2.5th to 97.5th 24 h 40 (continued) Values to represent ‘normal ranges’ Ayling Gibson Gibney and Marshall taken et al. from [13], Lentner [12], Milne [11], [10], Phosphorus phosphorus Serum/plasma (1) 0.81 Potassium 24-hour urinary(1) potassium body Total (2) K Zinc [22] Serum/plasma zinc(1) Hair(2) zinc Table 2 Table Biomarkers of exposure or status (body levels) Adult ‘normal range’ 1 Magnesium magnesium Serum/plasma (1) magnesium Erythrocyte (2) 24-hour(3) urinary magnesium Selenium Serum/plasma selenium(1) Plasma(2) selenoprotein P Plasma GPx3(3) selenium Toenail (4) Hair(5) selenium Sodium Serum/plasma sodium(1) 24-hour(2) urinary sodium

48 Fairweather-Tait /Cashman

Table 3. Signs and symptoms of deficiency and toxicity of minerals and trace elements

Deficiency Causes Excess Causes

Calcium osteoporosis, pre-eclampsia low intake or impaired kidney stones; excessive intake of calcium absorption over many years hypercalcemia; renal supplements; peptic ulcer insufficiency treatment

Copper anemia, neutropenia, bone premature birth; excessive acute toxicity causes contaminated drinks and fractures; Menkes syndrome; intakes of zinc; Menkes vomiting, diarrhea, foods (copper pipes); X-linked cutis laxa (sagging caused by a mutation of the hemolytic anemia; chronic Wilson’s caused by a skin, impaired connective ATP7A gene that encodes for toxicity causes hepatitis, mutation of the ATP7B tissues) Cu transport protein; cutis cirrhosis, jaundice; Wilson’s gene that encodes for laxa is a mild form of Menkes disease protein that transports copper into bile

Iodine iodine deficiency disorders low intakes in areas where rapid heart rate, trembling, high intakes of seafood or (goiter, cretinism); Pendred’s soil is iodine deficient; excessive sweating, lack of seaweed contaminated syndrome excessive intakes of sleep, weight loss with iodine goitrogens (brassica vegetables); mutations in Pendrin gene resulting in defective iodination of thyroglobulin

Iron iron deficiency anemia low bioavailable diets, acute toxicity causes GI overuse of iron (tiredness, impaired work increased requirement (blood problems (constipation, supplements; HH is caused performance, failure to thrive loss, growth) diarrhea, cramps); chronic by mutations of the HFE in infants) toxicity increased risk for gene which result in bacterial infections, inappropriately high iron arthropathy, absorption cardiomyopathy, endocrine dysfunctions; HH

Phos- anorexia, muscle weakness, near-total starvation adverse effects on calcium excessive intake of cola phorus bone pain, rickets, economy beverages and food osteomalacia phosphate additives

Potas- severe: cardiac arrhythmias, low intake, diuretics; cardiac arrest excessive intake of sium muscle weakness, glucose Cushing’s disease, chronic potassium supplements, intolerance; moderate: high renal disease, diarrhea, metabolic acidosis, chronic BP, high risk of kidney stones, vomiting, laxative abuse renal failure, ACE inhibitors, CVD (stroke), increased bone Addison’s disease, turnover angiotensin receptor blockers and potassium- sparing diuretics

Selenium associated with Keshan low intakes in areas where brittle hair and nails, skin excessive intake of disease (cardiomyopathy) soil is selenium deficient lesions, garlic breath supplements and high and Kashin-Beck disease selenium foods e.g. Brazil (osteoarthropathy); impaired nuts immune function

Sodium headache, muscle weakness acute diarrhea, excessive hypertension high intake and spasms/cramps, nausea, sweat loss, diuretic overuse, vomiting, confusion, lethargy, cachexia, congestive heart appetite loss failure

Zinc growth retardation, hair loss, low intake, high cereal fibre acute toxicity causes contaminated water skin lesions, loss of appetite, and legume (phytate) diet; nausea and vomiting; (galvanized containers) loss of taste sensation, acrodermatitis enteropathica chronic toxicity causes delayed sexual maturation; caused by a mutation of the copper deficiency acrodermatitis enteropathica SLC39A4 gene which encodes a zinc uptake protein

Minerals and Trace Elements 49 A low phosphorus (and protein) diet will re- menopausal patients, related and unrelated to duce calcium intake; therefore, calcium supple- corticosteroid use. In IBD, where a low BMI may ments may be required. Patients with renal failure be an additional factor, there is a high prevalence cannot maintain mineral homeostasis by urinary of osteopenia, with Crohn’s disease patients being excretion, and this increases the risk for develop- more severely affected than those with ulcerative ment of clinically hazardous blood or tissue con- colitis. Patients undergoing organ transplanta- centrations. Patients with chronic kidney disease tion are also at high risk of osteoporosis; bone loss (CKD) need to consume a diet low in sodium, po- is rapid after organ transplantation, and occurs tassium and phosphorus, but may need additional mainly in the first 6 months. High intakes of cal- calcium, iron and magnesium. CKD-mineral and cium (e.g. 1,000 mg/day) and vitamin D (e.g. 500 bone disorder is a new term for a common clinical IU/day) may reduce the rate of bone loss in some entity observed in patients with CKD that involves patients. abnormal mineral metabolism, bone disease and vascular calcification. CKD-mineral and bone Cardiovascular System disorder can manifest as one or more abnormali- Potassium deficiency or excess may predispose to ties of calcium, phosphorus, vitamin D metabo- cardiac rhythm disturbances. Intakes are inverse- lism, or parathyroid hormone; abnormalities in ly related to the incidence of hypertension and bone turnover, mineralization, volume, linear stroke. Water hardness (and hence calcium in- growth, or strength, and vascular or other soft-tis- take) is inversely related to coronary heart dis- sue calcification. Specific clinical practice guide- ease, as is magnesium intake. Recent evidence has lines for kidney transplant patients include moni- emerged showing that disease-specific mortality toring serum calcium and phosphorus and hema- risks are elevated for cardiovascular disease and tological measurements (to diagnose anemia) [3] . ischemic heart disease with calcium intakes >1,400 or <600 mg/day. Risk of stroke may be in- B o n e creased with low calcium intakes (<700 mg/day). The human skeleton contains 1–1.5 kg of calcium Sodium intakes are weakly associated with blood and 0.8–1 kg of phosphorus. Rickets and osteo- pressure in epidemiological studies, and the effect malacia are caused by calcium, phosphorus, and/ of reducing sodium intake varies between indi- or vitamin D deficiency, whereas osteoporosis is viduals, being most pronounced in the elderly characterized by a reduction in BMD due to a and in Afro-Caribbeans. combination of genetic and environmental factors. Long-standing calcium deficiency plays a Cancer contributory role in the etiology of osteoporosis, Mineral deficiencies can occur in some cancer pa- partly as a result of the reduced absorption associ- tients due to low intake (cachexia), excessive loss- ated with low vitamin D status (limited sunlight es (e.g. blood loss) and cytokine-mediated inflam- exposure and low dietary intake of vitamin D), matory response which reduces iron absorption. but also from increased calcium excretion with Low serum zinc can be normalized in a few weeks diuretics and renal failure. Vitamin D and calci- with zinc supplements of 50 mg/day. Serum cop- um supplements may be recommended for post- per, present mainly in ceruloplasmin, may be ele- menopausal women who are housebound. Corti- vated in patients with tumors due to changes in costeroid treatment for IBD, rheumatoid arthritis ceruloplasmin metabolism. It is homeostatically and other conditions leads to bone mineral loss. controlled by desialylation in the liver but may be In systemic lupus erythematosus, significant re- resialylated at the tumor cell surface leading to an ductions in BMD have been observed in pre- increase in blood copper concentration.

50 Fairweather-Tait /Cashman

Other Vulnerable Groups or Conditions with rent infections. Iodine and selenium deficiencies Increased Risk of Mineral Deficiency are endemic in particular geographical areas The Academy of Nutrition and Dietetics (former- where the mineral is lacking in the earth’s crust. ly American Dietetic Association) has published In infants and young children, deficiency impairs Evidence-Based Nutrition Practice Guidelines for thyroid function and may have a negative impact a number of diseases and vulnerable groups [4] . on brain development, causing cretinism.

Patients with Anorexia Nervosa Parenteral Nutrition Calcium deficiency is common due to low intakes This mode of nutrition should provide essential of dairy products. Iron and zinc deficiencies are minerals and trace elements appropriate for the also common because of the avoidance of red life stage [6], although not all essential nutrients meat, leading to iron deficiency anemia, lack of can be mixed in a parenteral solution, e.g. iron. appetite and loss of taste sensation. Potassium Mineral and trace element status should be and phosphate losses may be high from vomiting monitored and nutrients supplied via other and use of laxatives and diuretics, and this may routes if necessary. Requirements of young chil- lead to cardiac abnormalities and heart failure. dren are different from those of adults ( table 2 ) Refeeding places additional demands on the heart and specialist pediatric preparations must be through the increased requirements for potassi- used. Deficiencies in zinc and selenium occur um and phosphate, so care must be taken when most commonly because selenium is often not instituting nutritional therapy in order to avoid added to the solution and levels of added zinc refeeding syndrome. may be too low. There are nutrition guidelines for critical care patients [7]. There are also com- Pregnancy prehensive guidelines on pediatric parenteral Iron deficiency anemia is one of the most com- nutrition [8] . mon pregnancy complications. Screening should be carried out at the first prenatal visit and regu- Drugs/Medications larly throughout the pregnancy. The recent rec- Some drugs may induce mineral deficiencies, for ommendations for antenatal care from the WHO example: are a daily supplement of 30–60 mg iron, together • Aminoglycoside – magnesium and zinc with 400 μg folic acid, to reduce the risk of low • Antacids – phosphorus birthweight, maternal anemia and iron deficiency • Proton pump inhibitors – iron [5] . • Diuretics – sodium, potassium, magnesium, Studies have shown that high hemoglobin val- zinc ues are associated with adverse pregnancy out- • Laxatives – sodium, potassium, magnesium comes; however, iron supplementation cannot, in • Platinum – magnesium, zinc. itself, raise hemoglobin to these levels; thus, adverse outcomes are more likely secondary to underlying conditions that are responsible for the Examples of Genetic Disorders of Minerals/ high hemoglobin values. Trace Elements

Infants and Children Hereditary hemochromatosis (HH) is an iron- Deficiencies of trace elements, particularly iron loading disorder associated with HFE gene muta- and zinc, are common due to low body stores, im- tions. Wilson’s disease, which leads to copper proper feeding, and/or increased losses e.g. recur- overload, is caused by a mutation in the ATP7B

Minerals and Trace Elements 51 gene. Menkes’ syndrome, a neurodegenerative • For many minerals, there are no simple, sensi- disorder of infancy associated with copper defi- tive and specific biomarkers of status, so deficiency, is caused by a mutation in the ATP7A ciency or toxicity may not be diagnosed until gene. Acrodermatitis enteropathica, severe zinc fairly well advanced, at which point the patient deficiency observed in infants, is associated with may present with clinical signs and symptoms. mutations in the SLC39A4 gene. The impact of For some minerals, there are relatively good these genetic disorders on mineral and trace ele- biomarkers of status. ment status has been reviewed elsewhere [9] . • Vulnerable groups or conditions with increased risk of mineral deficiency include those with anorexia nervosa, pregnant wom- Conclusions en, infants and children, and patients on parenteral nutrition. • Inappropriate intakes and/or elevated require- • The use of certain drugs and medications can ments resulting from a range of conditions, in- also affect the body’s mineral and trace ele- cluding disease, malabsorption, medications, ment status. This can also be influenced by he- and excessive losses, eventually lead to a state reditary disorders such as HH, Wilson’s dis- of deficiency or toxicity. ease and Menkes’ syndrome.

References

1 http://www.nlm.nih.gov/medlineplus/ 9 Strain JJ, Cashman KD: Minerals and 16 http://www.nlm.nih.gov/medlineplus/ minerals.html. trace elements; in Gibney MJ, Lanham- ency/article/003690.htm. 2 http://www.iom.edu/Activities/Nutri- New S, Cassidy A, Vorster HH (eds): In- 17 EFSA Panel on Dietic Products, Nutri- tion/SummaryDRIs/∼ /media/Files/Ac- troduction to Human Nutrition (The Nu- tion and Allergies: Scientific opinion on tivity%20Files/Nutrition/DRIs/5_Sum- trition Society Textbook), ed 2. Chich- dietary reference values for iodine. EFSA mary%20Table%20Tables%201–4.pdf. ester, Wiley Blackwell, pp 188–237. J 2014;12:3660. 3 http://www.kdigo.org/clinical_practice_ 10 Milne DB: Laboratory assessment of 18 Zimmermann MB: Methods to assess

guidelines/kdigo_guideline_for_care_ trace element and mineral status; in iron and iodine status. Br J Nutr 2008; ktr.php. Bogden JD, Klevay LM (eds): Clinical 99(suppl 3):S2–S9. 4 http://andevidencelibrary.com/category. Nutrition of the Essential Trace Ele- 19 http://emedicine.medscape.com/ cfm?cid=14&cat=0. ments and Minerals: The Guide for article/2086300-overview. 5 http://www.who.int/nutrition/publica- Health Professionals. Totowa, Humana 2 0 WHO: Serum ferritin concentrations tions/micronutrients/guidelines/daily_ Press, 2000. for the assessment of iron status and ifa_supp_pregnanen/index.html. 11 Lentner C: Geigy Scientific Tables. Basel, iron deficiency in populations. WHO/ 6 https://www.nutritioncare.org/. Ciba-Geigy, vol 3, 1984. NMH/NHD/MNM/11.2. Geneva, 7 http://www.criticalcarenutrition.com/. 12 Ayling R, Marshall W: Nutrition and WHO, 2011. 8 Koletzko B, Goulet O, Hunt J, et al: Laboratory Medicine. London, Associa- 21 http://webarchive.nationalarchives.gov. Guidelines on Paediatric Parenteral Nu- tion for Clinical Biochemistry, 2007. uk/20130402145952/http://transparen- trition of the European Society of Paedi- 13 Gibney MJ, Elia M, Ljungqvist O, Dow- cy.dh.gov.uk/2012/06/21/sodium-levels- atric Gastroenterology, Hepatology and sett J: Clinical Nutrition. Oxford, Black- among-adults/. Nutrition (ESPGHAN) and the Europe- well Science, 2006. 2 2 McKenzie JM: Content of zinc in se- an Society for Clinical Nutrition and 14 Gibson RS: Principles of Nutritional rum, urine, hair, and toenails of New

Metabolism (ESPEN), Supported by the Assessment, ed 2. Oxford, Oxford Uni- Zealand adults. Am J Clin Nutr 1979;

European Society of Paediatric Research versity Press, 2005. 32: 570–579. (ESPR). J Pediatr Gastroenterol Nutr 15 http://www.mayomedicallaboratories. 23 http://multimedia.food.gov.uk/multi-

2005; 41(suppl 2):81–84. com/test-catalog/Clinical+and+Inter- media/pdfs/ndnsv3.pdf. pretive/28379.

52 Fairweather-Tait /Cashman

Nutrition for Health

Bier D, et al. (eds): Nutrition for the Primary Care Provider. World Rev Nutr Diet. Basel, Karger, 2015, vol 111, pp 53–57 DOI: 10.1159/000362297

Vegetarian Diets

Susan I. Barr

Food, Nutrition and Health, The University of British Columbia, Vancouver, BC , Canada

Key Words Introduction Vegetarian diets · Iron · Zinc · Calcium · Vitamin B12 · Omega-3 fatty acids Vegetarianism is said to be increasing in many Western countries, and is associated with significantly lower ischemic heart disease mortality and Key Messages cancer incidence [1] . Vegetarian diets are often defined as those excluding all meat, poultry, fish and • Dietary patterns of vegetarians fall on a continuum, ranging from minimal to complete avoidance of an- seafood, and may be adopted for a variety of rea- imal foods. The specific nutritional implications of sons including perceived health benefits, religious vegetarian diets therefore depend upon the foods or cultural practices, and concerns about animal included and excluded. welfare or environmental sustainability [2] . Among • The nutrients of concern for vegetarians are pro- US adults, the prevalence of vegetarianism (defined tein, iron, zinc, calcium, vitamin D, vitamin B12 and as ‘never’ eating meat, fish or poultry) appears to be omega-3 fatty acids. • Iron and zinc are less bioavailable in vegetarian about 4%, including 1% who are vegan [3] . Preva- diets. Accordingly, the recommended intakes of lence is slightly higher in women than men and in these minerals for vegetarians are higher than younger than older adults (in both cases, approx. 5 those for omnivores. vs. approx. 3%), but varies little according to in- • Although dairy products and eggs contain vitamin come and educational attainment [3] . Although B 12, deficiency of this nutrient is relatively common well-planned vegetarian diets can meet all nutrient among lacto-ovo vegetarians and vegans. Fortified foods or supplements are recommended. requirements and recommendations for health [2] , • Vegetarians should also include good dietary sourc- the nutritional implications vary depending on the es of the omega-3 fatty acid, α-linolenic acid. type of vegetarian diet followed. Accordingly, the • Though vegetarian diets vary widely in composi- purpose of this article is to describe different types tion, good dietary planning can meet the nutrition- of vegetarian diets, highlight particular nutrients or al needs of individuals across the entire spectrum of situations of potential concern, and identify vege- vegetarianism. © 2015 S. Karger AG, Basel tarian food sources of key nutrients. Table 1. Foods included in and excluded from vegetarian diets

Type of diet Animal foods excluded Animal foods included

Semi-vegetarian may avoid red meat but include poultry and/or fish and seafood dairy products, eggs Lacto-ovo-vegetarian all meat, poultry, fish and seafood dairy products, eggs Lacto-vegetarian meat, poultry, fish, seafood and eggs dairy products Vegan all none

Types of Vegetarian Diets Nutrients of Potential Concern

Vegetarian diets are typically classified based on Nutrients that may be of concern in vegetarian the exclusion of meat, fish, poultry, dairy prod- diets are discussed briefly below, and vegetarian ucts and eggs (table 1 ). However, this simple clas- food sources are listed in table 2 . sification does not convey the variability of the dietary practices of those who consider them- Protein selves to be vegetarian. In practice, there is a con- Although many consumers are concerned about tinuum from those who may avoid red meat but the adequacy of protein in vegetarian diets, these consume fish or poultry, through to vegans who concerns are generally unfounded [2]. Even veg- avoid all animal-derived foods or ingredients (e.g. an diets typically provide over 10% of energy as gelatin, honey, and vitamin D 3) and may also protein, and if energy needs are met, this intake avoid the use of any animal products (e.g. leather, level almost always exceeds the Recommended wool, silk, down). Dietary Allowance (RDA) for protein. Both dairy The nutritional implications of vegetarian products and eggs are high-quality proteins, as is diets depend upon the foods included and ex- soy protein. And while other plant-based proteins cluded. Thus, upon hearing that a patient or cli- are limiting in one or more indispensable amino ent is vegetarian, the healthcare practitioner acids, provided a variety of plant protein sources should always ask ‘Can you tell me which types is consumed throughout the day (e.g. soy prod- of foods you eat and which ones you avoid?’ It is ucts, legumes, nuts and seeds, grains), there is no also useful to ascertain how often various cat- need to consume complementary proteins (with egories of foods are consumed. For example, different limiting amino acids) at the same meal questioning might reveal that someone who [2] . says she is a lacto-ovo vegetarian consumes dairy products less than once a day, and only Iron eats eggs when they are included as ingredients The RDAs for iron are based on consumption of in other foods (e.g. baked goods). Further to an omnivorous diet including both heme and this, it is important to ask these questions at nonheme iron, in which iron absorption averages regular intervals, as many individuals transi- about 18% [4] . In contrast, iron absorption aver- tion their diets over time, in some cases revert- ages about 10% on vegetarian diets, which pro- ing to an omnivorous diet and in others provide only the less well-absorbed nonheme form of gressing farther along the vegetarian continu- iron. Accordingly, recommended iron intakes for um. vegetarians are 1.8 times higher than those for

54 Barr

Table 2. Nutrients of concern in vegetarian diets and se- Zinc lected food sources Bioavailability of zinc is lower in vegetarian diets, Nutrient Vegetarian food sources largely due to its binding by phytic acid (found in nuts, grains and legumes). For this reason, it is Iron dark leafy greens, legumes, enriched suggested that the requirement for zinc may be as grains, nuts, fortified1 breakfast cereals; much as 50% higher on vegan vegetarian diets [4] . include a vitamin C source (e.g. citrus The implications of this for Western vegetarians fruits, leafy greens, bell peppers, potatoes, cauliflower) to increase are not clear: although there is no evidence of absorption frank zinc deficiency, detection of marginal defi- Calcium milk and dairy products2, calcium- ciency is challenging. fortified1 beverages (e.g. soy milk, orange juice), calcium-set tofu, Calcium low-oxalate dark green vegetables Individuals who consume the recommended (e.g. kale, broccoli, collards), almonds amounts of milk and dairy products (or fortified Zinc legumes (e.g. baked beans, chickpeas), plant-based alternatives) as part of a healthy var- 2 soy products, dairy products , nuts, ied diet should meet RDAs for calcium (1,000 mg grains, fortified1 breakfast cereals; leavened breads have lower phytic acid for women aged 19–50 and men aged 19–70; content and improved zinc absorption 1,200 mg for women >50 and men >70), whether

2 2 they are omnivorous, vegetarian or vegan. How- Vitamin B12 milk and dairy products , eggs ; vitamin B12 is not found naturally in plant-based ever, many adults (regardless of their dietary pat- foods, but fortified1 products are tern) do not meet these recommendations, and available (e.g. meat analogues, fortified thus calcium is a nutrient of concern for much of soy beverages, nutritional yeast) the population. This is particularly true for vegan Vitamin D fortified cow’s milk2, fortified1 vegetarians who choose not to use fortified foods, plant-based beverages (e.g. soy, rice, 1 among whom very low calcium intakes and in- etc.), fortified orange juice; vitamin D2 is considered a ‘vegan’ source creased fracture risk have been reported [5] . Be- cause of unresolved concerns about potential ad- Omega-3 eggs2, flaxseed, walnuts, canola oil, fatty acids soybean oil, soybeans verse effects of high calcium intakes achieved through supplementation [6], the recommended 1 Note that fortification policies vary among countries; approach for those with low calcium intakes is to accordingly, the nutrient contribution of fortified foods first maximize calcium intake from food, and to 2 will also vary. Not a vegan source. recommend supplements only if necessary to meet the RDA. omnivores [3] : 32 mg/day (vs. 18 mg/day) for Vitamin D premenopausal adult women and 14 mg/day (vs. Vitamin D plays an established role in bone health 8 mg/day) for adult men and postmenopausal [4] , and is also being examined for other possible women. It is relatively easy for vegetarian men health outcomes. It is obtained through dietary and postmenopausal women to meet these rec- intake and sunlight exposure (with the amounts ommendations. However, since typical diets do synthesized influenced by latitude, season, time not provide iron in amounts recommended for of day, skin pigmentation, sunscreen use and premenopausal vegetarian women, occasional age). The RDAs for vitamin D reflect the intake monitoring of iron status may be warranted in needed to support adequate serum 25(OH)D lev- this group. els in the absence of sunlight exposure. Both vita-

Vegetarian Diets 55 min D 2 and vitamin D3 are used to fortify foods er extent in vegans, than in omnivores [9]. DHA is and are available as supplements. Vitamin D 2 is associated with protection against cardiovascular derived from ultraviolet (UV) irradiation of the disease and with eye and brain development; ac- plant sterol, ergosterol, and is considered accept- cordingly, questions have been raised about the able by vegetarians, while vitamin D 3 is consid- health consequences of lower DHA status among ered an animal source as it is derived from UV vegetarians. At this point, there is no good evi- irradiation of 7-dehydrocholesterol. When con- dence of any adverse health effects [9] . Neverthe- sumed on a daily basis, vitamin D 2 appears to be less, it seems prudent for vegetarians to include as effective as vitamin D 3 in supporting serum good dietary sources of ALA (see table 2 ). 25(OH)D levels [7] .

V i t a m i n B12 Vegetarian Diets and Eating Disorders Although dairy products and eggs contain vitamin B12 , deficiency is relatively common among A very high prevalence of vegetarianism (approx. both lacto-ovo vegetarians and vegans [8] . Unfor- 50%) has been reported in studies of patients with tified plant foods do not contain vitamin B 12 , so anorexia nervosa [e.g. 10 ], leading some to specu- fortified foods or supplements must be used by late that vegetarianism may contribute to the on- vegans. It is important to emphasize the need for set of eating disorders. However, subsequent adequate intakes of this nutrient as high folate in- work has demonstrated that eating attitudes and takes typical of vegetarian diets will prevent the behaviors of otherwise healthy individuals do not megaloblastic anemia typically seen with vitamin vary meaningfully between vegetarians and non- B12 deficiency. This means that neurological dam- vegetarians, suggesting that the eating disorder age may progress without being detected. may lead to the vegetarianism, rather than the converse. While further research is needed, unex- Omega-3 Fatty Acids pected weight loss in individuals who have re- The nutritionally essential fatty acids include cently transitioned to a vegetarian diet may serve linoleic acid (LA; C18: 2n-6) and α-linolenic acid as a warning sign of a developing eating disorder,

(ALA; C18: 3n-3). Both are formed in plants and and should be evaluated. undergo elongation and desaturation in animal tissues to form arachidonic acid (AA; C20: 4n-6, an eicosanoid precursor) and docosahexaenoic acid Conclusions

(DHA; C22: 6n-3, a constituent of membrane lipids in the brain and retina). These longer-chain • Well-planned vegetarian diets can satisfy all polyunsaturates are found in small amounts in an- nutrient requirements and recommendations imal foods, but do not occur in vegan diets. And for healthful eating. although AA and DHA can be synthesized from • Dietary patterns of those who consider them- LA and ALA, respectively, the amount of DHA selves to be vegetarian fall along a continuum, formed from ALA is limited. Moreover, n-3 and ranging from minimal to complete avoidance n-6 fatty acids compete for elongation and desatu- of animal foods. Clarifying where an individu- ration, and vegetarian diets typically contain a high al falls along this continuum is essential for ratio of LA (n-6):ALA (n-3), further limiting DHA providing appropriate dietary guidance. synthesis. This, in addition to minimal or zero in- • Potential ‘nutrients of concern’ for vegetarians take of preformed DHA, leads to tissue DHA levels include iron, calcium, zinc, vitamin B 12 , vita- that are lower in vegetarians, and to an even great- min D, and omega-3 fatty acids. In many cases,

56 Barr

good vegetarian sources of these nutrients are Table 3. Websites on vegetarianism and vegetarian diets available. For some nutrients (e.g. vitamin B12 , www.nlm.nih.gov/medlineplus/vegetariandiet.html. calcium, vitamin D, iron in younger women), Website on vegetarian diets from Medline Plus, use of supplements or sufficient quantities of US National Institutes of Health fortified foods may be required, particularly www.vegetariannutrition.net. Website of the Vegetarian for those following vegan diets. Nutrition Practice Group of the Academy of Nutrition • Referral to a dietitian with expertise in vege- and Dietetics tarian diets may be warranted for individuals www.vegsoc.org. Website of the Vegetarian Society of who choose to follow vegan diets. A number of the United Kingdom websites also provide additional information www.vrg.org. Website of the Vegetarian Resource Group and dietary guidance (table 3 ).

References

1 Huang T, Yang B, Zheng J, et al: Cardio- 4 Otten JJ, Hellwig JP, Meyers LD (eds): 7 Tripkovic L, Lambert H, Hart K, et al: vascular disease mortality and cancer Dietary Reference Intakes. The Essential Comparison of vitamin D2 and vitamin incidence in vegetarians: a meta-analy- Guide to Nutrient Requirements. Wash- D3 supplementation in raising serum sis and systematic review. Ann Nutr ington, The National Academies Press, 25-hydroxyvitamin D status: a system-

Metab 2012; 60: 233–240. 2006. atic review and meta-analysis. Am J Clin

2 American Dietetic Association: Position 5 Appleby P, Roddam A, Allen N, Key T: Nutr 2012; 95: 1357–1364. of the American Dietetic Association: Comparative fracture risk in vegetarians 8 Pawlak R, Parrott SJ, Raj S, et al: How

vegetarian diets. J Am Diet Assoc 2009; and nonvegetarians in EPIC-Oxford. Eur prevalent is vitamin B12 deficiency

109: 1266–1282. J Clin Nutr 2007; 61: 1400–1406. among vegetarians? Nutr Rev 2013; 71: 3 Stahler C: How often do Americans eat 6 Spence LA, Weaver CM: Calcium intake, 110–117. vegetarian meals? And how many adults vascular calcification, and vascular dis- 9 Sanders TAB: DHA status of vegetar-

in the US are vegetarian? http://www. ease. Nutr Rev 2013; 71: 15–22. ians. Prostaglandins Leukot Essent Fatty

vrg.org/blog/2012/05/18/how-often-do- Acids 2009; 81: 137–141. americans-eat-vegetarian-meals-and- 10 O’Connor MA, Touyz SW, Dunn SM, how-many-adults-in-the-u-s-are-vege- Beumont PJV: Vegetarianism in anorex- tarian/ (accessed April 25, 2013). ia nervosa? A review of 116 consecutive

cases. Med J Aust 1987; 147: 540–542.

Vegetarian Diets 57 Nutrition for Health

Bier D, et al. (eds): Nutrition for the Primary Care Provider. World Rev Nutr Diet. Basel, Karger, 2015, vol 111, pp 58–63 DOI: 10.1159/000362298

Dietary Supplements

Paul M. Coates Paul R. Thomas

Office of Dietary Supplements, National Institutes of Health, Bethesda, Md. , USA

Key Words Introduction Dietary supplements · Multivitamin-multimineral supplements · Efficacy · Safety · Food and Drug Dietary supplements contain one or any combi- Administration nation of nutrients, herbs and botanicals, amino acids, enzymes, and other ingredients. These constituents are either extracted from their natural Key Messages sources or chemically synthesized into finished • Dietary supplements are widely available and are products. Widely available for purchase without commonly used by the general public. • The two main categories of dietary supplements a prescription, they are found in many forms, in- are products composed of vitamins and minerals, cluding pills, powders, drinks, and energy bars. and products used for specific health purposes. Dietary supplements are often promoted as pro- • Some dietary supplements, such as calcium, vita- viding health benefits beyond basic nutrition. min D and folic acid, may benefit certain groups. They are used by people of all ages as a health • For the many dietary supplements whose market- measure to ensure adequate intake of nutrients, ing implies specific health benefits, one should re- maintain health, prevent illnesses, and to treat or fer to recommendations made on their usage by relevant professional societies or other expert bod- manage various health problems and diseases, ies. both minor (such as indigestion) and those re- • Primary-care practitioners should carefully balance quiring medical attention (such as cancer). the efficacy and safety of a particular supplement to The number and diversity of dietary supple- maximize its potential benefits and minimize any ment products in the US marketplace continue to risks to the patient. © 2015 S. Karger AG, Basel grow. More than 85,000 are estimated to be avail- Table 1. Recommended Dietary Allowances (RDAs) and tolerable upper intake levels (ULs) for selected nutrients for adults in the United States and Canada

Nutrient RDA Tolerable UL

Vitamin B12 2.4 μg (men and women ≥19 years) data insufficient to set Vitamin C 90 mg (men ≥19 years) 2,000 mg 75 mg (women ≥19 years)

Vitamin D 600 IU (men and women 19 – 70 years) 4,000 IU 800 IU (men and women >70 years)

Calcium 1,000 mg (men 19 – 70 years) 2,500 mg (men and women 19 – 50 years) 1,200 mg (men >70 years) 2,000 mg (men and women >50 years)

1,000 mg (women 19 – 50 years) 1,200 mg (women >50 years) Iron 8 mg (men ≥19 years) 45 mg

18 mg (women 19 – 50 years) 8 mg (women >50 years)

For simplicity, this table provides the RDAs and ULs for only a few nutrients for adults. The NIH Office of Dietary Supplements website provides the full set of nutrient recommendations as established by the Food and Nutrition Board of the Institute of Medicine, National Academy of Sciences (at http://ods.od.nih.gov/Health_Information/ Dietary_Reference_Intakes.aspx).

able, with total sales exceeding USD 32 billion per whose nutrients are in amounts that approxi- year in 2012 – an average of almost USD 100 spent mate a good-quality diet [2]. For people who do by each individual in the United States [1] . Prima- not eat as well as they should, supplements may ry-care practitioners (PCPs) should query patients help them to receive adequate amounts of nutri- about their supplement use and interests in these ents, even though these products cannot replace products to provide them with the best health care. the variety of foods that are important to a healthy diet. Individual nutrients may also be used for nu- Use of Dietary Supplements tritional purposes; for example, calcium and vitamin D for bone health and iron for anemia. One There are two broad categories of dietary supple- reason consumers give for taking dietary supplements: products composed of vitamins and min- ments is ‘to supplement the diet,’ but the two most erals, for which recommended and tolerable up- common reasons are ‘to improve overall health’ per levels of intake exist (table 1 ), and products and ‘to maintain health (stay healthy)’ [3] . used for specific purposes, such as for managing Dietary supplements taken for nonnutritional bodily discomforts and illnesses or more gener- purposes include coenzyme Q10 to lower blood ally in the hope of enhancing health or resistance pressure and reduce side effects from treatment to disease. with a statin medication, the herb echinacea to Approximately one-half of all Americans use boost immunity and prevent or treat colds and dietary supplements, most commonly basic mul- the flu, and probiotics to treat antibiotic-associ- tivitamin-multimineral (MVMM) supplements ated diarrhea or constipation. Available scientific

Dietary Supplements 59 research may or may not support these uses, and they are pregnant) reduces the risk of neural in many cases the evidence is insufficient to make tube defects in newborns. a definitive judgment. • People over the age of 50 should obtain the rec- To address the appropriate use of dietary sup- ommended intakes of vitamin B12 mainly from plements with individual patients, the PCP fortified foods or dietary supplements, because should consider the efficacy and safety of the in- they may be less able than younger people to gredients and the quality of available product op- absorb the protein-bound, naturally occurring tions. vitamin B12 in food. In addition, vegans should ensure that their intakes of vitamin B 12 from fortified foods or supplements are adequate. E f f i c a c y • Pregnant women should take an iron supplement as recommended by an obstetrician or Manufacturers of dietary supplements are not re- other healthcare provider. quired to prove effectiveness prior to marketing • The American Academy of Pediatrics recom- these products. The PCP and patients must use mends that exclusively and partially breastfed in- various resources to learn which supplements fants receive supplements of 400 IU/day of vita- may promote or improve health, and in whom min D shortly after birth and continue to receive and under what conditions they may do so. these supplements until they are weaned and No US government health agency, private consume at least 1,000 ml/day of vitamin D-for- health group, or health professional organization tified formula or whole milk [5] . Similarly, all promotes regular use of an MVMM or individu- nonbreastfed infants ingesting less than 1,000 ml/ al nutrients without considering first the quality day of vitamin D-fortified formula or milk should of a person’s diet. Food, enriched and fortified receive a vitamin D supplement of 400 IU/day. food products, and even water contribute to one’s • The American Academy of Pediatrics advises total nutrient intake. However, individuals with that children at nutritional risk who might poor nutrient intakes from diet alone, who con- benefit from supplementation include those sume low-calorie diets, or who avoid certain who have anorexia or an inadequate appetite, foods (such as strict vegetarians and vegans) follow fad diets, have chronic disease, come might benefit from taking MVMMs. PCPs may from deprived families or suffer parental ne- prescribe MVMMs for people with medical con- glect or abuse, participate in dietary programs ditions and diseases that impair digestion, ab- for managing obesity, consume a vegetarian sorption, or use of nutrients. They may also rec- diet without adequate dairy products, and ommend prenatal MVMMs to pregnant patients. have failure to thrive [6] . Some nutrients might benefit certain popula- For the many dietary supplements whose tion groups [4] . For example: marketing implies or suggests more specific • Supplementation with calcium and vitamin D health benefits and improvements, recommen- might increase bone mineral density and de- dations about their use are in some cases made by crease fracture rates in postmenopausal women. relevant professional societies or other expert • Women of childbearing age who might be- bodies. For example, the American Heart Asso- come pregnant should obtain 400 μg/day of ciation recommends consumption of approxi- synthetic folic acid from fortified foods or di- mately 1 g/day of the fatty acids EPA and DHA for etary supplements. Taking sufficient amounts patients with documented heart disease, from of folic acid in the first month of pregnancy (a oily fish or supplements [7] . The American Asso- time when many women do not yet know that ciation of Orthopedic Surgeons advises that glu-

60 Coates/Thomas

Table 2. Information sources on dietary supplements

Source Access Notes

Office of Dietary http://ods.od.nih.gov/ comprehensive source of information on supplements, Supplements (NIH) free including fact sheets for health professionals and consumers on many supplement ingredients National Center for http://nccam.nih.gov news, information, and fact sheets on dietary Complementary and free supplements, especially nonnutrient ingredients (e.g. Alternative Medicine (NIH) botanicals) PubMed, National Library www.ncbi.nlm.nih.gov/pubmed search the biomedical literature on a supplement topic of Medicine (NIH) free of interest by applying the subject filter of ‘dietary supplements’ MedlinePlus, National http://www.nlm.nih.gov/medlineplus/ consumer-friendly reviews of supplement ingredients Library of Medicine (NIH) free addressing effectiveness, usual dosage, and drug interactions US Food and Drug http://www.fda.gov/Food/ information on dietary supplement regulations and Administration DietarySupplements/ policies, alerts, and product warnings free Natural Medicines http://naturaldatabase.com comprehensive monographs on supplement Comprehensive Database subscription based ingredients; search by ingredient, product name, or medical condition Natural Standard http://www.naturalstandard.com comprehensive monographs on supplement subscription based ingredients; search by ingredient, product name, or medical condition ConsumerLab.com http://www.consumerlab.com monographs on dietary supplement ingredients with subscription based independent evaluations of product quality

NIH = National Institutes of Health.

cosamine and chondroitin not be prescribed for Nutrients are usually safe when consumed be- symptomatic osteoarthritis of the knee [8] . low the tolerable upper intake levels. Most pa- Other resources to discover evidence-based tients who take a basic MVMM or recommended information on dietary supplements are de- doses of individual nutrients do not exceed these scribed in table 2 . amounts. In some cases, under the care of a healthcare provider, nutrients may be used in high doses for specific medical reasons, and the S a f e t y potential for adverse effects must be monitored. Large doses of the B vitamin niacin, for example, Most biologically active constituents in dietary may be used in the medical management of dys- supplements are toxic at some dose. Too much lipidemia. vitamin A can cause headaches, liver damage and The PCP should consider that some dietary birth defects, for example, and excess iron causes supplements may interact with certain medica- nausea and vomiting and may damage the liver tions and lead to adverse events. For example, vi- and other organs. Good information sources on tamin K supplements can reduce warfarin’s ability supplement efficacy will address dosing as well as to reduce blood clotting. St. John’s wort can speed symptoms associated with toxicity. the breakdown of many drugs from the body (in-

Dietary Supplements 61 cluding antidepressants and birth control pills), Some supplements in the marketplace are of thereby reducing their effectiveness. Antioxidant substandard quality, but the extent of the prob- supplements such as those with large amounts of lem is not known. ConsumerLab.com, a private vitamins C and E may reduce the effectiveness of company that has independently tested the con- some types of cancer chemotherapy. tents of >2,400 supplement products over more The PCP and patient should be alert to the than 12 years, identifies approximately 1 in 4 possibility of an unexpected side effect from tak- with a quality problem, primarily because of an ing a dietary supplement, especially from a prod- ingredient present below the labeled amounts or uct with ingredients other than nutrients at nu- of substandard quality, followed by contamina- tritional levels. PCPs in the United States who tion with heavy metals [9] . FDA has identified believe a patient suffered an adverse event from hundreds of dietary supplements marketed for taking a supplement should report it to the sexual enhancement, weight loss, and bodybuild- US Food and Drug Administration (FDA), call ing that have been adulterated with prescription 800-FDA-1088 or complete a form at http://www. medications [10] . fda.gov/Safety/MedWatch/HowToReport. (Other The PCP should recommend supplement countries may have their own reporting systems.) products from well-known and established The FDA relies on these voluntary reports as sig- brands and those that have a reputation for rig- nals that a product may present safety risks to orous quality control. Several independent or- consumers. Also, report the event to the supple- ganizations offer quality testing and allow the ment’s manufacturer using contact information products that pass these tests to display their on the label. A company is required to report to seals of approval. Organizations that offer this the FDA any serious adverse event report it re- quality testing include the US Pharmacopeia, ceives (e.g. resulting in hospitalization, being life ConsumerLab.com, and NSF International. threatening, or causing disability). Such seals are no guarantee of product safety PCPs may well be wary about supplement use and effectiveness, however. (beyond basic nutrients at nutritional levels) by children or by pregnant or lactating women. The safety aspects of most supplements have not been Regulation and Oversight well tested in these groups. In the United States, dietary supplements, like medications, are overseen by the FDA but are reg- Q u a l i t y ulated quite differently. Supplements do not require premarket review or approval. They are al- Dietary supplements are often complex products lowed to make certain health-related, though not containing multiple ingredients sourced from disease-related, claims. across the globe. Ensuring consistent high quality The FDA has the authority to remove supple- in products is a critical task. In the United States, ments from the market shown to be unsafe or im- the FDA has established quality standards to help properly manufactured. The agency may also ensure product identity, purity, strength, and take legal action when companies make false or composition by preventing the inclusion of the deceptive statements about their products or pro- wrong ingredient, too much or too little of an in- mote them as disease treatments or cures. The gredient, the possibility of contamination, and Federal Trade Commission monitors and regu- improper packaging and labeling. The FDA peri- lates advertising, marketing, and promotion of odically inspects manufacturing facilities. supplements in the various media.

62 Coates/Thomas

Many countries have their own regulatory • The PCP may need to initiate the conversa- structure for products known as dietary supple- tion, as many patients are reluctant to do so. ments in the United States. In Canada, for exam- Use of dietary supplements is largely self-deple, they are called Natural Health Products and termined. Less than a quarter of supplements must be authorized for sale. used by adults are recommended by a physician or other healthcare provider [2] . • The PCP and patient should discuss what sup- R e s o u r c e s plements may be helpful in particular situations and which may pose any risks. Ideally, Helpful information sources on dietary sup- they should come to agreement on the best ap- plements are listed in table 2 . proaches to maximize potential benefits and minimize any risk of harm from using these products. Conclusions • Among the questions to discuss are: What are the potential health benefits of each supple- • As PCPs pay attention to the health and life- ment? Might it provide specific benefits to the style practices of their patients to provide the patient? Does it pose any safety risks? What is best medical care, discussions about the di- a proper dose to take? How, when, and for how etary supplements they take, or those that long should it be taken? might be recommended, are of value.

References

1 NBJ’s Supplement Business Report 5 Wagner CL, Greer FR; American Acad- 9 Cooperman T: Third party dietary sup- 2013. Nutr Bus J 2013. emy of Pediatrics Section on Breastfeed- plement testing: ConsumerLab.com; in 2 Bailey RL, Gahche JJ, Lentino CV, et al: ing; American Academy of Pediatrics Bonakdar RA (ed): The H.E.R.B.A.L. Dietary supplement use in the United Committee on Nutrition: Prevention of Guide: Dietary Supplement Resources

States, 2003–2006. J Nutr 2011; 141: 261– rickets and vitamin D deficiency in infor the Clinician. Philadelphia, Lippin- 266. fants, children, and adolescents. Pediat- cott Williams & Wilkins, 2010, pp 126–

3 Bailey RL, Gahche JJ, Miller PE, et al: rics 2008; 122: 1142–1152. 130. Why US adults use dietary supplements. 6 Kleinman RE (ed): Feeding the child; in 10 US Food and Drug Administration: Be-

JAMA Intern Med 2013; 173: 355–361. Pediatric Nutrition Handbook, ed 5. ware of fraudulent ‘dietary supple- 4 Office of Dietary Supplements, National Washington, American Academy of Pe- ments’. FDA Consumer Health Informa- Institutes of Health: Dietary supplement diatrics, chapter 7, 2004. tion, March 2011. http://www.fda.gov/ fact sheet for the health professional: 7 Kris-Etherton PM, Harris WS, Appel LJ: downloads/ForConsumers/Consum- multivitamin/mineral supplements. Jan- AHA scientific statement: fish consump- erUpdates/UCM247107.pdf. uary 2013. http://ods.od.nih.gov/fact- tion, fish oil, omega-3 fatty acids, and

sheets/MVMS-HealthProfessional/. cardiovascular disease. Circulation 2002;

106: 2747–2757. 8 American Academy of Orthopaedic Sur- geons: Treatment of osteoarthritis of the knee (non-arthroplasty). December 6, 2008. www.aaos.org/Research/guidelines/GuidelineOAKnee.asp.

Dietary Supplements 63 Nutrition for Special Circumstances

Bier D, et al. (eds): Nutrition for the Primary Care Provider. World Rev Nutr Diet. Basel, Karger, 2015, vol 111, pp 64–70 DOI: 10.1159/000362299

Nutrition in Pregnancy and Lactation

a b H. Salome Kruger Nancy F. Butte a b Centre of Excellence for Nutrition, North-West University, Potchefstroom , South Africa; USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Tex. , USA

Key Words Introduction Pregnancy · Lactation · Weight gain · Iron deficiency · Supplements · Hypertension · Optimal maternal health during pregnancy re- Gestational diabetes duces the risk of suboptimal fetal development [1] . Obesity prevalence is increasing among women of childbearing age in both developed and Key Messages developing countries. Although teenage pregnan- • Target women to prevent both insufficient and ex- cies remain common in some countries, generally cessive weight gain. women are getting pregnant at an older age, re- • Provide prenatal dietary supplementation for nutritionally at-risk mothers to reduce perinatal morbid- sulting in increased prevalence of hypertension ity. and gestational diabetes [1] . Weight gain within • Implement weight monitoring and supplementa- the Institute of Medicine’s recommendations is tion through primary healthcare. associated with favorable fetal and maternal out- • Implement periconceptional folic acid supplemen- comes, whereas insufficient weight gain is associ- tation for the prevention of neural tube defects in ated with low birthweight (LBW), and excessive populations with low folate intakes. • Promote intermittent rather than daily iron or iron gain is associated with infant macrosomia [1] . + folic acid supplementation to reduce risk of ma- The key components of nutritional management ternal anemia and iron deficiency at term. during pregnancy include consumption of a vari- • Counsel pregnant and lactating women to omit al- ety of foods, appropriate weight gain, appropriate cohol and to drink caffeine-containing drinks in micronutrient supplementation, physical activity moderation (equivalent of two cups of coffee). and avoidance of alcohol, tobacco, and other © 2015 S. Karger AG, Basel harmful substances [2] . Table 1. New recommendations for total and rate of weight gain during pregnancy, by prepregnancy BMI

Prepregnancy BMI Total weight gain range Rates of weight gain1 kg lb kg/week lb/week

Underweight (<18.5) 12.5 – 18 28 – 40 0.51 (0.44 – 0.58) 1 (1 – 1.3)

Normal weight (18.5 – 24.9) 11.5 – 16 25 – 35 0.42 (0.35 – 0.50) 1 (0.8 – 1)

Overweight (25.0 – 29.9) 7 – 11.5 15 – 25 0.28 (0.23 – 0.33) 0.6 (0.5 – 0.7)

Obese (≥30.0) 5 – 911 – 20 0.22 (0.17 – 0.27) 0.5 (0.4 – 0.6)

Data from Institute of Medicine and National Research Council [1]. Reproduced with permission. 1 Second and third trimester. Calculations assume a 0.5 – 2 kg (1.1 – 4.4 lb) weight gain in the first trimester. Values are expressed as mean (range).

Nutritional Assessment during Pregnancy week for obese women to 0.51 kg/week for underweight women from the second trimester of preg- Weight monitoring in pregnancy helps clinicians nancy onwards (table 1 ) [1] . Women with estab- to target women at risk of poor pregnancy out- lished weight gain deviations, less than 1 kg per come. Body mass index (BMI) remains a useful month or more than 3 kg per month, should re- index for evaluating prepregnancy nutritional ceive individualized dietary counseling. Errati- status in clinical settings; thus, measuring height cally high weight gain is likely to represent ede- at the first visit is recommended [1] . Chronically ma. A sharp increase in weight gain, edema and energy-deficient women with short stature (<145 hypertension indicate preeclampsia, a serious cm), and/or low prepregnancy weight (<45 kg), pregnancy complication [1] . and/or mid-upper arm circumference <22 cm are A review of studies supports prenatal pro- considered to be vulnerable to poor pregnancy gramming of childhood obesity. The Dutch fam- outcomes such as obstructed labor due to cepha- ine study found that exposure to maternal malnu- lopelvic disproportion [3]. Adolescent pregnan- trition in early, but not late, gestation was associ- cy, high caffeine consumption, smoking and psy- ated with increased odds of childhood obesity chosocial stress of the mother were associated [5] . Furthermore, prenatal exposure to maternal with LBW in underweight mothers [1] . Obese smoking showed significantly increased odds of women were more likely to deliver infants with childhood obesity [6] . The use of anthropometric macrosomia and require admittance to intensive indicators becomes more complex in developing care than their normal-weight counterparts. countries, where a large proportion of women are Obese women were also more likely to develop short, but overweight and the prevalence of HIV hypertension, diabetes mellitus, or urinary tract infection is high among pregnant women [4] . infections during pregnancy than normal-weight women [3] . Most pregnant women in developing coun- Energy and Nutrient Requirements and tries seek antenatal care late during pregnancy, so Supplementation during Pregnancy that prepregnancy weight is not available and therefore antenatal care can be based only on rate The energy requirement of pregnant women in- of gestational weight gain [4] . The recommended creases throughout pregnancy [7]. For most vita- mean weekly weight gains range from 0.22 kg/ mins and minerals, adequate intakes can be

Pregnancy and Lactation 65 achieved by increasing dietary intake of a variety populations at risk. Multiple micronutrient sup- of foods according to increased energy require- plements reduced the risk of LBW and small- ments, but for others, such as folate and iron, sup- for-gestational-age births in vulnerable popula- plementation is necessary [2]. There is an associations [14] . tion between periconceptional folate intake and Evidence suggests that adequate intakes of the prevention of neural tube defects. Few women omega-3 fatty acids, docosahexaenoic acid (DHA) use supplements regularly during the periconcep- and eicosapentaenoic acid, reduce the incidence tional period, but national fortification programs of preterm birth and improve infant cognitive usually ensure sufficient folate intakes in women and visual performance. Research results on pre- of childbearing age to prevent neural tube defects natal omega-3 intake and outcomes are, however, [8, 9] . inconclusive [15] . Still, studies in low-income Anemia in pregnancy remains a public health countries showed that omega-3 fatty acid intakes problem associated with increased risk of LBW were below the recommended minimum for in developing countries. A study in Indian preg- pregnant women [14] . nant women showed that iron supplementation International agencies recommend similar was associated with significantly increased intakes of calcium for pregnant and nonpreg- mean birthweight [10] . Oral iron supplements nant women [2, 9]. A review of studies in devel- improve maternal health and pregnancy out- oped countries on the relationship between sup- comes, but may cause side effects, such as con- plemental calcium and hypertension concluded stipation and nausea. A systematic review to as- that a relationship between calcium and risk sess the effectiveness and safety of daily versus of pregnancy-induced hypertension and pre- intermittent iron supplementation in pregnant eclampsia is unlikely [16] . A more recent system- women showed reduced risk of maternal iron atic review of studies including populations deficiency at term, with no significant differ- with low calcium intakes indicates that risk of ence between the two groups. Side effects were high blood pressure, preeclampsia and preterm reported more often only in daily supplement birth was reduced with calcium supplementa- users than in placebo groups [11] . Another re- tion [14, 17]. Iodine deficiency during pregnan- view showed that fortified beverages and foods cy is the main cause of preventable mental retar- generally decreased maternal anemia and iron dation in childhood [18] . The results of a sys- deficiency and increased birthweight, and also tematic review suggest that iodized salt is an increased birth length and reduced preterm de- effective means of improving iodine status [19] . livery in some studies in developing countries The WHO recommendation for iodine intake [12]. A systematic review comparing the effect of during pregnancy and lactation has recently in- supplementation with multiple micronutrients creased from 200 to 250 μg/day in countries versus iron and folic acid on pregnancy out- where less than 90% of households use iodized comes in developing countries showed that mul- salt. The use of iodized salt in households might tiple micronutrient supplementation was more not be sufficient to cope with the increased io- effective than iron and folic acid supplementa- dine demand during pregnancy. Therefore, io- tion at reducing the risk of LBW [13] . Findings dine supplementation of 150 μg/day in pregnant summarized in a recent review of evidence- women is recommended [8] . There is currently based interventions for improvement of mater- insufficient evidence to draw conclusions on the nal and child nutrition support the replacement usefulness and safety of isolated zinc supple- of iron-folate supplements with multiple micro- mentation or vitamin D supplementation dur- nutrient supplements for pregnant women in ing pregnancy [14] .

66 Kruger /Butte

Table 2. The management of nutrition-related complications of pregnancy [16, 17, 20]

Complication Nutritional management

Insufficient weight gain dietary counseling, food supplementation Excessive weight gain dietary counseling, physical activity under supervision Nausea, hyperemesis small frequent meals, limit intakes of fats and fried foods; fluid and electrolyte replacement, hospitalization if necessary for intravenous fluids and electrolytes Poor dietary habits dietary counseling Constipation with/without dietary counseling to increase fiber and fluid intakes, fiber hemorrhoids supplements, dried prunes and figs Heartburn smaller, more frequent meals, sit upright after meals Edema lie down to rest during the day Diabetes mellitus/gestational diabetes individually adapted meal plan in consultation with a dietitian Pregnancy-induced hypertension hospitalization, individually adapted meal plan in consultation with a dietitian, calcium supplementation may be useful in persons with low calcium intakes

Nutrition-Related Complications of received DHA versus placebo during lactation Pregnancy performed significantly better on the Sustained Attention Subscale of the Leiter International Pregnant women with inappropriate weight gain, Performance Scale, but there were no statistically hyperemesis, poor dietary habits, gestational dia- significant differences between groups on other betes or hypertension should be referred to a neuropsychological domains. At the age of 5 qualified nutrition professional [2] . Pregnancy years, the children performed better on a test of during adolescence is a time of nutritional risk sustained attention. This suggests that DHA in- due to competition for nutrients between the take during early infancy confers long-term ben- growing pregnant adolescent and her fetus. The efits on specific aspects of neurodevelopment management of nutrition-related complications [21] . of pregnancy is summarized in table 2 [20] .

Problems Experienced by Lactating Women Nutritional Assessment and Supplementation during Lactation There is a negative association between maternal obesity and the initiation as well as the continua- Energy requirements of lactating women are in- tion of breastfeeding, suggesting that excessive creased up to 6 months postpartum [7] . For most body fat may inhibit lactation performance [22] . vitamins and minerals, adequate intakes can be Excessive gestational weight gain, insufficient achieved by increasing dietary intake from a va- physical activity, excessive food intake and short riety of foods according to increased energy re- period or no breastfeeding were each significant- quirements [12] . Breastfed infants whose mothers ly related to postpartum weight retention [23] .

Pregnancy and Lactation 67 Women who report at clinics within the first trimester of pregnancy

Height: <145 cm and/or Weight: <45 kg Specialized nutritional care for underweight:

Height 145 cm+ 45 kg+ Assess dietary intake Assess socioeconomic situation Encourage HIV testing if not done

Calculate BMI:

25+20–24.0 <18.5

Specialized nutritional care for Routine care overweight/obese: Assess dietary intake

Provide nutrition and lifestyle education Energy and nutrient supplementation Arrange for support from social services and feeding schemes Provide nutrition and lifestyle education Monitor weekly weight gain (0.5 kg/week) Monitor blood pressure and urine glucose Test urine for signs of urinary tract infections Monitor weekly weight gain (0.28/0.22 kg/week) for overweight/obese women

Women who report at clinics after 20 weeks gestation:

Weight: apparently underweight MUAC: <22 cm obviously overweight 22 cm+ not obviously over-/under weight

Height: <145 cm 145 cm+

Monitor weekly weight gain: Insufficient weight gain (IOM guidelines) (0.42 kg/week) Adequate weight gain Excessive weight gain Routine care

Fig. 1. A framework for the management of pregnancy weight gain [24]. Reproduced with permission from Curationis, AOSIS Open Journals under the Creative Commons Attribution License; http://dx.doi.org/10.4102/curationis. v28i4.1012. MUAC = Mid-upper arm circumference; IOM = Institute of Medicine.

68 Kruger /Butte

Integrated Intervention Conclusions

Figure 1 shows a proposed framework for the • Women with a weight below 45 kg and/or a management of pregnancy weight gain [24] . height below 145 cm and/or a mid-upper arm Health care providers should explain to under- circumference smaller than 22 cm during any weight women why weight gain is important, and stage of pregnancy should be referred for spe- they should be counseled to promote a balanced cialized nutritional care during pregnancy. diet consistent with cultural and financial consid- • Women who gain less than 1 kg per month or erations. Undernourished women should receive more than 3 kg per month should be referred micronutrient-rich food supplements for at least to a dietician. the last trimester of pregnancy [12] . Special atten- • Overweight women should also receive nutrition to foods rich in or supplements of iron, cal- tional care, and their weekly weight gain, blood cium, and folate may help to decrease perinatal pressure, urinary glucose and indicators of uri- morbidity [2]. Overweight women should receive nary tract infections should be monitored closely. advice about a balanced diet and be monitored to • More overweight but micronutrient-deficient prevent excessive weight gain [1] . women enter pregnancy and produce malnourished infants. • Strategies to ensure the optimal nutritional status of pregnant and lactating women and their infants include nutrition education, micronutrient fortification and supplementation programs [2, 8, 11, 19] .

References

1 Institute of Medicine and National Re- are the consequences? Lessons from the 11 Peña-Rosas JP, Viteri FE: Effects and

search Council: Weight Gain During Dutch famine. Maturitas 2011; 70: 141– safety of preventive oral iron or Pregnancy: Reexamining the Guidelines. 145. iron+folic acid supplementation for Washington, The National Academies 6 Huang JS, Lee TA, Lu MC: Prenatal pro- women during pregnancy. Cochrane Press, 2009. gramming of childhood overweight and Database Syst Rev 2009;CD004736.

2 Kaiser LL, Allen LH: Position of the obesity. Matern Child Health J 2007; 12 Yang Z, Huffman SL: Review of fortified American Dietetic Association: nutri- 11(suppl 5):461–473. food and beverage products for preg- tion and lifestyle for a healthy pregnan- 7 Butte NF, King JC: Energy requirements nant and lactating women and their im-

cy outcome. J Am Dietet Assoc 2008; during pregnancy and lactation. Public pact on nutritional status. Matern Child

108: 553–561. Health Nutr 2005; 8: 1010–1027. Nutr 2011; 7(suppl 3):19–43. 3 Perlow JH, Morgan MA, Montgomery 8 Berti C, Biesalski HK, Gärtner R, et al: 13 Kawai K, Spiegelman D, Shankarb AH, D, et al: Perinatal outcome in pregnancy Micronutrients in pregnancy: current et al: Maternal multiple micronutrient complicated by massive obesity. Am J knowledge and unresolved questions. supplementation and pregnancy out-

Obstet Gynecol 1992; 167(suppl 4):958– Clin Nutr 2011; 30: 689–701. comes in developing countries: meta- 962. 9 WHO: Vitamin and mineral require- analysis and meta-regression. Bull WHO

4 Villamor E, Msamanga G, Spiegelman D, ments in human nutrition. Geneva, 2011; 89: 402–411. et al: HIV status and sociodemographic WHO, 2004. 14 Bhutta ZA, Das JK, Rizvi A, et al: Mater- correlates of maternal body size and 10 Sharma A, Patnaik R, Garg S, et al: De- nal and child nutrition 2. Evidence- wasting during pregnancy. Eur J Clin tection and management of anaemia in based interventions for improvement of

Nutr 2002; 56: 415–424. pregnancy in an urban primary health maternal and child nutrition: what can

5 Roseboom TJ, Painter RC, van Abeelen care institution. Indian J Med Res 2008; be done and at what cost? Lancet 2013;

AFM, et al: Hungry in the womb: what 128: 45–51. 382: 452–477.

Pregnancy and Lactation 69 15 Guesnet P, Alessandri JM: Docosahexae- 18 Walker SP, Wachs TD, Gardner JM, et 22 Rasmussen KM: Association of maternal noic acid (DHA) and the developing al: Child development: risk factors for obesity before conception with poor central nervous system (CNS). Implica- adverse outcomes in developing coun- lactation performance. Annu Rev Nutr

tions for dietary recommendations. Bio- tries. Lancet 2007; 369: 145–157. 2007; 27: 103–121.

chimie 2011; 93: 7–12. 19 Wu T, Liu GJ, Li P, et al: Iodised salt for 23 Olson CM, Strawderman MS, Hinton 16 Trumbo PR, Ellwood KC: Supplemental preventing iodine deficiency disorders. PS, et al: Gestational weight gain and calcium and risk reduction of hyperten- Cochrane Database Syst Rev 2002; postpartum behaviors associated with sion, pregnancy-induced hypertension, CD003204. weight change from early pregnancy to and preeclampsia: an evidence-based 20 Erick M: Nutrition in pregnancy and 1 y postpartum. Int J Obes Relat Metab

review by the US Food and Drug Ad- lactation; in Mahan LK, Escott-Stump S, Disord 2003; 27: 117–127.

ministration. Nutr Rev 2007; 65: 78–87. Raymond JL (eds): Krause’s Food and 24 Kruger HS: Maternal anthropometry 17 Hofmeyr GJ, Lawrie TA, Atallah AN, et the Nutrition Care Process. St Louis, and pregnancy outcomes: a proposal for al: Calcium supplementation during Elsevier Saunders, 2011, pp 340–374. the monitoring of pregnancy weight pregnancy for preventing hypertensive 21 Jensen CL, Voigt RG, Llorente AM, et al: gain in outpatient clinics in South Af-

disorders and related problems. Coch- Effects of early maternal docosahexae- rica. Curationis 2005; 28: 40–49. rane Database Syst Rev 2010;CD001059. noic acid intake on neuropsychological status and visual acuity at five years of age of breast-fed term infants. J Pediatr

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Nutrition for Special Circumstances

Bier D, et al. (eds): Nutrition for the Primary Care Provider. World Rev Nutr Diet. Basel, Karger, 2015, vol 111, pp 71–75 DOI: 10.1159/000362301

Exercise and Sports

a b Ronald J. Maughan Susan M. Shirreffs a School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough , and b New Product Research, GlaxoSmithKline, Brentford , UK

Key Words Introduction Exercise · Athlete · Diet · Energy requirements · Nutrient requirements · Hydration With the growing recognition that lifestyle choices have a profound effect on health outcomes, the population has become increasingly polarized. Key Messages At a time when rates of obesity, diabetes and oth- • Diet and food choices can have a significant impact er noncommunicable diseases continue to rise on athletic performance, with profound implica- rapidly, so too is regular recreational exercise be- tions for health and performance. • The metabolic and nutritional demands vary becoming more common in at least some parts of tween different sports, as well as across the annual the general population. Diet and exercise go hand cycle of training versus competition. in hand as key parts of a healthy lifestyle. Neither • Both fat and carbohydrate contribute to energy is completely effective on its own, and attention supply during exercise, with protein contributing a to both will pay many rewards over a lifetime. relatively low amount. At low intensities, fat oxida- Along with recreational exercise, many are tion predominates with a progressive increase in tempted to engage in competitive sports: the tens the relative contribution of carbohydrate with increasing intensity. of thousands who successfully complete the big • Hydration status is important for health and perfor- city marathon races are testimony to what can be mance as exercise increases water requirements achieved with regular training, though many due to additional loss in sweat. others have more modest goals. The elite athlete • Athletes should be aware of their needs for specific is often seen as a role model for healthy active nutrients, especially calcium, iron and vitamin D. Al- lifestyles, but these athletes face a number of nu- though supplements do not compensate for an inadequate diet, supplements may be a short-term op- tritional challenges. It is clear that diet can sig- tion when food intake or food choices are restricted. nificantly influence athletic performance and the • Athletes should adopt specific nutrition strategies food choices that an athlete makes will have pro- tailored to their exercise and training needs in order found implications for both health and perfor- to optimize performance and support good health. mance. © 2015 S. Karger AG, Basel 0.3 20

15 0.2 10 Body fat (%)

Energy intake (MJ/kg/day) intake Energy 0.1 5 0 40 80 120 160 0 40 80 120 160 a Weekly running distance (km) b Weekly running distance (km)

Fig. 1. a Cross-sectional data showing the relationship (expressed as average weekly running distance for the between energy intake and exercise load (expressed as preceding 10 weeks). All subjects were weight stable and average weekly running distance for the preceding 10 had been active (or sedentary) for at least 2 years. In spite weeks). All subjects were weight stable and had been ac- of the higher energy intake, those with the highest train- tive (or sedentary) for at least 2 years. Based on data from ing loads had the lowest body fat content. Based on data Maughan et al. [11]. b Cross-sectional data showing the from Maughan et al. [11]. relationship between body fat content and exercise load

Energy and Nutrient Needs for the Physically food intake will attenuate any reduction in body Active fat content, but the compensation is not complete and a fall in fat mass should ensue if the exercise The most obvious effect of exercise is to increase program is adhered to (fig. 1 ). This may require the rate of energy expenditure. Resting metabolic more exercise than is currently recommended to rate is about 1–1.5 kcal/min, but the energy cost improve cardiovascular and metabolic health: of walking, jogging or running is about 1 kcal per about 200 min or more of moderately vigorous kg of body mass per km covered, independent of exercise may be required to achieve long-term speed. Completing a distance of 5 km therefore weight loss and prevent weight regain [2] . Recent requires about 350 kcal for a 70-kg person. At studies have suggested that many of the cardio- walking speed, this takes an hour, at jogging speed vascular benefits of exercise can be achieved with about 30 min and for the serious athlete about 13– only a few high-intensity efforts on a few days of 16 min. Exercise, if sufficiently intense and pro- the week [3], even though this has little impact on longed, can therefore impose a high energy de- energy balance. Studies with modest exercise pro- mand, and this energy demand must be met from grams and diets that are high in protein content food that is consumed or from the body’s endog- have confirmed that it is possible to lose fat mass enous stores, including especially the fat stores. and gain muscle mass at the same time [4] . Many of the health benefits of exercise are inde- Both fat and carbohydrate contribute to ener- pendent of its effects on body mass and fat levels gy supply during exercise: there is little change in [1], but if energy intake stays constant, a regular the rate of net protein catabolism. At low intensi- program of exercise should reduce body fat con- ties, fat oxidation predominates with a progres- tent. Most exercise programs will also increase sive increase in the relative contribution of carbo- muscle mass. The available evidence suggests that hydrate as intensity increases. At low intensities, exercise does stimulate appetite, and an increased however, the rate of energy expenditure is also

72 Maughan /Shirreffs

low, and moderate exercise intensity is likely to exercise program. In longer exercise sessions, par- have the greatest impact on fat oxidation and po- ticularly in warm and humid weather, sweat losses tentially also on energy balance [5] . Exercise in- may be substantial and consumption of water or a tensities that are too high are uncomfortable, and carbohydrate-electrolyte sports drink may be en- only the most motivated will persist. couraged [7] . One of the primary benefits of main- Although the body has ample fat stores, the taining hydration may be a reduction in the per- carbohydrate store is small – about 80–100 g as ception of effort during exercise: if the exercise glycogen in the liver and about 300–500 g in skel- feels easier, adherence is likely to be improved. etal muscle. Obligatory glucose use amounts to There is now some evidence that simply rinsing about 100 g per day, and glycogen use in endur- the mouth with a carbohydrate-containing drink ance exercise can reach 2–4 g/min, so an adequate may enhance performance, perhaps by activation intake of carbohydrate is essential, especially for of carbohydrate receptors in the mouth [8] . those who are active. A carbohydrate intake of 4–6 g/kg/day may be recommended on exercise days [6] . Exercise with low carbohydrate availabil- Energy and Nutrient Needs for Competitive ity increases fat use, but the exercise is harder and Sport feels harder. For those likely to be discouraged by effort, this may lead to lack of adherence, espe- The elite athlete is characterized by a unique ge- cially in the early stages of an exercise program. netic endowment, to which is allied a high degree Hard physical exercise may lead to a slight in- of motivation and the changes induced by consis- crease in the requirement for protein due to a tent intensive training. The impact of nutrition is greater protein oxidation during exercise, espe- relatively small, but at the highest level of sport, the cially during the early stages of a training pro- outcome is determined by such small differences. gram. Protein catabolism is also increased during The metabolic and nutritional demands of exercise if glycogen stores are inadequate or if sport vary greatly between different sports, and carbohydrate is not consumed during exercise. the balance between training and competition The extra protein required can, however, be met also varies between sports and across the annual from the diet: if the training load is sufficient to cycle of training and competition. It is well estab- increase protein requirement, it will usually also lished that diet significantly influences athletic increase total energy intake and therefore protein performance, and athletes are encouraged to intake. The exception might be when energy in- adopt specific nutritional strategies before, dur- take is restricted to achieve weight loss, when a ing and after training and competition to maxi- higher protein intake is advised. A similar con- mize their mental and physical performance. En- sideration is applied to vitamin and mineral re- ergy demands depend on the periodized training quirements. High energy intake will generally re- load and competition program, and will vary sult in all needs being met, provided that a varied from day to day and across the season. A diet that diet is consumed. provides adequate energy from a wide range of Hydration status is important for health and commonly available foods can meet the carbohy- performance, and regular exercise will increase drate, protein, fat and micronutrient require- water requirements because of additional losses in ments of training and competition. Low energy sweat. It is seldom necessary to drink during exer- availability should be avoided, as it can impair cise that lasts less than about 30–40 min, but oc- performance and adaptation to training and may casional sips of water may help reduce the percep- be harmful to brain, reproductive, metabolic and tion of effort and thus encourage adherence to the immune function, and to bone health. An appro-

Exercise and Sports 73 priate diet will help athletes reach an optimum in quantities sufficient to maximize the synthesis physique to achieve success in their sport. Care- of proteins, to aid in long-term maintenance or ful selection of nutrient-rich foods to reduce the gain of muscle and bone and in the repair of dam- risk of developing nutrient deficiencies that im- aged tissues. Ingestion of foods or drinks provid- pair both health and performance is especially ing 15–25 g of such protein after each training important when energy intake is restricted to re- session will maximize the synthesis of proteins duce body and/or fat mass. that underpin these goals. During high-intensity training, particularly Dehydration, if sufficiently severe, can impair of long duration, athletes should aim to achieve performance in most events, particularly in carbohydrate intakes that meet the needs of their warm and high-altitude environments. Athletes training programs and also adequately replace should be well hydrated before exercise, and carbohydrate stores during recovery between should generally drink sufficient fluid during ex- training sessions and competitions: this may re- ercise to limit dehydration to less than about 2% quire up to 10–12 g/kg/day of carbohydrate from of body mass [7]. Chilled fluids may benefit per- various sources for some athletes in peak training formance in hot conditions. Athletes should not periods, but athletes in technical events may need drink so much that they gain weight during exer- only 4–6 g/kg/day [6] . For events lasting an hour cise. There are large individual differences in the or more, the athlete should aim to begin competi- amount of salt lost in sweat, and some sodium tion with body carbohydrate stores sufficient to should be included in drinks when sweat losses meet their needs by consuming carbohydrate- are high, especially when exercise lasts more than rich foods in the hours and days beforehand. In- about 2 h. During recovery from exercise, rehy- gestion of even small amounts of carbohydrate dration should include replacement of both water during exercise can enhance cognitive and phys- and salts lost in sweat [9] . ical performance in competition lasting 1 h. As Athletes should be particularly aware of their the duration of the event increases, so does the needs for some specific nutrients, especially cal- amount of carbohydrate needed to optimize per- cium, iron and vitamin D, but supplements are formance. To achieve the high rates of intake not generally necessary if a varied diet is chosen. (up to 90 g/h) needed to optimize performance The use of supplements does not compensate for in events lasting more than about 3 h, athletes poor food choices and an inadequate diet, but should practice consuming carbohydrate during supplements that provide essential nutrients may training to develop an individual strategy, and be a short-term option when food intake or food should make use of sports foods and drinks con- choices are restricted due to travel or other fac- taining carbohydrate combinations that will tors [10] . Vitamin D may be needed in supple- maximize absorption from the gut and minimize mental form when sun exposure is inadequate. gastrointestinal disturbances. Of the many different dietary ergogenic aids Dietary protein may be needed in amounts available to athletes, a very small number may greater (1.2–1.8 g/kg/day) than those recom- enhance performance for some athletes when mended for the general population (0.8 g/kg/ used appropriately: examples might include caf- day), but a varied diet that meets energy needs feine, creatine, buffering agents and nitrate. Ath- will generally provide protein in excess of re- letes contemplating the use of supplements and quirements. Foods or snacks that contain high- sports foods should consider their efficacy, their quality proteins should be consumed regularly cost, the risk to health and performance, and the throughout the day as part of the day’s total pro- potential for a positive doping test. Supplement tein intake, and in particular soon after exercise, use in young athletes should be discouraged, and

74 Maughan /Shirreffs

the focus should be on consuming a nutrient- • An active lifestyle allows more food to be eaten rich, well-chosen diet to allow for growth while without unwanted weight gain and, provided maintaining a healthy body composition. Robust that a varied diet is eaten, this will provide in- immunity and reduced risk of infection can be creased amounts of all essential nutrients. achieved by consuming a varied diet adequate in • A high carbohydrate diet supports a regular energy and micronutrients, ensuring adequate exercise program, as carbohydrate is the pri- sleep and limiting other life stress. mary fuel for the exercising muscles. • Protein requirements are increased by regular exercise, but a varied diet that meets energy Conclusions needs will provide more than enough protein. • Maintaining hydration status is important, • To enjoy all the benefits of sport, athletes and and extra salt may be needed by some individ- active individuals, whether they compete at uals when sweat losses are high. the elite level or exercise on a recreational ba- • Dietary supplements are heavily promoted to sis, should adopt specific nutrition strategies athletes and active individuals: most are not that can optimize mental and physical perfor- beneficial, but a few may help if used appropri- mance and support good health. ately.

References

1 Lee DC, Sui X, Blair SN: Does physical 5 Achten J, Jeukendrup AE: Maximal fat 8 Carter JM, Jeukendrup AE, Jones DA: activity ameliorate the health hazards of oxidation during exercise in trained The effect of carbohydrate mouth rinse

obesity? Br J Sports Med 2009; 43: 49–51. men. Int J Sports Med 2003; 24: 603–608. on 1-h cycle time trial performance.

2 Jakicic JM, Davis KK: Obesity and physi- 6 Burke LM, Hawley JA, Wong SH, Jeuk- Med Sci Sports Exerc 2004; 36: 2107– cal activity. Psychiatr Clin North Am endrup AE: Carbohydrates for training 2111.

2011; 34: 829–840. and competition. J Sports Sci 2011; 29 9 Maughan RJ, Shirreffs SM: Dehydration 3 Gibala MJ, McGee SL: Metabolic adapta- (suppl 1):S17–S27. and rehydration in competitive sport.

tions to short-term high-intensity inter- 7 Shirreffs SM, Sawka MN: Fluid and elec- Scand J Med Sci Sports 2010; 20(suppl val training: a little pain for a lot of gain? trolyte needs for training, competition 3):40–47.

Exerc Sport Sci Rev 2008; 36: 58–63. and recovery. J Sports Sci 2011; 29(suppl 10 Maughan RJ, Greenhaff PL, Hespel P: 4 Josse AR, Atkinson SA, Tarnopolsky 1):S39–S46. Dietary supplements for athletes: MA, Phillips SM: Increased consump- emerging trends and recurring themes. J

tion of dairy foods and protein during Sports Sci 2011; 29(suppl 1):S57–S66. diet- and exercise-induced weight loss 11 Maughan RJ, Robertson JD, Bruce AC: promotes fat mass loss and lean mass Dietary energy and carbohydrate intakes gain in overweight and obese premeno- of runners in relation to training load.

pausal women. J Nutr 2011; 1419: 1626– Proc Nutr Soc 1989; 48: 170A. 1634.

Exercise and Sports 75 Nutrition for Special Circumstances

Bier D, et al. (eds): Nutrition for the Primary Care Provider. World Rev Nutr Diet. Basel, Karger, 2015, vol 111, pp 76–81 DOI: 10.1159/000362302

Food Allergy and Food Intolerance

a–d e John Leung Sheila E. Crowe a Food Allergy Center at Tufts Medical Center and Floating Hospital for Children, and Departments of b c d Gastroenterology, Pediatric Gastroenterology, and Allergy and Immunology, Tufts Medical Center, e Boston, Mass. , and Division of Gastroenterology, Department of Medicine, University of California at San Diego, San Diego, Calif. , USA

• Appropriate diagnosis is important in order to Key Words avoid the unnecessary elimination of a particular Food allergy · Food intolerance · IgE · Dietary food item from the diet. restriction · Nutritional deficiency • When a restricted diet is clinically indicated for long-term management, it should be undertaken under close supervision from an experienced nutri- Key Messages tionist and expert physician to reduce the risk of nutritional deficiencies. © 2015 S. Karger AG, Basel • Adverse reactions to food can be classified as either immune mediated (e.g. food allergy, FA) or nonimmune mediated (e.g. food intolerance, FI). Non- immune-mediated reactions are the most prevalent. • Eight foods (milk, eggs, peanuts, tree nuts, soy, wheat, fish and shellfish) account for 90% of all IgE- Introduction mediated food allergies. • Celiac disease is a classical example of a non-IgE- Food allergy (FA) is defined as an adverse health mediated adverse food reaction that affects 1% of effect arising from a specific immune response the population. Examples of other immune-medi- that occurs reproducibly on exposure to a given ated adverse food reactions are food protein-in- food. FA is a growing public health concern and duced enterocolitis syndrome, eosinophilic esophagitis and eosinophilic gastrointestinal disorders. its prevalence seems to be on the rise. It is esti- • FI is much more common than FA. Examples of FI mated that 9 million, or 4%, of adults have FA in include food poisoning, lactose intolerance, as well the United States. Up to 20% of the population, as toxic, pharmacological, and functional adverse however, frequently confuses food intolerance reactions to foods. Quite often, these reactions (FI) with FA, leading to unnecessary dietary re- mimic reactions due to FA. striction and potential nutritional deficiency. In Adverse food reaction

Immune Nonimmune (food allergy) (food intolerance)

IgE Non-IgE Metabolic Pharmacological (OAS, hives, (FPIES, celiac) (lactose (tyramine) anaphylaxis) intolerance)

Mixed IgE and non-IgE Cell mediated Toxic Other (eosinophilic (Allergic contact (scombroid) (mechanical, gastroenteritis) dermatitis) physiological)

Fig. 1. Classification of adverse food reactions. FPIES = Food protein-induced enterocolitis syndrome; OAS = oral allergy syndrome. Adapted from Boyce et al. [1].

this chapter, we will discuss the key clinical fea- Food Allergy tures that distinguish FA from FI, with a special focus on the nutritional deficiency and its man- To understand FA, we first need to understand agement. the nomenclature. ‘Allergy’ has conventionally been associated with IgE-mediated processes. It is therefore not surprising that FA is often equated Food Allergy versus Food Intolerance to IgE-mediated FA, though there are other food allergies that are not IgE mediated. For our dis- In general, any adverse reaction to food can be cussion, we will use the term ‘IgE-mediated food classified into either immune mediated (e.g. FA) allergy’ to specifically refer to FA that are medi- or nonimmune mediated (FI), with the latter be- ated by IgE. Another term you may encounter in ing the most prevalent (fig. 1 ). The fundamental the literature is food hypersensitivity. It is often difference between FA and FI is that the former is used to describe FA, although some have used immune mediated, while the latter is not [1] . In this term more broadly to include FI. For this rea- clinical practice, it is of paramount importance to son, we will avoid using the term food hypersen- distinguish the two, because their clinical impli- sitivity in our discussion. cation and nutritional needs are distinctly differ- Eight foods account for 90% of all IgE-medi- ent. For instance, while consumption of milk in a ated food allergies: milk, eggs, peanuts, tree nuts, patient with lactose intolerance causes self-limit- soy, wheat, fish and shellfish [1] .The onset of ed symptoms such as diarrhea, bloating and ab- symptoms is rapid and even minute amounts of dominal discomfort, ingestion of even a trace the allergen can trigger severe reactions. The re- amount of milk by a patient with cow milk allergy actions can range from self-limited localized (CMA) can trigger potentially life-threatening hives to life-threatening generalized anaphylaxis. anaphylactic shock. Common symptoms include hives, pruritus, ery-

Food Allergy and Food Intolerance 77 thema, angioedema, nasal congestion, cough, Non-IgE-Mediated Adverse Reactions to Food chest tightness, vomiting, nausea, diarrhea, dizziness, wheezing and rhinoconjunctivitis. Pa- Celiac disease is a classical example of non-IgE- tients with suspected IgE-mediated FA should be mediated adverse food reaction found in adults. It referred to an allergist for evaluation and man- is caused by an abnormal immune reaction to agement. gluten and affects 1% of the population [3] . Life- Shellfish, peanut, tree nuts and fish are re- long elimination of gluten is the only treatment. sponsible for most of the FA in adults. Although Since gluten is present in a variety of food items, these foods contain valuable nutrients, they do the diagnosis should be confirmed by a specialist not usually account for a large percentage of dai- before committing patients to a life-long gluten- ly dietary intake in a Western diet. Many other free diet. Gluten-free diets are often low in vita- foods can supply the nutrients found in these min B, calcium, vitamin D, iron, zinc, magnesium specific foods, and substitution can easily be and fiber. Until fairly recently, few gluten-free made. Although significant nutritional deficien- products were enriched or fortified, adding to the cy secondary to a single FA is rare among adults risk of nutritional deficiency. Food protein-in- in the US, CMA, wheat allergy and multiple food duced enteropathy is another non-IgE-mediated allergies (MFA) remain a significant challenge adverse reaction to food, and is most commonly for nutritionists and clinicians. Adults with seen in young infants. CMA are at risk of vitamin D and calcium deficiency because it is difficult to meet calcium needs through nondairy sources without careful Other Immune-Mediated Adverse Reactions substitution. Therefore, calcium supplements to Food should always be considered in patients with CMA to reduce the risk of osteoporosis and frac- Examples of other immune-mediated adverse ture [2] . food reactions are food-induced allergic contact Wheat is present in many processed foods dermatitis, eosinophilic gastrointestinal disor- such as crackers, cookies, cakes, pasta, bread and ders and eosinophilic esophagitis (EoE). EoE cereal. Moreover, wheat is also a minor ingredi- deserves special attention because a subset of ent in condiments, marinades, cold cuts, soy patients respond very well to elimination di- sauce, hard candies, low-fat products, etc. The ets, which pose significant nutritional risks. EoE major product of wheat, wheat flour, is a great is a chronic immune-/antigen-mediated disorder source of carbohydrates, iron, thiamine, ribofla- characterized by eosinophilic infiltration of the vin, niacin, folic acid, vitamin B6 , magnesium esophagus [4]. Adults with EoE often present and fiber. Fortunately, there are a wide variety of with refractory reflux, epigastric or chest pain, wheat-free products made from alternative flours dysphagia and food impaction. The majority of (rice, corn, oat, barley, buckwheat, rye, amaranth, affected adults are men in their 20s or 30s. Over millet and quinoa). The availability of gluten-free the past few years, the treatment modality for foods can also benefit those with wheat allergy. It adults has shifted from primarily medical (swal- is important to note that up to 20% of the indi- lowed topical corticosteroids) to dietary approach viduals with an allergy to one grain will have al- (elimination diet) [5]. The three primary dietary lergies to other grains. Use of these alternative treatment options are testing-directed elimina- grain products should be individualized and tion (foods are eliminated based on allergy testing based upon tolerance as determined by an allergy results), empirical elimination (milk, soy, egg, specialist. wheat, peanut/tree nuts, and fish/shellfish are

78 Leung /Crowe

eliminated) and elemental diet (amino-acid based lower calcium intake, calcium supplementation formula that eliminates all potential food aller- should be considered to reduce the risk for osteo- gens). If a dietary approach is employed, patients porosis and fracture [7] . should be closely followed by a registered dieti- Scombroid fish poisoning is the most com- tian to avoid nutritional deficiency. mon seafood-associated disease in the US. Short- ly after ingesting contaminated fish, patients experience acute onset of flushing, a sensation of Food Intolerance warmth, an erythematous rash, palpations and tachycardia [8] . The symptoms resemble an IgE- FI is much more common than FA. Examples of mediated allergic reaction and are often misdiag- FI include food poisoning, lactose intolerance, as nosed as FA, leading to unnecessary diet restric- well as toxic, pharmacological, and functional ad- tion and nutritional compromise. verse reactions to foods. Quite often, these reac- Pharmacological reactions to food or food ad- tions mimic reactions due to FA. It is therefore ditives represent a relatively common type of FI. important to keep in mind the differential diag- Ingestion of foods with high histamine content nosis when evaluating patients with suspected such as well-ripened cheese, pickled cabbage, red FA. wine and tuna fish can cause a wide range of al- Food poisoning typically manifests as nausea, lergic-like symptoms in susceptible individuals vomiting, fever, abdominal pain and diarrhea. A with a genetic defect in the metabolism of exoge- good history and physical examination is usually nous histamine [9] . In some instances, FI can re- sufficient to distinguish such reactions from FA. sult from drug-food interactions. A classic exam- GI infections can also result in transient lactose ple is hypertensive crisis observed in individuals intolerance. Since most food poisoning episodes taking monoamine oxidase inhibitors and ingest- are self-limited, they do not pose a significant ing tyramine-rich food (e.g. wine and cheese). risk for malnutrition. Adverse reactions to food additives such as artifi- Lactose intolerance is the most common ad- cial colors (FD&C yellow No. 5) and various pre- verse reaction to a specific food, with most cases servatives (for example, sulfites) are other exam- resulting from a genetically regulated reduction ples of FI. Avoidance is the only treatment. Man- of intestinal lactase activity later in adult life [6] . agement of the nutritional needs for these FI is The lactose intolerance breath test provides a similar to that of food allergies, but they are typi- simple, accurate and noninvasive way to confirm cally not a concern given a less restricted list of the diagnosis. It is important to confirm the di- foods to be avoided in such disorders. Functional agnosis so patients will not unnecessarily avoid FI no doubt exists and appears to be more preva- milk consumption, which is one of the most bio- lent in patients with irritable bowel syndrome and available sources of ingested calcium and vita- other functional GI disorders with or without un- min D. Naturally low-lactose dairy products such derlying psychiatric disorders [10] . Patients often as yogurt, hard cheeses and kefir are typically report adverse reactions to multiple foods. They well tolerated in patients with lactose intolerance. often self-eliminate multiple food classes from Commercially available lactase enzymes can be their diet and are at particular high risk for nutri- added to lactose-containing food or ingested tional deficiency. Since some patients may be will- with meals containing lactose to reduce symp- ing to reintroduce foods into their diet if diagnos- toms. Moreover, lactose-free milk products are tic tests fail to confirm a food-related reaction, readily available in grocery stores. Since patients targeted skin testing, specific IgE serology and/or with lactose intolerance often have significantly food challenges may be helpful in liberalizing

Food Allergy and Food Intolerance 79 Table 1. Useful resources for patients suffering from FA

General information http://www.foodallergy.org/ http://www.niaid.nih.gov/topics/foodallergy/Pages/default.aspx http://www.aaaai.org/conditions-and-treatments/allergies/food-allergies.aspx http://www.acaai.org/allergist/allergies/Types/food-allergies/Pages/default.aspx http://community.kidswithfoodallergies.org/about Food allergy recipes http://www.realfoodallergyfree.com/allergy-free-recipe-index/ http://www.kidswithfoodallergies.org/recipes/allergy-friendly-recipes.php http://www.foodallergykitchen.com/pages/recipes.php

their diet and minimizing nutritional risk. On the tic and nutritional challenge. They are at high risk other hand, this same group of patients is also for malnutrition. Although MFA is more com- more likely to supplement their diet with suprath- monly seen in pediatric patients, it is infrequently erapeutic amounts of ‘health food’ preparations seen in adults. One example is adult patients un- and nutritional supplements. The dangers of dergoing multiple food elimination diet for the oversupplementation are well described. treatment of EoE. Close monitoring of nutrition- Symptoms triggered by physiological reac- al status is warranted, and supplements should be tions to food are frequently encountered in clini- considered in appropriate settings. The same ap- cal practice. Fatty foods, chocolate, peppermint, plies to patients with specific immune-mediated colas, red wine, orange juice and excessive alco- food-induced conditions who are on a restricted hol are known to reduce lower esophageal sphinc- diet for other reasons (e.g. a strict vegetarian with ter pressure and worsen symptoms of gastro- celiac disease). Clinicians should be sensitive to a esophageal reflux disease. Legumes, onions, cab- patient’s dietary preference and understand that bage, bran fiber, and grains serve as a substrate changing one’s diet might not be acceptable to the for gas production by colonic flora and can ag- individual for cultural, religious or other reasons. gravate bloating symptoms. These physiological Some useful resources for patients suffering from reactions to foods are typically noted by patients FA are listed in table 1 . with functional GI disease, many of whom appear to exhibit heightened sensory responses to normal digestive events. As long as a balanced Conclusions diet is maintained, avoidance of the specific food items described herein has virtually no impact on • Dietary limitation due to adverse reactions to nutritional status. food can have a significant impact on nutritional intake. • It is therefore important to identify individuals Special Nutritional Issues of Multiple Food in whom restricted diets are truly justified. Allergies • When a restricted diet is clinically indicated for long-term management, it should be un- In the previous sections, we discussed the nutri- dertaken under close supervision from an ex- tional management of patients with a particular perienced nutritionist and expert physician to FA. Patients with MFA present a unique diagnos- reduce the risk of nutritional deficiencies.

80 Leung /Crowe

References

1 Boyce JA, Assa’ad A, Burks AW, et al: 4 Dellon ES, Gonsalves N, Hirano I, et al: 6 Swagerty DL, Walling AD, Klein RM: Guidelines for the diagnosis and man- ACG clinical guideline: evidenced based Lactose intolerance. Am Fam Physician

agement of food allergy in the United approach to the diagnosis and manage- 2002; 65: 1845–1850. States: report of the NIAID-sponsored ment of esophageal eosinophilia and 7 Di Stefano M, Veneto G, Malservisi S, et expert panel. J Allergy Clin Immunol eosinophilic esophagitis (EoE). Am J al: Lactose malabsorption and intoler-

2010; 126:S1–S58. Gastroenterol 2013;108:679–692 . ance and peak bone mass. Gastroenter-

2 Jensen VB, Jørgensen IM, Rasmussen 5 Vashi R, Hirano I: Diet therapy for eo- ology 2002; 122: 1793–1799. KB, et al: Bone mineral status in chil- sinophilic esophagitis: when, why and 8 Hungerford JM: Scombroid poisoning: a

dren with cow milk allergy. Pediatr Al- how. Curr Opin Gastroenterol 2013;29: review. Toxicon 2010; 56: 231–243.

lergy Immunol 2004; 15: 562–565. 407–415. 9 Maintz L, Novak N: Histamine and his- 3 Rubio-Tapia A, Hill ID, Kelly CP, et al: tamine intolerance. Am J Clin Nutr

ACG clinical guidelines: diagnosis and 2007; 85: 1185–1196. management of celiac disease. Am J 10 Kelsay K: Psychological aspects of food

Gastroenterol 2013;108:656–676. allergy. Curr Allergy Asthma Rep 2003;

3: 41–46.

Food Allergy and Food Intolerance 81 Nutrition for Special Circumstances

Bier D, et al. (eds): Nutrition for the Primary Care Provider. World Rev Nutr Diet. Basel, Karger, 2015, vol 111, pp 82–86 DOI: 10.1159/000362303

Religion and Culture

H.H. Vorster

Centre of Excellence for Nutrition, North-West University, Potchefstroom Campus, Potchefstroom , South Africa

Key Words Introduction Religion · Culture · Ethnicity · Traditional dietary practices · Medical and spiritual care Modern medicine is evidence based. Neverthe- less, all health professionals (HPs) will at some time in their career have to consult and treat cli- Key Messages ents and patients with religious beliefs and from • Health professionals (HPs) should be aware, sensi- cultures other than their own, who may regard tive and respectfully support differences in religion, evidence less important than their own convic- cultural values and dietary practices of clients and patients. tions. HPs should therefore develop awareness • HPs should develop cultural competency and fol- and skills to become culturally competent. low ethical guidelines to interact with patients to A patient’s religion and culture will determine ensure good communication and treatment com- what it means to be ill and how an individual will pliance. behave as a client or patient. Religion and culture • HPs should not depart from evidence-based prac- will influence communication and rapport be- tices, nor use religious and cultural practices as tween HPs and patients, as well as treatment part of treatment, but may discuss medical and dietary issues in context of a shared faith and cul- compliance and follow through. It could, there- ture. fore, determine a patient’s response to treatment • In the cultural process, HPs should not generalize, recommendations, including dietary prescrip- be condescending, biased or patronizing. tions. Dietary practice is a learned behavior, and • A good caring relationship may overcome cultural food has great symbolic meaning in many cul- missteps and mistakes. © 2015 S. Karger AG, Basel tures and religions. Development of Cultural Competency genetics, age, sex, education, socioeconomic status, health status, and health behaviors such as To develop cultural competency for the best pos- vegetarianism, smoking, alcohol consumption, sible treatment and prevention outcomes, three stress and sexual activity. Most studies that remain facets of culture, ethnicity, religion, spiritu- port a relationship did not control for all con- ality and health should be understood by HPs: founders, while well-conducted studies report (1) the problematic area about the scientific evi- conflicting findings [2] . dence that religion and prayer influence health On the other hand, modern nutrition abounds outcomes; (2) the need to acquire knowledge with evidence that certain dietary practices con- about the beliefs and practices of different reli- tribute to nutrient adequacy and protection gions and cultures that could impact on dietary against diseases by influencing biological risk practices and health care; (3) the necessity to de- factors. This evidence forms the basis of authori- velop awareness about ethical guidelines for in- tative dietary recommendations to prevent and teraction with patients with different religious treat disease. Fortunately, many of these practic- and cultural persuasions and eating patterns, and es form part of religious dietary rules and/or tra- skills to apply these guidelines in practice. ditional (cultural) eating patterns.

Religion Culture and Ethnicity

An individual’s religion is the personal aware- Culture is the total pattern of human behavior in ness, conviction, belief and commitment to and thoughts, speech, actions and artifacts. It is the serving of God or a god (a supreme being of su- body of acquired knowledge, values, morals, be- pernatural powers) with worshipful devotion and liefs, practices and customs, opinions, laws, tradi- conduct in accordance with divine commands as tions, religion, superstition and art, possessed and found in sacred writings or declared by authorita- expressed by a designated group. It is: all human, tive teachers [1] . nongenetic or nonmetabiological phenomena [1, Science and religion share a complex history 3] . Ethnicity is that part of our identity derived and relationship. In the past, spiritual and medi- from membership, usually through birth, in a ra- cal care, including dietary prescriptions and cial, religious, national, social or linguistic group advice, were often dispensed by the same per- or subgroup with its associated culture [3] . son [2] . Culture is often characterized by ethnicity, Although many believe that religion and traditional values and specific religious and spir- prayers contribute to healing, and many can cope itual practices. Culture influences attitudes to better with ill-health because of the comfort and medical treatment, determines special meaning strength of their religion, there is no convincing of medicines and diet (dietary preferences, food scientific evidence that prayers can heal [2] . The selection and preparation), childcare practices, evidence is weak and inconsistent. Part of the power relationships within communities, house- problem to prove the relationship between reli- hold relationships, and many other everyday life gion and health is methodological. Examining practices. this relationship would depend on how religion The same religion can be found in different as exposure and health as outcome are defined cultural groups and one cultural group may have and measured. Such a relationship would be con- subgroups or individuals with different religious founded by a host of factors such as genetics, epi- beliefs.

Religion and Culture 83 Table 1. Religious dietary practices

Religion Dietary practices Background

Buddhism Vegetarian diet (refrain from meat); moderation A religion about lifestyle; natural foods of the in all foods; fasting (monks after noon) earth considered to be the most ‘pure’ Christianity: (many Selective fasting and restrictions during holy Bible: Old and New Testament: bread and wine different denominations) days, slightly different in the different at communion symbolic of Christ’s body and denominations blood shed for salvation of man Eastern Orthodox Selective fasting; restrictions on meat and fish Bible: fasting and restrictions on holy days to increase spiritual progress Protestant (different Few restrictions of food or fasting; moderation Bible: God made all plants, fish and animals for sub-groups) in eating and drinking advised mankind’s husbandry and enjoyment, for use in moderation Roman Catholic and Fasting practiced; meat restricted on certain Bible: restrictions consistent with specified days related faiths days on church calendar Seventh-day adventist Vegetarianism advised; pork, alcohol, tea, and Bible: Sabbath on Saturday; dietary practices (Sabbatarians) coffee prohibited and meat and fish avoided; must honor and glorify God by practicing fasting practiced moderation Mormonism (Church of Alcohol and beverages containing caffeine Word of Wisdom; Book of Mormon; fasting is Jesus Christ of the prohibited; moderation in all foods; fasting the discipline of self-control and honoring God; Latter Day Saints) practiced; meat to be eaten sparingly caffeine is addictive and leads to poor health Hinduism Fasting on specific days; beef prohibited; From the Vedic-Brahman civilization; the cow is other meat and fish restricted or avoided; sacred and cannot be eaten, but products lacto-ovo-vegetarian (dairy) from the cow are pure and desirable; fasting promotes spiritual growth; respect for life is the basis for abstaining from meat and fish Islam Only ‘halal’ meat allowed; pork, certain birds Halal meat (animals slaughtered according to and alcohol prohibited; tea, coffee and religious prescription from the Qur’an (Koran); stimulants avoided; fasting on certain days fasting has a cleansing effect of evil elements; (no food and drinks during daytime) correct eating is for good health and spiritual awareness Judaism ‘Kosher’ laws guide eating; pork and non-fish Torah: Kosher practices prescribed; land sea foods, and meat and dairy in the same meal animals without cloven hoofs and not chewing prohibited; leavened foods restricted during their cud (e.g. pig, hare, camel) are ‘unclean’ certain periods; fasting on certain days and forbidden; separate kitchen utensils for meat and dairy Rastafarianism Vegetarian (meat and fish restricted); added A lifestyle based on individual meditation; pigs (Ital religion and diet) salt(s), preservatives and condiments restricted; and shellfish are scavengers and not allowed; alcohol, soft drinks, tea and coffee prohibited marijuana used for medicinal and medical but herbal drinks allowed purposes and seen as one of the herbs allowed

Dietary Practices of Different Religions and either restricted to holy days or are general reli- Cultures gious prescriptions. These include abstaining, fasting, restriction or totally forbidden foods. Ta- Many religious dietary practices developed be- ble 1 gives a brief description of some dietary cause of religious rules or ethnic heritage, often practices of a few religions. based on food hygiene and safety issues. In differ- In different parts of the world, many cultural ent religions, specific foods have different mean- groups and individuals follow diets based on tra- ings, and certain foods, drinks and practices are ditions and foods (especially staples) that were

84 Vorster

available in the past. Examples are the Paleolithic religions. Show a willingness to understand diet (no starchy vegetables and grains, no dairy theirs. and no alcohol); carnivore diet (no carbohydrate- (2) Be aware of the different cultural values containing foods); omnivore diet (our typical that influence decision making, compli- ‘modern Western’ diet with a wide variety of ance to dietary recommendations and plant and animal derived foods); Mediterranean health behaviors. These include inter alia diet (rich in vegetables, olive oil and fish); vegan people’s relationship with nature (subju- and vegetarian diets (from total to selective re- gating, submitting or in harmony), how the striction of animal-derived foods), as well as client sees disease (as punishment?) and the many traditional eating patterns [4, 5] of indige- client’s interpersonal relationships (vertical nous peoples all over the world. and authoritarian, horizontal and com- It is useful to gain knowledge of dietary sta- munal, egalitarian and sharing or individu- ples, any forbidden foods and practices, rituals, alistic). The client’s time orientation (past, indigenous foods, traditional dishes, recipes, present or future) will determine actions preparation methods and nutrient content of the taken towards health matters. The child-el- diets of cultures in the HPs environment [5] . This der orientation will determine who is tak- information can help to analyze cultural influ- ing decisions in a family. ences on nutrient intakes and also for culture- (3) Because of the diversity and wide variety in sensitive dietary recommendations [5] . However, eating patterns, it is advised that HPs should although some of these traditional diets, such as assess cultural dietary practices of patients the hunter-gatherer diet followed by Australian by asking appropriate and relevant ques- aborigines in the past, are known to protect tions before planning a dietary prescription against cardiovascular and other diseases [6] , and menus. This will ensure compliance to they are not practical, accessible or acceptable recommended diets. any more. (4) For these assessments, good communication skills are necessary. A few guidelines are: Recommendations for Becoming Culturally • A hospital or other health setting may be ex- Competent perienced as being ‘intrusive’. Approach the client with care and make sure you are speak- (1) Be cautious about the cultural process. Be ing to the right person (for example in some careful not to generalize, be condescend- cultures, in the case of a child, it may be the ing, biased and patronizing. Treat all pa- grandmother and not the parents). tients and clients with respect, empathy, • Some cultures regard formality of address as and interest. Culture is not restricted to a sign of respect. Introduce yourself and ask people of color. Some people are not com- the client how he or she would like to be ad- fortable with an ethnic label; they want to dressed. This is also valid for ‘touch’. Ask the be treated like ‘everyone else’. Also, many client what is allowable. immigrants from different cultures may be • Ensure that the right ‘distance’ between you in a process of acculturation, adopting a and the client is kept. People from some cul- new, and ‘Westernized’ culture and diet [7] . tures prefer close proximity while others pre- ‘Remove’ or ignore your own cultural and fer more distance. This may even be applica- religious assumptions when communicat- ble in the way the furniture in the interview/ ing with patients with other cultures and assessment room is arranged.

Religion and Culture 85 • The use of interpreters in the case of culture practices as part of treatment can do harm. and language barriers may be helpful, but However, there is no ethical problem for some may ‘distort’ the message based on the HP and patient to discuss medical is- their own knowledge or interpretation of sues in context of a shared culture and faith. cultural issues. The fact that the interview (6) A good caring relationship may overcome language is probably not the first language of cultural missteps and mistakes. the client may cause misunderstandings and ‘crosstalk’. Therefore, gain knowledge of special meanings of specific words in the rele- Conclusion vant culture. (5) When interviewing or treating clients from • Dietary assessments, advice and treatment of religions different from your own, take ac- clients or patients from cultures and religions count of the differences, be respectful but different from your own can be a challenge. never try to influence the religious com- • But with goodwill, knowledge of and respect mitment of the client. It is unethical and for dietary practices determined or influ- inappropriate for HPs to depart from enced by religion, tradition, or a specific cul- established, evidence-based practices into ture, barriers can be overcome to ensure alternative medicine [2] . Using religious compliance to dietary recommendations.

References

1 Gove PB (ed): Webster’s Third New In- 4 Kuhnlein HV, Recevuer O: Dietary 6 Naughton JM, O’Dea K, Sinclair A: Ani- ternational Dictionary of the English change and traditional food systems of mal foods in traditional Australian ab-

Language. Cologne, Köneman, 1993, p indigenous peoples. Ann Rev Nut 1996; original diets: polyunsaturated and low

2662. 16: 417–442. in fat. Lipids 1986; 21: 684–690. 2 Sloan RP, Bagiella E, Powell T: Religion, 5 Vorster HH, Oosthuizen W, Jerling JC, 7 Salant T, Lauderdale DS: Measuring

spirituality, and medicine. Lancet 1999; et al: The nutritional status of South culture: a critical review of acculturation

353: 664–667. Africans: a review of the literature from and health in Asian immigrant popula-

3 Hartog J, Hartog EA: Cultural aspects of 1975–1996. Chapter 5: cultural influ- tions. Soc Sci Med 2003; 57: 71–90. health and illness behavior in hospitals. ences on dietary patterns. Durban,

West J Med 1983; 139: 910–916. Health Systems Trust, 1997, pp 29–30. http://www.healthlink.org.za/hst.

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Nutrition for Disease States

Bier D, et al. (eds): Nutrition for the Primary Care Provider. World Rev Nutr Diet. Basel, Karger, 2015, vol 111, pp 87–93 DOI: 10.1159/000362304

Approach to the Patient and Differential Diagnosis

a b L. John Hoffer Bruce R. Bistrian a Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, Que. , Canada; b Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass. , USA

Key Words Introduction Protein-energy malnutrition · Micronutrient deficiency · Intestinal malabsorption · Primary care physicians encounter two general Inflammation · Weight loss · Cachexia · Starvation · kinds of malnutrition, protein-energy malnutri- Vitamins · Minerals tion (PEM) and micronutrient (vitamin and mineral) deficiency. Key Messages PEM is the disease that results from chronic starvation or severe intestinal malabsorption. • Protein-energy malnutrition (PEM) ordinarily develops after a period of prolonged inadequate protein The clinical course of PEM is strongly influenced and energy consumption. The hallmarks of PEM are by systemic inflammation and coexisting muscle generalized muscle atrophy and subcutaneous adi- atrophy due to physical inactivity, a primary neu- pose tissue depletion. romuscular disease, or old age (sarcopenia). By • Except for cachexia associated with chronic inflam- definition, starving people do not consume (or matory, end-organ, and malignant diseases, the absorb) enough food, so they are also at risk of most common cause of weight loss in adults is de- micronutrient deficiencies. pression. Chronic diseases, especially of the gastrointestinal tract, can negatively affect diet and nutri- With two important exceptions (vitamin D ent absorption. and iron), overt micronutrient deficiencies are • Assessment of the severity of PEM and of the extent rare in healthy adults whose body weight is main- of systemic inflammation is important to determine tained on a conventional diet. The development when to begin invasive feeding (either by feeding of a vitamin or mineral deficiency in such people tube or intravenously). strongly suggests the possibility of a drug-nutri- • The appearance of a vitamin or mineral deficiency in a normal adult eating a conventional diet suggests ent interaction or an as yet undiagnosed disease the possibility of a drug-nutrient interaction or an of the gastrointestinal system. Conversely, sever- undiagnosed disease of the gastrointestinal system. al chronic diseases affect diet and can impair nu- • It is important to identify the cause(s) of a diag- trient absorption. People with these diseases are nosed micronutrient deficiency in order to adminis- at risk of micronutrient deficiencies, even when ter the appropriate treatment and to address the their overall food intake is adequate and their underlying disease. © 2015 S. Karger AG, Basel body weight is normal. Table 1. Characteristics of successfully adapted PEM bolic adaptation strongly influences the clinical course and prognosis of PEM. Survival is com- Metabolic and endocrine Hypothermia mon even in prolonged uncomplicated semi- Secondary amenorrhea starvation, thanks to an adaptive reduction in Serum free thyroxin and TSH normal resting and total energy expenditure, which, to- Neurocardiovascular gether with the reduction in the body’s metabol- Sinus bradycardia ically active tissue mass, lowers energy expendi- Reduced cardiac output Hypotension ture enough to match the low rate of energy pro- Reduced sympathetic tone vision. Metabolic adaptation also increases the Muscular and functional efficiency of dietary protein assimilation, and Generalized muscle atrophy and weakness modifies endogenous protein turnover to rees- Reduced myocardial mass tablish whole body protein homeostasis despite Ineffective cough Reduced ventilatory response to hypoxia the subnormal level of protein consumption. Drug disposition Successfully adapted PEM is sometimes referred May be altered [9] to as adult ‘marasmus,’ a term borrowed from pe- Immune function diatric medicine, and more recently, as ‘starva- Weakened body barriers due to skin thinning and ineffective cough tion-related malnutrition’. The metabolic re- Reduced febrile response to infection sponse to systemic inflammatory disease, severe Normal humoral and cellular immunity in the injury or severe infection amplifies body protein absence of micronutrient deficiencies catabolism and prevents the adaptation to PEM, Psychological abnormalities Apathy creating a potentially lethal condition. The terms Anorexia ‘adult kwashiorkor’ and ‘acute disease or injury- related malnutrition’ are used to describe PEM that is induced or complicated by intense systemic inflammation. The terms ‘cachexia’ or There are differences of opinion amongst ex- ‘chronic disease-related malnutrition’ refer to perts as to the implications of subclinical defi- partially adapted PEM in the context of chronic ciencies of vitamin D, omega-3 fatty acids, folic mild systemic inflammation, as occurs in in- acid and cobalamin (vitamin B12 ) with regard to flammatory polyarthritis, advanced renal, liver, cancer and cardiovascular disease risk, and age- heart or pulmonary disease, and some cancers. related cognitive decline. PEM has a worse prognosis in the elderly, largely because their primary medical or surgical diseases tend to be more serious, and because sarco- Protein-Energy Malnutrition penia has already reduced their body protein reserve [1–5] . Also known also as ‘hunger disease’, PEM PEM and sarcopenia are not uncommon in typically develops after a period of prolonged in- obese people. The diagnosis will be missed in adequate protein and energy consumption. The these patients unless the physician specifically cardinal signs of PEM are generalized muscle at- inquires about changes in food intake and body rophy and subcutaneous adipose tissue deple- weight, and physically examines their muscles. tion. The pathologic features of PEM emerge At especially high risk are previously seriously when the body’s protein reserve, skeletal muscle, obese people who have undergone gastric restric- has become depleted seriously enough to impair tion surgery, or who have developed a serious specific physiological functions ( table 1 ). Meta- chronic medical or surgical disease that induces

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Table 2. Adapted and maladapted PEM

Feature Adapted PEM Maladapted PEM

BMI reduced normal or reduced Muscle mass reduced reduced Edema usually absent often present Body weight reduced but stable tissue loss often masked by extracellular fluid accumulation Drug disposition may be altered may be altered Immune function normal impaired Serum albumin normal reduced C-reactive protein normal increased Transthyretin reduced reduced

the cachexia syndrome. In such cases, the loss of and medical evaluation in the large grey zone muscle outstrips that of fat, and can reach a criti- that lies between adequate nutritional status and cal degree even in the presence of ample residual clinically important PEM. adipose tissue. The most useful way to diagnose PEM is in the classical medical-narrative tradition, which rec- ognizes PEM as a pathophysiological entity with Diagnosis and Assessment of Protein-Energy well-defined signs and symptoms, all of which Malnutrition are strongly modified by the patient’s primary disease, the presence or absence of systemic in- Several screening tools are available for identify- flammation, and the presence or absence of other ing people who have PEM or are at high risk of causes of muscle atrophy (table 2 ). For example, it developing it [4] . The simple and well-studied is entirely possible to have a BMI <18.5 but nor- Malnutrition Universal Screening Tool (MUST) mal health. The MUST will correctly flag such a categorizes a patient’s risk of ‘malnutrition’ (and person for evaluation, which may disclose a natu- directs the management response) as low, medi- rally lean phenotype, constant body weight and um, or high, based on a MUST score of 0, 1 or 2. normal appetite and diet. This person is healthy. The MUST score is calculated as the sum of points Conversely, severe PEM is entirely possible in a awarded by considering body mass index (BMI, person whose BMI is 30. weight/height2 ): >20, 18.5–20, or <18 (0, 1, or 2 points, respectively), history of involuntary weight loss: <5%, 5–10%, or >10% (0, 1, or 2 points, re- Importance of Identifying Protein-Energy spectively), and acute illness or no food intake for Malnutrition and Systemic Inflammation >5 days (2 points; http://www.scottishintensive- care.org.uk/nutrition/docs/must.pdf). The principal reason for identifying PEM and de- Tools such as the MUST are valuable in high termining the presence and extent of systemic inpatient flow situations for they are easy for para- flammation is to determine when invasive feed- medical staff to use and draw attention to high- ing (either by feeding tube or intravenously) is risk situations and overt cases of severe PEM. helpful, and when to commence it. Well-adapt- However, they cannot replace specific diagnosis ed, moderately severe PEM (e.g. BMI approx.

Approach to the Patient and Differential Diagnosis 89 17), as often occurs in anorexia nervosa, calls for ease commonly report abdominal bloating, but careful monitoring and a serious, well-organized they may also be asymptomatic. Coexistent iron, program to improve the patient’s energy and folic acid, vitamin D or magnesium deficiency in- protein intake by voluntary means, but it does creases the likelihood of the diagnosis. Some pa- not represent a medical emergency that requires tients present to their physician with osteomala- invasive feeding, except when weight loss is con- cia or premature osteoporosis due to chronic vi- tinuing, electrolyte disturbances occur, and the tamin D malabsorption. potential for cardiac dysfunction is serious. By Only rarely is an undiagnosed malignancy the contrast, critically ill patients with severe closed cause of weight loss in the absence of symptoms head injury, major third-degree body burns, se- or signs that point to serious disease, and espe- vere sepsis, pancreatitis or multiple injury syn- cially if the complete blood count is normal. Re- dromes require invasive nutritional support nal cell cancer, painless cancer of the pancreas, within the first 48 h even if they are well nour- and some types of lung cancer may present with ished for this therapy can improve their outcome serious constitutional symptoms and weight loss, by modulating systemic inflammation and miti- but these rare diagnoses can usually be excluded gating body protein loss. When PEM is absent or by means of a careful physical examination, chest only mild, and systemic inflammation is only radiograph, urinalysis, and routine blood tests. moderate (as occurs after uncomplicated major The diagnosis of adrenocortical insufficiency abdominal surgery, mild systemic infections, and should always be considered when a patient pres- in chronic inflammatory conditions), invasive ents with weight loss, fatigue, postural hypo- nutritional support can often be withheld for up tension, and nonspecific gastrointestinal symp- to one week, as long as the resumption of normal toms [5] . food intake is anticipated in the near future. Pa- Except for cachexia associated with chronic tients with inflammatory disease and already ex- inflammatory, end-organ, and malignant dis- isting moderate or severe PEM require earlier in- eases, the commonest cause of weight loss in tervention [6] . adults is depression. Weight loss and depression are often exacerbated by social, economic and mechanical difficulties such as reduced mobility Evaluation of Involuntary Weight Loss and impaired physical or sensory function, chewing or swallowing disorders, or ill-fitting Any patient who reports sustained involuntary dentures. Concurrent thiamine, folic acid, vita- weight loss requires careful evaluation. The eval- min D or vitamin C deficiency can worsen the uation should start by measuring body height and mood disturbance of a depressed person and weight and seeking objective evidence that weight further reduce their food intake in a vicious cy- loss actually has occurred, and its extent. The cle. People suffering from dementia often dem- most important question to ask early in the evalu- onstrate a disinclination to eat much food when ation of such patients is whether their appetite their disease reaches the far-advanced stage. Be- and overall food intake are normal or decreased. cause they have adapted PEM, these people actu- Normal appetite and food intake in someone with ally require relatively little food. As long as their important involuntary weight loss strongly sug- subnormal body weight remains relatively con- gests the possibility of uncontrolled diabetes mel- stant, there is no medical indication for invasive litus, hyperthyroidism or malabsorption, and evi- feeding. There is no good evidence that forced dence to support or refute these diagnoses should feeding improves either the length or quality of be obtained. Patients with undiagnosed celiac dis- life at this stage of dementia, and some evidence

90 Hoffer /Bistrian

Table 3. Important drug- and diet-nutrient interactions

Anticonvulsant drugs increased catabolism of folic acid, vitamin D, and possibly thiamine Methotrexate impaired folic acid utilization High-dose loop diuretics increased urinary thiamine excretion Proton pump inhibitors iron, folic acid and cobalamin malabsorption Metformin impaired cobalamin absorption Aminoglycoside antibiotics urinary magnesium wasting Systemic glucocorticoid therapy blocked vitamin D action Certain cancer chemotherapeutic agents magnesium, zinc deficiency Excessive alcohol consumption B vitamin malabsorption, urinary magnesium wasting Cigarette smoking increased vitamin C catabolism Excessive consumption of tea, coffee or betel nuts thiamine malabsorption Grapefruit juice inhibits intestinal CYP3A4, slowing metabolism of many commonly used drugs including (but not limited to) amiodarone, amlopidine, atorvastatin, budesonide, buspirone, carbamazepine, cisapride, cyclosporine, felodipine, lapatinib, lovastatin, nicardipine, nifedipine, nilotinib, simvastatin, sirolimus, tacrolimus, triazolam, and verapamil [10] Vegan diet inadequate cobalamin and zinc Vegetable- and fruit-deficient diet inadequate vitamin C, folic acid and carotenoid Low-fat diet reduced digestion and absorption of vitamins D and E Protein-deficient diet inadequate B vitamins and zinc Seafood-free diet inadequate long-chain omega-3 fatty acids Sunlight avoidance vitamin D deficiency

that it worsens both of them [7] . On the other due to folic acid or cobalamin (vitamin B 12 ) defi- hand, simple micronutrient supplementation is ciency. These topics are covered in detail else- safe and rational in this setting since the para- where in this textbook. mount consideration at this time is quality of life, and several micronutrient deficiencies adversely affect mood. Glossitis

Atrophic glossitis – a reddened tongue that is Micronutrient Deficiencies smooth in appearance because of atrophy of the filiform papillae – is a nonspecific inflammatory The important micronutrient deficiencies are ex- condition that is associated with iron, folic acid, plained in detail in other chapters in this text- cobalamin, niacin, or riboflavin deficiency. book. This section provides a short list of practical tips and an overall diagnostic strategy for evaluating vitamin and mineral deficiencies. Drug- and Diet-Nutrient Interactions

Several widely used drugs affect micronutrient Nutritional Anemias metabolism or excretion and can cause micronutrient deficiency. Certain general dietary patterns The nutritional anemias comprise microcytic are associated with an increased risk of specific anemia (due to iron, and more rarely copper de- micronutrient deficiencies. Examples of such in- ficiency) and macrocytic megaloblastic anemia teractions are provided in table 3 .

Approach to the Patient and Differential Diagnosis 91 When Should a Micronutrient Deficiency Be malabsorb the fat-soluble vitamins (vitamins A, Investigated or Searched For? D, E and K) even when receiving appropriate pancreatic enzyme replacement. Patients with In a classic article, Victor Herbert explained the 5 generalized malabsorption (celiac disease or possible causes of any micronutrient deficiency: Crohn’s disease involving the small intestine) inadequate intake, impaired intestinal absorp- malabsorb most micronutrients, especially vita- tion, impaired metabolic utilization, increased min A, certain B vitamins (including cobala- excretion or catabolism, and increased metabolic min), magnesium and zinc. Even a mild reduc- requirement [8]. Herbert’s scheme can be used to tion in the consumption of these micronutrients formulate two general dictums regarding micro- places these patients at high risk of the corre- nutrients: sponding deficiency diseases. People who have Rule 1: When a micronutrient deficiency is di- undergone a subtotal or total gastrectomy (in- agnosed but only one cause is apparent, search for cluding gastric restriction surgery for obesity) the second cause. usually require lifelong supplementation with Rule 2: When a patient has (or is at risk of) two iron, folic acid, and cobalamin. Patients with independent causes of a micronutrient deficien- chronic or severe inflammatory diarrhea require cy, it is appropriate to prescribe a suitable supple- zinc supplementation to replace their fecal zinc ment, test for the pertinent biochemical deficien- losses. cy, or both. For example, women with a normal men- strual cycle and inadequate iron intake are fre- Conclusions quently iron deficient, but no investigation is usually required since two causes are apparent. • The hallmarks of PEM are generalized muscle Iron deficiency in a man or nonmenstruating atrophy and usually, but not always, subcuta- woman requires a search for the second cause neous adipose tissue depletion. (gastrointestinal bleeding, parasitic infection, • The severity of PEM, intensity of systemic in- or celiac disease). A patient with folic acid defi- flammation, and inability to voluntarily meet ciency and a history of poor diet and chronic nutrient needs determine when artificial nu- hemolytic anemia (which increases folic acid tritional support is required. utilization), or poor diet and treatment with • The cause of involuntary weight loss can al- methotrexate or phenytoin (impaired utiliza- most always be identified from a careful his- tion and increased catabolism, respectively) tory, physical examination, and routine tests requires correction of the deficiency but no as explained in this chapter. further investigation since two causes are ap- • The appearance of a vitamin or mineral defi- parent. On the other hand, a patient with iso- ciency in a normal adult eating a conventional lated folic acid deficiency should be evaluated diet requires an explanation. The diagnosis for a drug-nutrient interaction (including alco- can usually be made using the rules described hol abuse), malabsorption, or hemolytic ane- in this chapter. mia. Given the high prevalence of vitamin D • Patients with diseases that increase their risk deficiency in the general population, any per- of specific vitamin or mineral deficiencies son prescribed phenytoin requires vitamin D should be assessed with regard to these defi- supplementation ( table 3 ). ciencies and prescribed preventive supple- Patients with fat maldigestion (pancreatic in- ments. sufficiency, biliary cirrhosis, or cystic fibrosis)

92 Hoffer /Bistrian

References

1 Hoffer LJ: Clinical nutrition: protein- 4 Barker LA, Gout BS, Crowe TC: Hospital 7 Hoffer LJ: Tube feeding in advanced energy malnutrition in the inpatient. malnutrition: prevalence, identification dementia: the metabolic perspective.

CMAJ 2001; 165: 1345–1349. and impact on patients and the health- BMJ 2006; 333: 1214–1215. 2 Jensen GL, Mirtallo J, Compher C, et al: care system. Int J Environ Res Public 8 Herbert V: The five possible causes of all

Adult starvation and disease-related Health 2011; 8: 514–527. nutrient deficiency: illustrated by defi- malnutrition: a proposal for etiology- 5 Bistrian BR: Nutritional assessment; in ciencies of vitamin B12. Am J Clin Nutr

based diagnosis in the clinical practice Goldman L, Schafer AI (eds): Goldman’s 1973; 26: 77–86. setting from the International Consen- Cecil Medicine. Philadelphia, Elsevier 9 Boullata JI: Drug disposition in obesity sus Guideline Committee. JPEN J Par- Saunders, 2012, pp 1384–1388. and protein-energy malnutrition. Proc

enter Enteral Nutr 2010; 34: 156–159. 6 Raynaud-Simon A, Revel-Delhom C, Nutr Soc 2010; 69: 543–550. 3 Macallan D: Infection and malnutrition. Hebuterne X, et al: Clinical practice 10 Seden K, Dickinson L, Khoo S, Back D:

Medicine 2009; 37: 525–528. guidelines from the French Health High Grapefruit-drug interactions. Drugs

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Approach to the Patient and Differential Diagnosis 93 Nutrition for Disease States

Bier D, et al. (eds): Nutrition for the Primary Care Provider. World Rev Nutr Diet. Basel, Karger, 2015, vol 111, pp 94–99 DOI: 10.1159/000362305

Cardiovascular Disease

Ulf Risérus

Clinical Nutrition and Metabolism, Department of Public Health and Caring Sciences, Faculty of Medicine, Uppsala University, Uppsala , Sweden

Key Words • Improvement of dietary habits can have beneficial effects on most CVD risk factors, including hyperlip- Cardiovascular disease · Dietary patterns · idemia, hyperglycemia and elevated blood pres- LDL cholesterol · HDL cholesterol · Triglycerides · sure. Modification of dietary habits is a key inter- Blood glucose vention for reducing CVD-related mortality. © 2015 S. Karger AG, Basel

Key Messages • The risk factors that drive cardiovascular disease Introduction (CVD) such as elevated LDL cholesterol and dyslipidemia, hypertension and impaired glucose tolerance, The global burden of cardiovascular disease are largely influenced by diet and lifestyle habits. (CVD) is huge as it causes substantial mortality • Prudent dietary patterns that can reduce CVD in- and morbidity in both developed and nondevel- clude the Mediterranean diet, the Dietary Ap- proaches to Stop Hypertension diet, and other sim- oped countries [1, 2] . CVD is the leading cause of ilar diets rich in fruits, vegetables, nuts, low-fat death in most developed countries, representing dairy, and plant oils. 30% of all global deaths [1]. Notably, most of • The type of fat, rather than the total amount of fat these cases could be prevented or postponed by in the diet, appears to be most important for pre- lifestyle intervention [2, 3]. Together with smok- vention and management of CVD. The majority of ing and sedentary lifestyle, an excess caloric in- dietary fat should be unsaturated and derive from take and poor dietary quality are responsible for plant sources and fish. • Similarly, favoring whole grains, fiber-rich cereals the majority of CVD deaths. An ‘unhealthy’ diet, and raw fruits and vegetables above highly refined/ i.e. a diet far from that currently recommended by processed carbohydrates has favorable cardiomet- international health organizations, has been esti- abolic effects, including lowered postprandial glu- mated to account for approximately 30% of all cose and insulin fluctuations, and lowered serum acute myocardial infarctions [3] . Importantly, re- triglycerides. alistic dietary changes can reduce mortality rates Table 1. Effects of recommended key foods on CVD risk factors

Foods to increase Key nutrients(s) Risk factor effects

Fruits and fiber, vitamins/minerals, phenols ↓ LDL-C, ↓ BP, ↑ glycemic control, vegetables ↓ oxidative stress Whole grains fiber, B vitamins, minerals ↓ LDL-C, ↓ BP, ↑ glycemic control Low-fat dairy calcium, vitamin D, potassium ↓ BP Legumes, soy fiber, sterols, isoflavones ↓ LDL-C, ↑ HDL-C Nuts, seeds unsaturated fatty acids (omega-6 and -3), sterols ↓ LDL-C, ↓ oxidative stress, ↑ HDL-C Seafood unsaturated fatty acids (omega-3) ↓ TG, ↓ BP, ↓ heart rate, ↓ LDL-C, ↓ arrhythmic effect, ↓ inflammation Vegetable oils unsaturated fatty acids (omega-6 and -3) ↓LDL-C

Adapted and slightly modified from Flock and Kris-Etherton [5]. BP = Blood pressure; TG = triglycerides; LDL-C = LDL cholesterol; HDL-C = HDL cholesterol.

substantially [1, 2, 4, 5]. Apart from patients with tant. For example, long-chain n-3 fatty acids in diagnosed CVD, patients with type 2 diabetes and fish have been suggested to have anti-arrhythmic the metabolic syndrome are at high risk of CVD effects, whereas plant-derived n-6 long-chain fat- and can benefit from dietary intervention. ty acids lower serum LDL cholesterol. Conse- quently, fatty acids of both marine and vegetable origin should be included in a healthy diet to pre- Pathophysiology vent CVD [2, 5]. Other dietary components could influence CVD risk by other mechanisms, e.g. re- Atherosclerosis is a key driver of CVD, and the ducing salt lowers blood pressure, and whole- process is accelerated by modifiable risk CVD grain foods rich in fiber improve blood lipids, and factors such as elevated LDL cholesterol and dys- may possibly lower low-grade inflammation and lipidemia, hypertension, impaired glucose toler- endothelial dysfunction. ance and insulin resistance, endothelial dysfunction, inflammation and oxidative stress. In com- pliant patients, diet has favorable effects on most Changing Dietary Risk Patterns CVD risk factors, especially hyperlipidemia, hyperglycemia and elevated blood pressure ( ta- High adherence to dietary patterns such as the ble 1 ). Successful secondary prevention of CVD ‘Western diet’ has been consistently associated by dietary interventions such as the Mediterra- with CVD in various populations [3, 6] . Such di- nean diet may result in reduced coronary athero- etary patterns include foods high in animal fats, sclerosis/thrombosis and reduced risk of fatal salt, red meats, added sugars, fried and processed complications such as sudden cardiac death and foods, but are low in fruits, vegetables and fish. It heart failure [4] . It is still uncertain which dietary is important to identify and interrupt such haz- components are responsible for the reduced CVD ardous dietary habits in CVD patients as well as risk as the multifactorial effect is probably impor- in individuals at high CVD risk. In both these

Cardiovascular Disease 95 groups, dietary change should be a major target processed meats, salty fast foods, bakery, sweets, for intervention in order to prevent CVD. To ob- refined carbohydrates and added sugars. These tain optimal effect on CVD risk, the aim should diets are suitable both for prevention and treat- always be to improve the overall dietary pattern ment of CVD. However, to achieve an optimal [7] , although small changes may also have a sig- effect of treatment, dietary intervention of CVD nificant impact. Meaningful dietary changes in- may be slightly individualized based on the CVD clude several substitutions, e.g. replacing fried risk profile, pathophysiology and lifestyle habits foods with nonfried foods, limiting sugar-sweet- of the patients. For example, in a patient with ened beverages (soft drinks and fruit juices), in- obesity, type 2 diabetes or the metabolic syn- creasing fruits and vegetables and replacing but- drome, energy reduction in the diet should be ter with vegetable oils and soft margarines (free of specifically targeted to induce weight loss [9] . In trans-fatty acids) and replacing white bread with clinical practice, it is usually not meaningful, nor whole-grain bread high in fiber and preferably in- is there any advantage in the implementation of cluding some whole kernels. dietary recommendations, to discuss relative proportions of macronutrients in a prescribed diet. Instead, practical advice on cooking, food Healthy Diet for Prevention and Treatment of preparation and healthy food choices should be CVD exemplified and advocated to the patients [2, 7] ( table 2 ). In contrast to the Westernized dietary pattern associated with adverse CVD outcomes, there are food patterns consistently associated with re- Diet and Blood Lipids duced CVD [3, 6, 7]. Data from observational studies and randomized trials suggest that di- In addition to blood pressure-lowering effects etary changes reduce CVD risk factors as well as from avoidance of salty foods ( table 2 ), hyperlip- reduce the risk of recurrent myocardial infarc- idemia is common and highly responsive to di- tion in secondary prevention trials [4, 8] . Dietary etary changes and is thus a relevant target [10] . patterns that can reduce CVD and/or secondary Total cholesterol, LDL cholesterol and triglycer- prevention of CVD include the Mediterranean ides are risk factors closely linked to CVD, and at diet, the Dietary Approaches to Stop Hyperten- elevated concentrations they should be treated sion (DASH) diet and other similar diets and with dietary modification alone or in conjunction food patterns currently recommended world- with lipid-lowering drugs if indicated [10] . wide by health organizations and authorities [1– In patients with elevated LDL cholesterol, an 3, 6, 7] . The DASH diet is rich in fruits, vegeta- increased fiber intake and increased intake of un- bles, low-fat dairy, and reduced in saturated fats saturated fats from vegetable oils and nuts are rel- and cholesterol. The dietary composition of the evant interventions [5, 7, 10] ( table 2 ). For exam- Mediterranean diet and DASH is very similar, ple, replacing butter and high-fat dairy with but the Mediterranean diet may be somewhat canola oil or other vegetable oils, alone may de- higher in unsaturated fat from vegetable oils and crease plasma LDL cholesterol as well as the total fish. Thus, these recommended diets are very cholesterol to HDL cholesterol ratio by 10–20% in similar in terms of the dietary pattern and food a few weeks. Notably, such lipid-lowering effects composition, and they all include a high intake of can be achieved without weight loss. Table 1 sum- fruits, vegetables, legumes, vegetable oils, fish, marizes the effects of different dietary compo- low-fat milk products, but a low intake of red and nents on blood lipids and other risk factors.

96 Risérus

Role of Dietary Fats Table 2. Healthy food choices and preparation

Eat fresh and frozen vegetables and fruits without The type of fat, rather than the total amount of high-calorie sauces and added salt and sugars fat in the diet, appears to be most important for prevention as well as for the management of Replace high-calorie foods with fruits and vegetables CVD [2] . Partial replacement of saturated fats Increase fiber intake by eating beans (legumes), from animal products with unsaturated fats whole-grain products, fruits, and vegetables from nontropical vegetable oils could alone Use liquid vegetable oils (e.g. canola oil, olive oil, have a small but clinically meaningful cardio- sunflower oil) or soft margarines in place of solid fats protective effect [2, 5, 7]. Such benefit has been such as butter mainly ascribed to reduced LDL cholesterol. Limit beverages and foods high in added sugars; Other potential beneficial effects of dietary fat common forms of added sugars are sucrose, glucose, fructose, maltose, dextrose, corn syrups, concentrated modification have also been reported on blood fruit juice, and honey pressure, insulin resistance, hepatic steatosis, Choose foods made with whole grains rather than and inflammation, but those data are less con- refined cereals; common forms of whole grains are clusive. It should be noted that in order to whole wheat, oats/oatmeal, rye, barley, corn, brown achieve a clinical benefit of saturated fat reduc- rice, wild rice, buckwheat, triticale, bulgur (cracked tion, it is important that foods rich in saturated wheat), millet, and quinoa fat (e.g. butter and processed meats) are re- Cut back on pastries and high-calorie bakery products placed with foods rich in polyunsaturated fat (e.g. muffins, buns, cookies, doughnuts) and/or fiber-rich unrefined carbohydrates [2] . Mainly select milk and dairy products that are low in fat If saturated fat instead is replaced by refined Reduce salt intake by comparing the sodium contents carbohydrates or added sugars, the benefit of re- of similar products (e.g. different brands of tomato ducing saturated fat may be abolished or even sauce and choosing products with less salt (e.g. reversed. Regardless of the amount of total fat unsalted nuts) and carbohydrates in any given diet, the major- Choose versions of processed foods, including cereals ity of the fat should be unsaturated from plant and baked goods, that are reduced in salt sources (e.g. vegetable oils, nuts and seeds) and Limit the use of condiments (e.g. soy sauce, ketchup) fish. If the majority (approx. two thirds) of fat in Use lean cuts of meat and remove skin from poultry a diet is unsaturated, cardiometabolic benefits before eating can be observed also at total fat intakes above Limit processed meats that are high in saturated fat and that usually recommended. Rapeseed (canola) sodium oil and olive oil are oils that can be used fre- Grill, bake, or boil fish, meat, and poultry quently in dressings, cooking and baking, but other oils e.g. soybean oil and sunflower oil can Incorporate vegetable-based meat substitutes (e.g. also be used in diets with a regular intake of fat- beans and lentils) into favorite recipes ty fish. Omega-3 supplements (fish oil capsules) Encourage the consumption of whole vegetables and have been suggested to have cardioprotective fruits in place of juices effects in secondary prevention of CVD, al- Adapted and slightly modified with kind permission though the evidence is not consistent. The most from Springer Science+Business Media from Gidding et established metabolic effect of daily fish oil sup- al. [7]. plementation is lowering of serum triglycerides (approx. 5–25% reduction). Patients should however primarily be advised to consume fish

Cardiovascular Disease 97 2–3 times per week rather than taking omega-3 processed or red meat). Thus, to avoid potential supplements. The latter may be an alternative long-term adverse effects on CVD risk (e.g. me- for patients with myocardial infarction and/or diated by elevation of LDL cholesterol or endo- high triglyceride levels, especially for those who thelial function by high amounts of saturated or do not eat fish for various reasons. total fat), diets that are lower in carbohydrates but higher in protein and fat should consist of similar healthy foods as those recommended in Role of Carbohydrates any diet ( table 2 ).

Not only the type of fat, but also the type of carbohydrates plays a clear role in the management Conclusions of CVD. Refined carbohydrates and foods high in added sugars could elevate both triglycerides • Dietary goals in CVD prevention and treat- and LDL cholesterol, and lower HDL cholester- ment are to consume an overall healthy diet. ol. They also cause more elevated blood glucose • Aim for a healthy body weight; aim for rec- and insulin levels after ingestion as compared to ommended levels of LDL cholesterol, HDL nonrefined carbohydrates with lower glycemic cholesterol, and triglycerides; aim for normal index. With regard to carbohydrate-rich foods, blood pressure and blood glucose level. a dietary substitution of whole grains, fiber- • Prescribe more fruits, vegetables, legumes rich cereals and raw fruits and vegetables for (beans and lentils), whole grains, fish (2–3 highly refined/processed carbohydrates (e.g. times per week) and shellfish, unsalted nuts, white bread) and starches could have multiple dairy products (mainly low-fat), lean meats favorable cardiometabolic effects including low- (preferably poultry), vegetable oils and soft ered postprandial glucose and insulin excur- margarines (free of trans-fats). sions and lowered serum triglycerides ( table 1 ). • This advice is appropriate in patients with- Low-fat/high carbohydrate diets have been out as well as in patients with CVD. widely recommended for weight loss, but reduc- • Limit fats and oils containing partially hy- ing the total amount of carbohydrates could be drogenated vegetable oils (e.g. sweets, fast an alternative dietary approach to reduce total food, processed foods), red meats and espe- energy intake, resulting in weight loss and low- cially processed meats (e.g. sausages, bacon), ered CVD risk factors. A moderate decrease in sugar-sweetened beverages, sweets, grain- carbohydrate amount (down to about 30–40 en- based desserts and bakery products. ergy percent) has been examined in clinical stud- • Moderate weight loss also reduces CVD risk ies with longer duration, and such diets produce factors of clinical significance. Reduce ener- similar weight loss and overall CVD risk reduc- gy-dense foods high in fat, refined carbohy- tion as conventional low-fat diets. Importantly, drates and added sugars (e.g. fried foods such if a low-carbohydrate diet is to be used in obese as potato chips and French fries). patients to induce weight loss, it should be em- • A healthier eating pattern should always be phasized that the diet should be rich in unsatu- given together with advice on how to in- rated fats rather than high in saturated fats (e.g. crease physical activity and, if relevant, stop vegetable oils, avocado, nuts and fish instead of smoking. butter and processed meat products) as well as protein from vegetable sources rather than solely from animals (e.g. lentils and beans instead of

98 Risérus

References

1 Mendis S, Puska P, Norrving B (eds): 6 Mente A, de Koning L, Shannon HS, 8 Esposito K, Marfella R, Ciotola M, et al: Global Atlas on Cardiovascular Disease Anand SS: A systematic review of the Effect of a Mediterranean-style diet on Prevention and Control. Geneva, WHO, evidence supporting a causal link be- endothelial dysfunction and markers of 2011. tween dietary factors and coronary heart vascular inflammation in the metabolic

2 Mozaffarian D, Appel LJ, Van Horn L: disease. Arch Intern Med 2009; 169: 659– syndrome: a randomized trial. JAMA

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new insights. Circulation 2011; 123: 7 Gidding SS, Lichtenstein AH, Faith MS, 9 Mann JI: Nutrition recommendations 2870–2891. et al: Implementing American Heart for the treatment and prevention of type 3 Iqbal R, Anand S, Ounpuu S, et al: Di- Association pediatric and adult nutri- 2 diabetes and the metabolic syndrome: etary patterns and the risk of acute myo- tion guidelines: a scientific statement an evidenced-based review. Nutr Rev

cardial infarction in 52 countries: results from the American Heart Association 2006; 64: 422–427. of the INTERHEART study. Circulation Nutrition Committee of the Council on 10 Reiner Z, Catapano AL, De Backer G, et

2008; 118: 1929–1937. Nutrition, Physical Activity and Metab- al: ESC/EAS Guidelines for the manage- 4 de Lorgeril M, Salen P: Mediterranean olism, Council on Cardiovascular Dis- ment of dyslipidaemias. The Task Force diet in secondary prevention of CHD. ease in the Young, Council on Arterio- for the management of dyslipidaemias

Public Health Nutr 2011; 14: 2333–2337. sclerosis, Thrombosis and Vascular of the European Society of Cardiology 5 Flock MR, Kris-Etherton PM: Dietary Biology, Council on Cardiovascular (ESC) and the European Atherosclerosis

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Cardiovascular Disease 99 Nutrition for Disease States

Bier D, et al. (eds): Nutrition for the Primary Care Provider. World Rev Nutr Diet. Basel, Karger, 2015, vol 111, pp 100–103 DOI: 10.1159/000362306

Hypertension

Rachael M. McLean

Departments of Preventive and Social Medicine and Human Nutrition, University of Otago, Dunedin , New Zealand

Key Words sponsible for 7.5 million (or 12.8%) of deaths [1] . Blood pressure · Hypertension · Sodium · Potassium · Observational studies of over one million adults Body weight · Physical activity · Alcohol show that systolic blood pressures above 115 mm Hg and diastolic blood pressures above 75 mm Hg are associated with increasing risk of coronary Key Messages heart disease and stroke. In most populations, • High blood pressure is a leading cause of death blood pressure rises with increasing age, with worldwide. more than half of adults ≥ 60 years of age reported • Nutritional and other lifestyle interventions can to have high blood pressure in high-income coun- have beneficial effects on blood pressure and car- tries [2] . The American Heart Association classi- diovascular disease risk. • Lowering blood pressure is beneficial even in pa- fication of blood pressure for adults is outlined in tients not generally considered to be hypertensive. table 1 . Given the continuous relationship be- • The optimal nutritional approach to blood pressure tween increasing levels of blood pressure and risk control is a dietary pattern low in sodium, high in of cardiovascular disease, the cutoff values given fresh fruit and vegetables and low-fat dairy prod- in table 1 are inevitably arbitrary. Any individu- ucts, and low in saturated fats. al’s blood pressure is determined by a combina- • Maintaining a healthy body weight and limiting alcohol intake are also important for blood pressure tion of genetic and environmental influences. control. © 2015 S. Karger AG, Basel Nutritional factors are some of the most important environmental influences, although individual responses to specific dietary changes will vary.

Introduction Nutritional Determinants of Blood Pressure High blood pressure, an important modifiable risk factor for cardiovascular and kidney disease, Sodium has been identified as the leading cause of death There is conclusive evidence from a range of stud- worldwide. The World Health Organization esti- ies of a positive association between dietary so- mated that in 2004 high blood pressure was re- dium intake and blood pressure. In the 1980s, the Table 1. Classification of blood pressure for adults: Joint dium for adults, with a more restricted intake in National Committee on Prevention, Detection, Evalua- those at high risk of cardiovascular disease, i.e. tion, and Treatment of High Blood Pressure [12] 1,500 mg for middle-aged or older adults, Afri- Blood pressure classification SBP, mm Hg DBP, mm Hg can-Americans, and those who have hypertension, diabetes or chronic kidney disease [6] . This Normal <120 and <80

Prehypertension 120 – 139 or 80 – 89 represents an appreciable reduction for popula-

Stage 1 hypertension or 90 – 99 140 – 159 tions consuming a typical Western style diet in Stage 2 hypertension ≥160 or ≥100 which intakes are usually around 3,500 mg/day. SBP = Systolic blood pressure; DBP = diastolic blood pressure. In such diets, 90% of dietary sodium is consumed as salt (sodium chloride). Most (75–80%) is consumed as sodium within processed foods, with only around 10% added in the home in cooking or INTERSALT study of 52 populations in 32 coun- at the table [7] . Attempts to reduce dietary sodium tries demonstrated that a high-sodium diet was in populations at large as well as in individuals associated with higher blood pressure levels. need to involve not only limiting the use of salt INTERSALT also demonstrated that in popula- and salty snacks in the home, but limiting the in- tions that typically consume a low-sodium diet gestion of processed foods known to contribute to there was no rise in blood pressure with age, sug- sodium intake such as bread, processed meats, gesting there is an adverse effect of long-term ex- and processed soups and sauces. This requires posure to a high-sodium diet. Intervention stud- better interpretation of sodium concentration in- ies have shown that reduction in dietary sodium formation on food labels, and industry reformula- results in significantly reduced blood pressure. tion of processed foods to contain less sodium. Such changes in blood pressure can take up to 30 Dietary sodium reduction at a population level is days to develop, but if sustained lead to long-term regarded as one of the most important public reductions in cardiovascular disease outcomes [3, health nutrition approaches to reduce the risk of 4] . A Cochrane systematic review and meta-anal- cardiovascular disease. Reducing dietary sodium ysis showed that a reduction of dietary sodium has the potential to reduce blood pressure further intake of around 1,700 mg/day would lead to an even in people on blood pressure-lowering drugs. average reduction in blood pressure of 5/3 mm Hg (systolic/diastolic) for hypertensive and 2/1 P o t a s s i u m mm Hg for normotensive adults. This might be The INTERSALT study also demonstrated a neg- expected to translate into reductions in mortality ative association between dietary potassium and from stroke of up to 24%, and from coronary blood pressure, and further studies have suggest- heart disease of up to 18% [5] . Some population ed a potential interaction between dietary sodium groups (such as African-Americans) appear to be and potassium and blood pressure. A meta-anal- more salt sensitive than others with larger chang- ysis of trials of potassium supplementation es in blood pressure in response to changes in di- showed that potassium supplementation to a etary sodium intake; however, there are no wide- mean intake of 4.7 g/day (120 mmol/day) resulted ly accepted criteria for identifying salt-sensitive in a mean reduction in systolic blood pressure of individuals. 3/2 mm Hg, with greater reductions in blood Few populations are able to achieve dietary so- pressure shown in those individuals on a high- dium intakes consistent with dietary guidelines. sodium diet [8] . Although these trials used potas- The United States Department of Agriculture rec- sium supplements, it is generally recommended ommends maximum daily intake of 2,300 mg so- that potassium intake be increased through di-

Hypertension 101 Table 2. Diet-related lifestyle recommendations to lower control diet [3]. Several components of the DASH blood pressure diet have the potential to beneficially influence Lifestyle Recommendation blood pressure, but the combined effect justifies modification the recommendation of this dietary pattern.

Body weight aim for a normal BMI (18.5 – 24.9) Body Weight Reduced limit dietary sodium intake to a As body weight increases, blood pressure increas- sodium maximum of 2,300 mg/day for adults, es. A meta-analysis of intervention trials showed intake aiming for a maximum of 1,500 mg/day that in overweight and obese people, a weight loss for high-risk individuals (equivalent to approximately 6 and 4 g of salt, of 5.1 kg was associated with a decrease in blood respectively) pressure of 4/4 mm Hg [10] . Weight loss interventions that involved decreased energy intake DASH-style adopt a DASH-style diet: high in fresh decreased blood pressure even when dietary so- dietary fruit and vegetables (8 – 10 servings per pattern day), high in dietary fiber and low-fat dium intake remained constant. Maintaining dairy products, and low in saturated fats body mass index (BMI) within the normal range Moderation limit alcohol intake to no more than 1 (between 18.5 and 25) is regarded as a further im- of alcohol standard drink per day for women or 2 portant recommendation for helping to optimize intake standard drinks for men blood pressure.

Alcohol Observational studies and intervention trials etary change; consuming 8–10 servings of fruit show a positive association between blood pres- and vegetables daily is recommended [9] . This sure and alcohol intake above 3 standard drinks way, individuals will obtain the added nutritional per day. A meta-analysis of intervention trials in benefit of dietary fiber, and minimize any poten- those consuming alcohol showed that a reduction tial adverse effects of potassium supplementation of alcohol consumption to below this level is as- in people with impaired renal function. sociated with a mean reduction in blood pressure of 3/2 mm Hg [11] . The Dietary Approaches to Stop Hypertension Diet The Dietary Approaches to Stop Hypertension Other Lifestyle-Related Factors (DASH) Trial provides the best evidence of a suc- Increased physical activity has been shown to be cessful nutritional intervention to reduce blood associated with some reduction in blood pressure, pressure. This randomized controlled trial independent of body weight or weight loss. A num- showed that a diet high in fresh fruit and vegeta- ber of other individual dietary factors have been bles, dietary fiber, low-fat dairy products and low identified as having a possible beneficial effect on in saturated fat (the DASH diet) was associated blood pressure, although in general the evidence is with a significant decrease in blood pressure, not strong enough to be included in current rec- compared with a ‘typical American diet’ even ommendations. These include vitamin C supple- when daily sodium intake was similar in the two mentation, increased calcium intake, increased diets. When dietary sodium intake was altered, magnesium intake and limiting consumption of the low-sodium DASH diet was associated with a caffeine and sugar-sweetened beverages. The best further reduction in mean blood pressure. Over- evidence remains to support an overall dietary ap- all reduction in systolic/diastolic blood pressure proach, that of a low-sodium DASH-style dietary was 9/5 mm Hg compared with the high-sodium intervention, including advice to optimize BMI.

102 McLean

Recommendations Conclusions

Based on the available evidence, the optimal nu- • Nutritional approaches for the prevention and tritional approach to controlling blood pressure management of elevated blood pressure pro- is to: vide important opportunities to: (1) Limit dietary sodium intake to a maximum – Decrease blood pressure (and therefore car- of 2,300 mg/day for adults, aiming for a diovascular disease risk) in people with maximum of 1,500 mg/day for high-risk in- blood pressure greater than 115/75 mm Hg dividuals. but not considered to require medication. (2) Adopt a DASH-style diet: high in fresh fruit – Delay or prevent the usual rise in blood pres- and vegetables (8–10 servings per day), sure with increasing age. high in dietary fiber and low-fat dairy – Further decrease blood pressure in people products, and low in saturated fats. on antihypertensive medication and mini- (3) Maintain a healthy body weight. mize the need for multiple antihypertensive (4) Limit alcohol intake to no more than 1 medications. standard drink per day for women or 2 • The optimal nutritional approach to blood standard drinks for men. pressure control is to consume a low-sodium These recommendations are outlined in DASH-style diet, maintain a healthy body table 2 . weight, and limit alcohol intake.

References

1 WHO: Global health risks: mortality and 5 He FJ, Li J, MacGregor GA: Effect of lon- 8 Whelton PK, He J, Cutler JA, et al: Ef- burden of disease attributable to select- ger term modest salt reduction on blood fects of oral potassium on blood pres-

ed major risks. Geneva, WHO, 2009. pressure: Cochrane systematic review sure. JAMA 1997; 277: 1624–1632. 2 Kearney PM, Whelton M, Reynolds K, et and meta-analysis of randomised trials. 9 Appel LJ: ASH position paper: dietary

al: Global burden of hypertension: anal- BMJ 2013; 346:f1325. approaches to lower blood pressure. J

ysis of worldwide data. Lancet 2005; 365: 6 US Department of Health and Human Clin Hypertens 2009; 11: 358–368. 217–223. Services and US Department of Agricul- 10 Neter JE, Stam BE, Kok FJ, et al: Influ- 3 Sacks FM, Svetkey LP, Vollmer WM, et ture: Dietary Guidelines for Americans, ence of weight reduction on blood pres-

al: Effects on blood pressure of reduced 2010. Washington, US Department of sure. Hypertension 2003; 42: 878–884. dietary sodium and the Dietary Ap- Agriculture, 2010. 11 Xin X, He J, Frontini MG, et al: Effects of proaches to Stop Hypertension (DASH) 7 Medical Research Council Human Nu- alcohol reduction on blood pressure.

diet. N Engl J Med 2001; 344: 3–10. trition Research: Why 6g? A summary Hypertension 2001; 38: 1112–1117. 4 Cook NR, Cutler JA, Obarzanek E, al: of the scientific evidence for the salt in- 12 Chobanian AV, Bakris GL, Black HR, et Long term effects of dietary sodium re- take target. Cambridge, Medical Re- al: Seventh report of the Joint National duction on cardiovascular disease out- search Council, 2005. Committee on Prevention, Detection, comes: observational follow-up of the Evaluation, and Treatment of High

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(TOHP). BMJ 2007; 334: 885–892. 1206–1252.

Hypertension 103 Nutrition for Disease States

Bier D, et al. (eds): Nutrition for the Primary Care Provider. World Rev Nutr Diet. Basel, Karger, 2015, vol 111, pp 104–109 DOI: 10.1159/000362307

Obesity

Alice A. Gibson Kyra A. Sim Ian D. Caterson

The Boden Institute of Obesity, Nutrition, Exercise and Eating Disorders, The University of Sydney, Sydney, N.S.W. , Australia

Key Words Introduction Obesity · Body mass index · Obesity management · Weight loss · Lifestyle modifications · Adjunctive Obesity is the result of a long-term positive en- therapies ergy balance. However, attributing obesity to excessive energy intake and insufficient physical activity is an oversimplification. The factors con- Key Messages tributing to the disease state of obesity are com- • Obesity management plans should incorporate plex due to an interaction between varying ge- both an active weight loss phase and a weight netic or biological tendencies, and cultural and maintenance phase. socioeconomic drivers of weight gain. Factors • A negative energy balance is essential for weight may act alone or in combination to modulate en- loss, but how such an energy deficit is to be achieved ergy intake and/or expenditure and hence deter- is dependent upon the individual. The major challenge for patients and healthcare providers is to mine the likelihood of an individual becoming maintain the weight management solutions over obese. The current ‘obesogenic’ environment is the long term. propelling the epidemic by providing an unfa- • Lifestyle modifications, through alterations in diet, vorable situation that overwhelms sophisticated physical activity and behavior should be the main regulatory systems controlling appetite and therapeutic approaches. maintaining energy balance [1] . • The key strategies in behavioral therapy for weight control are self-monitoring, stimulus control, problem solving, contingency management, cognitive restructuring and social support. D e f i n i n g O b e s i t y • Adjunctive therapies, including very-low-energy diets, pharmacotherapy and bariatric surgery, may be Obesity is defined as an abnormal or excessive ac- considered for high-risk patients when lifestyle in- cumulation of adipose tissue in the body resulting terventions have failed. © 2015 S. Karger AG, Basel in adverse effects on the health and well-being of Fig. 1. Hierarchical approach to Bariatric obesity management. All patients surgery %0,DQGKLJKULVN should receive lifestyle modification. Additional therapies can be consid- VLEDs ered as indicated. High risk: a WC ≥ 102 cm in men and ≥ 88 cm in Pharmacotherapy %0,RU!DQGKLJKULVN women, or the presence of risk factors including type 2 diabetes/impaired glucose tolerance, hyperten- Lifestyle modification %0, sion, coronary heart disease, dyslip- (healthy eating and physical activity) idemia, obstructive sleep apnea.

Table 1. Classification of overweight and obesity by cut- preobese and those with a BMI ≥30 as obese (ta- points of BMI and WC (cm), and their related health risks ble 1 ). The BMI cutoff points are however not ap- a BMI plicable to all ethnic groups [2] , extremes of age, Classification BMI Risk of muscularity and height. comorbidities Obesity is regarded as a disease in its own right [1] and is also a risk factor for a large number of Normal range average 18.5 – 24.9 noncommunicable, metabolic and mechanically Overweight ≥25 induced disorders, the risk of which increases on Preobese 25 – 29.9 increased a continuum with increasing adiposity. It is not Obese class I 30 – 34.9 moderate only the amount, but also the distribution of adi- Obese class II 35 – 39.9 severe Obese class III ≥40 very severe pose tissue which underlies the health risks and diseases associated with obesity. Waist circumfer- b WC ence (WC), a surrogate marker of visceral fat, has been shown to be a more sensitive measure of GroupIncreased Substantial long-term health risks ( table 1 ) [1] . WC (really an risk increased risk abdominal circumference at a defined level) Men ≥94 ≥102 should be measured mid-way between the lowest Women ≥80 ≥88 rib and the upper border of the iliac crest. Asian men ≥90 Asian women ≥80

Values are those suggested by the WHO [1]. Goals of Obesity Management

Any obesity management plan should be struc- tured to include both an active weight loss phase the individual [1]. In clinical practice, a useful and a weight maintenance phase. Modification of clinical definition of obesity is the body mass in- lifestyle, through dietary change, alterations in dex (BMI) which gives a reasonable approxima- physical activity and behavior modification tion of adiposity. BMI is derived by dividing an should be the main therapeutic approaches in the individual’s weight (in kilograms) by height (in management of obesity (fig. 1 ). Effective weight metres) squared (kg/m2 ). Adults with a BMI be- management is defined as weight loss of 5–10% of tween 25–29.9 are categorized as overweight or body weight which is maintained for at least 2

Obesity 105 years. Health benefits associated with this moder- The most important factor determining the ate weight loss include improvements in the fol- success of any diet is the ability to maintain long- lowing [3] : term adherence to the new lifestyle changes. It • Glycemic control is better to prescribe a ‘healthy eating plan’ as • Dyslipidemia (particularly high triglyceride opposed to a ‘diet’ as the word diet carries con- and low HDL cholesterol levels) notations of short-term adherence. Temporary • Blood pressure changes will lead to temporary weight loss; if the • Nonalcoholic fatty liver disease predisposing factors remain, so too does the pro- • Sleep apnea pensity for weight regain [8]. Any dietary advice • All-cause mortality [4] for weight loss should ensure that it does not • The risk of heart disease, stroke and some can- compromise micronutrient nutritional status. cers Table 2 gives an overview of common dietary ap- • Psychological problems (social isolation and proaches to weight loss, and all approaches are depression) effective; the actual choice of eating intervention • Musculoskeletal problems, osteoarthritis will depend on the needs or habits of the indi- • Reproductive abnormalities, impaired fertili- vidual patient. ty, polycystic ovaries.

P h y s i c a l A c t i v i t y Dietary Approaches Patients should be encouraged to increase daily A negative energy balance is essential for weight physical activity to between 60 and 90 min each loss. How such an energy deficit is achieved is de- day. Additionally, it is important to encourage pendent upon the individual. Weight loss is dy- patients to reduce their ‘inactivity’ and to stand namic and needs to be reviewed on a regular basis. more. Pedometers may be useful to set daily or A prescribed energy deficit of 2–4 MJ/day (approx. weekly targets, which can be gradually increased. 500–2,000 kcal) will lead to a steady rate of weight loss of 0.5–1 kg/week for a period until the body adapts and plateaus. There are dynamic physiolog- Behavior Modification ical adaptations that manifest with weight loss; namely a reduced resting metabolic rate, increased The main strategies in behavioral therapy for appetite and decreased energy cost of physical ac- weight control are self-monitoring, stimulus tivity [5, 6]. Dynamic models that allow prediction control, problem solving, contingency manage- of how changes of diet or physical activity will ment, cognitive restructuring and social support. translate into weight changes over time have been There appears to be no evidence that any single developed and are available online (http:// behavioral strategy is superior to any other in bwsimulator.niddk.nih.gov/ [5] and http://www. terms of effects on weight loss or weight mainte- pbrc.edu/research-and-faculty/calculators/ nance. Self-monitoring by recording food intake weight-loss-predictor/ [7] ). These models may be or exercise can help patients gain insight into useful in clinical practice to establish a target energy their own habits and provides a useful starting intake for a patient, based on the desired weight loss point for developing a plan of action. The key to outcome and duration. Furthermore, they can pro- successful behavior change is frequent contact vide guidance on the energy intake necessary to and support to ensure that lifestyle changes are maintain the new weight once it is reached. sustained.

106 Gibson/Sim/Caterson

Table 2. Overview of common dietary approaches to weight loss

Dietary approach Description Reasoning

Low fat, high <30% of energy from fat, or fat is the most energy-dense macronutrient, so a carbohydrate approx. 30 g/day for women and reduction in fat intake will lead to a reduction in total 40 g/day for men energy intake Low carbohydrate <40% of energy from depletion of glycogen stores leads to utilization of fat carbohydrate as an energy substrate (and rapid initial weight loss); circulating ketones thought to suppress appetite; decreased range of food choices may also lead to a decreased energy intake High protein >20% of energy from protein increased satiety leading to reduced energy intake; higher thermic effect of food compared with carbohydrate and fat; preservation of lean body mass Low GI eating carbohydrate foods with a consuming low-GI foods reduces hunger, which in turn GI <55 leads to decreased food and energy intake; this, combined with the reduced anabolic effect of reduced insulin secretion, promotes weight loss Portion control decreasing portion of food eaten people often eat what is offered and tend to on each eating occasion; also overconsume if offered large portions; paying attention includes using portion-controlled to portion size and actively choosing smaller portions foods or meal replacements will reduce energy intake

GI = Glycemic index.

Adjunctive Therapies tein, but must provide the recommended daily allowances of minerals, vitamins, trace elements Adjunctive therapies, including very-low-energy and essential fatty acids. Most commonly used diets (VLEDs), pharmacotherapy and bariatric VLEDs are commercially prepared liquid or pow- surgery, may be considered for high-risk patients der formulas, or bars. It is important that VLEDs when lifestyle interventions have failed to achieve are not misused. They are intended for those with sufficient weight loss after a minimum of 3 a BMI >30 requiring significant weight loss, but months (fig. 1 ). should not be first-line treatment for moderate weight loss. VLEDs are contraindicated for several specif- Very-Low-Energy Diet ic patient groups (those with severe renal or hepatic disease, for example), though they may be VLEDs are nutritionally complete, formulated used in those with diabetes, even type 1 diabetes, meals defined as diets providing <3.4 MJ/day, and provided there is appropriate alteration in oral are typically implemented between 8 and 16 hypoglycemics (metformin may be continued) weeks, but may be continued for as long as neces- or insulin with regular blood sugar monitoring. sary. They usually supply a daily minimum of They may, however, be considered as an option 50 g of carbohydrate and 50 g of high-quality pro- for adolescents with grade III obesity, or with a

Obesity 107 • Measure weight, waist circumference, height, and calculate BMI. Take a detailed weight history, including a family weight history as well as assess patients’ behaviours, knowledge, beliefs and Assess attitudes surrounding their weight problem.

• Advise patient according to the assessment of risk. Advice is most effective when it is personalized according to an individual‘s behaviors, knowledge, beliefs and attitudes. Advise

• In collaboration with the patients, identify and set goals and help them to develop a plan on how they will achieve them. For example, if the goal is to increase fruit and vegetable consumption, the Agree plan may include the purchasing of them.

• Use different strategies to help patients to identify, address and overcome barriers, and build their skills and confidence in lifestyle changes necessary to achieve and maintain weight loss. This step may also be complemented by referral to another specially trained clinician such as a psycholgist, Assist exercise physiologist or dietitian if a more intensive intervention or approach is needed.

• This involves making specific plans for subsequent contacts. There is evidence that high-intensity counseling with behavioral interventions produces sustained weight loss in obese individuals. Arrange High intensity is defined as more than one session per month for at least 3 months. follow-up

Fig. 2. The 5 As approach to weight management in the primary care setting. Concept adapted from Goldstein et al. [10] .

BMI >35 with a severe comorbidity, under strict term weight loss. In the US, low-dose topiramate/ medical supervision and as an alternative to bar- phentermine combinations are available. Avail- iatric surgery. Commonly-reported side effects ability of these agents will depend on country- of some VLEDs include dry mouth, constipation specific regulatory authorities. or diarrhea, headache, dizziness, nausea, and Pharmacotherapy can augment the weight- cold intolerance. However, these are usually reducing effects of lifestyle changes and can fa- transient. cilitate long-term maintenance of weight loss as well as the improvement in cardiometabolic risks. Pharmacotherapy should be considered as Pharmacotherapy an adjunct to lifestyle modification for patients who have a BMI ≥ 30 or if lifestyle changes have Pharmacologic agents indicated for the manage- failed to produce weight loss within 12 weeks. It ment of obesity are limited to phentermine for should be used under appropriate medical su- short-term weight loss and orlistat for longer- pervision.

108 Gibson/Sim/Caterson

Bariatric Surgery Assist, Arrange follow-up) can be used as a guide to structure weight management counselling There are different techniques of bariatric surgery; ( fig. 2 ). gastric bypass, sleeve gastrectomy and laparoscopic gastric banding procedures are the most widely used. Bariatric surgical intervention combined with Conclusions permanent lifestyle change is the most effective therapy for weight reduction in terms of the extent • Obesity is a complex issue. Identifying patients and duration of weight loss [9]. Surgery is indicated who are overweight and obese, and particular- for patients with a BMI ≥ 40 or with a BMI ≥ 35 and ly those with an increased WC, is essential for medical comorbidities, and is best suited for well- preventing obesity and its complications. motivated obese patients. Careful medical and nu- • Patients with obesity need to recognize it is tritional supervision is necessary after surgery to a serious health problem and work collab- prevent nutritional or digestive complications. oratively with primary healthcare providers and other healthcare professionals towards a weight management solution, understanding The 5 As Approach to Managing Obesity the long-term nature of the treatment. • It is easy to simply tell patients that they need The primary care setting provides an ideal oppor- to eat better and exercise more to lose weight. tunity for providing health behavior advice and The major challenge, however, is helping pa- counselling across multiple counselling sessions tients to achieve behavioral changes rather [10]. The 5 As approach (Assess, Advise, Agree, than just suggesting them.

References

1 WHO: Obesity: preventing and manag- 4 Caterson ID, Finer N, Coutinho W, et al: 8 Wyatt HR, et al: Lessons from patients ing the global epidemic. World Health Maintained intentional weight loss re- who have successfully maintained

Organ Tech Rep Ser 2000; 894:i–xii, 1– duces cardiovascular outcomes: results weight loss. Obes Manag 2005; 1: 56–61. 253. from the Sibutramine Cardiovascular 9 Sjöström L, Narbro K, Sjöström CD, et 2 WHO Expert Consultation: Appropriate OUTcomes (SCOUT) trial. Diabetes al: Effects of bariatric surgery on mortal-

body-mass index for Asian populations Obes Metab 2012; 14: 523–530. ity in Swedish obese subjects. N Engl J

and its implications for policy and inter- 5 Hall KD, Sacks G, Chandramohan D, et Med 2007; 357: 741–752.

vention strategies. Lancet 2004; 363: al: Quantification of the effect of energy 10 Goldstein MG, Whitlock EP, DePue J:

157–163. imbalance on bodyweight. Lancet 2011; Multiple behavioral risk factor interven-

3 Goldstein DJ: Beneficial health effects 378: 826–837. tions in primary care. Summary of re-

of modest weight loss. Int J Obes Relat 6 Casazza K, Pate R, Allison DB: Myths, search evidence. Am J Prev Med 2004;

Metab Disord 1992; 16: 397–415. presumptions, and facts about obesity. 27(suppl 2):61–79.

N Engl J Med 2013; 368: 446–454. 7 Thomas DM, Martin CK, Heymsfield S, et al: A simple model predicting individual weight change in humans. J Biol Dyn

2011; 5: 579–599.

Obesity 109 Nutrition for Disease States

Bier D, et al. (eds): Nutrition for the Primary Care Provider. World Rev Nutr Diet. Basel, Karger, 2015, vol 111, pp 110–115 DOI: 10.1159/000362770

Diabetes Mellitus

Jim Mann

Department of Human Nutrition, University of Otago, Dunedin , New Zealand

Key Words Introduction Type 2 diabetes · Lifestyle · Complications · Management · Prevention The term ‘diabetes mellitus’ describes a group of conditions characterized by raised blood glucose levels (hyperglycemia) resulting from an absolute Key Messages or relative deficiency in insulin. Type 1 diabetes is • Rates of type 2 diabetes mellitus (T2DM) have characterized by destruction of the insulin-pro- reached epidemic proportions in many countries and are high throughout the world. ducing pancreatic islet β-cells, typically resulting • In predisposed families or populations, genetic and from an autoimmune process. Insulin treatment is lifestyle factors combine to result in the develop- essential to maintain life. In type 2 diabetes melli- ment of insulin resistance and T2DM. tus (T2DM), a key abnormality is resistance to the • Excess body fatness appears to be the main driver action of insulin and in the early stages of the dis- of the increasing rates of T2DM. ease, insulin levels may actually be raised as the • Decreasing energy-dense foods, increasing physi- β-cells of the pancreas produce more insulin in an cal activity and achieving a body mass index as close as possible to the recommended range are attempt to overcome insulin resistance. In many the cornerstones of management and attempts to patients with T2DM, the insulin-producing β-cells ‘prevent’ T2DM or reduce progression of prediabe- may show a degree of failure at some stage during tes. the course of the disease process. Patients with • A wide range of macronutrient intakes is accept- T2DM are initially treated with ‘lifestyle modifica- able with particular emphasis on the nature of car- tion’ therapy. Oral hypoglycemic (blood glucose- bohydrate- and fat-containing food choices. • In some situations, inappropriate nutrition from the lowering) agents may be added. Insulin may be re- time of conception through to early life may result quired later. Impaired glucose tolerance, impaired in epigenetic changes which increase subsequent fasting glucose and gestational diabetes (diabetes risk of T2DM. Appropriate nutrition throughout the developing during pregnancy) may represent the lifecycle may help to reduce the global epidemic. earliest stages of T2DM and are often referred to as © 2015 S. Karger AG, Basel prediabetes. <4 7–9 4–5 9–12 5–7 >12

Fig. 1. Prevalence estimates (%) of diabetes in individuals aged 20–79 years (2013). Source: Inter- national Diabetes Federation [3] .

Diabetes is believed to affect 8% of the world’s there are many with prediabetes. Thus, T2DM adult population, with 382 million individuals may be regarded as one of the major epidemics of having the condition. Rates are especially high in the 21st century. Worldwide prevalence estimates some indigenous populations which have under- of diabetes are shown in figure 1. The vast major- gone rapid acculturation (e.g. American Pima In- ity are affected by T2DM, and this chapter there- dians, Polynesians, Melanesians and Australian fore considers the causes, management and pos- Aboriginals) and other populations which have sibilities for prevention of T2DM. migrated, typically to countries of greater affluence (e.g. Asian Indian migrants to the UK and other countries). India and China have relatively Lifestyle-Related Determinants of Type 2 high rates of diabetes and are two of the most Diabetes and Its Complications populous countries in the world. Thus, China is the country with the highest number of people The risk of developing T2DM is greatly increased with diabetes, with a current figure of 98.4 mil- when one or more close family members have the lion, followed by India with 65.1 million. If the condition, although the precise mode of inheri- current rates of growth continue unchecked, it tance has not yet been resolved. It appears that, in has been estimated that by 2035, the total number predisposed populations or families, genetic and of people with diabetes worldwide will exceed lifestyle factors combine to result in the develop- 592 million. In addition to those with diabetes, ment of insulin resistance and consequently, dia-

Diabetes Mellitus 111 betes. The striking association between the risk of nopathy, nephropathy, and neuropathy) appear T2DM and increasing body fatness, particularly to be a result of hyperglycemia and other meta- when the excess body fat is centrally distributed bolic consequences of diabetes and hypertension. (i.e. in association with a high waist circumfer- Diet plays a major role in their prevention and ence), has been repeatedly reported in people of treatment, principally by helping to improve different ethnicities. Dietary attributes and lack of blood glucose control and lower blood pressure. physical activity which contribute to the development of excess body fat also contribute to T2DM. There have been several attempts to implicate Nutritional Management of People with individual foods or nutrients as causal or protec- Diabetes tive factors independently of any association they may have with overweight or obesity. It is likely Dietary modification is the cornerstone of treat- that more than one of the attributes that charac- ment for people with T2DM, and many who com- terize the Western lifestyle (excessive intakes of ply with dietary advice will show improvement in energy-dense foods; relatively low intakes of veg- the metabolic abnormalities associated with this etables, fruits, and lightly processed cereal foods condition, possibly abrogating the need for oral with intact cellular structure; inadequate physi- medications and insulin. However, even when cal activity) is likely to contribute to the etiology drug treatment is required, attention to diet may of T2DM. One very large prospective study has further improve blood glucose control and mod- suggested that diets with a high glycemic load ify cardiovascular risk factors. The principles of and low cereal fiber content increase the risk of treatment are summarized in table 1 . These guide- T2DM. The glycemic load provides an indication lines are based on the advice of the American of both glycemic index (GI) and quantity of car- Diabetes Association and the European Associa- bohydrate. A high intake of saturated fatty acids tion for the Study of Diabetes. Much publicity may increase resistance to the action of insulin has arisen from claims of the ‘unique’ benefits as- and therefore increase the risk of developing sociated with Mediterranean, high-protein (e.g. T2DM. Sugar does not appear to be an indepen- Zone), high-fiber, low-carbohydrate, and even dent risk factor for T2DM, though high intakes of high-fat (e.g. Atkins) diets for people with diabe- sugar-sweetened beverages have been associated tes. While the majority of experts would agree with a subsequent increase in risk. Intrauterine that a high-fat diet is undesirable in the long term, growth retardation leading to babies born small the consensus is that most dietary patterns would for gestational age and prematurity have also be acceptable for the majority of people with dia- been suggested as risk factors for the develop- betes, provided they comply with the recommen- ment T2DM in later life. This appears to be espe- dations for energy and nutrients. No single di- cially the case when rapid catch-up growth oc- etary pattern has been shown to be associated curs in infancy and childhood (fetal program- with better long-term outcomes than any others. ming or ‘Barker’ hypothesis). Cardiovascular The key recommendation for those who are disease is responsible for the greatest number of overweight (BMI >25) is that calorie intake should deaths and a large proportion of nonfatal illness- be reduced and energy expenditure increased so es in people with T2DM. Therefore, nutritional that the BMI moves towards the recommended determinants of cardiovascular disease need to range (18.5–25). Prevention of weight regain is an be taken into account when considering the nu- important aim once weight loss has been achieved. tritional management of people with diabetes. For those who are overweight or obese, reducing Several other complications of diabetes (e.g. reti- energy-dense foods (those high in fats and added

112 Mann

Table 1. Key aspects of the current recommendations for diabetic diet and lifestyle

Parameter Recommendations

EASD Nutrition Study Group

Dietary energy and body Achieve and/or maintain BMI of 18.5 – 25. Diet and exercise important. weight Dietary fat Saturated plus trans-unsaturated fatty acids: <10% total energy, <8% if low-density lipoprotein levels are raised.

Polyunsaturated fatty acids: 6 – 10% total energy.

Monounsaturated fatty acids: 10 – 20% total energy. Total fat: <35% total energy (if overweight <30%). Oily fish, soybean and rapeseed oil, nuts and green leafy vegetables to provide ω-3 fatty acids. Cholesterol: <300 g/day.

Carbohydrate Total carbohydrate: 45 – 60% total energy, influenced by metabolic characteristics. Vegetables, fruits, legumes and cereal-derived foods preferred. Dietary fiber and GI/load Naturally occurring foods rich in dietary fiber are encouraged. Ideal dietary fiber intake should be more than 40 g/day (or 20 g/1,000 kcal/day), half soluble fiber (lesser amounts also beneficial). Five servings/day of fiber-rich vegetables and fruit and four or more servings of legumes/week help to provide minimum requirements. Cereal-based foods should be wholegrain and high in fiber. Carbohydrate-rich low-glycemic-index foods are suitable choices, provided other attributes are appropriate. Sucrose and other free If desired and blood glucose levels are satisfactory, free sugars up to 50 g/day may sugars be incorporated into the diet. Total free sugars should not exceed 10% of total energy (less for those who are overweight).

Protein Protein should provide 10 – 20% total energy. Vitamins, antioxidant Increase foods rich in tocopherols, carotenoids, vitamin C and flavonoids, trace nutrients, minerals and elements and other vitamins. trace elements Fruits, vegetables, and wholegrains rather than supplements are recommended. Restrict salt to <6 g/day (<2.3 g sodium). Alcohol Up to 10 g/day for women and 20 g/day for men is acceptable for most people with diabetes who choose to drink alcohol. Special precautions apply to those on insulin or sulphonylureas, those who are overweight and those with hypertriglyceridemia. Special ‘diabetic’ or Nonalcoholic beverages sweetened with nonnutritive sweeteners are useful. functional foods and Other special foods not encouraged. supplements Nonnutritive and No particular merit of fructose and other ‘special’ nutritive sweeteners over sucrose. hypocaloric sweeteners Families Most recommendations suitable for the whole family.

Diabetes Mellitus 113 Table 1 (continued)

Parameter Recommendations

American Diabetes Association Dietary energy and body Overweight and obese adults with T2DM should reduce energy intake while weight maintaining a healthy eating pattern. Modest weight loss may provide clinical benefit. Provide ongoing support to achieve lifestyle change. Dietary fat Fat quality more important than quantity. Amounts of saturated fat and trans fat and dietary cholesterol same as for general population. Mediterranean style, MUFA-rich eating pattern may benefit glycemic control and CVD risk, therefore effective alternative to lower fat, higher carbohydrate eating pattern. Foods rich in ω3. Supplements of ω3 not recommended. Carbohydrate No certainty regarding ideal amount, but total amount of carbohydrate and available insulin determine glycemic response after eating. Monitoring carbohydrate remains key to achieving glycemic control. Carbohydrate from vegetables, fruits, wholegrains, legumes and dairy products preferred to others, especially those containing added fats, sugars or sodium. Dietary fiber and GI Substituting low-glycemic-load foods for higher-glycemic-load foods may improve glycemic control. Consume at least the amount of fiber and wholegrains recommended for the general public. Sucrose and other free Consumption should be minimized to avoid displacing nutrient-dense foods. Sugar- sugars sweetened beverages should be limited or avoided to reduce risk for weight gain and worsening of cardiometabolic risk profile. Fructose in foods such as fruit may result in better glycemic control compared with isocaloric intake of sucrose or starch. Protein Intake should be individualized. Reducing protein below usual intakes not recommended. Vitamins, antioxidant No clear evidence of benefit of supplementation in people who do not have nutrients, minerals and deficiencies. trace elements Concern regarding long-term safety of supplementation with vitamins E and C and carotene and lack of evidence of efficacy. Sodium reduced to 2,300 mg/day, further individualized reduction with hypertension. Families Not applicable.

Sources: Mann et al. [1], American Diabetes Association [2] and Evert et al. [4].

sugars) and regular exercise are usually sufficient proves insulin sensitivity, glycemic control and to achieve weight loss, prescription of precise en- cardiovascular risk factors. ergy requirements only being necessary for those A wide range of macronutrient intakes is ac- unable to achieve the desired weight reduction. ceptable, the emphasis being on the nutritional Even modest weight reduction (a loss of less than attributes of food choices. To enhance glycemic 10% body weight) in the overweight or obese im- control, the nature of carbohydrate is particular-

114 Mann

ly important. Vegetables, legumes, intact fruits changes which might be expected to achieve the and manually processed wholegrain cereals are approximately 60% reduction in rates of progres- preferred choices. Rapidly digested carbohy- sion from impaired glucose tolerance to T2DM drates (e.g. sugars, potatoes, rice, many types of demonstrated in the trials for periods of 10 years breads and pastas) should be limited. The GI of or more are similar to those recommended for carbohydrate-rich foods (e.g. breads, pastas) may treatment of T2DM. Achieving a weight loss of at provide a useful indication of their suitability. least 5–7% initial body weight in those who are However, GI is unhelpful when considering ener- overweight or obese is a pivotal component of the gy-dense foods rich in fats and sugar. Such ener- ‘prevention’ program. gy-dense foods typically have low GIs but should be severely restricted by most people with T2DM. The advice relating to dietary fat is based princi- Conclusions pally on the guidelines for reducing cardiovascular risk. • Excess body fat is the main driver of T2DM. In some individuals, genetic and lifestyle factors also play a role in the development of insulin Potential for ‘Preventing’ Type 2 Diabetes resistance and the onset of T2DM. • Another contributing factor is inappropriate While the precise mechanisms by which genes nutrition from conception to early life, which and lifestyle interact to result in T2DM remain may increase an individual’s subsequent risk elusive, the geographic variation, rapid changes of T2DM. over time, and dietary patterns related to risk sug- • Decreased intake of energy-dense foods, ingest that lifestyle modification might help to pre- creasing physical activity and achieving the vent, or at least delay, the onset of T2DM in pre- recommended body mass index are key as- disposed individuals. Randomized controlled tri- pects of the management of T2DM and for reals, first reported from Finland, the USA, and ducing the progression of prediabetes. China and more recently from other countries, • Appropriate nutrition throughout the lifecycle confirm that this is indeed the case. The lifestyle may help to reduce this global epidemic.

References

1 Mann JI, De Leeuw I, Hermansen K, et 2 American Diabetes Association: Clinical 4 Evert AB, Boucher JL, Cypress M, et al: al: Evidence-based nutritional approach- practice recommendations. Diabetes Nutrition therapy recommendations for

es to the treatment and prevention of Care 2014; 37(suppl 1):S1–S155. the management of adults with diabetes.

diabetes mellitus. Nutr Metab Cardio- 3 International Diabetes Federation: IDF Diabetes Care 2014; 37(suppl 1):S120–

vasc Dis 2004; 14: 373–394. Diabetes Atlas, ed 6. Brussels, Interna- S543. tional Diabetes Federation, 2013. www. idf.org/diabetesatlas.

Diabetes Mellitus 115 Nutrition for Disease States

Bier D, et al. (eds): Nutrition for the Primary Care Provider. World Rev Nutr Diet. Basel, Karger, 2015, vol 111, pp 116–122 DOI: 10.1159/000362308

Obesity, Diabetes and the Asian Phenotype

a–c a–e Swati Bhardwaj Anoop Misra a b National Diabetes, Obesity and Cholesterol Diseases Foundation (N-DOC), SDA, Diabetes Foundation (India), SDA, c d Center of Nutrition and Metabolic Research (C-NET), Fortis C-DOC Center of Excellence for Diabetes, Metabolic e Diseases and Endocrinology, and Center for Internal Medicine, Fortis Flt. Lt. Rajan Dhall Hospital, New Delhi , India

Key Words genetic and phenotypic factors, resulting in obesity, insulin resistance, the metabolic syndrome, type Obesity · Metabolic syndrome · South Asians · 2 diabetes and cardiovascular disease. Nutrition transition · Phenotype · • Health interventions required to prevent or reduce Population-based prevention morbidity/mortality need to be addressed in both children and adults. Interventions should aim to increase physical activity and encourage healthier Key Messages food patterns and health education. • Rapid economic, demographic, and nutritional © 2015 S. Karger AG, Basel changes occurring in India and other south Asian countries contribute towards a sedentary lifestyle and imbalanced dietary profile, leading to a rise in Introduction obesity and the metabolic syndrome. • Several phenotypic features may contribute to insulin resistance and the metabolic syndrome in The prevalence of obesity and the metabolic syn- South Asians: despite lower average body mass in- drome is rapidly increasing in India and other dex (BMI) values, South Asians have a high percent- south Asian countries, leading to increased mor- age of body fat compared to Caucasians or Blacks, bidity and mortality due to type 2 diabetes mel- which is partly explained by body build, low muscu- litus (T2DM) and cardiovascular disease (CVD) larity, adaptation to chronic calorie deprivation, [1]. Rapid economic, demographic, and nutri- and ethnicity. • Consequently, morbidities related to higher body tional changes are occurring in India and other fat (diabetes, hypertension, dyslipidemia, etc.) oc- neighboring South Asian countries, contribut- cur more frequently at lower BMI levels in Asians ing towards a sedentary lifestyle and imbalanced than in Caucasians. dietary profile, further leading to obesity ( fig. 1 ). • Other contributing factors are the nutrition transi- Persistent obesity dysregulates metabolic pro- tion, an increasingly sedentary lifestyle, and the ru- cesses including the action of insulin on glucose- ral-to-urban migration. These act in concert with lipid-free fatty acid metabolism, and severely af- Pattern 1: Diets rich in carbohydrates, fiber, low in fats, saturated fats, high activity profile and lean body phenotype

Pattern 2: Famine-like situation, low-calorie, low-protein and fat diets, low body fat and fat-free mass, growth retardation

Economic changes: Pattern 3: Demographic changes: Urbanization, open market Decreasing food scarcity and Rural-urban migration, increasing economy, increasing affluence famine, labor-intensive work elderly population, mechanization

Improved food supply, increased food availability (longer shelf life, 24-hour supermarkets), competitive prices of energy-dense foods

Increased intake of fat (saturated and trans fats), salt and sugar; dietary liberalization and Westernization

Plattern 4: Pattern 5: Rise of obesity, the metabolic syndrome Increased intake of improved quality fats, green leafy and T2DM vegetables, and fibre; decreased intake of refined carbohydrates, energy-dense foods

Fig. 1. Relationship between nutrition transition, urban- different rates of progression in different developing ization, and the rise in obesity and the metabolic syn- countries. Pattern 4 is likely to affect all socioeconomic drome in developing countries. Pattern 3 may be seen at strata. Adapted from Misra and Khurana [4] .

fects other processes that regulate blood glucose, advantaged people residing in urban slums and blood pressure, and lipids. Thus begin a cluster rural areas. This increasing burden of obesity, of conditions: dysglycemia, dyslipidemia, hyper- the metabolic syndrome, T2DM, and CVD in tension, and a procoagulant state, known as the South Asian countries has created an urgent metabolic syndrome. Data suggest that obesity need to strategize health policies and mass inter- and the metabolic syndrome are immediate prevention programs to tackle nutrition and con- cursors of T2DM and CVD [2]. A high preva- tinue efforts to manage undernutrition. Clearly, lence of the metabolic syndrome and associated these efforts require a thorough understanding cardiovascular risk factors has been observed of the factors influencing and driving obesity, not only in urban South Asian/Asian-Indian the metabolic syndrome and T2DM in develop- adults and children but also in economically dis- ing countries.

Obesity, Diabetes and The Asian Phenotype 117 Table 1. Average values of various measures of obesity in South Asians/Asian Indians and other ethnic groups

ParametersAsian-Indians White Blacks Mexican- Caucasians Americans rural urban slums urban migrant1

BMI 19.6 20.9 22.4 24.7 26.3 28.5 25.7 Body fat, % 20.4 24.4 28.2 33.1 26.6 29.7 48.8 Waist circumference, cm 79.4 83.7 85.2 83.7 91.3 83.9 94.5 Waist-hip ratio 0.87 0.92 0.87 0.92 0.91 0.86 0.92

Adapted from Misra and Vikram [3]. 1 Migrant South Asians and Asian Indians.

Phenotypic Features of Obesity That May in white Caucasians (in both adults and children), Contribute to Insulin Resistance and the which correlates better with insulin resistance Metabolic Syndrome in South Asians than intra-abdominal adipose tissue. Fat deposition may occur at ‘ectopic sites’ and may have rel- The phenotype of obesity and body fat distribu- evance to insulin resistance in Asian-Indians, e.g. tion are distinctive in South Asians. The average intramyocellular lipids may be one such site. An- value of body mass index (BMI) in South Asians is other, and perhaps more important, ectopic site of lower than that seen in white Caucasians, Mexi- fat deposition is the liver. Fat accumulation in liv- can-Americans and Blacks. However, BMI in er (fatty liver) in the absence of significant alcohol Asian-Indians increases as they become affluent intake (nonalcoholic fatty liver disease, NAFLD) and urbanized (table 1 ). South Asians have a high is now recognized as a disease risk in overweight/ percentage of body fat as compared to white Cau- obese subjects. NAFLD is strongly related to insu- casians and Blacks, despite lower average BMI val- lin resistance independent of obesity and abdomi- ues (table 1 ), which is partly explained by body nal adiposity. Limited data in South Asians sug- build (trunk-to-leg length ratio and slenderness), gest that approximately 25% of the urban popula- low muscularity, adaptation to chronic calorie de- tion has NAFLD [6] . Furthermore, Asian-Indians privation, and ethnicity [3] . Importantly, morbid- have comparatively higher deposition of triglyc- ities related to higher body fat (diabetes, hyperten- erides in liver as compared to white Caucasians sion, dyslipidemia etc.) occur more frequently at [7] . Overall, excess hepatic fat accumulation in lower BMI levels in Asians than in white Cauca- Asian-Indians may be important in the genesis of sians [4]. A high prevalence of abdominal obesity insulin resistance, the metabolic syndrome and is seen in South Asians, and is also reported in diabetes, and constitutes a prime area for research. Asian-Indians with BMI <25 [3] . Although the av- Fat deposition has also been reported in other erage waist circumference in South Asians ap- sites of the body: ‘buffalo hump’ (excess fat depo- pears to be lower, abdominal adiposity is signifi- sition in dorsocervical region) and double chin cantly more than in white Caucasians. For exam- (excess fat deposition under the chin). A Meta- ple, intra-abdominal adipose tissue in South bolic Syndrome Screening Score, including buf- Asians is comparatively more than in Caucasians falo hump, double chin, age and gender, was gen- [5] . Furthermore, truncal subcutaneous adipose erated based on these data and showed a sensitiv- tissue (measured by subscapular and supra-iliac ity and specificity of 82 and 71%, respectively, in skinfold thickness) is thicker in South Asians than detecting metabolic syndrome [8] .

118 Bhardwaj /Misra

Table 2. Cutoffs for obesity and abdominal obesity in Asian Indians vs. international criteria

Variable Category Consensus Prevalent guidelines international for Asian Indians1 criteria

2 Generalized obesity normal 18.0 – 22.9 18.5 – 24.9 2 (BMI cutoffs) overweight 23.0 – 24.9 25.0 – 29.9 obesity >25 >30

Abdominal obesity (waist men >903 >1024 circumference cutoffs in cm) women >803 >884

Adapted from Misra and Khurana [9]. 1 From Consensus guidelines for Asian Indians [10]. 2Accor- ding to World Health Organization guidelines [11]. 3 Both as per Consensus Guidelines and the International Diabetes Federation (for Asian Indians) [12]. 4 According to Modified National Cho- lesterol Education Program, Adult Treatment Panel III guidelines [13].

Finally, South Asians could be termed as ‘met- and non-traditional energy-dense imbalanced abolically obese’, though BMI levels may fall in foods (‘fast-foods’; high in calories, carbohy- the category of ‘nonobese’. This phenomenon is drates, SFA, trans-fatty acid and low in fiber) are partially explained by high body fat, high in- being increasingly consumed in India [5] . High- traabdominal and subcutaneous fat, NAFLD, er intakes of carbohydrate, SFA, trans-fatty acid and fat deposition at other ectopic sites which and n-6 PUFA, and lower intakes of n-3 PUFA contribute to insulin resistance, dyslipidemia, and fiber, and a higher n-3:n-6 PUFA ratio have hyperglycemia, and excess procoagulant milieu been reported in South Asians, as compared to in South Asians [5] . other populations [5] . Furthermore, high dietary n-6 PUFA and SFA are significant independent predictors of fasting hyperinsulinaemia Definition of Generalized and Abdominal and high levels of C-reactive protein, respective- Obesity in Asian-Indians ly, in adolescent Asian-Indians. Specifically, in children and young individuals in North India, The definitions of abdominal and generalized high intake of omega-6 PUFAs has been shown obesity are different in South Asians as compared to correlate with fasting hyperinsulinemia [5] . to Caucasians, as indicated in table 2 [9] . High consumption of partially hydrogenated oils (Vanaspati) containing high amount of trans-fatty acid has been noted in India, particu- Obesity, the Metabolic Syndrome and Type 2 larly in socioeconomically disadvantaged popu- Diabetes: Determinants and Correlates for lations. South Asians/Asian-Indians P h y s i c a l A c t i v i t y Diets South Asians are more sedentary as compared to With the nutrition transition, consumption of other ethnic groups [14] . Increasingly, sedentary traditional foods (low in saturated fat, SFA, low lifestyle is attributed to increased mechanization in simple sugars and high in fiber) has declined, in work places and household work. Leisure time

Obesity, Diabetes and The Asian Phenotype 119 Perinatal factors: Maternal, neonatal and excess Physical inactivity childhood adiposity/accelerated velocity of BMI change Hypertension

Dyslipidemia Abnormal body composition: Excess body fat, truncal fat, High free fatty acids subcutaneous fat, abdominal obesity, low muscle mass T2DM CHD

Fatty liver Muscle fat

Imbalanced nutrition: High energy and fat intake, low Decreased insulin sensitivity High CRP fiber and omega-3 fatty acid intake

High proinflammatory cytokines

Genetic factors

Fig. 2. Complex interactions of genetic, perinatal, nutri- South Asians. CRP = C-reactive protein; CHD = coronary tional and other acquired factors in the development of heart disease. Dashed lines represent weak relationships insulin resistance, T2DM and coronary heart disease in [20] .

physical activities have also shifted from outdoor guage disparities, job challenges and lack of so- play to indoor entertainment (television and cial support, which may lead to metabolic de- computer games) [4]. In a recent study done in rangements and diabetes. An adverse coronary South India, 79% of the industrial populations risk profile was reported among rural-to-urban were demonstrated to follow a sedentary lifestyle migrant populations living in urban slums in [15] . India [17] .

Migration Genetic versus Environmental Factors The effect of migration on adiposity and diabe- A role of genetic predisposition in the develop- tes has been discussed by us in a published re- ment of obesity, the metabolic syndrome, dys- view [16] . Migration (both intra- as well as in- lipidemia, and T2DM in Asian-Indians has been tercountry) leads to significant stress due to the reported [18] . Adverse intrauterine environ- new environment, social, economic, and lan- ment has been reported to contribute to insulin

120 Bhardwaj /Misra

resistance and the metabolic syndrome. Both fe- dressed in both children and adults. Interven- tal undernutrition (low birth weight, LBW) and tions should be aimed at increasing the physi- over-nutrition increase the risk of future diabe- cal activity along with healthier food patterns tes and adiposity in children in later life. LBW and health education. was associated with higher systolic blood pres- • Successful community-based intervention sure, fasting and postprandial hyperinsulinemia, programs have been reported in developed subscapular/triceps skinfold ratio, plasma LDL, countries, and a similar approach is required along with insulin resistance. Small and thin In- specifically in developing South Asian coun- dian newborns (weight 2.7 kg and ponderal in- tries. Various other health strategies consist- dex 2.4, calculated as kg/m2 ) were shown to have ing of individual and community initiatives, poor muscle mass but higher adiposity for a giv- backed up by governmental and legislative ef- en weight compared with white Caucasian ba- forts, would also help in minimizing the in- bies. Furthermore, ‘catch up’ obesity seen in creasing prevalence of obesity and the meta- LBW offspring seems to be important for adult- bolic syndrome in developing countries (see onset insulin resistance and associated cardio- box). vascular risk factors. Interestingly, normal to high folate levels coupled with low vitamin B12 levels in mothers predicted higher adiposity and Box. Community intervention programs for childhood insulin resistance in Indian babies [19] . These obesity in India preliminary data need to be confirmed in further studies. The complex interplay of genetic, meta- Community-based interventions are aimed at gen- bolic and environmental risk factors resulting in erating awareness and providing a conductive en- obesity insulin resistance, the metabolic syn- vironment for children to follow a healthy lifestyle (balanced diet and increased physical activity) and drome, T2DM and coronary heart disease is promote healthy food alternatives. In India, we have shown in figure 2 [20] . initiated comprehensive programs aiming at childhood obesity, namely ‘CHETNA’ (Hindi for ‘The Awa- reness’; Children Health Education through Nutri- tion and Health Awareness program), which was car- Conclusions ried out in New Delhi, and ‘MARG’ (Hindi for ‘The Path’; Medical Education for Children/Adolescents • The prevalence of obesity, the metabolic syn- for Realistic Prevention of Obesity and Diabetes and drome and T2DM has shown a rapid rise in for Healthy Ageing), carried out in 15 cities of North South Asian countries in the past few decades India covering nearly 700,000 children. Under these programs, children are given nutritional and physi- and has led to increased risk of CVD and con- cal activity education with the help of lectures, sequent morbidity and mortality. leaflets, debates and skits. These comprehensive • The various factors responsible for increasing programs initiated on a large scale for the first time noncommunicable diseases are rapid nutri- in South Asia are aimed to impart education regarding healthy lifestyle not only to children, but also to tion transition, rural-to-urban migration, in- teachers and parents. The ‘MARG’ program is the creasingly sedentary occupations and lifestyle, first large-scale community intervention project in and maternal-fetal factors. South Asia which focuses 100% on primary preven- • Both genetic and environmental factors seem tion of not only diabetes, but noncommunicable di- to contribute to this; however, the role of envi- seases in general. ronment seems to be predominant. • Health interventions required to prevent or reduce the morbidity/mortality need to be ad-

Obesity, Diabetes and The Asian Phenotype 121 References

1 Misra A, Khurana L: The metabolic syn- 8 Misra A, Jaiswal A, Shakti D, et al: Novel 15 Mohan V, Deepa M, Farooq S, et al: Sur- drome in South Asians: epidemiology, phenotypic markers and screening score veillance for risk factors of cardiovascu- determinants, and prevention. Metab for the metabolic syndrome in adult lar disease among an industrial popula-

Syndr Relat Disord 2009; 7: 497–514. Asian Indians. Diabetes Res Clin Pract tion in southern India. Natl Med J India

2 Third Report of the National Cholesterol 2008; 79: 1–5. 2008; 21: 8–13. Education Program (NCEP) Expert Pan- 9 Misra A, Khurana L: Obesity-related 16 Misra A, Ganda OP: Migration and its el on Detection, Evaluation, and Treat- non-communicable diseases: South impact on adiposity and type 2 diabetes.

ment of High Blood Cholesterol in Asians vs White Caucasians. Int J Obes Nutrition 2007; 23: 696–708.

Adults (Adult Treatment Panel III): final (Lond) 2011; 35: 167–187. 17 Misra A, Vikram NK, Pandey RM, et al:

report. Circulation 2002; 106: 3143–3421. 10 Misra A, Chowbey PK, Makkar BM, et Hyperhomocysteinemia, and low in- 3 Misra A, Vikram NK: Insulin resistance al: Consensus statement for diagnosis of takes of folic acid and vitamin B12 in

syndrome (metabolic syndrome) and obesity, abdominal obesity and the met- urban North India. Eur J Nutr 2002; 41: obesity in Asian Indians: evidence and abolic syndrome for Asian Indians and 68–77.

implications. Nutrition 2004; 20: 482– recommendations for physical activity, 18 Misra A, Nishanth S, Pasha ST, et al: 491. medical and surgical management. J Relationship of Xba1 and EcoR1 poly-

4 Misra A, Khurana L: Obesity and the Assoc Physicians India 2009; 57: 163– morphisms of apolipoprotein-B gene to metabolic syndrome in developing 170. dyslipidemia and obesity in Asian Indi-

countries. J Clin Endocrinol Metab 2008; 11 WHO: Obesity and overweight. http:// ans in North India. Indian Heart J 2001;

93(suppl 1):S9–S30. www.who.int/mediacentre/factsheets/ 53: 177–183. 5 Misra A, Khurana L, Isharwal S, Bhard- fs311/en/ (accessed May 2013). 19 Yajnik CS, Deshmukh US: Maternal nu- waj S: South Asian diets and insulin re- 12 International Diabetes Federation: IDF trition, intrauterine programming and

sistance. Br J Nutr 2008: 1–9. worldwide definition of the metabolic consequential risks in the offspring. Rev

6 Sharma R, Sinha S, Danishad KA, et al: syndrome. http://www.idf.org/webdata/ Endocr Metab Disord 2008; 9: 203–211. Investigation of hepatic gluconeogenesis docs/MetS_def_update2006.pdf (ac- 20 Misra A, Bhardwaj S: Obesity and the pathway in non-diabetic Asian Indians cessed May 2013). metabolic syndrome in developing with non-alcoholic fatty liver disease us- 13 Grundy SM, Brewer HB Jr, Cleeman JI, countries: focus on South Asians; in ing in vivo (31P) phosphorus magnetic et al: Definition of metabolic syndrome: Black RE, Singhal A, Uauy R (eds): In- resonance spectroscopy. Atherosclerosis report of the National Heart, Lung, and ternational Nutrition: Achieving Millen-

2009; 203: 291–297. Blood Institute/American Heart Asso- nium Goals and Beyond. Nestle Nutr 7 Petersen KF, Dufour S, Feng J, et al: In- ciation conference on scientific issues Inst Workshop Ser. Vevey, Nestec/Basel,

creased prevalence of insulin resistance related to definition. Circulation 2004; Karger, 2014, vol 78, pp 133–140.

and nonalcoholic fatty liver disease in 109: 433–438. Asian-Indian men. Proc Natl Acad Sci 14 Bedi US, Singh S, Syed A, et al: Coronary

USA 2006; 103: 18273–18277. artery disease in South Asians: an

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Nutrition for Disease States

Bier D, et al. (eds): Nutrition for the Primary Care Provider. World Rev Nutr Diet. Basel, Karger, 2015, vol 111, pp 123–129 DOI: 10.1159/000362309

Cancer Prevention and Treatment

Timothy Key

Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford , UK

Key Words are cancers of the lung, breast and colorectum. Cancer · Obesity · Alcohol · Meat · Dietary fiber · The most common causes of cancer death are Fruit and vegetables lung, stomach and liver cancers (fig. 1 ). The most important cause of cancer in developed countries is tobacco, which causes around 30% Key Messages of cancer deaths. Other important causes of can- • Nutritional factors and alcohol may be responsible cer are reproductive and hormonal factors, infor around 30% of cancers in developed countries. fections, occupational exposures, ionizing radia- • Overweight/obesity increases the risk for cancers tion, pollution and ultraviolet radiation [2] . Di- of the esophagus (adenocarcinoma), colorectum, etary factors, including obesity, are estimated to breast (postmenopausal), endometrium, and kidney. cause around 25% of cancer deaths in developed • Alcohol causes cancers of the oral cavity, pharynx, countries, and alcohol causes about 6% of cancer larynx, esophagus, colorectum, liver, and breast. deaths. • High intakes of red and processed meat and low in- Evidence on the effects of nutrition on cancer takes of dietary fiber probably increase the risk for risk comes from observational epidemiological colorectal cancer. studies, randomized trials, clinical studies and • Healthy diets should provide adequate amounts of all nutrients and of fruit and vegetables. laboratory research. The strongest evidence • For patients being treated for cancer, diets should comes from randomized trials, but these trials provide adequate amounts of all nutrients, and obe- need to be very large and few have been per- sity should be avoided. © 2015 S. Karger AG, Basel formed. The majority of direct evidence on the associations of diet with cancer risk comes from observational studies; these need to be inter- Introduction preted carefully because measurements of long- term diet are only moderately accurate and be- Worldwide, there are nearly 13 million new cas- cause differences in particular dietary factors es of cancer and 8 million deaths from cancer can be confounded by other aspects of diet, as each year [1]. The most commonly diagnosed well as by smoking and other lifestyle factors. Lung

Breast

Colorectum

Stomach

Prostate

Liver

Cervix

Esophagus Number of cases Number of deaths Bladder

NHL

0 500,000 1,000,000 1,500,000 2,000,000

Fig. 1. The ten most common cancers in the world; estimates for 2008. NHL = Non-Hodgkin lym- phoma. Data from GLOBOCAN 2008 [1] .

Mechanisms for Dietary and Nutritional Factors China and southern Africa than in most parts of Predisposing to or Protecting from Cancer Europe, North America and West Africa. Cancers of the oral cavity and pharynx are less common, Dietary factors may be associated with cancer de- but share several etiological factors with cancer of velopment in various ways (table 1 ). The most ob- the esophagus. In developed countries the main vious is the ingestion of dietary carcinogens or risk factors for this group of cancers are alcohol precarcinogens, but there are currently only two and tobacco, and up to 75% of these cancers are at- established examples which are clearly related to tributable to these two lifestyle factors [3–5] . There cancer in humans, both largely restricted to paris also evidence that consuming drinks and foods ticular populations in developing countries. It at a very high temperature probably increases the therefore seems that the major effects of dietary risk for these cancers. Obesity is an established risk and nutritional factors on cancer risk are through factor specifically for adenocarcinoma (but not less direct means, such as by affecting hormone squamous cell carcinoma) of the esophagus, in- levels and thus cell behavior [2] . creasing the risk by over 2-fold [6] . In some developing countries, a substantial proportion of these cancers may be due to micronutrient deficiencies Cancers of the Esophagus, Oral Cavity and related to a restricted diet that is low in fruit and Pharynx vegetables and animal products; the relative roles of various micronutrients are not clear, but defi- Cancer of the esophagus is the eighth most com- ciencies of riboflavin, folate, vitamin C and zinc mon cancer in the world; incidence rates are over may be involved [7, 8]. One type of cancer within a hundred times higher in parts of central Asia, this classification, nasopharyngeal cancer, is rela-

124 Key

Table 1. Dietary and nutritional factors which may influence cancer risk

Factor Examples and possible mechanisms

Dietary carcinogens aflatoxin; mutagens in Chinese-style salted fish; possibly N-nitroso compounds formed from dietary nitrites Alcohol may act through conversion to acetaldehyde which is mutagenic, as a co-carcinogen that increases the absorption of other carcinogens, or by mucosal damage, hormonal changes, inflammation and impaired immunity Energy balance excess energy causing obesity and hormonal changes such as increased estrogens which stimulate cell division; may increase inflammation Dietary fiber effects on large intestine: dilutes gut contents, reduces transit time through the colon, may reduce absorption of carcinogens, ferments to short-chain fatty acids which may promote differentiation and lower pH thus inhibiting production of carcinogenic secondary bile acids; may also influence endogenous hormones Vitamins and minerals deficiency may damage tissues; deficiency, e.g. of folate, may lead to abnormal DNA methylation; no evidence that levels above those needed to prevent deficiency have any benefit, and might be detrimental Possible plant many hypothesized beneficial effects, but none is established to be important anti-carcinogens

tively common in parts of Southeast Asia and is increased by high intakes of some traditionally associated with a high intake of Chinese-style salt- preserved salted foods, especially meats and pick- ed fish, especially during early childhood, as well as les, and salt itself, and that risk is decreased by with infection with the Epstein-Barr virus [2, 5] . adequate intakes of fruit and vegetables, perhaps due to their vitamin C content [2, 7, 8] .

Stomach Cancer Colorectal Cancer Stomach cancer is the fourth most common cancer [1] . Until about 1980, stomach cancer was the Colorectal cancer is the third most common can- most common cause of cancer death in the world, cer. Incidence rates are approximately 10-fold but incidence rates have fallen dramatically in higher in developed than in developing countries Western countries since the middle of the 20th [1] . Diet-related factors may account for up to century, and stomach cancer is now much less 80% of the between-country differences in rates common in Europe and North America than in of colorectal cancer. The best established dietary- Asia. Infection with the bacterium Helicobacter related risk factors are overweight/obesity and al- pylori is an established risk factor [2, 4] . Diet is cohol, but these factors do not explain all of the thought to be important in the etiology of this dis- large variation in rates between countries, and it ease, and dietary changes are implicated in the re- is likely that some aspects of a Western diet are a cent decline in stomach cancer incidence and major determinant of risk [3, 7]. It has proved dif- mortality rates in many countries. Substantial ev- ficult to identify which aspects of diet are most idence suggests that the risk of stomach cancer is important, but there is now substantial evidence

Cancer Prevention and Treatment 125 that high intakes of red and processed meat and over 80% of lung cancers in Western countries low intakes of dietary fiber probably increase risk [2] . Many observational studies have found a [7, 8] . Further research is needed to clarify these weak inverse association between consumption relationships and to determine whether other nu- of fruits, vegetables and related nutrients and tritional factors such as fruit and vegetables, folic lung cancer risk, but this apparent relationship acid and vitamin D also modify risk. may be due to residual confounding by smoking, since smokers generally consume less fruit and vegetables than nonsmokers [7] . Liver Cancer

Liver cancer is the sixth most common cancer. Ap- Breast Cancer proximately 75% of cases of liver cancer occur in developing countries, and liver cancer rates vary Breast cancer is the second most common cancer over 20-fold between countries, being much high- in the world, and accounts for 23% of cancers in er in sub-Saharan Africa and Southeast Asia than women. Incidence rates are about four times in Europe and North America. The major risk fac- higher in Western countries than in less devel- tor is chronic infection with hepatitis B virus, and oped countries. Much of this international varia- to a lesser extent, hepatitis C virus [2, 4] . Ingestion tion is due to differences in reproductive factors of foods contaminated with the mycotoxin aflatox- such as age at menarche, parity, age at birth and in is an important risk factor among people in de- breastfeeding, but differences in diet may also veloping countries with active hepatitis virus infec- contribute [7] . Obesity increases breast cancer tion [2, 3]. Excessive alcohol consumption is the risk in postmenopausal women by around 50%, main diet-related risk factor for liver cancer in probably by increasing serum concentrations of Western countries, probably via the development estradiol. The only other established dietary risk of cirrhosis and alcoholic hepatitis [2, 3, 5] . factor for breast cancer is alcohol, with about a 10% increase in risk for an average of one alcoholic drink every day [5, 7] . There has been much Pancreatic Cancer interest in the hypothesis that a high fat intake increases breast cancer risk, but the extensive data Cancer of the pancreas is more common in West- now available have not confirmed this hypothe- ern countries than in developing countries. Smok- sis. The results of studies of other dietary factors ing increases the risk by about 3-fold. Overweight/ including meat, dairy products, fruit, vegetables obesity increases the risk, but this association is and fiber are inconclusive. relatively small with some inconsistencies in the evidence, and no associations with dietary intakes have been conclusively demonstrated [2, 7, 8] . Endometrial Cancer

The highest incidence rates of endometrial cancer Lung Cancer occur in Western countries. Risk is about 3-fold higher in obese women than lean women. As with Lung cancer is the most common cancer in the breast cancer, the effect of obesity in postmeno- world and was estimated to account for almost 1.4 pausal women on the risk for endometrial cancer million deaths in 2008. Heavy smoking increases is probably mediated by the increase in serum the risk by around 30-fold, and smoking causes concentrations of estrogens [7] .

126 Key

Cervical Cancer Kidney Cancer

Cancer of the cervix is the seventh most com- Obesity is an established risk factor for cancer of mon cancer in the world, and it is the third most the kidney, increasing the risk by at least 50% and common cancer in women. The highest rates are accounting for up to 30% of kidney cancers in in sub-Saharan Africa, Central and South Amer- both men and women [3, 6]. There are only lim- ica, and Southeast Asia. The major cause of cer- ited data on the possible role of diet in the etiol- vical cancer is infection with certain subtypes of ogy of kidney cancer. the human papillomavirus, and there is no strong evidence that nutritional factors affect risk [2, 7, 8] . Nutritional Factors in Cancer Treatment

The effects of nutrition on the progress of cancer Prostate Cancer after diagnosis are particularly difficult to study. Observational studies are hard to interpret be- Prostate cancer is the fifth most common cancer cause the diet of patients can be strongly linked to in the world and the second most common in the stage of their cancer, their overall health, and men. Prostate cancer incidence rates are strongly the type of treatment. Randomized controlled tri- affected by diagnostic practices and therefore dif- als are therefore needed to provide reliable evi- ficult to interpret, but mortality rates are less af- dence, but are difficult to conduct and few have fected by diagnostic practices and are about ten been performed. The available evidence suggests times higher in North America and Europe than that obesity has an adverse effect on prognosis in Asia. Little is known about the etiology of among patients with colorectal cancer and breast prostate cancer. Diets high in red meat, dairy cancer, and therefore that avoidance of obesity products and animal fat have frequently been im- may improve survival [8, 10]. Trials have not plicated, but the data overall are inconclusive. A shown that supplements of micronutrients have recent large trial showed no benefit of supple- benefits. mentation with selenium and/or vitamin E [9] . Patients with cancer have a serious disease, Prospective studies have shown that risk is posi- and their medical treatment may include surgery, tively associated with high levels of insulin-like radiation, toxic chemotherapy and hormonal growth factor-1, and more research is needed to therapy. Both the disease itself and the treatment explore whether dietary factors such as animal may cause nutritional stress and adversely affect protein may influence risk through insulin-like appetite. For these patients, adequate nutritional growth factor-1 [7] . support is of great importance.

Bladder Cancer Conclusions

Cancer of the bladder is the ninth most common • The most important known effects of nutri- cancer in the world. Tobacco smoking increases tion and related factors on cancer risk are the the risk for bladder cancer, accounting for be- adverse effects of obesity and alcohol ( table 2 ). tween a third to two thirds of all bladder cancers, • Obesity increases the risk for cancers of and there is no strong evidence that nutritional the esophagus (adenocarcinoma), colorectum, factors affect risk [2, 8] . breast (postmenopausal), endometrium and

Cancer Prevention and Treatment 127 Table 2. Diet, nutrition and cancer: summary Increase risk Decrease risk

Convincing Evidence Overweight and obesity esophagus (adenocarcinoma) colorectum breast (postmenopausal women) endometrium kidney Alcohol oral cavity pharynx larynx esophagus colorectum liver breast Aflatoxin liver Chinese-style salted fish nasopharynx Probable Evidence Preserved meat and red meat Fruits and vegetables colorectum oral cavity Salt-preserved foods and salt esophagus stomach stomach Very hot (thermally) drinks and food colorectum oral cavity Dietary fiber pharynx colorectum esophagus

kidney; alcohol causes cancers of the oral cav- • High intakes of dietary fiber probably reduce ity, pharynx, larynx, esophagus, colorectum, the risk of colorectal cancer, and adequate liver, and breast. intakes of fruit and vegetables may reduce • In particular populations, aflatoxin in moldy the risk for cancers of the gastrointestinal foods causes liver cancer, and Chinese-style tract. salted fish causes nasopharyngeal cancer; • Very hot drinks and foods probably increase these risk factors are prevalent in some popu- the risk for cancers of the oral cavity, pharynx lations but are absent in many parts of the and esophagus. Further research is needed to world. clarify these relationships. • The majority of the evidence suggests that high intakes of red and processed meat probably increase the risk for colorectal cancer, and that high intakes of salt-preserved foods and salt probably increase the risk for stomach cancer.

128 Key

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Cancer Prevention and Treatment 129 Nutrition for Disease States

Bier D, et al. (eds): Nutrition for the Primary Care Provider. World Rev Nutr Diet. Basel, Karger, 2015, vol 111, pp 130–135 DOI: 10.1159/000362310

Nutritional Management in HIV/AIDS Infection

Averalda E. van Graan

Centre of Excellence for Nutrition, North-West University, Potchefstroom , South Africa

Key Words the disease and 1.5 g/kg/day during episodes of acute illness. HIV · AIDS · Nutritional management · Nutritional • In general, there is conflicting evidence on the op- assessment · Wasting · Nutrients timal protocols for nutrition support of these patients. Nutritional recommendations are guidelines only, and should always be viewed on a case-by- Key Messages case basis alongside the individual patient’s clinical • Nutritional support is one of the most immediate presentation. © 2015 S. Karger AG, Basel and critical needs of people living with HIV and AIDS, and nutritional management is integral to the care and management of the disease. • The virus and its associated conditions and symp- Introduction toms negatively influence nutritional status through decreased intake, increased requirements, and malabsorption, resulting in malnutrition. Ade- HIV remains one of the leading causes of mortal- quate nutrient intakes are therefore essential. ity in the world, with 1.5 million adults succumb- • Comprehensive nutritional assessments should be ing to the disease and 30.1 million adults living performed regularly to ensure optimal nutritional with the disease in 2010 [1] . These numbers are intervention. testament to the magnitude of the burden the • Optimal nutrition could assist to maintain lean body mass, reduce the severity of HIV-associated HIV pandemic continues to place on the interna- symptoms, support antiretroviral therapy, and im- tional community [2] . Nutritional support is of- prove quality of life. ten identified as one of the most immediate and • ESPEN guidelines state energy requirements to be critical needs of people living with HIV and AIDS increased by 20–30% during the recovery phase af- (PLWHA) [3], and nutritional management is inter opportunistic infections. The guidelines recom- tegral to the care and treatment of the disease [4] . mend protein intake of 1.2 g/kg in stable phases of HIV and nutrition are inextricably interrelated, and the well-known vicious cycle of malnutrition Table 1. Effect of common HIV symptoms and conditions and HIV eloquently illustrates the relationship on nutritional intake, requirements, absorption and losses between the virus, impairment of the immune Decreased intake system, increased susceptibility to infection, in- Loss of appetite creased nutritional needs, and poor nutrition [5] . Nausea While many developing countries are still strug- Dysphagia gling to increase antiretroviral therapy (ART) Analgesia Taste changes coverage, for many PLWHA the disease has be- Candidiasis come a long-term chronic condition. Nutritional Changes in mental condition care providers now manage severe wasting, tu- Lack of access to food berculosis, cancer, renal failure, hepatic disease GI tract discomfort and chronic complications related to highly ac- Absorption tive ART (HAART) [6] . Nutrition support and Malabsorption intervention strategies thus vary from nutrition GI ulcers and lesions Diarrhea education, supplementation to enteral and parental nutrition, to assist in symptom management, Increased requirements support medication therapy, improve resistance Fever, night sweats Weight loss against opportunistic infections (OI), complica- Wasting tions, and to increase quality of life [7] . Opportunistic infections Cancers Losses Pathophysiology in a Nutshell Vomiting Diarrhea The HIV retrovirus possesses the reverse tran- scriptase enzyme, which enables viral RNA to be transcribed to proviral DNA. The infection be- gins with the attachment of HIV virions to the cell Nutritional Status and HIV Infection surface of CD4+ T-lymphocytes via an interaction between gp120, CCR5 and CXCR4, chemo- In HIV infection, poor nutritional status is associ- kine coreceptors, which enables viral entry into ated with disease progression, as well as increased the cells. Glycoprotein 41 binds with cell chemo- morbidity and mortality. The virus, its commonly kines, leading to receptor fusion, uncoating of vi- related conditions and symptoms negatively in- ral RNA and the production of DNA copies from fluence nutritional status [6] through decreased both RNA templates by the polymerase enzyme. intake, increased requirements, malabsorption A double-stranded, unintegrated strand of DNA and losses, which result in malnutrition (table 1 ). is inserted into the host cell genome by the en- Malnutrition in HIV often manifests as weight, zyme integrase [8] . When the provirus is activat- muscle and adipose tissue loss, vitamin and mined, the DNA is converted back to RNA, trans- eral deficiencies, and abnormal biochemical pa- ported outside the nucleus and translated into rameters [4, 6]. The era of HAART has in addition new HIV proteins and enzymes. The protease en- brought new challenges such as hyperlipidemia zyme cleaves the long protein strands into smaller and lipodystrophy. Due to the heterogeneity of strands, incorporates it into HIV particles togeth- possible clinical presentations of the disease, nu- er with enzymes and the viral RNA, which are tritional assessment becomes an important step in then released from the host cell [9] . the nutritional management of HIV infection.

Nutrition in HIV 131 Table 2. Nutritional management in HIV

Assessment Nutritional requirements and management Anthropometry Energy Critical Asymptomatic: +10% Weight Symptomatic (opportunistic infection): no additions

Height (WG); +20 – 50% (ESPEN) BMI Protein Additional 12 – 15% of energy; 0.8 g/kg (WG) Waist circumference 1.2 g/kg (stable phase); 1.5 g/kg (acute illness) (ESPEN) Mid-upper arm circumference Determine nutritional risk Vitamins and minerals Body composition 1× RDA Biochemistry Implementation Markers that can be used in addition to routine blood In following order biochemistry Normal food intake, dietary modulation and Serum albumin nutritional counselling (basic nutrition, food safety, Lipid profile medication-nutrient interactions, medication Random blood glucose adverse effects1, timing considerations) Serum ferritin Oral nutritional supplements Folate Tube feeding Vitamins B12 and D Parenteral nutrition CD4 and viral load Adapted from references [4, 7, 10, 12, 13]. Clinical 1 Common: nausea, vomiting, diarrhea, taste alterations, In addition to standard nutrition-focused clinical loss of appetite, anemia, low vitamin B , copper, zinc, examination 12 hyperlipidemia. Weight change Dehydration GI tract symptoms Functional capacity Lipodystrophy be analyzed and interpreted alongside evidence- Dietary based standards, bearing in mind the effects, co- Diet history (usual intake, 24-hour recall, frequency) Lifestyle (smoking, exercise, alcohol use) morbidities and treatment of HIV infection [7] . Medication use (adverse effects, nutrient-medication interaction) Socioeconomic factors (food availability, food safety, Anthropometric Measurements food preparation) Complementary and alternative therapies Weight loss, wasting, obesity, and lipodystrophy are common in HIV patients. The etiology of HIV- associated wasting is multifactorial and alterations Nutritional Assessment in protein metabolism and body protein turnover has been well documented. Underlying nutritional A comprehensive nutritional assessment [4] should status, dietary intake, the severity of the inflamma- be performed regularly to ensure optimal nutri- tory response and disease are factors affecting the tional intervention. A complete nutritional assess- rate of weight loss. During cycles of repeated OI, ment entails anthropometric, biochemical, clinical weight loss and recovery, adipose tissue seems to be and dietary intake assessment, and includes the preferentially repleted, while loss in lean body mass timely collection of appropriate data, which should is increased during episodes of OI [6] . ART is as-

132 van Graan

sociated with many adverse effects and metabolic can provide insight into comorbidities that could abnormalities such as HIV-associated lipodystro- have nutritional implications [7] . Clinical param- phy syndrome, which is characterized by lipoatro- eters that should be assessed in conjunction with phy in the extremities and face and lipohypertro- a general nutrition-focused physical examination phy in the abdominal and dorsocervical region, and are listed in table 2 . Other key areas to assess in- breast hypertrophy [4, 6] . Measurements of body clude determining the presence of comorbid con- weight, dimensions, composition and calculation ditions, OI, and factors related to nutritional re- of BMI can be used to identify wasting and assess quirements [7, 12] . lean body mass and body fat [7] . Several anthropometry methods exist; however, in clinical practice anthropometric measurements usually include Dietary Assessment the measurements listed in table 2 [7, 10] . Dietary assessment is done to examine eating patterns, identify nutrient intake imbalances and iden- Biochemical Assessment tify factors influencing the ability to achieve adequate intakes. Food-drug interactions, nutrient The HI virus, coinciding with OI, immune dysfunc- supplements, complementary and alternative ther- tion, hormonal changes, and HAART is associated apies, potential medication-nutrition-related side with alterations in metabolism and endocrine func- effects, lifestyle patterns, and socioeconomic factors tion [7] . Abnormalities include lactic acidosis, glu- should form part of the dietary assessment [4, 7]. A cose intolerance, insulin resistance, and hyperlipid- diet history is the best means to obtain dietary in- emia. These disorders and ART are associated with take information and can be assessed by the meth- increased risk of cardiovascular disease, which to- ods listed in table 2 [4] . Nutritional assessment gether with classical risk factors account for 25% of plays an important role to ensure optimal nutrition the risk. Bone disease in this population is multifac- intervention in the nutritional care of PLWHA. torial and associated with the virus, HAART and traditional osteoporosis risk factors [2, 11]. Altered levels of nutrition-related markers have been well Nutritional Goals documented in HIV infection, and biochemical assessment provides additional information regard- Overarching nutritional goals include the following: ing nutritional status. Nutrition-related biochemi- • Maintain and improve body weight cal values listed in table 2 are seen as indicators of • Maintain and restore lean body mass nutritional status in disease complications and • Manage disease symptoms prognosis. Alterations in nutrition-related bio- • Manage metabolic abnormalities chemical values should be interpreted with caution • Maintain and correct nutrient deficiencies as these values could also reflect inflammatory re- • Support medication therapy [4, 7] . sponses and or altered metabolism [7] .

Nutritional Requirements Clinical Assessment For PLWHA, vigilance is needed to ensure di- Clinical assessment entails obtaining a medical etary adequacy, particularly in areas of high food history of the patient and performing a nutrition- insecurity or poor dietary diversity [2] . Ade- focused physical examination. A medical history quate nutrient intakes are essential, as optimal

Nutrition in HIV 133 nutrition could assist to maintain LBM, reduce increased or no increase in protein intake. Data the severity of HIV-associated symptoms, sup- were insufficient to support recommendations on port ART and improve quality of life [4]. Nutri- the amount or type of fat in HIV infection [2] . tional interventions for PLWHA include food- ESPEN guidelines, however, recommend protein based supplement interventions, oral supple- intake of 1.2 g/kg in stable phases of the disease ments with specific nutrients, enteral or total and 1.5 g/kg/day during episodes of acute illness parental therapy and appetite stimulants [13] . A [14]. Nutrition monitoring is thus important and working group (WG) on nutritional care in HIV is the best indication of the adequacy of intake for infection recently reviewed existing evidence to weight maintenance or gain [10] . support the development of new WHO guidelines [2], which in some categories differ from the previous recommendations and ESPEN Micronutrient Requirements guidelines for HIV. Recommendations on micronutrients remained unchanged at one RDA or a routine multivitamin Energy Requirements supplement, as the WG report insufficient evidence to change the recommendations. Sufficient evi- The WG reports an increased energy intake of dence exists to comment on the potential harm of 10% in asymptomatic HIV infection in normal- higher doses of selected micronutrients such as vi- weight individuals with untreated HIV [2, 14] . tamin A, zinc and multiple micronutrient supple- Data in asymptomatic HIV-infected patients on ments in some populations [2] . A Cochrane review ART and HIV wasting are less consistent, with reports zinc supplementation to be safe, but sug- some reporting increased requirements <10% gests that further evidence is needed to establish the and others reporting decreased requirements. benefits of vitamin A supplementation in adults Energy expenditure in HIV with secondary infec- [16] . It is thus clear that further investigation is war- tion is reported to be decreased, and previous rec- ranted regarding the nutritional requirements in ommendations for increased energy intake of HIV infection as shortcomings in knowledge exist. 30% now have limited supporting evidence. No recommendations for HIV lipodystrophy have been made despite evidence indicating an in- Nutritional Management crease in energy expenditure [2, 15] . This leaves nutritional care providers with no clear guide- Nutrition support in HIV infection has not been lines regarding the latter two groups. However, adequately investigated, resulting in a lack of evi- ESPEN guidelines state energy requirements to dence to demonstrate improved clinical outcomes be increased by 20–30% during the recovery [14] and thus little guidance for evidence-based phase after OI [14] . practice. A review on macronutrient interventions concluded that supplementation improved energy and protein intake, but did not have an ef- Macronutrient Requirements fect on weight, fat mass, fat-free mass, disease progression, and complications leading to death [17] . The WG recommends macronutrients to be con- Micronutrient supplementation is recommended sumed at amounts of the RDA and adjusted in at one RDA or a routine multivitamin [2] . The line with energy adjustments. On protein intake, choice of mode of nutrition support is based on the WG reports that no evidence exists to support expert opinion only [14] .

134 van Graan

Conclusions • Nutritional recommendations are guidelines, and should always be considered in conjunc- • The HI virus, coinciding OI, immune dysfunction with the individual patient’s clinical pre- tion, hormonal changes, ART and medication sentation. side effects, influences nutritional require- • Nutrition support entails providing adequate ments and management. nutrients through food intake, nutritional • Nutritional assessment involves anthropo- counseling, oral nutritional supplements, tube metric, biochemical, clinical and dietary as- feeding and parenteral nutrition. sessment.

References

1 WHO: HIV/AIDS fact sheet. November 6 Pribram V: Introduction to nutrition 12 Woodman S, Sutcliffe M, McDonald A: 2011. http://www.who.int/mediacentre/ and HIV; in Pribram V (ed): Nutrition Nutritional screening and assessment; factsheets/fs360/en/index.html. and HIV. Chichester, Wiley-Blackwell, in Pribram V (ed): Nutrition and HIV. 2 Raiten DJ, Mulligan K, Papathakis P, 2011, pp 18–31. Chichester, Wiley-Blackwell, 2011, pp Wanke C: Executive summary – nutri- 7 American Dietetic Association: Position 132–156. tional care of HIV-infected adolescents of the American Dietetic Association: 13 Nagata JM, Cohen CR, Young SL, et al: and adults, including pregnant and lac- nutrition intervention and human im- Descriptive characteristics and health tating women: what do we know, what munodeficiency virus infection. J Am outcomes of the food by prescription

do we do, and where do we go from Diet Assoc 2010; 110: 1105–1119. nutrition supplementation program for

here. Am J Clin Nutr 2011; 94(suppl): 8 Kumar P, Clark M: Infectious diseases, adults living with HIV in Nyanza Prov-

1667S–1676S. tropical medicine and sexually transmit- ince, Kenya. PLoS One 2014; 9: e91403. 3 WHO: Executive summary of a scientific ted diseases; in Kumar P, Clark M (eds): 14 Ockenga J, Grimble R, Jonkers- review. Consultation on nutrition and Clinical Medicine. Edinburgh, WB Schuitema C, et al: ESPEN guidelines on HIV/AIDS in Africa: evidence, lessons Saunders, 2002, pp 21–151. enteral nutrition: wasting in HIV and and recommendations for action. Dur- 9 Welz T, Samarawickrama A, Pribram V, other chronic infectious diseases. Clin

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ry%20WHO.pdf. trition and HIV. Chichester, Wiley- infection. Am J Clin Nutr 2011; 94(suppl): 4 Dong KR, Imai CM: Medical nutrition Blackwell, 2011, pp 3–17. 1677S–1682S. therapy for HIV and AIDS; in Mahan 10 Pribram V: Decreased nutritional status 16 Irlam JH, Visser MME, Rollins NN, Sieg- KL, Escott-Stump S, Raymond JL: and nutritional interventions for people fried N: Micronutrient supplementation Krause’s Food and Nutrition Care Pro- living with HIV; in Pribram V (ed): Nu- in children and adults with HIV infec- cess. Missouri, Elsevier Saunders, 2011, trition and HIV. Chichester, Wiley- tion. Cochrane Database Syst Rev pp 864–881. Blackwell, 2011, pp 107–131. 2010;CD003650. 5 FANTA project: Nutrition and HIV/ 11 Fitch K, Grinspoon S: Nutritional and 17 Mahlungulu S, Grobler LA, Visser ME, AIDS: a training manual nutritional metabolic correlates of cardiovascular Volmink J: Nutritional interventions for management of HIV/AIDS related and bone disease in HIV-infected pa- reducing morbidity and mortality in

symptoms. FANTA, RCQHC and the tients. Am J Clin Nutr 2011; 94(suppl): people with HIV. Cochrane Database linkages project; 2003. http://www.fan- 1721S–178S. Syst Rev 2007;CD004536. taproject.org/focus/preservice.html.

Nutrition in HIV 135 Nutrition for Disease States

Bier D, et al. (eds): Nutrition for the Primary Care Provider. World Rev Nutr Diet. Basel, Karger, 2015, vol 111, pp 136–140 DOI: 10.1159/000362311

Osteoporosis

Saira Adeel Vin Tangpricha

Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University School of Medicine, Atlanta, Ga. , USA

Key Words cence and early adulthood is important for the Vitamin D · Calcium · Osteoporosis prevention of osteoporosis. The quality and quantity of bone are influenced by a number of factors but are regulated by two key cells: the osteoblasts Key Messages which function as the bone-forming cells and os- • Vitamin D and calcium play an important role in teoclasts which function as the bone-resorbing bone physiology. cells. The balance between the number and activ- • A 10-year risk for fracture can be calculated by the ity of these cells determines the rate of bone loss FRAX tool and can assist physicians to determine in adults. Vitamin D maintains adequate calcium which patients should receive pharmacologic ther- and phosphorus homeostasis for adequate miner- apy for osteoporosis. • Several effective therapies have been approved for alization of bone. A number of other nutrients the treatment of osteoporosis in patients with a may play a role in skeletal health. Screening for high risk of fracture. © 2015 S. Karger AG, Basel osteoporosis is currently performed by dual-energy X-ray absorptiometry (DEXA). Individuals at highest risk of fracture should be offered pharmacologic therapy based on a number of risk fac- Introduction tors for future fracture.

Osteoporosis is a systemic skeletal disorder characterized by decreased bone mass and deteriora- Physiology tion of the bone microarchitecture leading to decreased bone strength and increased risk of frac- The skeleton is a dynamic organ undergoing con- tures [1]. Osteoporosis occurs more commonly in stant renewal and is replaced every 10 years [2] . elderly individuals; however, secondary causes of Osteoblast cells are responsible for the laying osteoporosis can be found in younger individuals. down of new bone by producing an extracellular Attainment of peak bone mass during adoles- matrix consisting of collagen and other proteins. The osteoblast cells in bone promote the deposi- dairy products such as milk, cheese, and yogurt tion of a hydroxyapatite crystal which is com- and some vegetables such as kale and turnip posed of calcium and phosphorus, providing greens. Most common calcium supplements con- strength and rigidity for the bone. The skeleton tain either calcium carbonate or calcium citrate. provides not only the structural support for the It is important to note that the total amount of human body but is also a storage organ for calci- calcium available in these supplements is listed as um and phosphorus, which is regulated by two the ‘elemental calcium’. key calciotropic hormones, parathyroid hormone Several recent studies have raised concerns and fibroblast growth factor-23. The osteoclast about potential increased risk of cardiovascular cells in bone resorb the extracellular matrix for mortality with the use of calcium supplements to release of calcium and phosphorus back into the prevent and treat osteoporosis. Michaëlsson and extracellular fluid and circulation, and remove colleagues [4] demonstrated in a prospective co- old bone for deposition of new bone. hort of over 60,000 women that intake of more Bone resorption and formation are tightly than 1,400 mg of calcium from diet and supple- regulated by two key proteins: receptor activator ments was associated with increased risk of car- of nuclear factor κ-B ligand (RANKL) and osteo- diovascular and all-cause mortality. The risk was protegerin. RANKL is a pro-osteoclast matura- more pronounced in women with high dietary tion protein which promotes maturation of os- and supplemental calcium use. Three recent co- teoclasts to increase bone resorption. Osteo- hort studies [5–7] and a meta-analysis of 15 trials protegerin is a decoy receptor that blocks the [8] have reported similar findings in increased risk signaling of RANKL on osteoclasts. The ratio of of cardiovascular disease with calcium supple- RANKL/osteoprotegerin is one of the factors that ment use. This is in contrast to a prospective co- determines the rate of bone turnover and has hort study of 35,000 postmenopausal women been a target for novel osteoporosis therapies. demonstrating increased risk of cardiovascular disease mortality with low calcium intake (<700 mg daily) compared to high calcium intake (1,400 Calcium and Phosphorus mg daily) [9] . The secondary analysis of 1,460 elderly women randomized to 1,200 mg of calcium Calcium and phosphorus are the key minerals for or placebo found no difference in the risk of car- the formation of the hydroxyapatite crystals in diovascular mortality [10] . The issue of whether bone. Inadequate intake of calcium and phospho- calcium supplementation results in increased car- rus from the diet can result in rickets in children diovascular disease risk clearly requires further and osteomalacia in adults. Decreased calcium investigation. Physicians should take a detailed di- intake will result in increased parathyroid hor- etary calcium intake history from their patients mone secretion from the parathyroid glands to with osteoporosis and prescribe calcium supple- increase mobilization of calcium from the bone, ments only when dietary calcium intake does not increase reabsorption of calcium from the kid- meet the recommendations of the IOM guidelines. neys, and to convert circulating 25-hydroxyvita- Low phosphorus intake is a rare cause of osteo- min D [25(OH)D] to more hormonally active malacia given that phosphorus is ubiquitous in 1,25-dihydroxyvitamin D to increase intestinal most foods. Most clinical causes of low phospho- absorption of calcium. rus causing poor skeletal mineralization result The Institute of Medicine (IOM) recommends from genetic diseases of phosphorus wasting such 1,000–1,300 mg of calcium daily for most chil- as X-linked hypophosphatemic rickets or ac- dren and adults [3] . Foods rich in calcium include quired diseases such as oncogenic osteomalacia.

Osteoporosis 137 V i t a m i n D fect of phytoestrogens on bone mineral density, and precise dietary recommendations are cur- Vitamin D is important for optimal absorption of rently not available [13] . calcium from the intestines. Vitamin D belongs to the steroid family of hormones. Vitamin D can be synthesized in the skin upon exposure to UVB ra- Vitamin K diation from the sun or obtained from the diet from limited foods. Vitamin D circulates to the Vitamin K is involved in the carboxylation of os- liver and is hydroxylated to 25(OH)D, the vita- teocalcin, thereby allowing it to bind to hydroxy- min D metabolite used to determine vitamin D apatite in bone. Some data suggest that vitamin K status. 25(OH)D circulates to the kidney and is supplementation (>45 mg/day given as mena- hydroxylated in the 1 position to form 1,25-dihy- quinone-4) may decrease bone loss and fracture droxyvitamin D, which is the hormonally active risk, but other studies have not confirmed this metabolite of vitamin D that enhances intestinal benefit [14] . absorption of calcium. There has been some debate over the amount of dietary vitamin D required and the level of Vitamin A serum 25(OH)D required for optimal skeletal health. The IOM recommends between 600–800 Both insufficient as well as excessive vitamin A IU of vitamin D for most adults. However, vita- intake has been associated with detrimental ef- min D requirements may vary according to sea- fects on bone health [15] . The Iowa Women’s son, latitude, adiposity, and skin tone. The Endo- Health Study showed an increased fracture risk crine Society recommends 1,500–2,000 IU of vi- associated with supplemental but not dietary vitamin D for those individuals at risk for vitamin tamin A intake, but this effect was not dose de- D deficiency including osteoporosis. They fur- pendent [16] . ther recommend that a target serum 25(OH)D level should be at least 30 ng/ml for patients with osteoporosis [11] . Vitamin C

Some but not all studies found a positive associa- Estrogens and Phytoestrogens tion between vitamin C intake and bone mineral density but other factors such as estrogen/hor- Estrogen therapy has been shown to prevent post- monal therapy, calcium intake and smoking may menopausal bone loss and reduce fracture risk be contributory factors [14] . [12] . Data from the Women’s Health Initiative showed increased incidence of breast cancer, coronary artery disease, stroke and venous thrombo- Magnesium embolism with estrogen-progestin therapy and increased risk of thromboembolism and stroke Magnesium is an essential nutrient that is re- with estrogen therapy alone [12]. In light of these quired for adequate calcium metabolism. Studies data, even though it has been FDA approved for have found a positive correlation between mag- the prevention of postmenopausal osteoporosis, nesium intake and bone mineral density in men estrogen is not recommended as first-line thera- as well as both premenopausal and postmeno- py. There is conflicting evidence regarding the ef- pausal women [17] .

138 Adeel/Tangpricha

Diagnosis and Treatment of Osteoporosis ology for osteoporosis [22] . Some common causes to consider include early menopause (women), Osteoporosis is diagnosed by DEXA or clinically hypogonadism (men), glucocorticoid excess (due with history of a low-trauma fracture [18, 19]. The to intake or Cushing’s syndrome), increased alco- National Osteoporosis Foundation and the US hol consumption, hyperthyroidism, hyperpara- Preventative Services Task Force recommends a thyroidism, hypercalciuria, insufficient vitamin screening DEXA of the hip and lumbar spine for D or calcium intake or chronic malabsorption all postmenopausal women 65 years and older [19, (due to celiac disease, inflammatory bowel dis- 20]. The National Osteoporosis Foundation also ease, short gut syndrome, etc.). Less common recommends a screening DEXA in men above the causes include multiple myeloma and genetic dis- age of 70 and in men and women above the age orders of collagen including Ehlers-Danlos syn- of 50 who have risk factors for osteoporosis (e.g. drome and osteogenesis imperfecta. early menopause, hypogonadism, glucocorticoid Several effective pharmacologic agents are use). An individual is diagnosed to have osteopo- available for the treatment of osteoporosis. These rosis when the bone mineral density of the hip or include oral and intravenous bisphosphonates, spine falls less than –2.5 standard deviations below anabolic agents such as teriparatide (Forteo® ) the mean of a young healthy sex-matched popula- and biologic agents such as denosumab (anti- tion (T score <–2.5). Individuals are considered to RANKL antibody) [23] . The bisphosphonates have low bone mineral density when the bone and denosumab reduce osteoclast formation and mineral density falls between –1.0 and –2.5 stan- maturation, resulting in reduced bone resorp- dard deviations compared to a young healthy sex- tion. The mechanism of how intermittent teripa- matched population (T score >–2.5 and ≤ 1.0). ratide works as an anabolic bone agent is unclear, The DEXA of the hip and spine are very im- but it appears to favor increased osteoblast over portant predictors of future fractures; however, osteoclast formation and function [24] . there are many other risk factors for a future fracture that are not taken into account by the DEXA alone including age, gender, previous history of Conclusions fracture, medical comorbidities, family history, and history of alcohol and tobacco use. Recently, • Osteoporosis is a disease that increases the risk the WHO released an online fracture risk assess- of fragility fracture in men and women. Evalu- ment tool named FRAX TM which takes into ac- ation of potential secondary causes of osteopo- count several risk factors for fracture and pro- rosis and modification of contributing risk vides a 10-year risk score for fracture [21] . The factors for continued bone loss is the first step National Osteoporosis Foundation recommends in the management of patients with osteopo- pharmacologic treatment of all individuals with rosis. hip or vertebral fractures, a femoral neck, total • Adequate vitamin D and calcium nutrition hip or lumbar spine T score of ≤ –2.5, or a FRAX and addressing modifiable risk factors remain 10-year risk score indicating ≥ 3% risk of a hip the cornerstone of therapy for prevention and fracture or ≥ 20% risk of any major osteoporosis treatment of osteoporosis. fracture in individuals with low bone mass (T • Lifestyle changes including increased physical score between –1.0 and –2.5) [20] . activity, fall prevention, and decreased con- Along with the DEXA measurement, a careful sumption of alcohol and smoking cessation history and physical examination should be per- are also important in counseling patients with formed to determine if there is an underlying eti- osteoporosis.

Osteoporosis 139 • Screening individuals at highest risk with • Pharmacologic therapy should be prescribed DEXA still remains the gold standard for to those with increased risk of fracture based diagnosing men and women with osteoporo- on past history of fractures, family history, sis. DEXA results, and the presence of secondary causes of accelerated bone loss.

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140 Adeel/Tangpricha

Nutrition for Disease States

Bier D, et al. (eds): Nutrition for the Primary Care Provider. World Rev Nutr Diet. Basel, Karger, 2015, vol 111, pp 141–145 DOI: 10.1159/000362312

Nutrition Support in Gastrointestinal Disease

James S. Scolapio Donna J. Smith

Division of Gastroenterology, University of Florida, Jacksonville, Fla. , USA

Key Words Introduction Total enteral nutrition · Total parenteral nutrition · Inflammatory bowel disease · Short This review focuses on the nutrition support of bowel syndrome hospitalized patients with gastrointestinal disease that require nutrition support with either total Key Messages enteral nutrition (TEN) or total parenteral nutrition (TPN). When to begin nutrition support, • When to begin total enteral nutrition (TEN) or total parenteral nutrition (TPN) is based on a patient’s how to deliver the formula, the type of formula nutritional state and disease severity. and the nutritional treatment for specific gastro- • Nutrition support is typically started when a patient intestinal disease states are discussed below. is unable to attain adequate oral intake for longer than 10 days. • TEN and TPN should supply approximately 25–30 When to Provide Nutrition Support kcal/kg/day. • TEN should be the method of choice for nutrition support as TPN is associated with metabolic com- The physician’s primary role includes taking a plications including hyperglycemia. complete medical history and physical examina- • Early enteral nutrition (within 48 h of admission) is tion to determine how best to manage the pa- preferred to TPN in patients with severe acute pan- tient’s nutritional needs including enteral access creatitis. for the gastroenterologist. It is also the physician’s • Small, frequent, low-fat, low-fiber meals are first line of therapy in patients with gastroparesis. responsibility to be knowledgeable of the current • Micronutrient deficiencies are common in patients nutrition literature and published guidelines and with inflammatory bowel disease and should be re- how these relate to the patient’s specific gastroin- placed accordingly. testinal disease process. • Patients with short bowel syndrome with a colonic No single laboratory test can assess the pres- remnant benefit from a high-complex carbohy- ence or severity of malnutrition. The medical drate diet low in oxalate. © 2015 S. Karger AG, Basel history including questions about nutrition intake and weight change along with a focused sidered in those patients that you suspect will re- physical examination are probably the best tools quire TEN for more than 4 weeks’ duration. A for determining a patient’s nutrition status, i.e. gastroenterologist plays a key role in providing normal or severely malnourished. The subjective enteral access for a patient. In patients requiring global assessment classification score for pa- short-term nutrition support, defined as less tients has been shown to correlate with more so- than 30 days, nasogastric or nasoenteric place- phisticated laboratory tests [1] . Patients are given ment of a 10- to 12-Fr polyurethane tube is ap- the following scores: ‘A’ normal nutrition re- propriate. Smaller tubes have a higher occur- serves, i.e. no weight loss history and no signs of rence of occlusion. Larger tubes, i.e. 16 Fr, may muscle or fat wasting on physical examination; inhibit LES (lower esophageal sphincter) func- ‘B’ less than 10% weight loss over the previous 6 tion, thereby increasing the risk of aspiration of months with some evidence of muscle or fat gastric contents and may cause significant nasal wasting, and ‘C’ greater than 10% weight loss irritation. In patients at risk of gastric aspiration over the previous 6 months with little or no oral (i.e. delayed gastric emptying, high gastric resid- intake of food over the previous 2 weeks. Patients uals, supine position) nasoenteric feeding should scored C usually have obvious muscle and fat be used. Feeding distal to the ligament of Treitz wasting upon physical examination and are con- reduces the risk of gastric regurgitation and pul- sidered at high risk of having severe malnutri- monary aspiration. Before starting the tube feed- tion. ing, correct tube position should be confirmed by In most patients who receive a score of A or B, X-ray. Percutaneous endoscopic gastrostomy the physician should wait 10–14 days before ad- tubes should be used when patient recovery is an- ministering TEN or TPN. Usually, the patient’s ticipated to take more than 30 days. Contradic- underlying medical problem that prohibited the tions to long-term placement devices may inadequate intake of food is corrected within this clude both mechanical and ethical end of life is- time period. Patients with severe malnutrition sues. A speech/swallow pathologist should assess (score C) probably derive the most benefit from a patient’s swallow function before placement of either TEN or TPN [2] . a long-term device, to prevent inappropriate The second factor for considering when to placement. feed a patient is his/her disease severity. An ex- TPN should only be used in those patients in ample would be a patient with severe pancreati- whom TEN is not possible. This may be the result tis who is scored A or B in whom it may take over of a mechanical intestinal obstruction, intestinal 2 weeks to regain the ability to take adequate fistula, or medical illness that does not allow safe oral nutrition; in this case, starting TEN or TPN passage of a feeding tube. TPN is associated with earlier than 14 days would be appropriate and complications including catheter sepsis and risk recommended. Patients scored C should have of hyperglycemia. TEN or TPN started within 48 h of hospitalization. Formula Selection TPN versus TEN If a patient cannot ingest an adequate amount of A dietician and pharmacist can be very helpful food by mouth, then TEN (nasogastric or naso- when designing the appropriate enteral or paren- enteric tube feeding) or TPN will be necessary [3, teral feeding formula. If a patient is not obtaining 4] . Percutaneous gastrostomy and percutaneous adequate oral nutrition, then TEN or TPN for- jejunostomy feeding tubes should only be con- mula should be calculated to provide approxi-

142 Scolapio/Smith

mately 25–30 kcal/kg/day [3] . The nutrient mix TEN formulas usually contain 1 kcal per mil- or ratio should contain approximately 30% of the liliter of formula and approximately 44 g of pro- total calories as lipid, protein should provide 1.0– tein per 1 liter of formula. Elemental and semi- 1.5 g/kg/day, and the remaining macronutrient elemental formulas have small-peptide proteins, should be given as carbohydrate. Patients should which are easier to absorb, as well as less total fat obtain their goal rate of nutrition infusion over a compared to traditional polymeric formulas. Most 48- to 72-hour period. of the polymeric formulas are isotonic and there- Tube feeding can be infused one of three fore dilution with water during infusion is not nec- ways: bolus syringe infusion, gravity infusion or essary. Enteral formulas contain approximately by continuous pump feeding [3] . Bolus and grav- 84% free water, and the remaining daily fluid ity feeding are also referred to as intermittent needs of the patient, which is approximately 30 ml/ feeding. Small bowel feeding should be done by kg/day, are given as tube flushes using regular tap continuous pump delivery to reduce gastrointes- water. Typically in the hospital setting, tube feeds tinal intolerance such as abdominal cramping are administered via a 24-hour pump infusion. and diarrhea. Infusion rates greater than 120 Standard polymeric formulas should be used ml/h may result in gastrointestinal bloating and in the majority of patients [3] . Most formulas con- diarrhea. If a patient cannot tolerate the higher tain 1 kcal per ml of fluid, 44 g of protein per liter, infusion rate, a calorically dense formula can be and approximately 30% lipid. These formulas are used. In patients at risk of aspiration of gastric lactose and gluten free. Formulas do not require contents, using a continuous pump infusion may dilution with water before infusion. minimize the risk of aspiration. Feeding should be started at 20 ml per hour and advanced to the target rate over a 48-hour period. Intermittent Specific Gastrointestinal Disease gastric feeding involves a larger volume per feed- Management ing than controlled continuous feeding using a pump. With gravity feeding, starting with one Acute Pancreatitis can of formula (approx. 240 ml) administered It had been standard practice to administer TPN to over 1 h and advancing to the target number of all patients with severe pancreatitis, assuming that feedings (4× per day) and volume (1–2 cans per this would rest the pancreas compared to stimula- feeding) is recommended. Bolus or syringe feed- tion of pancreatic enzyme secretion using enteral ing is not encouraged in most hospitalized pa- feeding. However, a study has questioned the wis- tients. Cyclic continuous feeding, i.e. 10–12 h dom of this practice [4] . In fact, acute severe pan- during sleep may help stimulate appetite and creatitis is an example where enteral nutrition ap- oral intake during the day while supplying nec- pears more favorable than TPN [4] . Although essary supplemental calories. Certain medica- there are no data to suggest enteral nutrition im- tions (Dilantin® , ciprofloxacin, and Sinemet® ) proves clinical outcome (faster resolution of pan- may bind to the formula and result in reduced creatitis) compared to nil per os and i.v. fluids, the absorption. Spacing of medications an hour be- data would suggest enteral nutrition is associated fore or after feeding is recommended. Feeding with less infectious complications, improved in- tubes should routinely be flushed with at least flammatory response and improved APACHE II 20–30 ml of additional water every 4 h during scores compared to TPN [4] . Nasojejunal feeding, continuous feeding and before and after inter- using either a polymeric formula or semi-elemen- mittent feedings and medication delivery to pre- tal formula, administered within 48 h of hospital- vent tube occlusion. ization, appears beneficial compared to TPN.

Nutrition Support in Gastrointestinal Disease 143 Gastroparesis in micronutrients such as vitamin D and iron. The diagnosis of gastroparesis is based on the Micronutrient levels in the blood should be combination of symptoms of early satiety and de- checked and replaced accordingly. The use of pre- lay of gastric emptying of a solid phase meal. operative TPN appears to only benefit those pa- Markedly uncontrolled glucose levels may aggra- tients with severe malnutrition. vate symptoms of gastroparesis and delay gastric emptying. Glycemic control should be optimized, Short Bowel Syndrome and medications that induce delayed gastric emp- S hort bowel syndrome and the need for TPN tying should be stopped when possible. Oral nu- usually results when a patient has had a surgical trition is preferable for nutrition and hydration, resection with less than 150 cm of small intes- using small, frequent low-fat, low-fiber meals. If tine remaining [8] . Short bowel results from inpatients are unable to tolerate solid foods, then testinal vascular events, larger resections for homogenized or liquid meals are recommended. Crohn’s disease and other intestinal disorders If oral intake is insufficient, then jejunal feeding such as volvulus and adhesive disease. TPN is should be pursued. Metoclopramide is the first usually required until intestinal adaptation oc- line of prokinetic therapy and should be adminis- curs. The type of oral diet given to a patient with tered in the lowest effective dose because of poten- short bowel syndrome depends on whether part tial side effects. Gastric electric stimulation may of the colon is remaining. Those patients with a be considered for compassionate treatment in pa- colonic remnant benefit from a high complex tients with refractory symptoms [5] . Completion carbohydrate diet low in fat. Likewise, patients gastrectomy should only be considered in patients should be placed on a low-oxalate diet. Those with severe refractory symptoms. Acupuncture patients without a colonic remnant do not re- can be considered as an alternative therapy [5] . quire a specific diet and are encouraged to eat small frequent meals throughout the day. An- Inflammatory Bowel Disease tidiarrheal medications are also helpful in slow- High dietary fats and meats are associated with an ing gastrointestinal transit, thus promoting flu- increased risk of inflammatory bowel disease. id and nutrient absorption. Trophic factors in- Among the various dietary interventions, none cluding growth hormone and glucagon-like have shown significant clinical efficacy. A meta- peptide-2 (GLP-2) have been FDA approved in analysis of 16 prospective randomized trials in a select group of patients with short bowel syn- Crohn’s patients reported that the frequency of drome. Intestinal transplant is also a treatment clinical remission of small bowel disease after option in a select group of patients with short treatment with steroids was 80%, compared with bowel syndrome. This would include those pa- 60% after treatment with an elemental or poly- tients with pending end-stage liver disease from meric diet alone [6, 7]. Pooled data of studies TPN, loss of venous access and recurrent cath- comparing polymeric (standard formulas) and el- eter infections. emental formulas showed no advantage with elemental formulas (65 vs. 61% remission rates). Published studies do not support the concept that Conclusions improved nutrition status coupled with ‘bowel rest’ improves clinical remission rate and avoids • Following the recommendations of peer-re- the need for colectomy in chronic ulcerative coli- viewed published guidelines is recommended tis and Crohn’s colitis patients. Patients with ac- in treating patients with gastrointestinal dis- tive inflammatory bowel disease may be deficient ease who require nutritional support.

144 Scolapio/Smith

• TPN or TEN should only be used in those pa- • Patients with IBD and SBS may have signifi- tients who cannot obtain adequate oral nutri- cant micronutrient deficiencies, and replace- tion and hydration. ment is usually recommended. • Although nutrition support is usually begun • Newer therapies for gastroparesis include elec- on day 10 of inadequate oral nutrition, pa- trical stimulation (pacemaker) and acupunc- tients with severe acute pancreatitis appear to ture. Novel trophic factors including glucagon- benefit when TEN is started within 48 h of like peptide-2 have been approved for the nu- hospital admission. tritional treatment of short bowel syndrome.

References

1 Detsky AS, Baker JP, Mendelson RA, et 3 Bankhead R, Boullata J, Brantley S, et al: 6 Yamamoto T: Nutrition and diet in in- al: Evaluating the accuracy of nutritional Enteral nutrition practice recommenda- flammatory bowel disease. Curr Opin

assessment techniques applied to hospi- tions. JPEN J Parenter Enteral Nutr Gastroenterol 2013; 29: 216–221.

talized patients: methodology and com- 2009; 33: 122–167. 7 Messori A, Trallori G, D’Albasio G, et al: parisons. JPEN J Parenter Enteral Nutr 4 Kalfarentoz F, Kehagias J, Mead N, et al: Defined formula diets versus steroids in

1984; 8: 153–159. Enteral nutrition is superior to paren- the treatment of active Crohn’s disease. 2 Mueller C, Compher C, Ellen D, et al: teral nutrition in severe acute pancreati- A meta-analysis. Scand J Gastroenterol-

A.S.P.E.N. clinical guidelines: nutrition tis: results of a randomized prospective ogy 1996; 31: 267–272.

screening, assessment, and intervention trial. Br J Surg 1997; 84: 1665–1669. 8 Scolapio JS: Current update in short in adults. JPEN J Parenter Enteral Nutr 5 Camilleri M, Parkman H, Shafi M, et al: bowel syndrome. Curr Opin Gastroen-

2011; 35: 16–24. Clinical guideline: management of gas- terol 2004; 20: 143–145.

troparesis. Am J Gastroenterol 2012; 373: 1–20.

Nutrition Support in Gastrointestinal Disease 145 Nutrition for Disease States

Bier D, et al. (eds): Nutrition for the Primary Care Provider. World Rev Nutr Diet. Basel, Karger, 2015, vol 111, pp 146–150 DOI: 10.1159/000362314

Liver Diseases

Jonathan Obert Matt Cave Luis Marsano

University of Louisville and Robley Rex VAMC, Louisville, Ky. , USA

Key Words Introduction Liver disease · Nutrition · Cirrhosis · Nonalcoholic fatty liver disease · Alcoholic liver disease Liver disease is ubiquitous in America, and all primary care providers will likely encounter patients with different types of liver disease fre- Key Messages quently throughout their careers. Nutrition is • Nutrition is an important aspect of the successful an important part of successfully treating liver treatment of liver disease. Nutritional regimens disease, but is often overlooked or misunder- should be tailored to the specific needs of patients stood. Liver disease is a broad term that can be with each category of liver disease. used to describe anything that causes damage to • Patients with cirrhosis should be given high-calorie the liver, ranging from an acute alcoholic hepa- diets (35–40 kcal/kg/day) along with multivitamin titis all the way to cirrhosis. Whatever process is and mineral supplements to overcome their hypermetabolic state and reverse malnutrition. Protein causing liver disease, one important aspect of restriction should be avoided in these patients. treatment is nutrition. The nutritional treat- • For nonalcoholic fatty liver disease, the first line of ment of many causes of liver diseases is similar, treatment is lifestyle modification, including de- but each cause of liver disease has an optimal creased caloric intake, increased exercise, and the nutritional regimen that will benefit that pa- addition of beneficial foods. Slow weight reduction tient. The objective of this chapter is to act as a has also shown to have beneficial effects. reference guide for some of the most common • Patients with alcoholic liver disease (alcoholic hepatitis) often suffer from protein and micronutrient types of liver disease. deficiencies. The key micronutrients for these patients include thiamine, zinc, magnesium, selenium, vitamin E, riboflavin, vitamin A, vitamin D, and folate. © 2015 S. Karger AG, Basel Cirrhosis time supplement. The supplement at bedtime is critical because it has been demonstrated to in- Malnutrition is often overlooked in patients with crease lean body mass (in contrast, supplements cirrhosis. The causes of malnutrition are multi- given during the day did not improve muscular ple, and include: (a) a hypermetabolic state with mass) [1] . increased nutritional needs (>110% of expect- Because the majority of patients with decom- ed), (b) decreased glycogen storing capacity that pensated cirrhosis have ‘covert’ (minimal or causes the patient to go into ‘starvation mode’ af- grade 1) hepatic encephalopathy, it is a good idea ter a few hours of fasting, leading to consumption to give ‘probiotic yogurt’ (with live cultures) as of his own muscular mass as a source of energy, two of the snacks because they have been shown (c) anorexia and dysgeusia, often manifestations to help control mild hepatic encephalopathy. of the low-grade endotoxemia and proinflamma- Patients with obesity still require the frequent tory state that develops due to increased intestinal meals, bedtime supplement, and 1.5 g protein per permeability, (d) gastrointestinal disorders such kg; however, in order to control weight, they can as delayed gastric emptying that often trigger have a daily calorie restriction of 500 kcal sub- nausea, abnormal small intestine motility with as- tracted from their calculated or measured caloric sociated bacterial overgrowth and maldigestion, needs. and decreased bile salts in patients with cholesta- Daily multivitamins and minerals supple- sis causing fat malabsorption and constipation, ments may correct undiagnosed micronutrient (e) medical interventions and diagnostic studies deficiencies. Zinc deficiency is common and can that require preprocedure fasting, and (f) pre- worsen dysgeusia, hepatic encephalopathy, and scription of unpalatable very low-sodium diets in exaggerate intestinal permeability; 50 mg/day of order to control fluid retention, and inappropri- elemental zinc is usually enough to correct this ate low-protein diets to control hepatic encepha- deficiency. Leg cramps are common in cirrhotics, lopathy. especially if they are receiving diuretics. Leg Patients with cirrhosis, unless they are obese, cramps interfere with sleep and have a negative require high-calorie diets with 35–40 kcal/kg/ effect on quality of life. Supplementation with day to overcome their hypermetabolic state and calcium, magnesium and zinc controls leg cramps reverse their malnutrition. Current evidence in- in most cirrhotics. dicates that protein restriction should be avoided Once the patient has fluid retention (edema because it does not help in preventing hepatic en- and/or ascites), sodium restriction is recom- cephalopathy, and worsens protein-calorie mal- mended in order to minimize the use of diuretics nutrition [1] . In prospective, randomized studies that can lead to renal dysfunction. The best prov- in patients with overt hepatic encephalopathy, en sodium restriction is 2 g/day sodium. Fluid re- normal protein intake is superior to protein restriction is not needed, unless the patient has sig- striction to control the disorder [2] . The diet nificant hyponatremia (below 126 or 128 mEq/l). should be divided into frequent small meals to prevent the onset of the ‘starvation mode’. Cir- rhotic patients should receive 1.2–1.5 g of protein Nonalcoholic Fatty Liver Disease per kg of weight [1]. A reasonable feeding protocol that is commonly utilized is to give 3 meals, 3 Nonalcoholic fatty liver disease (NAFLD) is the snacks, and a bedtime supplement with approxi- term given to all liver disorders that develop mately 500–750 kcal and 26–30 g of protein. Most due to abnormal fat deposition in the liver in of the protein is provided in the 3 meals and bed- the absence of alcohol consumption. Nonalco-

Liver Diseases 147 holic fatty liver is the term used when inflam- er study has determined that caffeine indepen- mation is not present, and nonalcoholic steato- dently has protective effects against the develop- hepatitis (NASH) is used when inflammation ment of NAFLD [6]. Modest alcohol consump- and fibrosis are present, and, in some instances, tion (defined as ≤2 drinks/day in men and ≤1 NASH can lead to cirrhosis [3]. NASH is drinks/day in women) has been found to be pro- thought to be the cause of up to three fourths of tective against the development of NASH when all cryptogenic cirrhosis [3] . The Western diet NAFLD has already been diagnosed [7] . Anti- has led to an increased prevalence of NAFLD in oxidant therapy has become a popular topic as a the United States. High fructose intake has been potential therapy for NASH, and evidence for vi- found to be an independent risk factor for tamin E treatment is promising. In nondiabetic NAFLD and the increased use of high fructose adults with proven NASH, the AASLD guide- corn syrup over the past few decades has been lines recommend using vitamin E (800 IU/day) associated with a dramatic increase in NAFLD [8] . in the United States. It is estimated that nearly 12% of total energy intake in Americans is from fructose [3] . Alcoholic Liver Disease

Nutrition in NAFLD Alcoholic liver disease (ALD) is due in part to ox- The first line of treatment for NAFLD is lifestyle idative stress in the liver. Alcohol is metabolized modification, including decreased caloric in- by the liver into acetaldehyde which can cause take, increased exercise, and possibly the addi- liver toxicity [2] . Alcohol alters the metabolic tion of known beneficial foods. Slow weight pathways in the liver and, with induction of cyto- reduction, avoiding a ketotic state, has been chrome P4502E, there is increased oxidative proven beneficial in decreasing liver enzymes, stress in the liver. decreasing the amount of hepatic fatty infiltra- It is well known that patients with alcoholic tion, and reducing progression of fibrosis and hepatitis are malnourished. The deficiency is not inflammation that can lead to cirrhosis [4] . A always caloric, but is often due to protein and mi- diet that is a net negative of 500 calories daily cronutrient deficiencies. There is a direct correla- (compared with the patient’s metabolic needs) is tion between nutrition and mortality in alcoholic a reasonable goal for slow weight reduction and hepatitis. One study has shown that patients who improved outcome with NAFLD. Although slow were able to consume over 3,000 kcal/day had weight reduction is the primary goal in treating nearly zero mortality, whereas patients who were NAFLD, studies have compared different diets unable to tolerate over 1,000 kcal/day had a great- and the one that seems most beneficial is the er than 80% 6-month mortality [2] . Steroids have Mediterranean diet [4] . The increased cost of the been shown to be beneficial in alcoholic hepatitis, Mediterranean diet makes compliance more of but enteral nutrition has been shown to be as ben- an issue, especially in patients with lower socio- eficial as steroids in improving short-term mor- economic status. Regular coffee as a source of tality and to be superior to steroids in improving caffeine consumption has been shown to reduce one-year mortality [2] . the risk of fibrosis in patients with NASH [5]. An It is very important to supplement micronu- exact amount of coffee or caffeine has not been trients in ALD. Thiamine is often deficient and studied, but it has been shown that drinking cof- must be supplemented before enteral feeding is fee with a caffeine consumption of up to 350 mg initiated. Overlooking thiamine supplementa- is possibly protective against NASH [5]. Anoth- tion can cause Wernicke’s encephalopathy,

148 Obert/Cave/Marsano

which is a serious complication of refeeding be- 750 750

fore supplementing with thiamine. Thiamine – – should be supplemented daily in all patients with ALD to correct baseline deficiency. Other micronutrients that are also deficient in ALD include zinc, magnesium, selenium, vitamin E, ribofla- 30 g of protein 30 g of protein

– – vin, vitamin A, vitamin D, and folate [2] . These can all be supplemented using a daily multivitamin with minerals and adding 50 mg/day of caffeine/coffee modest alcohol (<2 drinks/day for males and <1 for females) is okay Supplements zinc. Monitoring for signs of refeeding syndrome kcal and 26 kcal and 26 – – is important in alcoholic hepatitis as patients are – bedtime supplement with 500 – bedtime supplement with 500 often severely malnourished. It is important to closely monitor potassium, magnesium, and phosphorus in these patients after enteral nutrition is initiated, and to replace deficits immediately. corn syrup bedtime supplement watch for refeeding syndrome 3 meals + snacks bedtime supplement watch for refeeding syndrome and precautions – – 3 meals + snacks – – Conclusions

• Due to the prevalence of liver disease and the importance of nutrition in the treatment of those with liver disease, a reference guide would be beneficial to all physicians. • Malnutrition is often a complication of liver

disease, and it is important to recognize it. Fre- 2 g Na diet/day if ascites zinc 50 mg/day calcium magnesium multivitamin with minerals water restriction in serum Na <126 mEq/l thiamine initially potassium prn magnesium prn phosphorus prn multivitamin with minerals zinc quent feeding with no protein restriction as – – – – – – – – – – well as high protein snacks before bed are important in treating chronic liver disease. • Although coffee, caffeine, and vitamin E have been shown to be beneficial and/or protective in patients with NAFLD, the primary goal in 1.5 g/kg BW/day – 1.5 g/kg BW/day – vitamin E 800 IU/day1.5 g/kg BW/day – avoid high-fructose

– – –

treating this disease should be slow weight loss is ideal 1.2 1.2 – Mediterranean diet with diet and exercise. 1.2 • Micronutrients should never be overlooked in patients with any form of liver disease, and providing multivitamins with minerals is a good way to correct many of these deficiencies. 40 kcal/kg in 40 kcal/kg is

– – • Implementing the nutritional strategies out- frequent small feedings reasonable >3,000 calories/day is optimal 35 net negative 500 kcal/ day if patient is over-weight Calories Protein Micronutrients Distribution of meals lined in this chapter will benefit patients with

liver disease and hopefully serve as a quick ref- Summary of nutritional treatment regimens for patients with liver disease erence guide for physicians (table 1 ). Alcoholic hepatitis NAFLD and NASH Table 1. Liver disease Cirrhosis 35

Liver Diseases 149 References

1 Plauth M, Cabre E, Riggio O, et al: 3 Naniwadekar AS: Nutritional recom- 6 Biredinc A, Stepanova M, Pawloski L, ESPEN Guidelines on Enteral Nutrition: mendations for patients with non-alco- Younossi ZM: Caffeine is protective in

liver disease. Clin Nutr 2006; 25: 285– holic fatty liver disease: an evidence patients with non-alcoholic fatty liver

294. based review. Nutr Issues Gastroenterol disease. Aliment Pharmacol Ther 2012;

2 Beier J, Landes S, Mohammad M, Mc- 2010; 82: 8–16. 35: 76–82. Clain C: Nutrition in liver disorders and 4 Mahady SE, George J: Management of 7 Dunn W, Sanyal AJ, Brunt EM, et al: the role of alcohol; in Ross AC, Caballe- nonalcoholic steatohepatitis: an evi- Modest alcohol consumption is associ- ro B, Cousins RJ, et al (ed): Modern Nu- dence-based approach. Clin Liver Dis ated with decreased prevalence of ste-

trition in Health and Disease. Philadel- 2012; 16: 631–645. atohepatitis in patients with non-alco- phia, Lippincott Williams & Wilkins, 5 Molloy JW, Calcagno CJ, Williams CD, holic fatty liver disease (NAFLD). J

2012, pp 1115–1125. et al: Association of coffee and caffeine Hepatol 2012; 57: 384–391. consumption with fatty liver disease, 8 Al-Busafi A, Bhat M, Wong P, et al: An- nonalcoholic steatohepatitis, and degree tioxidant therapy in nonalcoholic ste-

of hepatic fibrosis. Hepatology 2012; 55: atohepatitis. Hepat Res Treat 2012; 429. 2012:947575.

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Nutrition for Disease States

Bier D, et al. (eds): Nutrition for the Primary Care Provider. World Rev Nutr Diet. Basel, Karger, 2015, vol 111, pp 151–163 DOI: 10.1159/000362315

Neurological Disorders

Neeraj Kumar

Department of Neurology, Mayo Clinic, Rochester, Minn. , USA

Key Words quate to prevent deficiency in individuals with minimal sun exposure, but larger doses may be required Nervous system · B-group vitamins · Thiamine · in individuals with signs of clinical deficiency. Folate · Niacin · Copper · Vitamin D · Vitamin E • Vitamin E deficiency is rare, although it sometimes occurs in patients with chronic cholestasis and pancreatic insufficiency. Treatment may require the use Key Messages of larger oral doses, intramuscular administration or • The B-group vitamins (vitamin B12 , thiamine, folate, a water-miscible product (d-α-tocopherol glycol). niacin, pyridoxine), copper, vitamin D, and vitamin © 2015 S. Karger AG, Basel E are important for optimal functioning of the nervous system. • Vitamin B12 deficiency is mainly seen in patients with intrinsic factor-related malabsorption such as Introduction in pernicious anemia. Treatment consists of a short course of daily or weekly therapy, often followed by Deficiency diseases such as kwashiorkor and monthly maintenance therapy. marasmus are endemic in underdeveloped • There are multiple causes of thiamine deficiency. countries. Individuals at risk in developed coun- High-risk patients should receive parenteral thiamine prior to any administration of glucose or par- tries include the poor and homeless, the elderly, enteral nutrition. patients on prolonged or inadequate parenteral • Daily folate supplements are recommended in nutrition, individuals with food fads or eating women of childbearing age as prophylaxis against disorders like anorexia nervosa and bulimia, fetal neural tube defects. Higher doses are needed those suffering from malnutrition secondary to in patients with malabsorption. chronic alcoholism, and patients with perni- • Niacin deficiency is mainly seen in populations dependent on corn as the primary carbohydrate cious anemia or disorders that result in malab- source, as well as in alcoholism. Deficiencies can be sorption like sprue, celiac disease, bacterial over- treated with oral or intramuscular nicotinic acid. growth, hepatobiliary or pancreatic disease, in- • Vitamin D deficiency is due to inadequate sun expo- flammatory bowel disease, and ileal resection. sure or malabsorption, affecting bone growth and Of particular concern in the developed world is mineralization. 400 IU of vitamin D per day is ade- the epidemic of obesity. The rising rates of bariatric surgery have been accompanied by neuro- ly significant deficiency. B 12 deficiency is com- logical complications related to nutrient defi- monly seen following gastric surgery (bariatric ciencies. surgery or gastrectomy). Other causes of B 12 The references cited in this chapter include re- deficiency include conditions associated with cent review articles. The accompanying table 1 malabsorption. Even in the presence of severe supplements the text. malabsorption, 2–5 years may pass before B 12 deficiency develops.

V i t a m i n B12 Clinical Significance The best-characterized neurological manifesta- The two active forms of vitamin B12 (B12 ) [1–4] tion of B 12 deficiency is a myelopathy that has are methylcobalamin and adenosylcobalamin. commonly been referred to as subacute com- Methylcobalamin is a cofactor for a cytosolic en- bined degeneration. The neurological features zyme, methionine synthase, in a methyl transfer typically include a spastic paraparesis, extensor reaction which converts homocysteine to methi- plantar response, and impaired perception of po- onine. Methionine is adenosylated to S-adeno- sition and vibration. Accompanying optic nerve sylmethionine, a methyl group donor required or peripheral nerve involvement may be present. for biologic methylation reactions involving Neuropsychiatric manifestations include de- proteins, neurotransmitters, and phospholipids. creased memory, personality change, and rarely, Methionine also facilitates the formation of for- delirium. Clinical, electrophysiological, and path- myltetrahydrofolate which is involved in purine ological involvement of the peripheral nervous synthesis. During the process of methionine system has been described with B 12 deficiency. formation, methyltetrahydrofolate donates the Clues to possible B 12 deficiency in a patient with methyl group and is converted into tetrahydrofo- polyneuropathy included a subacute onset of late, a precursor for purine and pyrimidine syn- symptoms, findings suggestive of an associated thesis. Impaired DNA synthesis could interfere myelopathy, onset of symptoms in the hands, with oligodendrocyte growth and myelin pro- macrocytic red blood cells, and the presence of a duction. Adenosylcobalamin is a cofactor for risk factor for B 12 deficiency. Subclinical B12 de- L-methylmalonyl coenzyme A mutase which ficiency refers to biochemical evidence of B 12 de- catalyzes the conversion of L -methylmalonyl co- ficiency in the absence of hematological or neuro- enzyme A to succinyl coenzyme A in an isomeri- logical manifestations. The incidence of crypto- zation reaction. Accumulation of methylmalo- genic polyneuropathy, cognitive impairment, nate may provide abnormal substrates for fatty and B 12 deficiency increase with age, and the lat- acid synthesis. ter may be a chance occurrence rather than caus- ative. Causes of Deficiency The majority of patients with clinically expressed Investigations B12 deficiency have intrinsic factor-related mal- Serum B12 determination has been the mainstay absorption such as that seen in pernicious ane- for evaluating B 12 status. Elevated levels of serum mia. B 12 deficiency is particularly common in the methylmalonic acid and plasma total homocyste- elderly and is most likely due to the high inci- ine are useful as ancillary diagnostic tests. The dence of atrophic gastritis and achlorhydria-in- specificity of methylmalonic acid is superior to duced food B 12 malabsorption. Food-bound B12 that of plasma homocysteine. Though plasma to- malabsorption is rarely associated with clinical- tal homocysteine is a very sensitive indicator of

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deficiency 12 develops at-risk patients should receive parenteral thiamine prior to administration of glucose or parenteral nutrition even in the presence of severe malabsorption, 2–5 years may pass before B clinically significant depletion of body folate stores may be seen in weeks/months; higher requirements in pregnancy, lactation, methotrexate toxicity deficiency state often unaccompanied by gastrointestinal or dermatologic manifestations s related to B12, thia- s related to B12,

12 50–300 mg a day of thiamine (intravenous, intramuscular, oral); higher doses may be required in Wernicke encephalopathy 1,000 mg daily for 5 days and monthly intramuscular B oral folate 1 mg three times a day followed by a maintenance dose of 1 mg/day; for acutely ill patients 1–5 mg/day (parenteral) 25–50 mg of nicotinic acid (intramuscular, oral) three times a day , serum 12 urinary thiamine, serum thiamine, erythrocyte transketolase activation assay, red blood cell thiamine diphosphate methylmalonic acid, plasma total homocystine, hematological tests (anemia, macrocytosis, neutrophil hypersegmentation), serum gastrin, intrinsic factor and parietal cell antibodies, increased signal on T2-weighted MRI involving dorsal column serum B Laboratory tests or imaging Treatment Additional comments serum folate, red blood cell folate, plasma total homocysteine erythrocyte nicotinamide adenine dinucleotide, urinary excretion of methylated niacin metabolites deficiency 12 beriberi (dry, wet, infantile), Wernicke encephalopathy, Korsakoff syndrome neurological manifestations are rare and indistinguishable from those due to B myelopathy or myeloneuropathy, peripheral neuropathy, neuropsychiatric manifestations, optic neuropathy, autonomic dysfunction significance encephalopathy (peripheral neuropathy) malabsorption), 12 recurrent vomiting, gastric surgery, alcoholism; increased demand (critically ill, hyperthyroidism, malignancy, systemic infection) with marginal nutritional status (decreased intake or absorption) alongside increased glucose intake alcoholism, gastrointestinal disease, folate antagonists (e.g. methotrexate, trimethoprim), errors of folate metabolism; folate deficiency generally coexists with other nutrient deficiencies pernicious anemia, elderly (due to atrophic gastritis and food B gastric surgery, acid reduction therapy, gastrointestinal disease, nitrous oxide toxicity, rarely strict vegetarianism, often unknown corn as primary carbohydrate source, alcoholism, malabsorption, carcinoid and Hartnup syndrome or whole-grain products, organ meats (spinach, yeast, peanuts, liver, beans, broccoli, grains and cereals fortified with folic acid) meats, egg, milk, fortified cereals, legumes enriched bread, fortified cereals Summary of the sources, causes of deficiency, neurological significance, laboratory tests, and treatment for deficiency state 12 Thiamine enriched, fortified, Folate in virtually all foods Nutrient Sources Major causes of deficiency Neurological B Niacin meat, fish, poultry, mine, folate, niacin, pyridoxine, vitamin and vitamin copper, D, E deficiency Table 1.

Neurological Disorders 153 pure sensory neuropathy with toxicity zinc toxicity may result from excess use of zinc supplements or zinc- containing denture creams some studies suggest inverse association between vitamin D intake and levels, risk of multiple sclerosis vitamin E deficiency is virtually never the consequence of a dietary inadequacy; neurological findings are rare in vitamin E-deficient adults with chronic cholestasis pyridoxine daily (oral); pyridoxine supplementation in patients on isoniazid oral elemental copper: 8 mg/day for a week, 6 mg/day for the second week, 4 mg/day for the third week and 2 mg/ day thereafter 50,000 IU of vitamin D weekly; 400 IU of vitamin D per day for maintenance vitamin E ranging from 200 mg/day to 200 mg/kg/day (oral, intramuscular); supplementation of bile salts in some patients -tocopherol to α plasma pyridoxal phosphate 50–100 mg of serum and urinary copper, serum ceruloplasmin, and urinary zinc, hematological parameters (anemia, neutropenia, vacuolated myeloid precursors, ringed sideroblasts, iron-containing plasma cells), increased signal on T2-weighted MRI involving dorsal column serum 25(OH) vitamin D, calcium and phosphorus, parathormone, radiologic changes of rickets or osteomalacia serum vitamin E, ratio of serum sum of serum cholesterol and triglycerides Laboratory tests or imaging Treatment Additional comments infantile seizures, peripheral neuropathy myelopathy or myeloneuropathy myopathy, myalgias spinocerebellar syndrome with peripheral neuropathy, ophthalmoplegia, pigmentary retinopathy significance antagonists (INH, 6 gastric surgery, zinc toxicity, gastrointestinal disease, total parenteral nutrition and enteral feeding inadequate sunlight exposure, dietary insufficiency, malabsorption, gastric surgery, older antiepileptic drugs, disease involving the pancreas, liver or kidney chronic cholestasis (particularly in children), pancreatic insufficiency, gastrointestinal disease, ataxia with vitamin E deficiency, homozygous hypobetalipoproteinemia, abetalipoproteinemia, chylomicron retention disease hydralazine, penicillamine), alcoholism, gastrointestinal disease B seafood, nuts, mushroom, cocoa, chocolate, beans, whole-grain products dairy products (often supplemented with vitamin D) (sunflower and olive), leafy vegetables, fruits, meats, nuts, unprocessed cereal grains soybeans, nuts, dairy products (continued) Copper organ meats, Vitamin D sunlight, liver, eggs, Vitamin E vegetable oils Nutrient Sources Major causes of deficiency Neurological Pyridoxine meat, fish, eggs, Table 1 Table

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sponse to therapy. A short course of daily or weekly therapy is often followed by monthly maintenance therapy. If the oral dose is large enough, even patients with an absorption defect may respond to oral B12 . Patients with pernicious anemia have a higher risk of gastric cancer and carcinoids and therefore should get an endosco- py. Patients with pernicious anemia also have a higher frequency of thyroid disease and iron deficiency and should be screened for these conditions. Response to treatment may relate to the extent a b of involvement and delay in starting treatment. Response of the neurological manifestations is Fig. 1. MRI showing increased signal involving the cervical dorsal column. Sagittal (a ) and axial ( b) T2-weighted often slow and incomplete. Response of the he- MRI showing increased signal in the paramedian aspect matologic derangements is prompt and complete. of the dorsal cervical cord (arrows). The signal change in- Methylmalonic acid and homocystine are more volves the dorsal columns. This can be seen in patients reliable ways for monitoring response to therapy with a myelopathy due to B12 or copper deficiency. than B 12 levels.

T h i a m i n e

B12 deficiency, its major limitation is its poor specificity. Hematologic manifestations of B 12 de- Thiamine [3–5] functions as a coenzyme in ficiency include anemia, macrocytosis, neutro- the metabolism of carbohydrates, lipids, and phil hypersegmentation, and megaloblastic bone branched-chain amino acids. It has a role in en- marrow changes. Anti-intrinsic factor antibodies ergy production in adenosine triphosphate syn- are specific (over 95%) but lack sensitivity and are thesis, in myelin sheath maintenance, and in neu- found in approximately 60% of patients with per- rotransmitter production. Following cellular up- nicious anemia. Patients with pernicious anemia take, thiamine is phosphorylated into thiamine may also have an elevated serum gastrin level. El- diphosphate, the metabolically active form that evated gastrin levels are a marker for hypochlor- is involved in several enzyme systems. Thia- hydria or achlorhydria. Electrophysiologic ab- mine diphosphate is a cofactor for pyruvate normalities include nerve conduction studies dehydrogenase, α-ketoglutarate dehydrogenase, suggestive of a sensorimotor axonopathy, and ab- and transketolase. Pyruvate dehydrogenase and normalities on somatosensory and visual evoked α-ketoglutarate dehydrogenase are involved in potentials. MRI abnormalities include a signal the tricarboxylic acid cycle in oxidative decarbox- change in the posterior and lateral columns and ylation of α-ketoacids such as pyruvate and subcortical white matter (fig. 1 ). α-ketoglutarate to acetyl coenzyme A and succi- nate, respectively. Transketolase transfers activat- Management ed aldehydes in the hexose monophosphate shunt The goals of treatment are to reverse the signs and (pentose-phosphate pathway) in the generation symptoms of deficiency, replete body stores, as- of nicotinamide adenine dinucleotide phosphate certain the cause of deficiency, and monitor re- for reductive biosynthesis.

Neurological Disorders 155 Causes of Deficiency ropathy. Wernicke encephalopathy often results Thiamine deficiency can result from reduced in- from severe, short-term thiamine deficiency, take or reduced absorption or increased metabol- whereas peripheral neuropathy is more often a ic requirement or increased losses or defective consequence of prolonged mild to moderate thia- transport. Often, multiple contributing factors mine deficiency. Dry beriberi is characterized by coexist. Thiamine requirements increase in chil- a sensorimotor, distal, axonal peripheral neurop- dren, during pregnancy and lactation, and with athy often associated with calf cramps, muscle vigorous exercise. Disorders such as systemic in- tenderness, and burning feet. Autonomic neu- fections, malignancy, and hyperthyroidism are ropathy may be present. A rapid progression of also associated with an increased metabolic de- the neuropathy may mimic Guillain-Barré syn- mand. Relative thiamine deficiency may be seen drome. Pedal edema may be seen due to coexist- in high-risk patients during periods of high caring wet beriberi. The symptoms of subclinical thi- bohydrate intake as is seen with nasogastric feed- amine deficiency are often vague and nonspecific ing, total parenteral nutrition, or intravenous hy- and include fatigue, irritability, headaches, and peralimentation. In these circumstances, a high lethargy. percentage of calories are derived from glucose, The clinical features of Wernicke encephalop- and the amount of corresponding thiamine re- athy include a subacute onset of the classic triad placement is inadequate. This is particularly com- of ocular abnormalities, gait ataxia, and mental mon when there is preceding starvation or where status changes. The onset may be gradual, the several days of intravenous nutrition without ad- classic triad is frequently absent, one or more equate vitamin replacement are followed by oral components of the triad may be seen later in the food intake. The well-recognized clinical setting course, and some patients may not have any of the for thiamine deficiency is alcoholism. Thiamine manifestations related to the classic triad. Reli- deficiency is being increasingly identified outside ance on the classic triad, not recognizing thia- the context of alcoholism. Early neurological mine deficiency outside the context of alcohol- complications following bariatric surgery are fre- ism, nonspecific or poorly recognized signs and quently related to thiamine deficiency. Due to a symptoms all result in missing the diagnosis. Oc- short half-life and absence of significant storage ular abnormalities include nystagmus (horizon- amounts, a continuous dietary supply of thiamine tal more common than vertical), ophthalmopa- is necessary. A thiamine-deficient diet may result resis (commonly involving the lateral recti), and in manifestations of thiamine deficiency in a few conjugate gaze palsies (usually horizontal). Gait days. and trunk ataxia is a consequence of cerebellar and vestibular dysfunction. A coexisting chronic Clinical Significance peripheral or acute neuropathy may be an addi- Thiamine deficiency affects the central nervous tional contributing factor for the gait difficulty. system, peripheral nervous system, and cardio- Mental status changes are the most constant vascular system in varying combinations. Cardiac component of the disease and include inability to involvement may manifest as high-output or low- concentrate, apathy, confusion, delirium, frank output cardiac failure. The best-characterized psychosis, and coma. It is important to recognize neurological disorders related to thiamine defi- that the intoxicated patient who does not recover ciency are beriberi, Wernicke encephalopathy, fully may be suffering from Wernicke encepha- and Korsakoff syndrome (Korsakoff psychosis). lopathy. Wernicke encephalopathy or Korsakoff syn- About 80% of patients with Wernicke enceph- drome may be associated with a peripheral neu- alopathy who survive develop Korsakoff syn-

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drome. Korsakoff syndrome is an amnestic-con- or parenteral nutrition. Patients suspected of fabulatory syndrome characterized by severe an- having beriberi or Wernicke encephalopathy terograde and retrograde amnesia that follows should promptly receive parenteral thiamine. A Wernicke encephalopathy; Korsakoff syndrome commonly used thiamine replacement regimen is emerges as ocular manifestations and encepha- 100 mg intravenously every 8 h. Higher doses lopathy subside. In Korsakoff syndrome, memo- may be required in Wernicke encephalopathy, ry is disproportionately impaired relative to oth- particularly when Wernicke encephalopathy oc- er aspects of cognitive function. curs in the setting of alcoholism. Long-term oral maintenance with 50–100 mg thiamine is com- I n v e s t i g a t i o n s monly employed. Wernicke encephalopathy of- Urinary thiamine excretion and serum thiamine ten develops in a predisposed individual because levels may be decreased in thiamine deficiency of increased metabolic demands related to coex- but do not accurately reflect tissue concentrations isting conditions like an infection which requires and are not reliable indicators of thiamine status. independent attention. A normal serum thiamine level does not exclude In wet beriberi, a rapid improvement is seen Wernicke encephalopathy. The preferred tests with clearing of symptoms within days. Improve- are the erythrocyte transketolase activation assay ment in motor and sensory symptoms takes or measurement of thiamine diphosphate in red weeks or months. Response in Wernicke enceph- blood cell hemolysates. alopathy is variable. Ocular signs improve in a MRI is the imaging modality of choice. Typi- few hours. A fine horizontal nystagmus may per- cal MRI findings include increased T2 or proton sist. Improvement is gait ataxia and memory is density or FLAIR signal in the paraventricular variable and often delayed. Mental status im- regions. Involved areas include the thalamus, hy- proves over days or weeks. Prompt treatment of pothalamus, mammillary body, periaqueductal Wernicke encephalopathy prevents the develop- midbrain, tectal plate, pons, fourth ventricle ment of Korsakoff syndrome. Korsakoff syn- floor, medulla, midline cerebellum, and, rarely, drome does not respond to thiamine therapy. in the splenium of the corpus callosum or basal ganglia structures. Mammillary body enhancement on MR has been reported as being the only F o l i c A c i d imaging abnormality in Wernicke encephalopathy. The signal abnormalities resolve with treat- Folate [2–4] functions as a coenzyme or cosub- ment, but shrunken mamillary bodies may per- strate by modifying, accepting, or transferring sist as sequelae. Additional findings in the chron- one-carbon moieties in single-carbon reactions ic stages include dilated aqueduct and third involved in the metabolism of nucleic and amino ventricles with atrophy of the midbrain tegmen- acids. The biologically active folates are in the tet- tum, paramedian thalamic nuclei, mamillary rahydrofolate form. Methyltetrahydrofolate is the bodies, and frontal lobes. predominant folate and is required for the B12 -dependent remethylation of homocysteine to methi- M a n a g e m e n t onine. Methylation of deoxyuridylate to thymi- Intravenous glucose infusion in patients with thi- dylate is mediated by methylene tetrahydrofolate. amine deficiency may consume the available thia- Impairment of this reaction results in accumula- mine and precipitate an acute Wernicke encepha- tion of uracil which replaces the decreased thy- lopathy. At-risk patients should receive paren- mine in nucleoprotein synthesis and initiates the teral thiamine prior to administration of glucose process that leads to megaloblastic anemia.

Neurological Disorders 157 Causes of Deficiency cular disease, venous thrombosis, and may cause Folate deficiency rarely exists in the pure state. It cognitive impairment. The precise significance is often associated with conditions that affect oth- of these observations awaits further studies. Fo- er nutrients. Hence, attribution of neurological late deficiency causes increased frequency of manifestations to folate deficiency requires exclu- neural tube defects in babies born to folate-defi- sion of other potential causes. Populations at in- cient mothers. creased risk of folate deficiency include alcoholics, premature infants, and adolescents. Increased Investigations folate requirements are seen in pregnancy, lacta- Plasma homocysteine levels have been shown to tion, and chronic hemolytic anemia. Folate defi- be elevated in a majority of patients with clini- ciency may be seen with small bowel disorders as- cally significant folate deficiency. Serum folate sociated with malabsorption. Folate absorption fluctuates daily and does not correlate with tissue may be decreased in conditions associated with stores. Red blood cell folate is more reliable than reduced gastric secretions such as gastric surgery, plasma folate because its levels are less affected by atrophic gastritis, acid-suppressive therapy, and short-term fluctuations in intake. acid neutralization by treatment of pancreatic insufficiency. Drugs such as aminopterin, metho- Management trexate, pyrimethamine, trimethoprim, and tri- In women of childbearing age with epilepsy daily amterene act as folate antagonists and produce folate supplement of 0.4 mg is recommended for folate deficiency by inhibiting dihydrofolate re- prophylaxis against neural tube defects. With ductase. Serum folate falls within 3 weeks after documented folate deficiency, an oral dose of decrease in folate intake or absorption, red blood 1 mg three times a day may be followed by a main- cell folate declines weeks later, and clinically sig- tenance dose of 1 mg a day. Daily doses as high as nificant depletion of folate stores may be seen 20 mg may be needed in patients with malabsorp- within months. Clinical features of folate defi- tion. Acutely ill patients may need parenteral ad- ciency occur more rapidly with low stores or co- ministration in a dose of 1–5 mg. Coexisting B 12 existing alcoholism. deficiency should be ruled out before instituting folate therapy. Plasma homocysteine is likely the Clinical Significance best biochemical tool for monitoring response to Theoretically, folate deficiency could cause the therapy. Since folate deficiency is generally seen same deficits as those seen with B12 deficiency be- in the context of a broader dietary inadequacy, cause of its importance in the production of me- the associated comorbidities need to be ad- thionine, S-adenosylmethionine, and tetrahydro- dressed. folate. For unclear reasons, neurological manifestations like those seen in B12 deficiency are rare in folate deficiency. The myeloneuropathy or neu- Niacin ropathy or megaloblastic anemia seen in association with folate deficiency is indistinguishable Niacin [1, 3, 4] in humans is an end product of from B12 deficiency. tryptophan metabolism. Niacin is converted in Folate deficiency has been associated with af- the body to nicotinamide adenine dinucleotide fective disorders. In recent years, there has been and nicotinamide adenine dinucleotide phos- some evidence suggesting that chronic folate de- phate, two coenzymes that have a role in carbohy- ficiency may increase the risk of cardiovascular drate metabolism. disease, cerebrovascular disease, peripheral vas-

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Causes of Deficiency measures of erythrocyte nicotinamide adenine Pellagra is rare in developed countries. Niacin de- dinucleotide and plasma metabolites of niacin ficiency is predominantly seen in populations de- may serve as indirect markers. pendent on corn as the primary carbohydrate source. Corn lacks niacin and tryptophan. Non- Management endemic pellagra may rarely be seen with alcohol- Oral or intramuscular nicotinic acid is used for ism and malabsorption. Pellagra may be seen in treatment of symptomatic patients. Advanced the carcinoid syndrome since tryptophan is con- stages of pellagra can be cured with intramuscular verted to serotonin instead of being used in niacin nicotinamide given in doses of 50–100 mg three synthesis. Biotransformation of tryptophan to times a day for 3–4 days followed by similar quan- nicotinic acid requires several vitamins and min- tities orally. erals like B 2 , B 6, iron, and copper. Since tryptophan is necessary for niacin synthesis, vitamin B 6 deficiency can result in secondary niacin defi- Vitamin B 6 ciency. Isonicotinic acid hydrazide (isoniazid) depletes B 6 and can trigger pellagra. An excess of Pyridoxal phosphate [1, 3, 4] serves as a coen- neutral amino acids in the diet, such as leucine, zyme in many reactions involved in the metabo- can compete with tryptophan for uptake and pre- lism of amino acids, lipids, nucleic acid, one-car- dispose the individual towards niacin deficiency bon units, and in the pathways of gluconeogene- by impairing its synthesis from tryptophan. Hart- sis, and neurotransmitter and heme biosynthesis. nup syndrome is an autosomal recessive disorder The interconversion and metabolism of B 6 is de- characterized by impaired synthesis of niacin pendent on riboflavin, niacin, and zinc. Niacin, from tryptophan and results in pellagra-like carnitine, and folate require B 6 for their metabo- symptoms. Bacterial colonization of the small in- lism. Humans and other mammals cannot syn- testines can lead to conversion of dietary trypto- thesize B 6 and thus must obtain this micronutri- phan to indoles. ent from exogenous sources via intestinal absorption. Clinical Significance Pellagra affects the gastrointestinal tract, skin, Causes of Deficiency and nervous system. The classical clinical hall- Most diets are adequate in B6 . Its deficiency is marks of pellagra have been alluded to by mne- seen with B6 antagonists like isonicotinic acid hy- monic dermatitis, diarrhea, and dementia. The drazide, cycloserine, hydralazine, and penicilla- dermatologic and gastrointestinal manifestations mine. Individuals at risk of developing B 6 defi- are frequently absent, particularly so in nonen- ciency include pregnant and lactating women, el- demic pellagra. Unexplained progressive enceph- derly individuals, alcoholics, and patients with alopathy in alcoholics that is not responsive to gastrointestinal disease. thiamine should raise the possibility of pellagra. The peripheral neuropathy seen in pellagra is in- Clinical Significance distinguishable from the peripheral neuropathy Dietary deficiency of pyridoxine or congenital de- seen with thiamine deficiency. pendency on pyridoxine may manifest as infantile seizures. Adults are much more tolerant of Investigations pyridoxine deficiency. Up to 50% of slow ac- There are no sensitive and specific blood mea- tivators may develop a dose-related peripheral sures of niacin status. It has been suggested that neuropathy when treated with isonicotinic acid

Neurological Disorders 159 hydrazide. Chronic B 6 deficiency results in a mi- tide and peptide hormone processing, mono- crocytic hypochromic anemia. A form of sidero- amine oxidase for serotonin synthesis, and ceru- blastic anemia can be treated with pyridoxine loplasmin for brain iron homeostasis. supplementation. Chronic vitamin B 6 -deficient patients may develop secondary hyperoxaluria Causes of Deficiency and thus are at higher risk for nephrolithiasis. As The most common identified cause of copper de- with other B vitamin deficiencies, glossitis, sto- ficiency in reported patients with a copper defi- matitis, cheilosis, and dermatitis may be seen. ciency myelopathy has been a prior history of gas- Excess consumption of B6 has been associated tric surgery. The duration between gastric surgery with a pure sensory peripheral neuropathy or and onset of neurological symptoms is generally ganglionopathy. It is characterized by sensory years. Excessive zinc ingestion is another cause of ataxia, areflexia, impaired cutaneous and deep copper deficiency. Unusual sources of excess zinc sensations, and positive Romberg’s sign. have included patients who consumed excessive amounts of denture cream for long periods and I n v e s t i g a t i o n s patients swallowing zinc-containing coins. Be- Vitamin B6 status can be assessed by measuring cause of copper’s ubiquitous distribution and low its levels in the blood or urine. The most com- daily requirement, acquired dietary copper defi- monly used measure is plasma pyridoxal phos- ciency is rare. Copper deficiency may occur in phate. Functional indicators of vitamin B 6 status premature or low-birthweight infants and in mal- are based on pyridoxal phosphate-dependent re- nourished infants. Copper deficiency may be a actions. complication of total parenteral or enteral nutrition. Other causes of copper deficiency include Management nephrotic syndrome, glomerulonephritis, and Isonicotinic acid hydrazide-induced neuropathy enteropathies associated with malabsorption is reversible by drug discontinuation or B 6 sup- such as celiac disease, cystic fibrosis, Crohn’s dis- plementation. Vitamin B 6 may be supplemented ease, sprue, and bacterial overgrowth. in a dose of 50–100 mg/day to prevent development of the neuropathy. Clinical Significance Menkes disease is a copper deficiency-related disease in humans and is due to congenital copper Copper deficiency. Impaired biliary copper excretion underlies copper toxicity in Wilson disease. Copper Copper [3, 4, 6] is a component of enzymes that deficiency-associated myelopathy has been de- have a critical role in maintaining the structure scribed in ruminants and other animal species and function of the nervous system. Copper per- and has been called swayback or enzootic ataxia. mits electron transfer in key enzymatic pathways. The well-recognized hematological manifesta- These copper-associated enzymes include cyto- tions of copper deficiency in humans include ane- chrome-c-oxidase for electron transport and oxi- mia and neutropenia. Thrombocytopenia and re- dative phosphorylation, copper/zinc superoxide sulting pancytopenia are relatively rare. Typical dismutase for antioxidant defense, tyrosinase for bone marrow findings include a left shift in gran- melanin synthesis, dopamine β-hydroxylase for ulocytic and erythroid maturation with cytoplas- catecholamine biosynthesis, lysyl oxidase for mic vacuolization in erythroid and myeloid pre- crosslinking of collagen and elastin, peptidylgly- cursors. Ringed sideroblasts and hemosiderin- cine α-amidating monooxygenase for neuropep- containing plasma cells may be present. Erythroid

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hyperplasia with decreased myeloid to erythroid placement, parenteral therapy is not preferred ratio and dyserythropoiesis including megalo- and generally not required. If oral therapy does blastic changes may be seen. Patients may be giv- not result in improvement or if there is rap- en a diagnosis of sideroblastic anemia or myeloid deterioration or significant hematological de- dysplastic syndrome or aplastic anemia. rangement, then 2 mg of elemental copper may be The neurological syndrome due to acquired administered intravenously daily for 5 days and copper deficiency may be present without the he- periodically thereafter. Response of the hemato- matological manifestations. The most common logical parameters (including bone marrow find- manifestation is that of a myelopathy or myelo- ings) is prompt and often complete. Recovery of neuropathy that resembles the subacute com- neurological signs and symptoms is variable. Im- bined degeneration seen with B12 deficiency. provement when present is often subjective and is Copper and B 12 deficiency may coexist. It pre- more so for sensory manifestations. Prevention of sents with a spastic gait and prominent sensory progression is often seen. ataxia. The sensory ataxia is primarily due to dorsal column dysfunction. Clinical or electrophysiological evidence of an associated axonal Vitamin D peripheral neuropathy is common. Vitamin D [3, 4] exists in two forms: vitamin D2 I n v e s t i g a t i o n s (ergocalciferol, produced by plants) and vitamin Laboratory indicators of copper deficiency in- D3 (cholecalciferol, produced with exposure to clude reduced serum copper or ceruloplasmin, ultraviolet light in the skin). Vitamin D functions and reduced urinary copper excretion. Changes more like a hormone than a vitamin. Orally in- in serum copper usually parallel the ceruloplas- gested vitamin D is absorbed and hydroxylated in min concentration. Ceruloplasmin is an acute- the liver to 25(OH) vitamin D. Further hydroxyl- phase reactant. Copper deficiency could be ation occurs in the kidney to 1,25(OH) vitamin D masked under conditions that increase cerulo- which is the active form. plasmin levels. Serum zinc elevation should prompt an aggressive search for possible exoge- Causes of Deficiency nous zinc ingestion. The most common abnor- Inadequate sun exposure may cause vitamin D mality on the spine MRI is increased T2 signal deficiency in chronically ill, institutionalized, or involving the dorsal columns ( fig. 1 ). The cervical housebound individuals. Vitamin D deficiency cord is most commonly involved. Somatosensory can also result from dietary insufficiency or mal- evoked potential and nerve conduction studies absorption. Advanced liver or kidney disease can suggest impaired central conduction and varying decrease the active form of vitamin D. The anti- degrees of peripheral neuropathy, respectively. epileptic drugs phenobarbital and phenytoin inhibit vitamin D hydroxylation in the liver and in- Management hibit calcium absorption in the intestines. In patients with copper deficiency due to excess zinc ingestion, stopping zinc supplementation Clinical Significance may suffice. Despite a suspected absorption de- Vitamin D deficiency results in defective miner- fect, oral copper is generally the preferred route of alization of newly formed bone. Vitamin D defi- supplementation. Periodic assessment of serum ciency results in hypocalcemia with secondary copper is essential to determine adequacy of re- hyperparathyroidism which further impairs nor- placement. Because of the need for long-term re- mal bone mineralization. This causes rickets in

Neurological Disorders 161 children and osteomalacia in adults. Vitamin D Vitamin E deficiency can cause a proximal myopathy which often exists in association with osteomalacia, In humans, α-tocopherol is the active and most pathological fractures, and bone pain. Severe hy- important biologic form of vitamin E [1, 3, 4] . Vi- pocalcemia may result in tetany. Hypovitamino- tamin E serves as an antioxidant and prevents the sis D has been associated with persistent, nonspe- formation of toxic free radical products. It appears cific musculoskeletal pain in some studies. Stud- to protect cellular membranes from oxidative ies have also noted an inverse association between stress, and inhibits the peroxidation of polyunsat- vitamin D (both dietary intake and blood levels) urated fatty acids of membrane phospholipids. and the risk of developing multiple sclerosis. Causes of Deficiency Investigations Due to the ubiquitous distribution of tocopherols Since 25(OH) vitamin D is hydroxylated to the ac- in foods, vitamin E deficiency is virtually never the tive form, the level of 1,25(OH) vitamin D may be consequence of a dietary inadequacy. Vitamin E normal, while levels of its immediate precursor absorption requires biliary and pancreatic secre- may be very low. Hence, vitamin D status is best as- tions. Hence, vitamin E deficiency is seen with sessed by measuring 25(OH) vitamin D levels. Oth- chronic cholestasis and pancreatic insufficiency. er laboratory abnormalities may include raised al- Vitamin E deficiency is also seen in other condi- kaline phosphatase of bone origin, hypocalcemia, tions associated with malabsorption. Vitamin E hypophosphatemia, raised parathormone, and re- deficiency may be seen due to genetic conditions duced urinary calcium excretion. Radiological like ataxia with vitamin E deficiency, hypobetali- changes of rickets or osteopenia may be present. poproteinemia, abetalipoproteinemia, and chylomicron retention disease. Vitamin E supplemen- Management tation in total parenteral nutrition may be inade- Vitamin D can be given orally as vitamin D2 or quate to maintain vitamin E stores. vitamin D 3 . 400 IU of vitamin D per day is adequate to prevent deficiency in individuals with Clinical Significance minimal sun exposure. With clinical deficiency, Development of neurological symptoms in adults 50,000 IU weekly may be required. Larger oral with acquired fat malabsorption syndromes takes doses or parenteral administration may be re- decades. Many years of malabsorption are required quired in the presence of malabsorption. Labora- to deplete vitamin E stores. The neurological mani- tory monitoring is required with doses of 50,000 festations of vitamin E deficiency include a spino- IU three times a week. Toxicity includes hyper- cerebellar syndrome with variable peripheral nerve calcemia, hypercalciuria, and renal failure. Serum involvement. The phenotype is similar to that of and urine calcium and serum 25 (OH) vitamin D Friedreich’s ataxia. The clinical features include cer- should be monitored and when urinary calcium ebellar ataxia, hyporeflexia, proprioceptive, and vi- excretion exceeds 100 mg/24 h, the vitamin D bratory loss, and an extensor plantar response. Cu- dose should be reduced. Associated secondary taneous sensations may be affected to a lesser degree. hyperparathyroidism can cause hypercalcemia, Ophthalmoplegia, ptosis, and pigmentary retinopa- hypercalciuria, and nephrolithiasis. This can be thy may be seen. An associated myopathy, at times prevented by ensuring that there is adequate cal- with inflammatory infiltrates and rimmed vacuoles, cium repletion and thus avoiding parathyroid has been described. The neuropathy associated with stimulation. An inappropriately high phosphate vitamin E deficiency preferentially involves centrally level suggests secondary hyperparathyroidism. directed fibers of large myelinated neurons.

162 Kumar

Investigations higher dose or parenteral formulation. Supple- Hyperlipidemia or hypolipidemia can indepen- ments of bile salts may be of value in some pa- dently increase or decrease serum vitamin E with- tients. The free radical scavenger and antioxidant out reflecting similar alterations in tissue levels of properties of vitamin E have led to its use in con- the vitamin. Effective serum α-tocopherol conditions like Alzheimer disease and amyotrophic centrations are calculated by dividing the serum lateral sclerosis. The use of vitamin E in these α-tocopherol by the sum of serum cholesterol and conditions is unproven. triglycerides. In patients with neurological manifestations due to vitamin E deficiency, the serum vitamin E levels are frequently undetectable. Ad- Conclusions ditional markers of fat malabsorption such as increased stool fat and decreased serum carotene • Optimal functioning of the nervous system is levels may be present. dependent on a constant supply of essential Somatosensory evoked potential studies may nutrients. show evidence of central delay, and nerve conduc- • Particularly important for optimal function- tion studies may show evidence of an axonal neu- ing of the nervous system are the B-group vi- ropathy. Spinal MRI in patients with vitamin E tamins (B12 , thiamine, folate, niacin, pyridox- deficiency-related myeloneuropathy may show in- ine), copper, vitamin D, and vitamin E. creased signal in the cervical cord dorsal column. • Not infrequently multiple nutritional deficiencies coexist. M a n a g e m e n t • The presence of multiple causes for a nutrient With cholestatic liver disease, treatment with deficiency increases the chances of the devel- standard doses of fat-soluble vitamin E may be opment of clinical manifestations related to ineffective because of fat malabsorption. Larger that particular nutrient deficiency. oral doses or intramuscular administration or a • The preventable and potentially treatable na- water-miscible product (d-α-tocopherol glycol) ture of these disorders makes this an impor- may be required. An empiric approach is to start tant subject. with a lower dose, increase it gradually, and based • Prognosis depends on prompt recognition on the clinical and laboratory response consider a and institution of appropriate therapy.

References 1 Chaudhry V, Umapathi T, Ravich WJ: 4 Kumar N: Neurologic presentations of Neuromuscular diseases and disorders nutritional deficiencies. Neurol Clin

of the alimentary system. Muscle Nerve 2010; 28: 107–170.

2002; 25: 768–784. 5 Sechi G, Serra A: Wernicke’s encepha- 2 Carmel R, Green R, Rosenblatt DS, Wat- lopathy: new clinical settings and recent kins D: Update on cobalamin, folate, and advances in diagnosis and management.

homocysteine. Hematology Am Soc He- Lancet Neurol 2007; 6: 442–455.

matol Educ Program 2003: 62–81. 6 Kumar N: Copper deficiency myelopa- 3 Kumar N: Nutritional neuropathies. thy: human swayback. Mayo Clin Proc

Neurol Clin 2007; 25: 209–255. 2006; 81: 1371–1384.

Neurological Disorders 163 Nutrition for Disease States

Bier D, et al. (eds): Nutrition for the Primary Care Provider. World Rev Nutr Diet. Basel, Karger, 2015, vol 111, pp 164–168 DOI: 10.1159/000362319

Anemias due to Essential Nutrient Deficiencies

Sally P. Stabler

Division of Hematology, School of Medicine, University of Colorado, Aurora, Colo. , USA

Key Words common hemoglobinopathies such as thalas-

Anemia · Iron deficiency · Vitamin B12 · Folate semia minor and Hgb E which also affect a population’s normal values. Anemia may be accompanied by other cytopenias such as leukopenia and Key Messages thrombocytopenia. Anemia impacts many as- • Iron deficiency results from decreased intake in the pects of health such as growth and development, setting of increased loss due to menstruation, child- perinatal health and even survival in seniors with birth or gastrointestinal bleeding. chronic conditions. Anemias due to nutritional • Diets low in animal source foods are deficient in deficiencies are easily treated; thus, prompt diag- both iron and vitamin B12 . nosis is important. Often, such anemias are a sign • Atrophic gastritis (pernicious anemia) and other malabsorption syndromes are the major cause of of other medical conditions that require investi- vitamin B12 deficiency megaloblastic anemia. gation. • Folate deficiency megaloblastic anemia is often the Iron deficiency is the most common cause of result of alcoholism, drug therapy or malabsorption anemia worldwide, especially in women due to syndromes. the difficulty of replacing iron lost from men- • Vitamin B12 deficiency causes elevated methylma- struation and childbearing [1] . Iron is most lonic acid levels, and both B12 deficiency and folate deficiency cause elevated homocysteine levels. readily absorbed when bound to heme, as found © 2015 S. Karger AG, Basel in animal foods; thus, nutritional iron deficiency is common in populations who do not eat meat. Iron deficiency anemia arises in occult bleeding of the gastrointestinal tract, and thus Introduction can be an early sign of malignancy or a consequence of aspirin and/or anticoagulant drug Anemia is defined as hemoglobin (Hgb) less than therapy. Both vitamin B12 (cobalamin) and fo- 13 g/dl for males and 12 g/dl for females. There late deficiency cause megaloblastic anemia, and are many factors influencing Hgb such as sex, the former also causes a demyelinating disorder age, race, altitude of residence and presence of of the nervous system. Mixed nutrient deficiencies frequently coexist because diets containing Laboratory Testing in Iron Deficiency little animal protein are also deficient in both iron and B 12, and gastrointestinal disorders may Serum ferritin <12 ng/ml is indicative of de- cause malabsorption of all three nutrients as creased iron stores (table 1 ). Unfortunately, ferri- well as occult blood loss. tin is an acute-phase reactant and may be in the normal range or actually high in patients with iron deficiency and inflammation. Seniors may I r o n D e f i c i e n c y have absent iron stores with ferritin values as high as 50 ng/ml [2] . Serum iron, the saturation of The largest quantity of iron is bound to Hgb in transferrin, and total iron-binding capacity are red blood cells. Absorbed iron is bound to serum also useful tests, best obtained in the fasting state. transferrin and is delivered to all tissues including A low serum iron (<50 μg/dl) and a high total the bone marrow. The percent saturation of iron-binding capacity (>450 μg/dl) translates into transferrin is a useful test in the diagnosis of iron a low transferrin saturation level, i.e. <15%. If deficiency. Iron that is not needed for heme syn- malabsorption of iron supplements is suspected, thesis is stored in ferritin, another useful mea- the patient may have the serum iron measured be- surement of iron status. Daily losses of iron are fore and after ingestion, where a rise in serum approximately 1 mg in men, which is compen- iron of 100 μg/dl after 2 h should be expected. sated by absorption of 1 mg of iron per day in males who store about 800 mg of iron in Western countries. Menstruating women have higher iron Treatment of Iron Deficiency requirements, needing to absorb 1.5–2 mg of iron daily. A total of 1,000 mg of iron may be required One ml unit of packed red blood cells contains during pregnancy and childbirth. 1 mg of iron; thus, 1 unit of transfused blood con- The bioavailability of dietary iron is much tains 250 mg of iron, which will raise Hgb levels lower from plant foods as compared to the heme by 1 g/dl. Therefore, a patient with 7 g/dl of Hgb iron found in animal foods. Small intestinal gas- will require 1,500 mg of absorbed iron. Iron salts trointestinal diseases cause iron malabsorption. such as ferrous sulfate, gluconate, and fumerate In developed countries, however, the major cause are used for oral supplementation; they contain of iron deficiency is bleeding. Besides peptic dis- between 30 and 60 mg of elemental iron, although ease and cancer, the widespread use of aspirin only about 15 mg is usually absorbed (table 1 ). and warfarin is associated with recurrent epi- Continue supplements for 2–3 months after reso- sodes of iron deficiency anemia. lution of the anemia in order to replace stores. In patients with ongoing bleeding, the final maximum Hgb and MCV values should be noted and Diagnosis of Iron Deficiency used to guide retreatment. There are excellent, safe, intravenous prepara- After depletion of stored iron, there is iron-defi- tions of iron that should be used in intolerant pa- cient erythropoiesis and eventually microcytic tients, especially when bleeding is brisk, and it is (mean cell volume, MCV <80 fl) and hypochro- unlikely that oral supplementation will be ade- mic anemia with occasional thrombocytosis. A quate [3] . The reformulated iron dextran can be fall in MCV levels in a patient known to be at risk used in large doses, up to 1,000 mg administered for iron deficiency is a sign that iron supplemen- i.v. over 4 h. There are also three new i.v. iron tation should begin. preparations: iron gluconate, iron sucrose and

Nutritional Anemias 165 ferumoxytol. Iron sucrose is dosed at 200–300 Table 1. Iron deficiency anemia mg, iron gluconate at 125 mg/dose and feru- Causes moxytol as high as 500 mg i.v. over 90 s, but the Bleeding, lack of animal-based food products latter only has approval in the United States for Laboratory tests dialysis patients. (1) Hypochromic, microcytic anemia or fall in MCV Iron deficiency anemia is undertreated. Regu- (2) Serum ferritin <12 ng/ml (<50 in seniors) lar monitoring for a fall in red cell MCV and ag- (3) Serum iron <50 μg/dl; TIBC >450 μg/dl; saturation <15% gressive replacement with oral or i.v. iron will Treatment prevent needless blood transfusion and hospital- (1) Iron salts, 30 – 60 mg tablets 1 – 3/day ization for acute anemia as well as maintain qual- (2) i.v. iron dextran, iron sucrose or iron gluconate, ity of life and productivity [1] . 1,000, 300 or 125 mg/session, respectively (3) Correct bleeding problem

Megaloblastic Anemia due to Vitamin B 12 or Folate Deficiency Table 2. Clinical abnormalities in vitamin B12 or folate deficiency Megaloblastic anemia is caused by a defect in

DNA synthesis which leads to the production of Megaloblastic anemia in B12 or folate deficiency larger cells than usual (macrocytosis and hyper- Macrocytic red blood cells, high MCV segmented neutrophils) and apoptosis and de- Hypersegmentated granulocytes High lactate dehydrogenase struction of red blood cells in the bone marrow High indirect bilirubin (ineffective erythropoiesis). Both vitamin B 12 Low haptoglobin and folate deficiency cause identical megaloblas- Hypercellular bone marrow with increased erythroblasts tic anemia, which can be confused with acute Neurologic disease in vitamin B12 deficiency leukemia or hemolytic syndromes when severe Paresthesia, ataxia, loss of position sense [4] . Spongy degeneration of spinal cord or brain Inverse relationship with anemia

Causes of Vitamin B12 Deficiency

Plants do not require vitamin B12 ; thus, the sourc- or the distal ileum will also cause severe B12 defi- es of B 12 in the human diet are all animal-based ciency. The breastfed infant of a B12 -deficient including meats, dairy products and seafood, and mother may develop severe B12 deficiency with especially shellfish. Low meat consumers and failure to thrive and severe developmental dis- vegetarians are at risk for vitamin B12 deficiency ability. [4, 5]. Although the RDA for vitamin B12 is 2.4 μg/day, diets containing 4–6 μg show improved status over lower quantities [5] . The most severe Diagnosis of Vitamin B 12 Deficiency vitamin B12 deficiency is seen in pernicious anemia which is caused by a lack of intrinsic factor Vitamin B12 deficiency should be suspected in pa- secreted by gastric parietal cells due to autoim- tients with anemia or pancytopenia of unclear eti- mune attack. Intrinsic factor normally carries ology, especially with macrocytosis and other au- bound B12 to the ileum, where it is absorbed. toimmune diseases such as autoimmune thyroid Thus, surgical removal or bypass of the stomach disease or vitiligo (table 2 ).

166 Stabler

Table 3. Vitamin B12 deficiency vs. folate deficiency

Vitamin B12 deficiency Folate deficiency

Causes Diet poor in meat Diet poor in vegetables Pernicious anemia Alcoholism, drugs, small bowel Gastric or ileal surgery or bypass disease or hemolysis Lack of gastric acid Diagnosis Low serum B12, positive intrinsic factor antibodies Low serum folate High methylmalonic acid and homocysteine High homocysteine Normal methylmalonic acid Treatment CN-cobalamin 1 mg/month i.m. Folic acid 1 mg/day oral

or 1 – 2 mg/day oral Correct the underlying cause

Values of serum B12 <100 or >400 pg/ml are ministration or high-dose (1–2 mg) oral tablets usually diagnostic. However, the vitamin B12 level must be used. One can inject 1 mg cyanocobalamin has poor specificity and sensitivity in the interme- i.m. daily for several days in cases of severe defi- diate ranges. Assays of methylmalonic acid and/or ciency, followed by weekly administration for the total homocysteine prior to treatment with vita- next 4–8 doses, then monthly for life [5] . A ran- min B12 will confirm or eliminate the diagnosis of domized trial showed that serum vitamin B12 levels vitamin B12 deficiency [6]. Intrinsic factor blocking were higher and methylmalonic acid levels were antibodies will confirm pernicious anemia; how- lower at 2 months with high-dose oral supplemen- ever, they are present in only 50% of cases. tation as compared to injections [8] . The most com- About 30% of patients with pernicious anemia mon problem in pernicious anemia is that treat- will present with predominant neurologic signs ment is discontinued; thus, patient education is an and symptoms, especially paresthesia, loss of essential part of the management of this disorder. proprioception, and ataxic gait. The severity of the neurologic findings is inversely related to the severity of the megaloblastic anemia, leading to Causes of Folate Deficiency delay in diagnosis [7] . Treatment with vitamin B12 will halt the progression of these lesions but In contrast to vitamin B12 , a diet rich in fruits, veg- often recovery is incomplete. etables and organ meats will supply an adequate amount of folate. Folates are absorbed in the jejunum, and some drugs and alcohol as well as dis- Treatment of Vitamin B12 Deficiency eases of the small intestine will interfere with absorption. Alcoholics have a higher than normal Dietary deficiency can be treated with multivitamin requirement for folate. Persons with hemolysis supplements, which contain between 6 and 100 μg also require more folate. Table 3 provides an over- of vitamin B12 . However, since most patients have view of the causes, diagnosis, and treatment of fo- malabsorption of vitamin B12 , either parenteral ad- late deficiency versus vitamin B12 deficiency.

Nutritional Anemias 167 Folates appear to play a role in preventing neu- bearing age are recommended to take a supple- ral tube defects. Thus, the United States, Canada ment of at least 400 μg/day and/or prenatal vita- and many other countries mandated folate forti- mins, since neural tube formation occurs prior to fication of grain products as early as 1998 in or- knowledge of the pregnancy. It is essential to der to prevent these tragic birth defects. As a re- avoid treating the vitamin B12 -deficient patient sult, folate deficiency has become rare with the with folic acid alone. The megaloblastic anemia exception of patients in the above-mentioned in vitamin B12 deficiency may respond to folate groups. There have been population-wide in- treatment, but any other neurologic disease will creases in the levels of serum folate and decreases remain untreated and may progress. in serum total homocysteine [9] .

Conclusions Diagnosis and Treatment of Folate Deficiency • Iron deficiency is common and suspected when Low serum folate (<3 ng/ml) indicates folate red blood cells are microcytic and hypochromic. deficiency with the following caveats: serum fo- • Either oral or i.v. iron replacement is safe and late can be depressed in vitamin B12 deficiency effective. and after a short period of poor dietary intake. • Vitamin B12 deficiency causes both megalo- Red blood cell folate assays are not recommend- blastic anemia and demyelinating neurologic ed. There are strong inverse correlations between disease curable with replacement. serum folate levels and serum total homocysteine • High-dose oral B12 (1–2 mg/day) is as effective [9] . Elevated total homocysteine levels can be as parenteral treatment. used to diagnose folate deficiency prior to treat- • Food folate fortification has improved popula- ment [6] . Most patients can be treated with an tion folate status and decreased neural tube oral folate supplement of 1 mg. Women of childbirth defects in many countries.

References

1 Boccio JR, Iyengar V: Iron deficiency: 5 Bor MV, von Castel-Roberts KM, Kau- 7 Healton EB, Savage DG, Brust JC, et al: causes, consequences, and strategies to well GP, et al: Daily intake of 4 to 7 mi- Neurologic aspects of cobalamin defi-

overcome this nutritional problem. Biol crog dietary vitamin B-12 is associated ciency. Medicine 1991; 70: 229–245.

Trace Elem Res 2003; 94: 1–32. with steady concentrations of vitamin 8 Kuzminski AM, Del Giacco EJ, Allen 2 Joosten E, Pelemans W, Hiele M, et al: B-12-related biomarkers in a healthy RH, et al: Effective treatment of cobala-

Prevalence and causes of anaemia in a young population. Am J Clin Nutr 2010; min deficiency with oral cobalamin.

geriatric hospitalized population. Ger- 91: 571–577. Blood 1998; 92: 1191–1198.

ontology 1992; 38: 111–117. 6 Savage DG, Lindenbaum J, Stabler SP, 9 Pfeiffer CM, Caudill SP, Gunter EW, et 3 Auerbach M, Ballard H: Clinical use of Allen RH: Sensitivity of serum methyl- al: Biochemical indicators of B vitamin intravenous iron: administration, efficacy, malonic acid and total homocysteine status in the US population after folic and safety. Hematology Am Soc Hematol determinations for diagnosing cobala- acid fortification: results from the Na-

Educ Program 2010; 2010: 338–347. min and folate deficiencies. Am J Med tional Health and Nutrition Examina-

4 Stabler SP: Vitamin B12 deficiency. N 1994; 96: 239–246. tion Survey 1999–2000. Am J Clin Nutr

Engl J Med 2013; 368: 149–160. 2005; 82: 442–450.

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Nutrition for Disease States

Bier D, et al. (eds): Nutrition for the Primary Care Provider. World Rev Nutr Diet. Basel, Karger, 2015, vol 111, pp 169–173 DOI: 10.1159/000362320

Anorexia Nervosa

a b Enrica Marzola Walter H. Kaye a Section of Psychiatry, Department of Neuroscience, University of Turin, Turin , Italy; b Department of Psychiatry, University of California at San Diego, San Diego, Calif. , USA

Key Words Introduction Anorexia nervosa · Weight restoration · Weight maintenance · Macronutrient · Micronutrient · Anorexia nervosa (AN) is a complex and difficult Nutrient restoration to treat illness that in a number of cases becomes chronic and disabling. It is a disorder of unknown etiology that most commonly occurs in adolescent Key Messages girls. AN individuals exhibit an egosyntonic resis- • There are two subtypes of eating behaviors in an- tance to eating leading to a significantly low body orexia nervosa (AN): the restricting type and the binge eating/purging type. weight, intense fear of gaining weight, body image • In addition to effectively treating mood and cogni- distortions, and severe weight loss due to a relent- tive disturbances, weight restoration is a central el- less pursuit of thinness and restrictive eating. ement of AN treatment. Improvements in the understanding and • Weight restoration can be divided into two phases: treatment of AN are of particular importance acute stabilization and weight maintenance. given its chronic and relapsing course, often en- • During hospitalization, AN patients tend to require tailing costly and severe medical morbidity. Im- escalating caloric intake in order to maintain a 1–1.5 kg/week weight gain. The caloric intake needs to be portantly, AN has the highest death rate of any increased stepwise over time, to around 60–100 psychiatric illness [1] , also because there are no kcal/kg/day, to achieve weight gain. proven effective treatments to reverse the symp- • After returning to a healthy body weight, AN indi- toms [2] . viduals are still energy inefficient and need at least Individuals with AN, particularly those with 50–60 kcal/kg/day for weight maintenance (com- the restricting type (R-AN), show altered neural pared to approx. 30 kcal/kg/day for healthy women). • A major long-term goal is to increase the variety of mechanisms and avoid eating because its results foods consumed. Daily essential macronutrient re- are anxiogenic and not rewarding [3, 4] . From a quirements to maintain weight are 110–140 g of clinical standpoint, individuals with AN appear carbohydrates, 15–20 g of essential fatty acids and to become hypermetabolic during weight resto- 1 g of protein per kilogram of body weight in adults ration [5] , and they need an increased caloric in- and adolescents. © 2015 S. Karger AG, Basel take to maintain a safe weight after recovery. The continuous restrictive eating and mal- ness becomes severe, also promoting dropout nutrition results in pervasive disturbances of from treatments [9] . An accurate differential di- most organ systems. Nutrition restoration is a agnosis with medical conditions (i.e. endocrine core element in treatment since weight restora- and gastrointestinal disorders) should be careful- tion is fundamental to avoid severe physical ly performed. complications and to improve cognitive function in order to render therapeutic interventions effective [6] . AN Eating Behavior

AN individuals tend to eat significantly fewer E t i o l o g y calories by restricting caloric intake and avoiding calorie-dense foods. AN patients show unusual The exact AN etiology is unknown, but it is influ- eating behaviors like slow and irregular eating, enced by biological, developmental, and social vegetarianism, and choosing a narrow range of processes with cultural attitudes toward physical foods. attractiveness being relevant though not preemi- Both adolescents and adults with AN, when nent. AN stereotypic clinical presentation, genet- compared with healthy individuals, tend to show ics, sex distribution, and age of onset support the macronutrient and micronutrient deficiencies role of intrinsic biological vulnerabilities. with lower intake of all types of fat, higher fiber intake, and usually normal protein and carbohydrate consumption. Epidemiology Interestingly, these eating behaviors persist during short-term recovery and are related to The onset of AN is common in adolescent fe- outcome; in fact, low-energy foods and limited males, and up to 0.7% of this age group may be variety are associated with poor outcome [10] . affected [7] , while the current lifetime prevalence In terms of caloric intake, it should be noted estimate of this illness is 0.9% in women and 0.3% that healthy young adult women tend to eat in men [8]. AN is usually a protracted illness; ap- about 30 kcal/kg/day (range: 20–40) [11] . For a proximately 50–70% of affected individuals im- 50-kg woman, this means eating 1,500 kcal/day, prove or recover, around 20% become chronical- with the normal range falling between 1,000 ly ill, and 5–10% die [8] . and 2,000 kcal/day. In our experience, individuals with AN tend to find it difficult to eat more than 10–20 kcal/kg/day (30 kg = 300–600 kcal/ Clinical Presentation day).

Two subtypes of eating-related behaviors in AN are typically described. First, R-AN lose weight T r e a t m e n t purely by dieting and exercising without binge eating or purging. Second, binge eating/purging The treatment of AN presents unique challenges; type anorexics (BP-AN) also restrict their food there are currently no FDA-approved medica- intake and exercise to lose weight, but periodi- tions, and few psychotherapies are evidence based cally engage in binge eating and/or purging. [for review, see 12]. In addition to effectively The egosyntonic nature of this syndrome of- treating mood and cognitive disturbances, it is ten prevents the evaluation of AN before the ill- critical to provide weight restoration.

170 Marzola /Kaye

Weight Restoration build tissue. AN people often complain of becoming hot and sweaty during nutritional resto- Given the high caloric needs during the process of ration. In fact, individuals become hyperther- weight restoration, many AN individuals are mic since the thermic effect of food in AN pa- treated in specialized inpatient, residential or day tients during renutrition is high, representing treatment programs. NICE [2] and APA [6] guide- up to the 30% of energy expenditure instead of lines specify clearly that the first goal of treat- the 14–16% in healthy controls, mostly at the be- ment is weight restoration, but both guidelines ginning of refeeding [14] . This can be explained lack specificity regarding this topic. by the higher energy intake during refeeding During weight restoration, R-AN need more and the low efficiency in the initial phases of re- calories than BP-AN to gain the same weight [5] . nutrition due to changes in hormones or auto- In our experience, during hospitalization, AN nomic functions. patients tend to require escalating caloric intake in order to maintain a 1–1.5 kg/week weight gain. Healthy women usually require about 30 kcal/ Medical Consequences kg/day to maintain their weight (range: 20–40). If we start a patient with AN on that amount of Emaciation in AN is commonly associated with calories, however, the patient tends not to gain medical complications (compromised cardiovas- weight. Rather, we have to increase their caloric cular status, hypoalbuminemia, anemia). At high intake stepwise over time, usually to somewhere risk are those with body mass index <12, BP-AN between 60–100 kcal/kg/day to achieve weight individuals, and those with physical comorbidi- gain. ty [2] . Refeeding syndrome is a rare but crucial side effect to be considered at the beginning of renu- Role of Exercise and Metabolism trition. It is caused by rapid refeeding of someone in a state of starvation, mainly if the patient is People with AN tend to become hypermetabol- chronically ill. Refeeding syndrome is character- ic. That is, they easily lose weight, and need to ized by hypophosphatemia, hypomagnesemia, eat large amounts of food to gain weight [5] , hypokalemia, glucose intolerance, fluid overload, also because in these patients caloric intake and thiamine deficiency. This syndrome can lead shows less efficiency in terms of being convert- to cardiac arrhythmias, congestive heart failure, ed into tissue. hypotension, encephalopathy, respiratory failure, In AN, excessive exercise (pacing, jogging, metabolic acidosis, rhabdomyolysis, coma, sei- making restless motions) is a common symptom zures, and skeletal-muscle weakness. To avoid even in the face of severe emaciation, contribut- refeeding syndrome, electrolyte levels should be ing to increased caloric requirements [5] . AN determined for the first 5 days and every other people who exercise need almost a 3-fold higher day for several weeks, in addition to performing range of calories to gain 1 kg [13] ; people who do EKG assessments [6] . If indicated, during the first little exercise only need an excess of 4,000 calo- days of refeeding, multivitamins and minerals ries to gain 1 kg of weight, whilst those who en- should be provided under strict monitoring to gage in extreme exercise need up to 12,000 addi- prevent toxicity in case of excessive supplementa- tional calories to gain 1 kg of weight. tion [2] . Another issue in AN is that energy intake may be converted into heat, rather than used to

Anorexia Nervosa 171 Phases of Weight Restoration hospital discharge represent a reliable predictor of outcome, with the presence of psychological Treatment approaches can be subdivided into two and organic causes being a hindrance to long- phases based on the patient’s therapeutic needs: term recovery. These increased caloric needs tend acute stabilization and weight maintenance. to normalize with time since over 3–6 months AN people show a normalization of their metabolism Acute Stabilization needing between 20 and 40 kcal/kg/day to main- At the start of weight gain, the caloric intake should tain weight as healthy women [5] . be of 30–40 kcal/kg/day for inpatients to achieve a safe clinical stabilization before beginning weight gain and 20 kcal/kg/day for outpatients [6] . Nutrients AN patients need 5,000–10,000 excess calories to gain a kg of weight, so a 35-kg patient needs From a nutrition standpoint, increasing the vari- about a 1,000 kcal/day (30 kcal/kg) to maintain ety of foods consumed is a major goal, although her weight and a minimum of 2,000 kcal/day to this represents a great difficulty for patients [10] . gain weight. Importantly, no specific recommendations for Later in refeeding, it is possible to gain about macronutrient distribution have been developed 1–1.5 kg/week for inpatients and 0.5 kg/week for in AN. According to the Institute of Medicine, outpatients [6] . Studies suggest that AN patients daily essential macronutrient requirements (in need a higher amount of calories – about 3,400 adolescents and adults) to maintain weight are kcal – to gain 0.5 kg/week above the calories 110–140 g of carbohydrates, 15–20 g of essential needed just to maintain weight. Over the course fatty acids and 1 g of protein per kilogram of body of 7 days, this amounts to approximately an extra weight [15] . 500 kcal/day in addition to the calories required Protein intake should be highly encouraged. for weight maintenance. For example, in the case Consuming small amounts of protein of high bi- of a 40-kg woman, if weight maintenance re- ological value, in conjunction with the AN pa- quires 30 kcal/kg/day = 1,200 kcal/day to gain tient’s preferred protein source foods (mostly weight, an extra 500 kcal/kg/day should be added vegetable) can provide a faster restoration of nu- (total caloric intake = 1,700 kcal/day). trient status even if still underweight. The maintenance amount of calories needs to Fat intake is a critical issue since AN patients be increased at intervals to continue weight gain. tend to avoid consuming fats, resulting in severe According to our experience, if there are plateaus lipid depletion entailing the risk of impaired neu- in weight gain, a progressive increase of 10 kcal/ ronal activity. Thus, AN patients particularly kg/day every 5–7 days may be necessary to main- need to replenish lipids during treatment, with a tain the rate of weight gain at 0.5 kg/week. focus on essential fatty acids. A variety of carbohydrates can be offered, both complex (bread, Weight Maintenance rice and potatoes) and simple (fruits, fruit juices Immediately after getting back to a healthy body and vegetables). weight, AN individuals are still energy inefficient Medical foods are a useful tool to reduce the [5]. In fact, they need at least 50–60 kcal/kg/day stomach and gastrointestinal discomfort that for weight maintenance, whilst healthy women refeeding tends to aggravate; they should be con- need 30 kcal/kg/day (range: 20–40). Without this sidered when patients have difficulties in achiev- substantial amount of food, rapid weight loss and ing weight restoration or as a useful addition in high rates of relapse occur [5]. Eating attitudes at case of unstable weight maintenance.

172 Marzola /Kaye

Conclusions encouraged since it is predictive of weight maintenance in AN patients. • AN is a puzzling psychiatric illness with un- • Caloric requirements in AN are high and vary predictable outcome and high mortality rates. between 30 and 40 kcal/kg/day (up to 70–100 Renourishment and weight restoration play a kcal/kg/day) for inpatients and 20 kcal/kg/ pivotal role in AN treatment since – in addi- day for outpatients; after the first phase of tion to life-threatening risks – a severely ema- treatment, it is possible to achieve a weight ciated status is likely to frustrate both psycho- gain of 1–1.5 kg/week in the inpatient setting logical and pharmacological therapeutic inter- and of 0.5 kg/week in the outpatient setting. ventions. Compared to the general population, AN pa- • Weight restoration in AN should start slow- tients also need higher caloric amounts – ly, accelerating as tolerated. Nutrient intake around 50–60 kcal/kg/day – for weight main- should be reinforced, as opposed to caloric in- tenance. take, coupled with psychotherapy to encour- • When severely malnourished, hospitalization age increasing amount and diversity in food may be required; to avoid refeeding syndrome, selection and preferences, and eventual fur- a strict monitoring of vital functions, electro- ther restoration of body weight to the individ- lyte levels and cardiac functions should be per- ual’s normal range. Dietary diversity should be formed.

References

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vosa. Am J Psychiatry 1995; 152: 1073– ment of patients with eating disorders, parison of calculated estimates and lab-

1074. third ed. Am J Psychiatry 2006; 163 oratory analysis of food offered to hospi- 2 National Institute for Health and Clini- (suppl):4–54. talized eating disorder patients. J Am

cal Excellence: Core interventions in the 7 Fitzpatrick KK, Lock J: Anorexia nervo- Diet Assoc 1986; 86: 490–492.

treatment and management of anorexia sa. Clin Evid 2011; 11. 12 Marzola E, Trunko ME, Grenesko-Ste- nervosa, bulimia nervosa and related 8 Hudson JI, Hiripi E, Pope HG Jr, Kessler vens E, Kaye WH: Anorexia and bulimia eating disorders (Clinical Guideline 9). RC: The prevalence and correlates of nervosa; in Nemeroff CB: Management London, National Collaborating Centre eating disorders in the National Comor- of Treatment-Resistant Major Psychiat- for Medical Health, 2004. bidity Survey Replication. Biol Psychia- ric Disorders. New York, Oxford Uni-

3 Wagner A, Aizenstein H, Venkatraman try 2007; 61: 348–358. versity Press, 2012. VK, et al: Altered reward processing in 9 Fassino S, Pierò A, Tomba E, Abbate- 13 Kaye WH, Gwirtsman HE, Obarzanek E, women recovered from anorexia ner- Daga G: Factors associated with dropout George DT: Relative importance of calo-

vosa. Am J Psychiatry 2007; 164: 1842– from treatment for eating disorders: a rie intake needed to gain weight and 1849. comprehensive literature review. BMC level of physical activity in anorexia ner-

4 Kaye WH, Fudge JL, Paulus M: New in- Psychiatry 2009; 9: 67. vosa. Am J Clin Nutr 1988; 47: 989–994. sights into symptoms and neurocircuit 10 Schebendach JE, Mayer LE, Devlin MJ, 14 Moukaddem M, Boulier A, Apfelbaum function of anorexia nervosa. Nat Rev et al: Dietary energy density and diet M, Rigaud D: Increase in diet-induced

Neurosci 2009; 10: 573–584. variety as predictors of outcome in an- thermogenesis at the start of refeeding

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et al: Caloric intake necessary for weight 810–816. vosa patients. Am J Clin Nutr 1997; 66: maintenance in anorexia nervosa: non- 133–140. bulimics require greater caloric intake 15 Otten J, Hellwig JP, Meyers LD (eds):

than bulimics. Am J Clin Nutr 1986; 44: DRI: Dietary Reference Intakes: The 435–443. Essential Guide to Nutrient Require- ments. Washington, National Acad- emies Press, 2006.

Anorexia Nervosa 173 Food Policy

Bier D, et al. (eds): Nutrition for the Primary Care Provider. World Rev Nutr Diet. Basel, Karger, 2015, vol 111, pp 174–178 DOI: 10.1159/000362321

Global Food Policy and Sustainability

Adam Drewnowski

Center for Public Health Nutrition, University of Washington, Seattle, Wash. , USA

Key Words Introduction Sustainable diet · Animal foods · Plant foods · Greenhouse gas emissions · Climate change The aims of global food policy are to ensure population access to nutritious and safe food, in quantities sufficient to support healthy, active Key Messages lives [1–3]. Implementing global food policy re- • Agriculture is the foundation of human nutrition quires the development of sustainable agriculture and health. However, global agriculture is vulnera- and the widespread adoption of healthy diets that ble to the depletion of natural resources and to cli- are sustainable in the long term. mate change. • Human diets need to be sustainable, affordable, ac- Agriculture is the foundation of human nutri- ceptable, and nutrient rich. tion and health. However, global agriculture is • Greenhouse gas emissions (GHGEs) are one way to highly vulnerable to the depletion of natural re- measure the carbon footprint of foods. Animal sources, land, water, and energy that may result products, including meat and dairy, have a higher from global warming. Feeding the world in the carbon footprint than do sugar or grains but can be face of population growth, poverty, and climate of higher nutritional value. • Paradoxically, some healthier diets may not be en- change poses new challenges to agro-food indus- vironmentally sustainable. Plant-based diets have tries. Among the many problems are land degra- higher carbon costs per calorie than do diets that dation, scarcity of water resources, limited biodi- include dairy and meat. Conversely, diets high in versity, diversion of food crops to biofuels, spik- sweets and snacks were associated with lower ing food prices and price volatility, and higher GHGE values. greenhouse gas emissions (GHGEs). • The competing demands of diet quality and sus- International agencies are beginning to recog- tainability will be compounded by climate change and the pressure to increase the yields of low-cost, nize that feeding an estimated 9 billion people by energy-dense crops. the year 2050 will be a major challenge. A drop in • Global food policies should review the complex in- global food production may lead to food insecu- terplay between diet quality, sustainability, and rity, social unrest, poverty, and malnutrition. monetary costs in relation to children’s health. That can cause irreversible nutritional damage, © 2015 S. Karger AG, Basel especially for children. Measures of Sustainable Agriculture GHGEs (mostly methane gas) are often calculated in carbon dioxide equivalents: grams of CO2 Agricultural production has an impact on soil, expressed per package, can, or bottle of the food water, air, agro-ecosystem biodiversity, wildlife product. Carbon footprint logos have been featured habitats, and landscape. Among the many indica- on food packaging in such supermarkets as Tesco tors of sustainable farming are soil quality and (UK) and Casino (France). While their impact on soil protection, fertilizer and pesticide use, land consumer purchases may have been mixed, GHGEs conservation, and other aspects of land manage- are a powerful tool for calculating the quality and ment. Other measures have included water qual- sustainability of individual and population diets. ity and resources, fertilizer runoff, air pollution, and GHGEs associated with farming and food production. Definition of Sustainable Diets The US legal definition of sustainable agriculture is based on the 1990 Farm Bill. It is suf- By common consensus, sustainable diets are ficiently broad to encompass the ecological, those with low environmental impact on land, economic, and social components of sustain- water and energy resources. The Food and Agri- able agriculture, referring not only to food pro- culture Organization has further defined sus- duction, but also to economic viability, and tainable diets as nutritionally adequate, economi- quality of life. Sustainable farms need to be vi- cally affordable, culturally acceptable, accessible, able businesses, contributing to rural economy healthy, and safe [1, 3]. Furthermore, such diets in terms of employment and incomes. This con- are sparing of both human and natural resources. cept holds for both developed and developing These multiple criteria demand the development countries. of new metrics to address nutrient density, af- According to US Code Title 7, Section 3103, fordability, cultural acceptability, and the carbon sustainable agriculture will, in the long term: footprint of individual foods and total diets. • Satisfy human food needs It is important to note that the concept of di- • Enhance natural resources and the environ- etary sustainability, as formulated by the Food ment and Agriculture Organization, does include both • Use nonrenewable resources in the most effi- diet quality and population health. Low environ- cient manner mental impact is one aspect of diet sustainability; • Make farming economically viable nutrient density of the diet is another. • Enhance the quality of life for farmers and society as a whole. Of these many indicators of agricultural pro- Nutrient Density Metrics duction, GHGEs have captured the popular imagination [4] . GHGEs, otherwise known as Nutrient density of foods can be assessed using a carbon footprint or carbon costs, are associated technique known as nutrient profiling. Nutrient with agricultural production, but also with food profile models assign ratings to foods based on processing, packaging, transport, distribution their nutrient composition. Key nutrients include and retail. Some life cycle analyses have been protein, fiber, and selected vitamins and miner- even more comprehensive, calculating carbon als, as well as nutrients of public health concern: cost through the postpurchase life of the food saturated fat, added (or free) sugars, and sodium. product, including preparation, cold storage, dis- Their content in foods is calculated per 100 g, 100 posal, and waste. kcal, or per serving.

Global Food Policy and Sustainability 175 The Nutrient Rich Foods (NRF) index is a for- of reference foods to set the food poverty line. mal metric of nutrient density [5] . The positive Studies on poverty in rural India calculated the nutrients are protein, fiber, vitamins A, C, and E, cost of food commodities in rupees per 1,000 kcal, calcium, iron, potassium and magnesium, where- showing that cereals and sugar provided calories as nutrients to limit are saturated fat, added sug- at far lower cost than did meat, dairy, or vegeta- ar, and sodium. The NRF algorithm is the sum of bles and fruit. percentage daily values (DVs) for the 9 positive Hidden hunger is the term used to describe nutrients, minus the sum of %DVs for 3 nutrients micronutrient malnutrition that can occur in to limit, each calculated per 100 kcal and capped both developed and developing countries. Here, at 100% DV. The NRF score has been validated the appropriate measure would not be calories, against the Healthy Eating Index, an indepen- but rather nutrients per unit cost. In the US, dent measure of a healthy diet. grains, added sugars and saturated fats are associ- The French SAIN,LIM score is the mean of ated with lower per-calorie diet cost, whereas pro- %DVs for 5 positive nutrients (protein, fiber, vita- tein, fiber, vitamin C, potassium and other nutri- min C, calcium and iron) minus the mean of ents are associated with higher diet costs. The cost %DV for the 3 nutrients to limit (saturated fat, gradient may vary depending on population eat- added sugar, sodium). Unlike the continuous ing habits, agricultural subsidies, or the use of for- NRF score, SAIN,LIM assigns foods into 1 of 4 tified or supplemented foods. For example, calci- categories. The SAIN,LIM model has been vali- um and folate intakes in the US are not associated dated using linear programming. with sharply higher diet costs, an important point These nutrient profiling models, designed to in the nutrition of children and pregnant women. capture nutrient quality of individual foods, can also be applied to meals and menus, and can be used to capture the overall nutrient density of the Are High-Quality Diets Environmentally habitual diet. Nutrient profiling models can also Sustainable? be used by the food industry to screen the nutritional quality of their product portfolio. Impor- Animal food products, meat and dairy, are said to tantly, having a global measure of nutrient den- consume land and water resources to excess and sity permits the subsequent calculations of nutri- contribute to GHGEs more than other foods. On ents per unit cost – where cost refers to monetary the other hand, transport of out-of-season fresh cost as well as carbon cost. produce by air has its own very considerable carbon costs. The question whether healthy diets are also Food Affordability Metrics good for the planet would benefit from a more extended debate. Some potential paradoxes were Measures of food affordability, designed to ad- recently explored by Vieux et al. [6, 7] in France dress hunger and calorie deprivation in develop- and Macdiarmid et al. [8, 9] in the UK. In gen- ing countries, are often based on price per calorie eral, healthy diets are supposed to be more envi- or calories per unit cost [5] . The Food and Agri- ronmentally friendly because plant-based foods culture Organization and the International Food have lower GHGEs per unit weight than do ani- Policy Research Institute have used the food mal-based foods. The relation between low-ener- price-per-calorie metric in evaluating food and gy-density plant foods and their carbon footprint agriculture policies for developing nations. The changes, however, when carbon costs are calcu- World Bank uses the price of a 2,100-kcal basket lated per calorie.

176 Drewnowski

Vieux et al. [7] estimated diet quality and car- Food Prices and Climate Change bon costs of the diets of 1,918 French adults by attaching GHGEs for 391 foods to dietary intake Sugars and grains are generally cheaper per calo- data. These techniques were analogous to those rie than are the more nutrient-rich foods [10] . Ce- used to estimate the monetary cost of different real and oilseed crops, not meat or dairy, account quality diets. The most nutrient-dense diets for most of the calories in the global food supply. were defined as those of lower energy density, Corn, wheat, rice, soy, and sugar cane are all sta- higher mean nutrient adequacy ratio, and lower ples that yield inexpensive dietary energy and intakes of nutrients to limit. As expected, the provide fat, refined carbohydrates, and protein. best diets contained more plant-based foods, Energy, land, and water resources for many other fruit and vegetables, and fewer sweets and salted crops are becoming scarce, leading to justifiable snacks than did lower-quality diets. However, concerns about hunger and food security world- on a per calorie basis, higher-quality diets were wide. associated with significantly higher GHGEs. Extreme weather events, including severe Whereas the consumption of sweets and grains drought conditions that damage crops, generally was associated with lower GHGEs, diets higher lead to sharp price increases, especially for dairy, in fruits, vegetables and animal products were eggs, and meat. The global food price crises of associated with higher GHGEs. The researchers 2007–2008 and 2010–2011 contributed to politi- were forced to come to the conclusion that the cal turmoil and social unrest and led to econom- best diets were not those with lower GHGEs, ic difficulties for the global poor. The crops af- even if they did contain large amounts of vege- fected by price spikes and price volatility were tables and fruit. rice, maize, wheat, and soybeans. Similarly, Macdiarmid et al. [8, 9] have now A rise in food prices caused by climate change questioned whether healthy diets were environ- will lead to higher, not lower, obesity rates in the mentally the most sustainable. In that study, lin- United States and likely worldwide. As food pric- ear programming, based on GHGE data for 82 es increase or incomes drop, refined grains, foods, was used to create optimized food patterns sweets, and fats become the best way to provide for women (aged 19–50 years) that reduced daily calories at a manageable cost [10] . Added GHGE while meeting dietary requirements for sugars and fats can be inexpensive, flavorful, health. Consumption constraints were added to satisfying, readily accessible, and convenient. As ensure that the food choices were socially and economic pressures mount, they are likely to dis- culturally acceptable. place healthier option in the diets of children, In the model, GHGEs could be reduced by as first for the poor and later for the middle class. much as 90%, provided that the diet was restrict- Food prices are a mechanism that links obesity ed to only 7 items in unacceptable amounts. Im- and poverty [10] . One consequence of rising glob- posing consumption constraints yielded more al food prices may be a parallel rise in childhood varied food patterns (52 foods), but GHGEs were obesity and diabetes. reduced by only 36%. The estimated retail cost of the diet was not increased. The authors concluded that a healthy and more environmentally sus- Conclusions tainable diet could be achieved without eliminat- ing meat or dairy products or increasing the cost • The current dilemma is that, simply put, not to the consumer. all healthy diets are sustainable and not all sustainable diets are particularly healthy.

Global Food Policy and Sustainability 177 • On one hand, sugars and grain-based snacks costs, but these lower GHGE diets may not be have lower GHGEs than meat and dairy, which optimal for population health. consume more agricultural resources. On the • The hoped-for convergence between diets that other hand, some animal-based products are are good for people and simultaneously good more calorie dense and more nutrient rich, so for the planet is slow in coming. What we need that their higher GHGEs are offset by their is a better harmonization between dietary higher nutritional value. guidelines and agricultural production. • In model systems, replacing meat with equica- • In future analyses of healthy sustainable diets, loric amounts of vegetables actually increased diet quality, food prices, carbon costs, and carbon costs [6] . Replacing meat, milk and likely health outcomes will all need to be taken milk products with sugar may reduce carbon into account.

References

1 Food and Agriculture Organization of 4 Kim B, Neff R: Measurement and com- 7 Vieux F, Soler L-G, Touazi D, Darmon the United Nations: Sustainable diets: munication of greenhouse gas emissions N: High nutritional quality is not associ- what it means, why it matters and what from US food consumption via carbon ated with low greenhouse gas emissions

can we do about it. http://www.fao.org/ calculators. Ecol Econ 2009; 69: 186–196. in self-selected diets of French adults.

food/sustainable-diets-and-biodiversity/ 5 Drewnowski A: The Nutrient Rich Foods Am J Clin Nutr 2013: 97: 569–583. en/. Index helps to identify healthy, afford- 8 Macdiarmid JI, Kye J, Horgan GW, Loe

2 Department for Environment Food and able foods. Am J Clin Nutr 2010; 91: J, et al: Sustainable diets for the future: Rural Affairs: Food 2030. London, HM 1095S–1101S. can we contribute to reducing green- Government, 2010. archive.defra.gov. 6 Vieux F, Darmon N, Touazi D, Soler LG: house gas emissions by eating a healthy

uk/foodfarm/food/pdf/food2030strat- Greenhouse gas emissions of self-select- diet? Am J Clin Nutr 2012: 96: 632–639. egy.pdf (accessed March 17, 2013). ed individual diets in France: changing 9 Macdiarmid JI: Is a healthy diet an envi- 3 Burlingame B, Dernini S (eds): Sustain- the diet structure or consuming less? ronmentally sustainable diet? Proc Nutr

able diets and biodiversity: directions Ecol Econ 2012: 75: 91–101. Soc 2013; 72: 13–20. and solutions for policy, research and 10 Drewnowski A, Specter SE: Poverty and action. http://www.fao.org/docrep/016/ obesity: diet quality, energy density and

i3004e/i3004e.pdf (accessed October 1, energy costs. Am J Clin Nutr 2004; 79: 2012). 6–16.

178 Drewnowski

Food Policy

Bier D, et al. (eds): Nutrition for the Primary Care Provider. World Rev Nutr Diet. Basel, Karger, 2015, vol 111, pp 179–185 DOI: 10.1159/000362322

Undernutrition in the Developing World

H.H. Vorster

Centre of Excellence for Nutrition, North-West University, Potchefstroom Campus, Potchefstroom , South Africa

Key Words Introduction Undernutrition · Developing countries · Poverty · Human capital · Food and nutrition insecurity Undernutrition in developing or low-income countries (LICs) is a major barrier to eradicating poverty and to timeously reach the Millennium Key Messages Development Goals [1] . Undernutrition leads to • Undernutrition is an outcome of many interlinked arrested physical and mental development of in- disadvantages rooted in poverty. dividuals [2], to low human capital (LHC) [3] , • It is also a major cause of poverty. There is a vicious and therefore has a detrimental impact on social cycle between undernutrition, low human capital, underdevelopment, and poverty. and economic development. Persistent under- • Under- and overnutrition often coexist, resulting in nutrition in LICs is unacceptable in the light of a double burden of nutrition-related diseases in the global overnutrition, with associated obesity and developing world. related noncommunicable diseases (NCDs). The • On the population level, undernutrition is a public latter are major causes of disability and death, health problem in low-income countries, and on also in LICs. This coexistence of under- and the individual level, a serious clinical health problem in all countries. overnutrition (malnutrition) is a consequence of • Health professionals should understand the causes food and nutrition insecurity, exacerbated by and consequences of undernutrition to support, the nutrition transition in LICs. It places a huge educate and empower patients to follow healthier burden on the fragile health economies and ser- diets when they are discharged from clinical set- vices in LICs. tings into unfavorable food and nutrition environ- Health professionals (HPs) can help to pre- ments. © 2015 S. Karger AG, Basel vent and treat undernutrition in all settings. Good nutrition Signs of (nutritional well-being) good nutrition

Adequate Absence Immediate dietary intake of disease conditions

Enjoyment Enjoyment of the Enjoyment of the of the right right to adequate right to health; Underlying to adequate food; prevention and conditions care for the food security control of disease vulnerable

Fulfilment of the state‘s obligations to control and manage the country‘s available resources for their progressively equitable utilization and the realization of rights

Basic conditions Political and economic ideology

Potential resources of the country

Fig. 1. Adapted UNICEF framework [4] to illustrate the necessary conditions for good nutrition.

However, to do so, they need to understand the The Causes of Undernutrition immediate, underlying and basic causes, as well as the far-reaching intergenerational biological The causes of undernutrition have been concep- and social consequences of both under- and tualized and classified in the UNICEF framework overnutrition (malnutrition). They should also [4]. Figure 1 shows a positive adaptation of this be familiar with the concept of the coexistence of framework, to illustrate the conditions necessary under- and overnutrition, and how this problem to obtain nutrient adequacy, security, and opti- could be addressed in LICs. Moreover, to support mal (good) nutrition. The conditions are multi- patients that are discharged after optimal nutri- sectorial, embracing food, health and caring tion has been restored, they should understand practices, and are classified as immediate, under- the usual food environment of these individuals lying, and basic to incorporate factors influenc- and how to educate them to make healthier food ing food and nutrition security. Many of these choices. factors are rooted in poverty, bad governance

180 Vorster

Biological mechanisms Malnourished (over-/undernutrition) fetus

Overweight Disproportionate/ Malnourished newborn low-birthweight girl/woman infant newborn infant (preconception) At risk infant and young child Frequent infections

Nutrition insults

Deprived individual Stunted/reduced mental capacity (poverty) Child-Adolescent-Adult-Elderly

Food environment

Individuals F NCDs with f human capital Child-Adolescent-Adult-Elderly

Fig. 2. The vicious cycle of poverty, malnutrition and LHC, also showing the coexistence of under- and overnutrition (malnutrition). With permission from JB Consultancy, RSA.

and natural disasters. The framework is used as a portance of fetal nutrition for long-term health. guide for assessing and analyzing the causes of The acknowledgement that malnutrition is a the nutrition problem and to help in identifying more complex phenomenon because of the coex- the most appropriate strategies and actions for istence of under- and overnutrition, as well as our interventions. inability to effectively address malnutrition on a global level, have resulted in several paradigm shifts in understanding the interlinked causes and The Intergenerational Vicious Cycle of consequences of malnutrition. These links are il- Poverty, LHC and Malnutrition lustrated in figure 2 . The figure shows that malnutrition during Developments in the genetic and epigenetic arena fetal life (because of malnourished mothers and [5] provided new insights into the biological links under- or overnutrition of the fetus), could re- between under- and overnutrition and of the im- sult in low-birthweight babies or overweight and

Undernutrition in the Developing World 181 disproportionate babies. These babies may be an example of the scope and burden of the prob- compromised with respect to normal physical lem. At present, at least 27% of South African and mental development, and especially with children in rural and 16.7% in urban areas are further nutritional insults, will be vulnerable to stunted, up to 17% of men are underweight, while infectious diseases. They may develop into more than 60% of adults are either overweight or stunted infants and children who cannot fully obese, ref lecting imbalances in energy intake and benefit from education, having difficulty in expenditure. The documented high prevalence of reaching their full genetic potential. They are, at both infectious diseases related to undernutri- the same time, metabolically programmed to be tion and of NCDs related to obesity and overnu- more vulnerable for NCDs in later life. There- trition [7] illustrates the double burden of disease fore, when these children are exposed to unfa- associated with the coexistence of under- and vorable, modern, energy-dense, micronutrient- overnutrition. The nutrition transition in devel- poor food environments, they are at greater risk oping countries is a principal cause of this situa- of becoming overweight and obese and of de- tion. veloping NCDs in adult life. The combination of underdevelopment, infectious diseases and NCDs could lead to adults with LHC, unable to The Nutrition Transition economically care for themselves and their offspring, eventually leading to deprivation and The epidemiological transition [8] , a result of ur- poverty. Human capital is defined [6] as ‘well- banization, modernization, and acculturation, is nourished, healthy, educated, skilled and alert characterized by a nutrition transition during individuals – an improved human condition – which traditional dietary patterns change to diets resulting in a labor force that could be any coun- associated with obesity and a high risk of NCDs try’s most productive asset’. Poverty is a cause of [9] . These diets are high in fat, animal-derived malnutrition, and expectant mothers from poor foods, salt, alcohol and sweetened beverages, and environments are at greater risk to give birth to low in whole grains, legumes and dietary fiber. babies who have been nutritionally compro- This transition is accompanied by physical inac- mised in the womb, perpetuating the poverty- tivity and often happens before the battle against malnutrition cycle. undernutrition has been won. Infants from undernourished mothers are ‘mismatched’ to cope with this new food environment and are at risk of The Dilemma of the Coexistence of Under- becoming obese and developing NCDs in later and Overnutrition in LICs life. Other factors associated with the nutrition The relationship between household food and transition that may contribute to the double bur- nutrition insecurity and the overweight status of den of malnutrition are ‘hidden hunger’ or mi- mothers and children are observed in both LICs cronutrient and dietary antioxidant deficiencies, and the developed world. However, in low- and large serving sizes, a cultural tolerance of obesity middle-income countries, the coexistence of un- (perceptions that obese individuals are more der- and overnutrition resulting in the double beautiful, happier, more prosperous and free burden of high prevalence of both infectious and from HIV/AIDS), an unfavorable food environ- NCD is a public health problem. ment, and lack of education and knowledge about The nutrition status of South Africans, and healthy food choices. consequent morbidity and mortality patterns, is

182 Vorster

An Integrated Systematic Approach to composition of processed foods; by legislation Optimize the Food and Nutrition to prevent advertising of obesogenic foods to Environment children. • The food industry is to a large extent respon- Modernization, economic development and in- sible for the safety of our food supply, and can creased buying power in LICs may result in food play a positive role. However, the industry is choices from an unfortunate ‘modernized’ food also aggressively marketing and promoting environment. This environment offers conve- the energy-dense, micronutrient-poor foods nient, very palatable, high-energy-dense but mi- and drinks that are associated with childhood cronutrient-poor foods and snacks at increasing- and adult obesity and the resultant NCD epi- ly affordable prices. The aggressive marketing demic. Public health nutritionists have been and promotion of these foods, and peer pressure concerned about this negative role of industry to consume them, especially when knowledge of for many years, realizing that the industry is healthful diets are lacking, contribute to both un- very good in protecting their profits and influ- der- and overnutrition. encing public opinion. Nutritionists know that To address the problem of optimizing the where public demand and actions decreased food environment in order to achieve nutrition profits in one country (usually high-industri- security for the whole population, two impor- alized developed countries), the industry sim- tant actions should be balanced, as shown in ply targets other markets, often in LICs [10] . figure 3 . Firstly, consumers (individuals, house- However, some of the multinational compa- holds, communities and populations) should be nies have tried to develop more healthful and empowered to create a demand for nutritious ‘functional food’ products (low in fat and sug- food at affordable prices. This can be done by ars, fortified or enriched with micronutrients implementing appropriate nutrition education or other plant substances that can lower serum programs. Secondly, all the role players (stake- cholesterol, etc.). These products are usually holders) responsible for the food environment much more expensive than the products they should be motivated to develop a common ethi- are supposed to replace and confuse custom- cal agenda and work in partnerships to supply ers about healthy choices from available foods. these nutritious foods at affordable prices. They are not the answer to optimize the food Therefore, a trans-disciplinary, multisectoral, environment. systematic but also integrated approach is ad- • There are other role players or stakeholders vised. that may influence the food environment, ei- There are many role players or stakeholders ther by influencing government and political that influence the food environment, each with a structures such as nongovernmental organiza- potential unique contribution to improve this en- tions (NGOs), civil, and public organizations; vironment: by supplying food to consumers (from street • Governments can influence the food supply by vendors, spaza shops, fast-food outlets, restau- inter alia controlling what is available: through rants and supermarkets); by influencing food policies and actions to support agriculture en- choices (media and advertisements), or by em- suring food security; by imports and exports of powering people to make healthier choices food; by providing the infrastructure for mar- (HPs, UN agencies and NGOs). Any nutrition keting of food; by national fortification and strategy should recognize the potential of part- supplementation and other nutrition aid pro- nerships between these role players and programs; by legislation to control labelling and vide opportunities for them to work together.

Undernutrition in the Developing World 183 Role players

Public/non- Food environment Industry profit Producer

Government ଯ Processor

ଯ UN agencies Individuals Households Manufacturer Families Communities ଯ Population NGOs Distributor

ଯ Retailer/wholesaler Civil society ଯ Informal retailer

Media

Fig. 3. A framework indicating how several role players determine the food environment. With permission from JB Consultancy, RSA.

Conclusions • To help them to avoid both undernutrition and overweight, knowledge of the links between • HPs in the developing world should be aware poverty, malnutrition and LHC is essential. of and understand the food and nutrition en- • Furthermore, HPs should be able to show in- vironment to support individuals in reaching dividuals how to choose healthier diets, often nutrient adequacy and optimal nutritional from unfavorable food environments, indicat- status. ing a need to understand the many factors influencing these environments.

184 Vorster

References

1 Schuftan C: The Millenium Develop- 4 UNICEF: Strategy for improved nutri- 7 Norman R, Bradshaw D, Schneider M, et ment Goals: who for, and what for? tion of children and women in develop- al: A comparative risk assessment for http://www.wphna.org/claudioschuf- ing countries, policy review paper, South Africa in 2000: towards promot- tanoct2010.asp (accessed October, E/ICEF/1990/1.6. New York, UNICEF, ing health and preventing disease. SA

2010). 1990. Med J 2007; 97: 637–641. 2 Grantham-McGregor SM, Fernald LC, 5 Gluckman PD, Hanson MA, Pinal C: The 8 Omran AR: The epidemiologic transi- Sethuraman K: Effects of health and developmental origins of adult disease. tion theory. A preliminary update. J

nutrition on cognitive and behavioural Matern Child Nutr 2005; 1: 130–141. Trop Pediatr 1983; 29: 305–316. development in children in the first 6 Streeten P: Human development: means 9 Vorster HH, Venter CS, Wissing MP,

three years of life. Part 1: low birth- and ends. Am Econ Rev 1994; 84: 232– Margetts BM: The nutrition and health weight, breastfeeding and protein-ener- 237. transition in the North-West Province of gy malnutrition. Part 2: Infections and South Africa: a review of the THUSA micronutrient deficiencies: iodine, iron (Transition and Health during Urban-

and zinc. Food Nutr Bull 1999; 20: 53–99. isation of South Africans) study. Public

3 Institute for Fiscal Studies: Human de- Health Nutr 2005; 8: 480–490. velopment and poverty reduction in 10 Ynvge A, Haapala I, Hodge A, et al: developing countries. www.ips.org.uk Making soft drinks the dietary version (accessed December 28, 2006). of the cigarette. Public Health Nutr

2012; 15: 1329–1330.

Undernutrition in the Developing World 185 Food Policy

Bier D, et al. (eds): Nutrition for the Primary Care Provider. World Rev Nutr Diet. Basel, Karger, 2015, vol 111, pp 186–192 DOI: 10.1159/000362323

The Changing Landscape of Malnutrition: Why It Matters

a a, b Rehana A. Salam Zulfiqar A. Bhutta a b Division of Women and Child Health, Aga Khan University, Karachi , Pakistan; Program for Global Pediatric Research, Hospital for Sick Children, Toronto, Ont. , Canada

Key Words • Many countries have achieved success in improving nutrition and health outcomes at the popula- Malnutrition · Nutrition goals · Nutrition tion levels through investments in agriculture, edu- interventions · Scale-up · Community-based cation, and social sector development alongside interventions implementing nutrition-specific interventions. • The scale-up of selected nutrition interventions through community-based approaches has the Key Messages greatest impact in the poorest social quintiles, sug- • Malnutrition is also dependent upon factors that gesting that community-based delivery platforms are not directly related to nutrition, such as growing have the potential to reach these inaccessible populations and urbanization, inflation, climate groups and reduce existing disparities in both ac- changes and water shortages, political conflicts and cess and mortality. © 2015 S. Karger AG, Basel natural disasters. • Alongside nutrition-specific interventions, large- scale programs that address these underlying determinants should also be considered to achieve Introduction specific nutrition goals. • The strategy for combatting malnutrition therefore requires a multipronged approach involving not only Despite the global economic growth, there is lit- interventions directed at the biological causes of subtle evidence of change in the burden of under- optimum growth and development, but also large- nutrition in many countries. According to a re- scale programs that broadly address the social, politi- port by the Food and Agriculture Organization, cal and environmental determinants of malnutrition. around 870 million people were undernour- Stunting

<20.0% 20.0–29.9% 30.0–39.9% 40.0% Data not available 0 1,250 2,500 5,000 Kilometers

Fig. 1. Latest prevalence estimates for stunting among children under 5 years of age shown by country. Reproduced from UNICEF, WHO, World Bank [6] .

ished in the period of 2010–2012, representing globally, especially among these vulnerable 12.5% of the global population with the vast groups, given their increased nutritional de- majority, 98% (852 million), from developing mands. Prevalence of iron deficiency anemia countries [1] . Likewise, maternal and child un- among pregnant women is around 19.2%, while dernutrition rates also remain high in these re- that of vitamin A deficiency is 15.3% [4] . Ac- gions, with prevalence of maternal undernutri- cording to the World Health Organization tion (defined as body mass index, BMI <18.5) as (WHO), globally around 190 million preschool high as over 20% in many countries of Africa, children and 19.1 million pregnant women are Southeast Asia, Latin America, and the Carib- vitamin A deficient, approximately 100 million bean [2]. In 2011, one third of the 6.9 million women of reproductive age have iodine defi- deaths of children under 5 years of age world- ciency, and an estimated 82% of pregnant wom- wide were attributable to suboptimal breast- en worldwide have inadequate zinc intakes to feeding and micronutrient deficiencies; particu- meet the normal needs of pregnancy [5] . larly vitamin A and zinc [3] . Moreover, around The following discussion in this chapter will 165 million children under 5 years of age were revolve around the malnutrition trends over stunted, 101 million underweight and 52 mil- the past decades, emerging challenges and ex- lion wasted globally; 90% of which live in just 36 iting inequities and how best to combat the is- countries, with the highest prevalence in South- sue taking into consideration the existing prov- east Asia and sub-Saharan Africa ( fig. 1 ) [4] . en interventions and their delivery mecha- Micronutrient deficiencies are also widespread nisms.

The Changing Landscape of Malnutrition 187 50 1980 1985 40 1990 1995 2000 30 2005 2008

20 Prevalence (%) Prevalence

0 BMI 18.5 BMI 25 BMI 30

Fig. 2. Global trends in thinness (BMI <18.5), overweight (BMI ≥ 25), and obesity (BMI ≥ 30) using population-weighted average prevalence for women aged 20–49 years; 1980–2008. Reproduced from Black et al. [4] .

Nutrition Trends creased from 4% in 1990 to 7% in 2011, whereas these figures are a little lower in Asia (5% in In the last few decades, there has been some im- 2011), though the absolute number of affected provements in the nutritional indicators; stunt- children is higher compared to Africa (17 and ing among children under 5 years of age has 12 million, respectively) [6] . These figures are shown a 35% decline from an estimated 253 mil- alarming and require immediate attention as lion in 1990 to 165 million in 2011, and the prev- childhood overweight is associated with multiple alence of low BMI in adult women has decreased immediate and long-term risks including: raised in Africa and Asia since 1980. Nonetheless, the cholesterol, triglycerides, and glucose; type 2 di- magnitude of malnutrition and associated detri- abetes; high blood pressure; adult obesity and its mental health consequences still remains high. associated consequences [7, 8] . Furthermore, many of the low- and middle- income countries now bear the double burden of malnutrition due to the emerging issues of over- Strategies to Combat Malnutrition weight and obesity along with the existing high rates of stunting and other micronutrient defi- Malnutrition is not only dependent upon the di- ciencies. Figure 2 depicts the global trends in rect determinants of nutrition and growth, in- thinness (BMI <18.5), overweight (BMI ≥ 25), cluding diet, behavior and health, but is also and obesity (BMI ≥ 30) prevalence for women greatly affected by certain indirect determinants aged 20–49 years, from 1980–2008. such as food security, education, environment, In 2011, an estimated 43 million children un- economic and social conditions, resources and der 5 years of age were overweight, marking a governance. Hence the agenda for combatting 54% increase from an estimated 28 million in malnutrition requires a multipronged approach 1990. In Africa, the estimated prevalence in- involving not only interventions directed at the

188 Salam /Bhutta

Therapeutic feeding – for severe wasting Zinc supplementation Promotion of breastfeeding

Appropriate complementary feeding Treatment for moderate-acute malnutrition Folic acid supplementation/fortification

Interventions Balanced energy supplementation Multiple micronutrient supplementation Vitamin A supplementation Calcium supplementation

0 50,000 100,000 150,000 200,000 250,000 300,000 350,000 400,000 Number of deaths of children <5 years averted

Fig. 3. Deaths averted by scale-up of selected nutrition interventions. Reproduced from Bhutta et al. [9] .

more immediate causes of suboptimum growth in early childhood, malnutrition prevention has and development but also the large-scale pro- undergone a paradigm shift from targeting preg- grams that broadly address the underlying deter- nant women to increased advocacy to target these minants of malnutrition. The recent Lancet Nu- deficiencies earlier in the life cycle through pro- trition Series highlights the existing promising moting adolescent health and nutrition, delaying interventions to improve maternal nutrition and age at first pregnancy and increased birth spacing consequently reduce fetal growth restriction and [9] . An estimated 10 million girls younger than 18 small-for-gestational-age births and improving years are married each year, putting them at a child nutrition specifically in developing coun- higher risk of delaying their own growth, poorer tries [9] . These include simple interventions like birth outcomes, delivery complications and mor- periconceptional folic acid supplementation/for- tality in mothers and children [10] . tification, maternal balanced energy protein, vita- As mentioned earlier, malnutrition is also min A, multiple micronutrient and calcium sup- greatly dependent upon factors that are not plementation, breastfeeding promotion, appro- directly related to nutrition such as growing priate complementary feeding, preventive zinc populations and urbanization, inflation, climate supplementation and management of acute mal- changes and related water shortages, conflicts nutrition in children. Scaling up of these identi- and emergencies, and natural disasters affecting fied interventions to 90% coverage could poten- agriculture production [11] . Hence, along with the tially reduce nearly 15% of deaths among children nutrition-specific interventions, large-scale pro- under 5 years of age, while also reducing stunting grams that address these underlying determi- and severe wasting by 20 and 61%, respectively nants should also be considered to achieve spe- ( fig. 3 ) [9] . Since maternal malnutrition, micro- cific nutrition goals. These programs involve nutrient deficiencies and small-for-gestational- complementary sectors such as agriculture, age births remain major determinants of stunting health, social protection, early child development,

The Changing Landscape of Malnutrition 189 education, and water and sanitation to improve in 3 children being stunted, while the median prev- the environment and health at the population lev- alence of wasting is 7.1%. Within countries, there el [4] . Targeted agricultural programs, early child is a wide disparity between the richest and poorest development and education, and social safety nets wealth quintiles as in one fifth of the Countdown have the potential to achieve large scale and high countries, more than half of the children in the coverage of nutritionally at-risk households and poorest 20% of all families are stunted. With these individuals [11] . With the emerging focus on ado- existing disparities, another challenge is the high lescent nutrition, these programs offer a unique rates of HIV that threaten to reverse all the nutri- opportunity to improve the preconception nutrition gains achieved through large-scale programs. tion status of young girls, consequently improving pregnancy and birth outcomes either through school-based or home-based programs. However, How Best to Deliver these programs would require specific nutrition goals with targeted nutrition outcomes for the While individual interventions such as micronu- evaluation of effectiveness and to bring about im- trient supplementation/fortification, exclusive provements in nutrition indicators. These pro- breastfeeding, appropriate complementary feed- grams can also serve as delivery platforms for the ing and management of childhood undernutri- nutrition-specific interventions and can be effec- tion have shown to be effective, an integrated ap- tive at reaching poor populations as these are of- proach is needed to achieve optimal results. The ten implemented at a larger scale [11] . Many coun- coverage of various proven interventions dis- tries including Brazil, China, Saudi Arabia, Ku- cussed above is below the acceptable cutoffs, and wait and Chile have achieved success in improving delivery of these interventions to the neediest nutrition and health outcomes at the population groups has to be ensured [14] . Various delivery levels through investments in agriculture, educa- strategies have been suggested to increase the up- tion, and social sector development alongside im- take of these interventions and at the same time plementing nutrition-specific interventions [12] . ensure equitable delivery. These include community-based delivery platforms for nutrition education and promotion, food fortification, finan- Challenges and Inequities cial incentives, school-based delivery platforms, Integrated Management of Childhood Illnesses Despite the existence of proven interventions and and Child Health Days. relative improvements in nutrition indicators Community-based delivery platforms are in- overall, nutrition data indicate considerable dis- creasingly being advocated and have the poten- parity between the developed and developing re- tial for scaling up coverage of nutrition interven- gions, with South Asia bearing the highest burden tions and reaching poor populations through [13] . Maternal undernutrition is particularly se- creating mass awareness and door-to-door ser- vere in the South Asian Countdown countries, vice delivery. Community-based interventions with a recent Demographic and Health Survey in- delivered by health-care personnel or lay individ- dicating that the median prevalence of low BMI uals, and implemented locally in homes, villages, among women of reproductive age is 10.9%, and or any defined community group, have shown to almost three quarters of all the world’s low-birth- reduce inequities in maternal child health inter- weight infants are born in South Asia alone. In the ventions and can be used as a platform for nutri- 75 Countdown countries globally, stunting rates tion intervention delivery. In many low- and are well above the 3% threshold with more than 1 middle-income countries, community health

190 Salam /Bhutta

service delivery through community health the health practices at health facilities, home and workers already exists and is utilized to deliver a in the community. Financial incentives including wide range of interventions and hence offer a conditional and unconditional cash transfers can unique opportunity to engage and reach poor also be utilized to counteract poverty, reduce fi- and difficult to access populations through com- nancial barriers and improve population health munication and outreach strategies. Equity anal- with a potential to promote increased coverage of ysis based on the data from three countries (Ban- several important child health interventions. Be- gladesh, Ethiopia and Pakistan) in the recent sides maternal, newborn, and child health inter- Lancet Nutrition Series has shown that scale-up ventions, food fortification is another attractive of the selected nutrition interventions through public health strategy which can reach wider at- community-based approaches has the greatest risk population groups through existing food de- impact in the poorest quintiles, suggesting that livery systems, and without major changes to ex- the community-based delivery platforms have isting consumption patterns [5] . All of these strat- the potential to reach these inaccessible groups egies can provide scale-up opportunities to reach and substantially reduce the existing disparities large segments of the vulnerable population. in both access and mortality [9] . Nutrition interventions could also be potentially integrated with other maternal, newborn, Conclusions and child health interventions since several countries are investing in programs to address mater- • Changing the landscape of global malnutrition nal, newborn, and child health [15] . School feed- will involve health system policies, actions, ing programs have been introduced in many and advocacy at all levels. countries to improve attendance, achievement, • Investments in the scale-up of large-scale nu- growth, and other health outcomes. Child Health trition programs should be prioritized by the Days have been introduced in response to the de- policy makers with an effort to maximize the clining coverage of many essential child survival implementation of large-scale nutrition-di- interventions as a result of weakening health sys- rected programs. tems. The Integrated Management of Childhood • Effective coordination between sectors, na- Illnesses strategy developed by the WHO in col- tional and subnational levels, private sector laboration with UNICEF and other agencies has engagement, resource mobilization, and state been implemented to provide both curative and accountability to its citizens are needed to pri- preventive interventions targeted at improving oritize political actions.

References

1 Food and Agriculture Organization: The 3 You D, Jin NR, Wardlaw T: Levels and 5 Das JK, Salam RA, Kumar R, Bhutta ZA: State of Food Insecurity in the World. Trends in Child Mortality: Report 2012. Micronutrients food fortification and its http://www.fao.org/docrep/016/i3027e/ New York, UNICEF, 2012. impact on woman and child health: a

i3027e.pdf. 4 Black RE, Victora CG, Walker SP, et al: systematic review. Syst Rev 2013; 2: 67. 2 Kothari MT, Abderrahim N, Macro ICF; Maternal and child undernutrition and 6 UNICEF, WHO, World Bank: Levels and United States Agency for International overweight in low-income and middle- trends in child malnutrition. Joint child

Development: Nutrition Update 2010. income countries. Lancet 2013; 382: 427– malnutrition estimates. New York, Washington, United States Agency for 451. UNICEF; Geneva, WHO; Washington, International Development, 2010. World Bank, 2012.

The Changing Landscape of Malnutrition 191 7 Koplan JP, Liverman CT, Kraak VI: Pre- 10 Gibbs CM, Wendt A, Peters S, Hogue CJ: 14 Bhutta ZA, Chopra M, Axelson H, et al: venting childhood obesity: health in the The impact of early age at first child- Countdown to 2015 decade report balance: executive summary. J Am Diet birth on maternal and infant health. (2000–10): taking stock of maternal,

Assoc 2005; 105: 131–138. Paediatr Perinat Epidemiol 2012; newborn, and child survival. Lancet

8 Lloyd LJ, Langley-Evans SC, McMullen 26(suppl 1):259–284. 2010; 375: 2032–2044. S: Childhood obesity and risk of the 11 Ruel MT, Alderman H: Nutrition-sensi- 15 Global Health Workforce Alliance: Glob- adult metabolic syndrome: a systematic tive interventions and programmes: al experience of community health

review. Int J Obes 2012; 36: 1–11. how can they help to accelerate progress workers for delivery of health related 9 Bhutta ZA, Das JK, Rizvi A, et al: Evi- in improving maternal and child nutri- millennium development goals: a sys-

dence-based interventions for improve- tion? Lancet 2013; 382: 536–551. tematic review, country case studies, ment of maternal and child nutrition: 12 UNICEF: Improving child nutrition: the and recommendations for integration what can be done and at what cost? Lan- increasing imperative for global prog- into national health systems. Geneva,

cet 2013; 382: 452–477. ress. New York, UNICEF, 2013. Global Health Workforce Alliance, 2010. 13 Stevens GA, Finucane MM, Paciorek CJ, et al: Trends in mild, moderate, and severe stunting and underweight, and progress towards MDG 1 in 141 developing countries: a systematic analysis of population representative data. Lancet

2012; 380: 824–834.

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Food Policy

Bier D, et al. (eds): Nutrition for the Primary Care Provider. World Rev Nutr Diet. Basel, Karger, 2015, vol 111, pp 193–197 DOI: 10.1159/000362324

Food Preparation, Processing, Labeling and Safety

Susanna Magrietha Hanekom

Center of Excellence for Nutrition, North-West University, Potchefstroom , South Africa

Key Words prone to a large number of food safety problems Food preparation · Processing · Labeling · Safety which may arise even before they buy or eat the products. It is important for consumers to buy from reputable producers, thereby ensuring Key Messages properly and safely prepared food, issued with a • It is easy to cook healthy food by making small label that lists all the food items included as well changes to the manner of food preparation. as other nutritional information, such as aller- • Learn how to read and interpret labels to be able to gens, nutrient information and ‘use by’ date. make better and healthier food choices. • Wash hands regularly when preparing food and be aware of food-borne illnesses. Definitions © 2015 S. Karger AG, Basel

• Food preparation and processing can be defined as any act or process to get something ready and Introduction a series of things that are done in order to achieve a particular result, respectively [1] . Although most modern consumers do not realize • Labeling is defined as ‘writing of information the efforts which go into preparing and serving on a label and fixing it to something’ [1]. healthy, safe food at their tables, they still demand • Safety means ‘to be safe and protected from safe food products in terms of hygiene and safety, danger or harm’ [1] . and take for granted that the food they buy is in- • Allergens are ‘substances that cause allergies’ [1] . trinsically safe. Consumers must be aware that In the next part of the chapter, some of the key the food preparation and processing process is issues will be addressed in more detail. Food Preparation and Processing instead for improvement of taste. Remove salt from the dining table and taste before adding Cooking healthy food does not need extra time additional salt to fresh or cooked food. Use and effort. Individuals with or without diagnosed lemon juice and other herbs for seasoning of illnesses, such as diabetes, hypertension, spastic salads instead of salt. colon, irritable bowel syndrome, obesity and • Include whole wheat flour and products in any chronic diseases, can reap the benefits of simple cooking and baking instead of refined flour to dietary adjustments which may be all that is need- increase fiber for gut health and improvement ed to improve the quality of their diet and lives. of constipation. Water-soluble fiber (e.g. oat Empty calories (energy) in most instances are the bran) also has the benefit of being able to ‘cap- easiest to address because decreasing the amount ture’ excess fats in the gut and excrete it unab- added to food does not decrease the portion size. sorbed. Other non-nutrient additions will also be ad- • Cook food in as short a time and using the least dressed. amount of fluids as possible. Water-soluble vi- • Reduce the amount of table sugar added to tamins (vitamin B-complex, vitamin C) are es- food and beverages before or after cooking by pecially vulnerable as they dissolve in water half, at least for a start, thereby reducing the and are heat sensitive. It is always good prac- amount of refined carbohydrates. Later on, tice to buy food as fresh as possible (be aware sugar can be reduced even further until it is left of the ‘use by’ date on packaging), store it for out of the cooking process completely. The as little time as possible and cook it for the benefit of this is that the actual taste of the food shortest possible time. item will become more apparent. • Any visible hard fat (or animal fat, which is solid at room temperature and high in satu- Hints rated fatty acids) should be removed from meat before cooking, thereby reducing the • Use vegetable oil spray to prevent food from energy contributed by fat considerably, with- sticking to cooking utensils, instead of oil or out compromising the taste or nutritional animal fat dripping. value of the food item. Never add additional • Invest in a non-stick pan, as this will reduce fat during the cooking process, as this will the need for oil or added fat during cooking. only add extra energy, without adding vol- • Remove fat from cooked food and liquids by ume or other nutritional benefits. Discard cooling it and removing the solid fat, which any cooked fat still visible after the cooking will rise to the top, skimming it off with a period, before a sauce is made from leftover spoon/fork. fluids. Fats emulsify with thickener when • Use oils and fats low in saturated fatty acids sauces are made and are not visible to the na- (read the labels on products), for example ol- ked eye, leading one to believe that there is ive oil, if affordable. no fat in the sauce. • Processed food items, such as soup powders, sauce powders, ready-to-eat meals, and stock Food Labeling cubes are traditionally high in added salt and should be avoided. Reduce salt intake by de- The best indicator for consumers to decide creasing its addition during the preparation when to discard food is the ‘use by’ date which, and cooking process, using spices and herbs according to international laws, should be avail-

194 Hanekom

able on all consumables and perishables. Labels son, mutton, goat, horsemeat, unpasteurized milk, will only help people if they have the knowl- fruit juice, raw unwashed vegetables), Listeria (un- edge, motivation and education to use the in- pasteurized cheese, smoked fish, pâté, products formation given on packaging [2] . Ingredients conserved in jelly) and Salmonella (cattle, poultry, labeled on processed food items are listed in or- seafood) [5] , which can cause life-threatening ill- der of most to least used in the product. This nesses, requires favorable hygienic conditions dur- may give an idea of what the main ingredient ing food preparation, a step in which the food han- for that product is. In addition, all food prod- dler plays an important role [6] . ucts are obliged by law to have a label indicating Food safety is a nonnegotiable attribute, and a the literal content of the product. Consumers ‘rational’ consumer would never purchase or prefer simplified, easy-to-use labels and nutri- consume unsafe food [7] . Prior to purchase, it is tional facts panels (e.g. recommended daily val- therefore important to always inspect the condi- ues) on the label to make food choices. It is also tion of the food for damages and leakages, dents important to understand any ‘claims’ which in cans, and torn plastic wrappings. Personal hy- may be indicated on the item label. ‘Reduced giene, best practices, workplace hygiene, hand fat’, for example, may mean that the product washing and basic microbiology are the basis for must contain at least 25% less fat than a compa- food safety [6] . rable product, while ‘low fat’ means the product must contain less than 3 g fat per serving. When a product indicates that it is ‘cholesterol free’, D e f i n i t i o n s consumers may interpret the product to be ‘healthier’ than another comparable product • FBD is usually caused when bacteria/patho- without this claim. It is, therefore, important gens are carried by a person or item to the food that the consumer understands the true mean- being prepared, causing contamination. Con- ing of the label. Front-of-pack nutrition logos sumers ingest the contaminated food and be- should be interpreted carefully, using the nutri- come ill (FBDs). Cooked food is less prone to tional fact panels on the back of the product. FBDs since bacteria are killed by heat. Not all of these logos use the same criteria when • Pathogens are defined as ‘something that causes identifying a specific nutrient or groups of nu- disease’ [1] . trients as (non-)preferable (e.g. trans-fatty acids, salt, sugars, etc.) [3] . The following safety tips may make shopping, preparing and storing food easier: • Insulated carry bags are available at all retail Food Safety suppliers for keeping frozen/chilled foods cold on the way home. Put these foods in the freez- The greater the distance food travels, the greater er or fridge on arrival at home. Never break the the adverse health and environment impact [4] . cold chain. Fresh food from a production unit is handled a • Keep raw meat, fish and poultry (which will be number of times before it reaches the consumer, cooked eventually) separate from any fresh in- whether it is in raw form or processed. Food con- gredients which will be used in the raw form as tamination may occur during storage, handling, salads (and not be cooked). Contamination of and cooking food at home or in shops. The preven- raw, uncooked food may be hazardous as con- tion of foodborne diseases (FBDs) caused by bac- taminants may cause severe FBD. Also store teria such as Escherichia coli (minced beef, veni- them separately in the fridge [8] .

Food Preparation, Processing, Labeling and Safety 195 • Wash fruits, vegetables and poultry before • Never refreeze thawed food. cooking or eating, even if the packaging sug- • Store raw and cooked food separately to pre- gests that it has already been pre-washed. vent contamination. Always store food which • Always use separate cutting boards, knives spoils first in the coolest part of the fridge. and containers for preparation of foods to be cooked and those which will not undergo any heat treatments, and sterilize the equip- Proper Hand Washing Technique ment with a disinfectant directly after use. Plastic and wooden cutting boards should • Wet hands using water as warm as possible. be washed daily and replaced regularly. • Soap hands from a dispenser which should be Work surfaces should be disinfected direct- available at the basin. ly after use. • Work soap to a lather up to the elbows. Re- • Most FBDs occur after eating raw or under- member to also wash between the fingers. Use cooked food. Only thorough cooking will kill a brush to remove any dirt from underneath most of the bacteria carried by foods of animal fingernails. origin. When the origin of the meat, fish or • Rinse with warm water. poultry is not in question, the general cooking • Repeat the soaping process. time according to a recipe should be enough to • Rinse hands and dry with a disposable paper kill most of these bacteria. If, on the other towel. Do not use a fabric towel or kitchen dry- hand, the origin is not clear, prolonged cooking cloth as these may harbor bacteria [8] . ing times may be needed to kill off harmful

bacteria (at least 30 min at 100 ° C – boiling point). Conclusions • Wash hands and utensils every time you han- dle and prepare food [8] . • It is evident that consumer education is an im- • Wash hands between tasks, especially when portant part of changing food preparation and preparing raw foods for cooking, and fresh processing behavior and habits. food which will be served raw. • Interventions to improve eating habits of (low- • Wash hands after smoking, using the tele- income) individuals should focus on educa- phone, toilet, blowing your nose, sneezing, or tion to improve knowledge, skills and attitudes any other task which could carry bacteria. If related to healthy eating and food preparation you are ill, try not to prepare food for other [9] . people as you may contaminate them. Use a • Nutrition labels are potentially a major instru- surgical mask to prevent bacteria from spread- ment for enabling and educating consumers to ing. make healthier food choices, but current in- • Do not wear rings, as food can become stuck sight into how nutrition labels are used by in them and contaminate other food items. consumers in real-world setting situations is • Cool leftover cooked food within 30 min after limited, making the science-based formula-

meals to below 10 ° C to prevent bacterial tion of new labeling policies and the evalua-

growth. Store in a fridge at below 5 ° C for 3–5 tion of existing ones difficult [10] . days, depending on the type of food. Cooked fish should not be stored for more than 2 days. Only reheat food once and discard any left- overs [8] .

196 Hanekom

References

1 Hornby AS, Ashby M, Wehmeier S: Ox- 5 Srianta I, Kusumawati N, Nugerahani I, 7 Tsakiridou E, Mattas K, Tsakiridou H, et ford Advanced Learner’s Dictionary, ed et al: The presence of Salmonella in al: Purchasing fresh produce on the ba- 7. New York, Oxford University Press, food: a challenge to detect it and to im- sis of food safety, origin, and traceability

2005, pp 1143, 1157, 823, 37. prove food safety continuously in a labels. J Food Prod Mark 2011; 17: 211– 2 Hieke S, Taulor R: A critical review of global scale. Int J Food Safety Nutr Pub 226.

the literature on labeling. J Consum Af- Health Tech 2009; 1: 6–10. 8 Payne-Palacio J, Theis M: Foodservice

fairs 2012; 46: 120–156. 6 Medeiros CO, Cavalli SB, Salay E, et al: Management: Principles and Practices. 3 Vyth EL, Steenhuis IHM, Vlot JA, et al: Assessment of the methodological strat- New York, Prentice Hall, 2012, p 600. Actual use of a front-of-pack nutrition egies adopted by food safety training 9 Mello JA, Gans KM, Risica PM, et al: logo in the supermarket: consumers’ programmes for food service workers: a How is food insecurity associated with

motives in food choice. Pub Health Nutr systematic review. Food Control 2011; dietary behaviours? J Am Diet Assoc

2010; 13: 1882–1889. 22: 1136–1144. 2010; 110: 1906–1911. 4 Calverley D: Keeping food local. Nurs 10 Bonsmann SS, Celemín LF, Grunert KG:

Standard 2007; 21: 18–19. Food labeling to advance better educa-

tion for life. Eur J Clin Nutr 2010; 64:S14–S19.

Food Preparation, Processing, Labeling and Safety 197 Food Policy

Bier D, et al. (eds): Nutrition for the Primary Care Provider. World Rev Nutr Diet. Basel, Karger, 2015, vol 111, pp 198–204 DOI: 10.1159/000362325

The Food Industry and Consumer Nutrition and Health

a b Denis Barclay Ferdinand Haschke a b Nestec SA, Vevey , Switzerland; Department of Pediatrics, Paracelsus Medical University, Salzburg , Austria

Key Words Introduction Malnutrition · Micronutrient malnutrition · Overweight/obesity · Medical foods · Functional Food processing dates back to prehistoric times foods · Food industry as our hunter-gatherer ancestors began to do- mesticate plants and animals, and food preservation and storage became necessary [1] . Tradition- Key Messages al processing methods such as fermentation, sun • The food industry is facing important challenges as it endeavors to help address over- and undernutri- drying, salt preservation and various types of tion against a background of major demographic cooking (e.g. roasting, smoking, baking) preced- trends of population ageing and rural-to-urban mi- ed modern methods such as bottling, canning, gration. pasteurization and ultra-high temperature treat- • To help prevent and manage overweight/obesity, ment. The second half of the 20th century wit- the most effective approaches combine nutrition- nessed increasing need for convenience foods, ally balanced and portioned foods with regular and companies marketed foods especially to mid- counselling from health-care professionals. • An important approach to reducing micronutrient dle-class working wives and mothers; these in- malnutrition is through fortification of staple and cluded instant soups and beverages, breakfast ce- packaged foods, which must be accessible, afford- reals and prepared meals. able and nutritionally and culturally relevant to the Today, the food industry is facing major chal- target population. lenges as it endeavors to feed the planet. As the • Medical foods and oral nutrition supplements are world population grows beyond 7 billion, 50% designed for patient groups, such as the elderly and those with specific diseases. live in urban settings; by 2050, this will rise to • Collaboration between the food industry and other two thirds. While this can improve dietary diver- public and private stakeholders is essential for im- sity for some population groups, it can also favor proving the nutritional value of food products and less nutritionally balanced diets and sedentary to ensure the sustainability of the food supply, in lifestyles, resulting in overnutrition and related addition to the safety and sensory aspects of food. noncommunicable diseases (NCDs), as well as © 2015 S. Karger AG, Basel undernutrition including micronutrient deficiencies [2] . The population over 60 years old is costs of which are enormous [5]. Although the growing faster than other age groups through in- prevalence of overnutrition and related NCDs creasing longevity and decreasing fertility [3] . In are higher in industrialized regions, the absolute this chapter, we focus on food industry efforts to numbers of affected people are considerably address the wide variety of nutritional and health higher in developing countries. The ageing trend needs of consumers against the background of is increasingly important for NCDs; by midlife evolving demographic trends. and in the later years, NCDs are responsible for the vast majority of deaths and diseases, as well as for decreased quality of life and independence Malnutrition at the Population Level during the latter decades of life. The industry is increasingly providing foods Malnutrition, encompassing both under- and and services for weight management; the most ef- overnutrition, affects the health, livelihood and fective approaches combine nutritionally bal- well-being of nearly half of the people in the anced and portioned foods with regular counsel- world, causing irreversible impairment to the ling and monitoring from specialized nutrition physical and cognitive development of infants professionals. Low-calorie (1,000–1,500 kcal/ and children, increased morbidity and mortality day), low-carbohydrate and low-fat diets are of- of all age groups, as well as decreased productiv- fered. In the case of an intended rapid weight loss, ity, both for individuals and for nations. Popula- patients can be prescribed commercially avail- tions in many developing countries are often af- able very-low-calorie diets (VLCD; 800 kcal or fected by a triple burden of malnutrition, with 3,300 kJ/day). They are formulated, nutritionally protein-energy malnutrition, micronutrient mal- complete, liquid meals containing the recom- nutrition, and overweight/obesity occurring to- mended daily requirements for vitamins, miner- gether. In general, lower-income populations in als, trace elements, fatty acids and protein. Car- all countries are at higher risk of suffering from bohydrate may be entirely absent, or substituted malnutrition in any form. for a portion of the protein. Commercially available VLCD products are usually powders which Overnutrition are mixed with water or another low-food-energy Over 1.4 billion people suffer from overnutrition, liquid. The VLCD is prescribed on a case-by-case with nearly 1 billion overweight and 0.5 billion basis for rapid weight loss (about 1.5–2.5 kg or obese globally [4]. The industry is responding to 3–5 lb per week) in patients with BMI of 30 and this challenge by improving the nutritional value above. The health care provider can also recom- of packaged foods though decreasing the levels of mend the diet to a patient with BMI between 27 public health-sensitive nutrients (sugar, salt, sat- and 30 if the patient’s medical complications due urated fat, trans-fatty acids) and increasing those to overweight present a serious health risk. This of essential nutrients (fiber, micronutrients, etc.), choice has important metabolic effects and med- as well providing appropriate portion guidance ical supervision is highly recommended. (labelling, portion size and consumption frequency). U n d e r n u t r i t i o n Although agriculture has made enormous ad- Diet-Related NCDs vances in increasing food productivity several- Poor diet is a major risk factor for overweight and fold in the past half century [6], one form of obesity, and related NCDs such as cardiovascular undernutrition, protein-energy malnutrition, af- diseases, cancers and type II diabetes, the health fects almost 1 billion people globally, principally

The Food Industry and Consumer Nutrition and Health 199 small-holder farming and fishing families in de- case of the elderly, maintain strength, functional veloping regions [7]. Since packaged foods are of- ability and independence. Specialized products ten inaccessible for undernourished populations, with claims on promotion of musculoskeletal the food industry cannot address their needs di- strength, support of the immune system, and re- rectly, but can contribute by supporting govern- duction of inflammatory response are already mental and NGO efforts though farmer develop- marketed. ment programs, as well as technology and knowl- Whenever possible, oral nutrition supple- edge sharing. ments should be used. If this is not possible or does not result in sustainable improvement of nu- Micronutrient Malnutrition tritional status, feeding via nasogastric or percu- The less visible form of undernutrition is micro- taneous endoscopic gastrostomy tubes needs to nutrient malnutrition or vitamin and mineral de- be considered. Industrial products include com- ficiencies, sometimes referred to as ‘hidden hun- plete (all nutrients according to daily require- ger’. Deficiencies in one or more micronutrients ments) and incomplete (key nutrients only) oral affect 2 billion people globally [8]. The food in- nutrition products. Tube feeding products have dustry contributes significantly through fortifica- to be complete and are continuously or inter- tion of staple and packaged foods, which must be mittently administered using medical devices affordable, accessible, nutritionally and culturally (pumps, tubes, giving sets, and accessories), relevant to the target population, consumed on a which must meet international standards [e.g. regular basis and provide nutritionally relevant ISO 18485, US Food and Drug Authority (FDA) and safe amounts of bioavailable micronutrients approval]. without negatively impacting taste and stability [9] . Y o u n g W o m e n

Medical Foods With the realization of the importance of nutrition in young women of childbearing age and es- Individuals at risk for malnutrition also include pecially during the first 1,000 days of life (i.e. from the elderly, patients recovering from acute inci- conception until the child has reached 2 years of dent/illness, patients with cancer, stroke, gastro- age), nutritional science is increasingly focusing intestinal, respiratory, or neurological disease. on their nutritional needs, not only during preg- Disease-related malnutrition increases hospital nancy and lactation, but also prior to pregnancy. costs by 30–70%, average length of hospital stay Maternal over- or undernutrition before and dur- by 40–70%, and results in substantial economic ing pregnancy can have long-term negative effects costs, e.g. USD 140 billion/year in the EU [10] . on the health of the offspring (‘metabolic pro- Screening and a rapid diagnosis of malnutrition is gramming’ hypothesis). The fuel-mediated ‘in necessary to identify those patients who need nu- utero’ hypothesis suggests that intrauterine expo- tritional support. A widely accepted and scientifi- sure to an excess of fuels causes permanent chang- cally validated method for screening and diagno- es in fetal metabolism that lead to obesity and sis is the Mini-Nutrition-Assessment (MNA ® ; related NCD in postnatal life; the accelerated www . mna-elderly.com). The industry needs to postnatal weight gain hypothesis proposes an as- provide adequate medical nutrition products/ sociation between rapid weight gain in infancy foods for special medical purposes (Codex Ali- and an increased risk of later obesity and adverse mentarius), which promote recovery and in the outcomes; and the mismatch hypothesis suggests

200 Barclay /Haschke

that experiencing a developmental ‘mismatch’ Nutritional Value of Foods (Nutritional between a suboptimal pre- and perinatal and an Profiling) ‘obesogenic’ childhood environment is related to a particular predisposition to obesity and corre- Nutrient profiling of foods, described as the sci- sponding comorbidities [11] . Therefore, before ence of ranking foods based on their nutrient pregnancy, undernourished young women should content, is fast becoming the basis for regulating have access to affordable, micronutrient-fortified nutrition labels, health claims, and marketing and food or supplements [12] , while obese women advertising to children [14]. A number of nutri- should reduce weight by eating safe, low-calorie ent profiling models have now been developed by diets or VLCDs whilst changing their lifestyle. research scientists and regulatory agencies. Whereas some of these models have focused on nutrients to limit, others have emphasized nutri- Nutrition and Health Research and ents known to be beneficial to health, or combina- Technology tions of both. For example, The Nutrient Rich Foods index ranks foods based on their nutrient In order to offer safe, good-tasting, nutritious content; combined with food prices, it can help and affordable foods to people across the globe, identify foods that are both nutritious and afford- closer collaboration between nutrition and food able [15] . scientists is essential [13] ; indeed food compa- In anticipation of and in response to consum- nies are increasingly investing not only in food er demand for nutritionally superior foods, com- processing research, but also in food science, nu- panies are increasingly using such nutritional trition, and in understanding consumer behav- profiling systems during development and reno- ior. Some of the world’s largest food and nutri- vation of food products. Many major food com- tion research centers are found within the food panies base nutritional improvement pledges on industry. Food industry research is ever more such systems, either voluntarily or in response to carried out in collaboration with leading food international or national nutritional guidelines and nutrition universities and institutes, each re- related to food advertising, in particular towards search partner bringing to the table specific com- children. petencies in order to better identify and implement solutions to address the specific nutritional needs of different population groups. One such Food Industry and Health-Care example is the micronutrient fortification of ap- Professionals propriate food vectors to effectively bring missing nutrients to target consumer groups. The Health-care professionals (HCP) such as family university partner may provide knowledge con- doctors, nurses and dieticians are primary sourc- cerning the extent, severity and geographical lo- es of nutritional information for consumers to cation of deficiencies in a population, as well as reduce risk of, or manage chronic diet-related appropriate methodologies to assess nutrient sta- conditions, as well as nondiet-related disorders. tus, whereas the food industry partner can pro- Since many such HCP do not have access to ap- vide the fortification technology and quality as- propriate nutritional training, the food industry surance for appropriate delivery vehicles, as well is increasingly making available independent, as consumer research on how to communicate science-based nutrition information to HCP en- the associated health message in the most com- compassing all life stages, geographies and cul- pelling way. tures. In this context, the information provided

The Food Industry and Consumer Nutrition and Health 201 must be noncommercial and provided by inde- Table 1. Conditions and situations requiring HCP coun- pendent scientists with no conflict of interest. selling For example, the Nestlé Nutrition Institute (www.nestlenutrition-institute.org) and the Da- Overweight and obesity none Institute (www.danoneinstitute.org/) pro- Metabolic disorders (e.g. diabetes) vide independent science-based nutritional in- Cardiovascular diseases formation and training to HCP. Table 1 lists a Osteoporosis number of health conditions and situations for Inflammatory bowel disease which nutritional guidance from HCP is neces- Lactose intolerance sary for efficient management. Gluten intolerance (celiac disease) HCP may sometimes receive invitations from Allergy the food industry to attend seminars which fo- Micronutrient deficiencies cus on the health benefits of food products. Sports nutrition Some may even be invited to participate in clinical trials designed to determine the efficacy of a functional food in the prevention or treatment of a health condition. In such cases, the manu- Table 2. EFSA favorable claim evaluations facturers should provide to the HCP all the relevant literature and in the case of clinical trials, Vitamins and minerals the full study protocol as well as the full protocol Specific dietary fibers related to blood glucose control, assessment and approval by the relevant ethical blood cholesterol, or weight management committee. If a product is already launched and Live yoghurt cultures and lactose digestion an HCP is invited to participate in a post-launch Antioxidant effects of polyphenols survey or ‘phase 4 study’, it is highly recom- Meal replacement and weight control mended to contact independent health agencies (e.g. FDA) to determine whether such an offer is Fatty acids and function of the heart ethical and for the benefit of the consumer. HCP The role of a range of sugar replacers (such as xylitol may also encounter reports of food industry and sorbitol) in maintaining tooth mineralization or practices apparently infringing environmental lowering the increase of blood glucose levels after meals (e.g. genetically modified organisms), social (e.g. child labor), and other regulations. In such Carbohydrate-electrolyte drinks/creatine and sports cases, the HCP may need to contact a govern- performance ment or company contact point to request full information relative to the reported infringe- ment. ol, and dairy products are enriched with probiotic bacteria or prebiotic carbohydrates for gas- F u n c t i o n a l F o o d s trointestinal health. In order to ensure that the health claims on such foods are factual and not Over the last 10 years, the food industry has de- misleading consumers, regulatory authorities veloped numerous functional foods targeting have established systems that assess their level common nutrition-related NCD; for example, of scientific substantiation based on objective foods such as milks and spreads are enriched evaluation. The FDA has published a summary with plant sterols for lowering blood cholester- of qualified health claims [16] , and the Europe-

202 Barclay /Haschke

an Food Safety Authority [17] developed and fuel usage and long-distance transportation of implemented a rigorous system used to assess raw materials and finished products, improved nearly 3,000 submitted claims, of which approx- farmer livelihood through production of high- imately 20% were approved, relating to a limited quality and high-yielding raw materials, increased number of areas (table 2 ). use of local raw materials and reinforcement of HCP may encounter product health claims local food cultures. Many food companies are al- with which they are not familiar, e.g. for import- ready undertaking research and implementing ed products. In order to be able to appropriately programs addressing these issues in order to en- advise patients on the validity of such claims, sure sustainability. they may consult local regulatory authorities; in countries where there are no health claim regulations, HCP may need to consult the opinions of Conclusions the European Food Safety Authority or FDA on such claims. • The food industry is addressing a number of important challenges as it endeavors to provide tasty and nutritious foods to a growing Consumer Awareness global population which is also ageing, increasingly urbanized and affected by overnu- The food industry has a responsibility to help trition and related NCDs, while undernutri- consumers make informed, healthier choices. tion and micronutrient malnutrition remain Many food companies have introduced self-reg- widespread. ulation regarding product information and ad- • The food industry has a key role to play in con- vertising to consumers. On-pack nutritional cert with the other public and private stake- information systems such as Guideline Daily holders, and is amplifying its efforts to im- Amounts and nutrition tables (e.g. Nestlé Nu- prove the nutritional value of food products tritional CompassTM ) have been designed for and related communication to consumers and this purpose. As above, nutrition claims and to ensure the sustainability of the food supply, health claims are increasingly controlled by reg- in addition to the safety and sensory aspects of ulatory authorities, allowing only claims with food. adequate scientific substantiation. This helps to • Consumers today are increasingly basing food reduce confusion amongst consumers and HCP purchases on these aspects, creating intense about the nutritional and health benefits of competition within the food industry, which foods. will ultimately improve the food supply with respect to these criteria. • The future of the food industry will thus in- Sustainable Food Supply creasingly depend on creation of shared value for all the players along the food chain. Another major challenge facing the agricultural and food sectors is that of sustainability encompassing the entire food chain from farm to fork [6, 18] . In addition to the essential aspects of safety, taste, nutrition and affordability, ensuring food supply sustainability necessitates reduction of its impact on the environment, including water and

The Food Industry and Consumer Nutrition and Health 203 References

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Author Index

Adeel, S. 136 Lau, J. 1 Leung, J. 76 Barclay, D. 198 Barr, S.I. 53 Mann, J. 24, 110 Bhardwaj, S. 116 Marsano, L. 146 Bhutta, Z.A. 186 Marzola, E. 169 Bistrian, B.R. 87 Mattes, R.D. 19 Butte, N.F. 64 Maughan, R.J. 71 McLean, R.M. 100 Cashman, K. 45 Misra, A. 116 Caterson, I.D. 104 Mohn, E.S. 38 Cave, M. 146 Chung, M. 1 Obert, J. 146 Coates, P.M. 58 Crowe, S.E. 76 Risérus, U. 94

Drewnowski, A. 174 Said, H.M. 30 Salam, R.A. 186 Fairweather-Tait, S.J. 45 Schoeller, D.A. 13 Scolapio, J.S. 141 Gibson, A.A. 104 Shirreff s, S.M. 71 Sim, K.A. 104 Hanekom, S.M. 193 Smith, D.J. 141 Haschke, F. 198 Stabler, S.P. 164 Hoff er, L.J. 87 Tangpricha, V. 136 Johnson, E.J. 38 Th omas, D. 13 Th omas, P.R. 58 Kaye, W.H. 169 Key, T. 123 van Graan, A.E. 130 Kruger, H.S. 64 Vorster, H.H. 7, 82, 179 Kumar, N. 151

205 Subject Index

Acrodermatitis enteropathica 52 medical consequences 171 Body mass index, see also Obesity Acute pancreatitis, management mineral defi ciency 51 hypertension studies 102 143 overview 169, 170 interpretation 13–15 Adequacy, see Nutrient adequacy treatment 170 pregnancy nutritional Afl atoxin, liver cancer risks 126 vegetarian diet concerns 56 assessment 65 AIDS, see Human weight restoration Breast cancer, see Cancer immunodefi ciency virus calories 171, 173 Alcohol nutrients 172 Calcium, see Minerals/trace cancer risks 124, 125 phases 172 elements hypertension studies 102 Appetite Cancer liver disease 148, 149 measurement 20–22 epidemiology 123, 124 Amino acids modulation through food mineral/trace element essential amino acids 25 properties and eating defi ciencies 50 intake recommendations 25 patterns 22, 23 nutrition studies Amylin, appetite regulation 21 overview 19, 20 bladder cancer 127 Anemia peptide hormones 21 breast cancer 126 defi nition 164 Ascorbate cervical cancer 127 iron-defi ciency anemia defi ciency 35, 36, 90 colorectal cancer 125, 126 diagnosis 165 dietary sources 36 endometrial cancer 125 dietary requirements 165 intake recommendations 36, 59 esophageal cancer 124 treatment 165, 166 osteoporosis studies 138 head and neck cancer 124, megaloblastic anemia overview 35 125 cobalamin defi ciency Athletes, see Physical activity/sports kidney cancer 127 causes 166 Average nutrient requirement 10 liver cancer 126 diagnosis 166, 167 lung cancer 126 treatment 167 Bariatric surgery, obesity mechanisms in risks and folate defi ciency management 109 protection 124, 125, 128 causes 167, 168 Bioelectric impedance analysis, pancreatic cancer 126 diagnosis 168 body composition assessment prostate cancer 127 treatment 168 15 stomach cancer 125 Anorexia nervosa Biotin treatment 127 clinical presentation 170 defi ciency 36 Carbohydrate eating behavior 170 dietary sources 36 athlete requirements 74 epidemiology 170 intake recommendations 36 cardiovascular disease etiology 170 overview 36 considerations 98 exercise and metabolism in Bladder cancer, see Cancer dietary sources 27, 28 anorexia nervosa 171 Body composition, assessment 15 glucose intake 28

206 intake recommendations 25, 28 genetic versus evidence application and low-carbohydrate diet 28, 29 environmental factors impact assessment 5 Cardiovascular disease 120, 121 evidence appraisal 3, 5 diet migration 120 Exercise, see Physical activity/sports blood lipid response 96 physical activity 119, 120 carbohydrate 98 generalized and abdominal Fat fat 97, 98 obesity defi nition 119 anorexia nervosa patients 172 prevention and treatment 96 overview 116, 117 cardiovascular disease protective foods 95, 97 phenotypic features of considerations 97, 98 risk pattern changes 95, 96 obesity contributing to intake recommendations 25–27 mineral defi ciency 50 insulin resistance and omega-3 fatty acids overview 94, 95 metabolic syndrome 118, overview 26 pathophysiology 95 119 pregnancy 66 Celiac disease 78 lifestyle-related determinants vegetarian diet concerns 55, Cervical cancer, see Cancer 111, 112 56 Cholecystokinin, appetite nutritional management Folate regulation 21 112–115 defi ciency 34, 153, 158, 167, 168 Chronic kidney disease, minerals overview 110, 111 dietary sources 35, 153 in diet 50 prevention 115 intake recommendations 35 Cirrhosis, nutritional management Dietary Approaches to Stop megaloblastic anemia, see 147 Hypertension 102 Anemia Climate change Dietary reference intakes 10 neurological manifestations of food price impact 177 Dietary supplements defi ciency 158 high-quality diets and effi cacy 60, 61 overview 34, 157 sustainability 176, 177 information sources 61 pregnancy intakes 66 Cobalamin popularity of use 58–60 Food allergy defi ciency 35, 152, 153, 155, 166, quality 62 allergens 77, 78 167 regulation and oversight 62, 63 food intolerance comparison 77 dietary sources 35, 153 safety 61, 62 multiple food allergy 80 intake recommendations 35, 59 Drug-induced nutrient defi ciency non-immunoglobulin E adverse megaloblastic anemia 166, 167 51, 91 reactions 78 megaloblastic anemia, see Dual X-ray absorptiometry prevalence 76 Anemia body composition assessment 15 resources 80 neurological manifestations of osteoporosis screening 136, 139 symptoms 78 defi ciency 152, 155 types 78, 79 overview 35, 152 Endometrial cancer, see Cancer Food-based dietary guidelines 10, 11 vegetarian diet concerns 55, 56 Energy balance Food industry Colorectal cancer, see Cancer calculation 16, 17 concerns Copper, see Minerals/trace elements imbalance and weight change 17 consumer awareness 203 Culture Enterostatin, appetite regulation 21 micronutrient defi ciency 200 cultural competency Esophageal cancer, see Cancer overnutrition 199 development 83, 85, 86 Estimated average requirement 10 sustainability 203 dietary practices 84, 85 European Food Safety Authority, undernutrition 199, 200 ethnicity 83 health claim evaluation 202, 203 young women 200, 201 Evidence-based practice functional foods 202, 203 Developing countries, see organizations providing global demands 198, 199 Undernutrition, developing nutritional guidelines 4, 5 health-care professional countries overview 1, 2 interactions 201, 202 Diabetes mellitus type 2 PI(E)CO approach 2, 3 medical foods 200 epidemiology 111 prospects 6 nutritional profi ling 201 India steps for nutrition practice research 20 determinants of obesity, type ask clinical question 2, 3 Food intolerance 2 diabetes, and metabolic evidence acquisition 3 food allergy comparison 77 syndrome diet 119 symptoms 79, 80

Subject Index 207 types 79 Individual nutrient levelx 10 defi ciency Food labeling 194, 195 Infl ammatory bowel disease causes 160 Food preparation and processing management 144 clinical signifi cance 160, 193, 194 mineral defi ciency 46, 50 161 Food safety 195, 196 Insulin, appetite regulation 21 investigations 161 INTERSALT study 101 management 161 Gastroparesis, management 144 Iodine, see Minerals/trace elements dietary sources 154 Ghrelin, appetite regulation 21 Iron, see Minerals/trace elements functions 160 Glossitis 91 Iron-defi ciency anemia, see Anemia defi ciency and disease Glucagon-like peptide-1, appetite anorexia nervosa 51 regulation 21 Kidney cancer, see Cancer assessment 92 Glucose, intake 28 Korsakoff syndrome 156, 157 bone 50 Greenhouse gas emissions, cancer 50 high-quality diets and Lactation cardiovascular disease 50 sustainability 176, 177 nutritional assessment 67 chronic kidney disease 50 postpartum weight retention 67 drug induction 51 Handwashing, technique 196 Leptin, appetite regulation 21 genetic disorders 51, 52 Head and neck cancer, see Cancer Liver cancer, see Cancer infl ammatory bowel disease Helicobacter pylori 125 Lung cancer, see Cancer 46, 50 Hepatitis C virus 126 liver 46 Herbert, Victor 92 Magnesium, see Minerals/trace pancreas 46 Hereditary hemochromatosis 51 elements parenteral nutrition 51 Homocysteine, folate status 158 Magnetic resonance imaging, body pregnancy 51 Human immunodefi ciency virus composition assessment 15 defi ciency and toxicity signs and epidemiology 130, 131 Malnutrition, see Protein-energy symptoms 48 nutritional assessment malnutrition, Undernutrition, functional overview 46 anthropometric developing countries hypertension studies measurements 132, 133 Malnutrition Universal Screening potassium 101, 102 biochemical assessment 133 Tool 89 sodium 100, 101 clinical assessment 133 Medical foods intake recommendations 59 dietary assessment 133 anorexia nervosa 170 osteoporosis studies nutritional goals 133 overview 200 calcium 137 nutritional management 134 Megaloblastic anemia, see Anemia magnesium 138 nutritional requirements Menkes, syndrome 52 phosphorous 137 energy 134 Metabolic syndrome, India pregnancy overview 133, 134 determinants of obesity, type 2 calcium 66 protein 134 diabetes, and metabolic iodine 66 nutritional status and infection syndrome diet 119 iron defi ciency 66 131, 132 genetic versus environmental supplements, see Dietary pathophysiology 131 factors 120, 121 supplements treatment 131 migration 120 vegetarian diet concerns Human papillomavirus 127 physical activity 119, 120 calcium 55 Hypertension generalized and abdominal iron 54, 55 mortality and morbidity 100 obesity defi nition 119 zinc 55 nutritional determinants overview 116, 117 Multivitamins, see Dietary alcohol 102 phenotypic features of obesity supplements body mass index 102 contributing to insulin Dietary Approaches to Stop resistance and metabolic Niacin Hypertension 102 syndrome 118, 119 defi ciency 33, 159 miscellaneous factors 102 Minerals/trace elements dietary sources 33, 153 potassium 101, 102 anemias 91, 165, 166 functional overview 33, 158 recommendations 102 biomarkers for status assessment intake recommendations 33 sodium 100, 101 47, 48 neurological manifestations of copper defi ciency 159

208 Subject Index Nonalcoholic fatty liver disease Osteoporosis energy and nutrient India 118, 119 diagnosis and treatment 139 requirements 65, 66 nutritional management 148 estrogen studies 138 food industry concerns for risk factors 147, 148 nutrient studies young women 200, 201 Nutrient adequacy, steps for minerals mineral defi ciency 51 restoration and maintenance 8, calcium 137 nutrition importance 64 11 magnesium 138 nutrition-related complications Nutrient intake values 10 phosphorous 137 67 Nutrient recommendations 10 recommendations 139, 140 nutritional assessment 65 Nutrient reference values 10 vitamin A 138 weight gain management 68, 69 Nutrient Rich Foods index 176 vitamin C 138 Prostate cancer, see Cancer Nutritional status vitamin D 138 Protein AIDS, see Human vitamin K 138 anorexia nervosa patients 172 immunodefi ciency virus overview 136 athlete requirements 74 assessment 8, 9 physiology 136, 137 essential amino acids 25 tools Osteoprotegerin, osteoporosis role human immunodefi ciency virus dietary goals 10 137 patients 134 food-based dietary Overnutrition intake recommendations 25, 26 guidelines 10, 11 developing countries 182 protein:energy ratio 25, 26 growth standards 11 epidemiology 199 vegetarian diet concerns 54 nutrient recommendations Oxyntomodulin, appetite weight loss diets 26 10 regulation 21 Protein-energy malnutrition adaptation 88, 89 Obesity, see also Body mass index Pancreatitis, see Acute pancreatitis diagnosis and assessment 89 cancer risks 126, 127 Pancreatic cancer, see Cancer food industry concerns 200 defi nition 104, 105 Pancreatic polypeptide, appetite importance of recognition 89, 90 India regulation 21 infl ammation 89, 90 determinants of obesity, type Pantothenic acid maladapted malnutrition 89 2 diabetes, and metabolic defi ciency 33 Pyridoxine syndrome diet 119 dietary sources 33 defi ciency 34, 154, 159, 160 genetic versus functional overview 33 dietary sources 34, 154 environmental factors intake recommendations 33 functional overview 34, 159 120, 121 Pellagra 159 intake recommendations 34 migration 120 Peptide YY, appetite regulation 21 neurological manifestations of physical activity 119, 120 Phentermine, obesity management defi ciency 159, 160 generalized and abdominal 108 obesity defi nition 119 Phosphorous, see Minerals/trace RANKL, osteoporosis role 137, 139 overview 116, 117 elements Recommended Dietary Allowance phenotypic features of Physical activity energy 10 obesity contributing to expenditure 16, 18 Reference nutrient intake 10 insulin resistance and Physical activity/sports Religion, dietary practices 83–85 metabolic syndrome 118, energy and nutrient needs Resting metabolic rate 16 119 competitive sports 73–75 Retinol, see Vitamin A management physically active individuals Ribofl avin bariatric surgery 109 72, 73 defi ciency 32 behavior modifi cation 106 exercise and metabolism 171 dietary sources 33 diet 105, 106 hypertension studies 102 functional overview 32 fi ve As approach 108, 109 popularity 71 intake recommendations 33 goals 105 PI(E)CO, see Evidence-based pharmacotherapy 108 practice SAIN,LIM score 176 physical activity 106 Population nutrient intake 10 Selenium, see Minerals/trace very-low energy diet 107, 108 Potassium, see Minerals/trace elements Omega-3 fatty acids, see Fat elements Short bowel syndrome, Orlistat, obesity management 108 Pregnancy management 144

Subject Index 209 Smoking, cancer risks 126, 127 trends 188 chemical structures 39 Sports, see Physical activity/sports optimization of food and defi ciency 42, 90, 161, 162 Stomach cancer, see Cancer nutrition environment 183, dietary sources 42, 154 Supplements, see Dietary 184, 190, 191 intake recommendations 40, 59 supplements overnutrition coexistence 182 neurological manifestations of Sustainability overview 179, 180 defi ciency 161, 162 aff ordability metrics 176 poverty, low human capital, and osteoporosis studies 138 food industry concerns 203 malnutrition 181, 182 overview 42, 161 food price impact of climate strategies to combat tolerable upper intake level 41 change 177 malnutrition 188–190 toxicity 42 high-quality diets 176, 177 Upper tolerable nutrient intake vegetarian diet concerns 55, 56 nutrient density metrics 175, 176 level 10 Vitamin E sustainable agriculture absorption and transport 43 measures 175 Vegetarian diet chemical structures 39 sustainable diet defi nition 175 anorexia nervosa association 56 defi ciency 43, 154, 155 classifi cation 54 dietary sources 43, 154 Th ermal eff ects of meals 16 concerns functions 43, 154 Th iamine calcium 55 intake recommendations 40 defi ciency 31, 32, 153, 155-157 cobalamin 55, 56 neurological manifestations of dietary sources 32, 153 iron 54, 55 defi ciency 154, 155 functional overview 31, 155, 157 omega-3 fatty acids 55, 56 tolerable upper intake levels 41 intake recommendations 32 protein 54 toxicity 43 neurological manifestations of vitamin D 55, 56 Vitamin H, see Biotin defi ciency 156 zinc 55 Vitamin K Total energy expenditure 16 prevalence 53 absorption and transport 43 Total enteral nutrition Very-low energy diet, obesity chemical structures 39 formula selection 142, 143 management 107, 108, 188 defi ciency 43, 44 indications 141, 142 Vitamin A dietary sources 43 Total parenteral nutrition absorption and transport 40, 41 functions 43 acute pancreatitis management chemical structures 39 intake recommendations 40 143 defi ciency 41 osteoporosis studies 138 formula selection 142, 143 dietary sources 38, 40 toxicity 44 indications 141, 142 functions 41 Vitamin supplements, see Dietary infl ammatory bowel disease intake recommendations 40 supplements management 144 osteoporosis studies 138 mineral defi ciency 51 tolerable upper intake levels 41 Waist circumference, interpretation short bowel syndrome toxicity 42 14, 15 management 144 Vitamin B1, see Th iamine Weight change, see also Obesity Trace elements, see Minerals/trace Vitamin B2, see Ribofl avin energy imbalance 17 elements Vitamin B3, see Niacin involuntary weight loss Vitamin B5, see Pantothenic acid evaluation 90, 91 Undernutrition, developing Vitamin B6, see Pyridoxine online models 17, 18 countries Vitamin B9, see Folate pregnancy, see Pregnancy causes 180, 181 Vitamin B12, see Cobalamin Wernicke encephalopathy 156, 157 , challenges and inequities 190 Vitamin C, see Ascorbate Wilson s disease 52 epidemiology 186, 187 Vitamin D nutrition absorption and transport 42 Zinc, see Minerals/trace elements transition 182 athlete requirements 74

210 Subject Index