Integrative gastroenterology

Integrative Gastroenterology

Weil Integrative Medicine Library Published and Forthcoming Volumes series editor andrew weil, md

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

Integrative Gastroenterology edited by

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

1

1 Published in the United States of America by Oxford University Press, Inc., 198 Madison Avenue, New York, NY, 10016 United States of America Oxford University Press, Inc. publishes works that further Oxford University’s objective of excellence in research, scholarship, and education Oxford is a registered trademark of Oxford University Press in the UK and in certain other countries

© Oxford University Press, Inc. 2011 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without the prior permission in writing of Oxford University Press, Inc., or as expressly permitted by law, by licence, or under terms agreed with the appropriate reproduction rights organization. Inquiries concerning reproduction outside the scope of the above should be sent to the Rights Department, Oxford University Press, Inc., at the address above You must not circulate this work in any other form and you must impose this same condition on any acquirer ____________________________________________ Library of Congress Cataloging-in-Publication Data Integrative gastroenterology/[edited by] Gerard E. Mullin. p.; cm.—(Weil integrative medicine library) Includes bibliographical references and index. ISBN-13: 978-0-19-537110-9 (alk. paper) ISBN-10: 0-19-537110-0 (alk. paper) 1. Gastrointestinal system—Diseases. 2. Integrative medicine. I. Mullin, Gerard E. II. Series: Weil integrative medicine library. [DNLM: 1. Gastrointestinal Diseases—therapy. 2. Complementary Therapies—methods. WI 140 I605 2010] RC817.I47 2010 616.3’3—dc22 2009023877 978-0-19537110-9 ____________________________________________ 1 3 5 7 9 10 8 6 4 2 Typeset in Minion Pro Regular Printed on acid-free paper Printed in the United States of America This material is not intended to be, and should not be considered, a substitute for medical or other professional advice. Treatment for the conditions described in this material is highly dependent on the individual circumstances. And, while this material is designed to offer accurate information with respect to the subject matter covered and to be current as of the time it was written, research and knowledge about medical and health issues is constantly evolving and dose schedules for medications are being revised continually, with new side effects recognized and accounted for regularly. Readers must therefore always check the product information and clinical procedures with the most up-to-date published product information and data sheets provided by the manufacturers and the most recent codes of conduct and safety regulation. The publisher and the authors make no representations or warranties to readers, express or implied, as to the accuracy or completeness of this material. Without limiting the foregoing, the publisher and the authors make no representations or warranties as to the accuracy or efficacy of the drug dosages mentioned in the material. The authors and the publisher do not accept, and expressly disclaim, any responsibility for any liability, loss or risk that may be claimed or incurred as a consequence of the use and/or application of any of the contents of this material.

To the more than 70 million Americans who are known to suffer from digestive disorders. To my loved ones for their unwavering support over the years. To the many who mentored me throughout my career. To Andrew Weil MD for selecting me to edit this textbook. And the beloved memory of my parents.

This page intentionally left blank

FOREWORD

A

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

viii FOREWORD

Anatomy and Cell Biology at Columbia University Medical Center, in an excellent book on enteric neurology, refers to the gut as the “second brain.” Many common GI disorders arise from disturbed function of the gut—in particular, an imbalance between its intrinsic motility and extrinsic control by the autonomic nervous system (often caused by stress-related overactivity of the sympathetic nerves). Without harmonious coordination, gut motility is abnormal and digestion impaired. In late stages of these disorders, we can visualize or otherwise detect pathological changes, but early on they present as functional complaints. Patients seek relief of GI symptoms; there are few or no measurable correlates of the symptoms. “Functional disorder” is a loaded term in conventional medicine. Often it is used to dismiss complaints of patients without visible pathology; at worst, it is used as a synonym for “imagined disease.” Patients are easily angered by suggestions that their GI problems are all in the mind. Practitioners must be able to help them understand the underlying somatopsychic mechanism that accounts for their very real symptoms. Traditional Chinese medicine (TCM) classifies diseases as “visible” or “invisible” and postulates that all visible disease is preceded by an invisible stage, in which “energy” (chi) circulation through the body is disturbed. TCM practitioners believe that if invisible disease goes untreated (by acupuncture, herbal therapy, dietary adjustment, etc.), it will eventually produce pathological changes in the physical structure of the body. Therefore, TCM prioritizes the diagnosis and treatment of what conventional Western medicine often dismisses as functional disorders. Doctors here tend to minimize the significance of these problems, in part because they find it frustrating to manage them. Their training does not enable them to do so. Because dietary habits and other lifestyle factors can both trigger and aggravate this class of GI disorders, it is not sufficient to send patients to stressmanagement training or hypnotherapy. Physicians must also give them specific recommendations about foods, beverages, physical activity, rest and sleep, and more. And they should know when the pharmaceutical drugs now so widely prescribed for GI problems are really indicated, and for how long patients should be on them. Proton-pump inhibitors for GERD and steroids for inflammatory bowel disease may be useful for short-term suppression of symptoms, but over time the benefit-to-risk ratio changes significantly and unfavorably, and data on the risks are accumulating. Practitioners of integrative medicine are fully trained to diagnose and treat invisible and functional disease before it damages tissues and organs and requires drastic, costly intervention. They work from the premise that the body can heal itself if given a chance, that mind/body interactions are real and often very relevant to issues of health and illness, that all aspects of lifestyle must be

FOREWORD

ix

considered in evaluating patients, and that the doctor/patient relationship is a key factor in the outcome of treatment. In addition, they are familiar with a wide range of therapeutic options other than drugs. In recommending therapies not commonly included in mainstream practice, they pay attention to the evidence that supports them, always working from the principle that the greater the potential of a treatment to cause harm, the stricter the standards of evidence for efficacy it must be held to. A major initiative of the Arizona Center for Integrative Medicine is “Integrative Medicine in Residency” (IMR). We have developed a 200-hour, comprehensive curriculum in IM, much of it taught online, that is currently a required component of eight residency programs around the United States. This is a pilot phase of IMR; the center’s long-range goal is to have this comprehensive curriculum become a required, accredited part of all residency training, including that of specialists and subspecialists. Then all physicians (and surgeons), including gastroenterologists, will know the basics of nutritional medicine, botanical medicine, mind/body medicine, lifestyle influences on health, the indications for and strengths and weaknesses of other systems (like Chinese and Ayurvedic medicine) and of complementary and alternative therapies. I am certain that the resulting transformation of medicine is a prerequisite for building a functional, cost-effective health care system, one that emphasizes disease prevention and health promotion and that uses costly, technology-based interventions (including pharmaceutical drugs) only when they are really indicated, managing common forms of illness with simpler, less expensive interventions. It is my hope that this series of volumes from Oxford University Press will help achieve these goals. I have looked forward to the publication of Integrative Gastroenterology with great anticipation. Not only does it give all clinicians an overview of the subject and specific guidance about the integrative management of common GI problems, it has the potential to hasten the day when integrative gastroenterology will be a vital field of research and practice. The editor, Gerard Mullin, MD, has done a commendable job of assembling expert contributors and informative articles. I have learned much from working with him on the project, and I hope the information in these pages will lessen the frustration of practitioners faced with GI problems that conventional education and training does not enable them to solve. Andrew Weil, MD Series Editor Tucson, Arizona May, 2009

This page intentionally left blank

CONTENTS

Contributors 1. Why Integrative Gastroenterology?

xv 

Gerard E. Mullin

2. The American Digestive Disease Epidemic



Gerard E. Mullin

3. An Overview of Digestive, Sensing, and Immune Functions of the Gut



Patrick J. Hanaway, Laura K. Turnbull, and Gerard E. Mullin

4. The Intestinal Microbiota in Health and Disease: Bystanders, Guardians, or Villains?



Fergus Shanahan

5. Alternative Laboratory Testing for Gastrointestinal Disease



David M. Brady, J. Alexander Bralley, Richard S. Lord, and Gerard E. Mullin

6. New Molecular Techniques Revolutionize Understanding of the Influence of Gut Microbiota on Health and Disease



J. Alexander Bralley

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



Laura K. Turnbull, Gerard E. Mullin, and Leonard B. Weinstock

8. The Skin and the Gastrointestinal Tract



Andrew G. Franks, Jr.

9. Premenstrual and Menstrual Exacerbation of IBS: An Integrative Medicine Analysis of the Bi-Directional Connection between Female Hormones and Gut Health



Joel M. Evans

xi

xii

CONTENTS

10. Fibromyalgia and Gastrointestinal Disorders



David M. Brady and Michael J. Schneider

11. Acupuncture for Digestive System



Sanghoon Lee and Ta-Ya Lee

12. Ayurveda and Digestive Health



David Simon and Valencia Porter

13. Osteopathic Medicine



Diane Clawson

14. Gastroenterology and an Integrative Chiropractic Approach



Loren Marks and David M. Durkin

15. Energy Medicine and Gastrointestinal Disorders



Ann Marie Chiasson

16. Guided Imagery and Gastroenterology



Martin L. Rossman

17. Hypnosis and Gastrointestinal Disorders



Anastasia Rowland-Seymour

18. Homeopathy Origins and Therapeutic Principles



Savely Yurkovsky

19. Massage for Digestive Health



Stephanie Porcaro and Gerard E. Mullin

20. Mindfulness Based Stress Reduction for Health and Diseases



Padmini D. Ranasinghe

21. Naturopathic Medicine and Digestion



Joseph Pizzorno

22. Taiji, Qigong, and Digestive Health



Yang Yang and Bob Schlagal

23. Digestive Health and Reiki Energy



Beth Nolan

24. Self-Care Journaling for Digestive Health



Danna M. Park

25. Spirituality



Frederic C. Craigie, Jr.

26. What Patients Want from Their Doctors Donna Jackson Nakazawa



CONTENTS xiii

27. The Value of Support Groups



Pearl L. Lewis and Gerard E. Mullin, with a foreword by Bernie Siegel

28. Overview of Visceral Manipulation for the Integrative Gastroenterologist



Jean-Pierre Barral and Gail Wetzler

29. Probiotics in the Prevention and Treatment of Gastrointestinal Disease



Gerald Friedman

30. The Role of Nutritional Genomics and Functional Medicine in the Management of Crohn’s Disease



Sheila G. Dean and Kathie M. Swift

31. Functional Foods for Digestive Health and Disease



Elizabeth Lipski

32. The Role of Herbal Medicine in Integrative Gastroenterology



Tieraona Low Dog

33. Brief Review of Mind–Body Medicine in Gastroenterology Practice



Miranda A.L. van Tilburg, Stephan R. Weinland, and Olafur S. Palsson

34. Mind–Body Medicine in Digestive Disease



Douglas A. Drossman and William E. Whitehead

35. Yoga and Digestive Health



Sajida Chaudry and Beth Nolan

36. Integrative Approaches to Abdominal Pain



Robert A. Bonakdar and Emily G. Singh

37. Over-the-Counter Remedies for Digestive Health: Potion or Poison?



Jerry Hickey and Gerard E. Mullin

38. Systemic Interactions Between Dental and Gastroenterological Diseases



Philip E. Memoli

39. Upper Gastrointestinal Disorders: Dyspepsia, Heartburn, Peptic Ulcer Disease, and Helicobacter pylori Anil Minocha



xiv

CONTENTS

40. Celiac Disease



S. Devi Rampertab and Peter H.R. Green

41. Food Reactions and Their Implications in the Irritable Bowel Syndrome



Trent W. Nichols, Gerard E. Mullin, and Laura K. Turnbull

42. An Evidence-Based Review of Complementary and Integrative Approaches for Irritable Bowel Syndrome



Octavia Pickett-Blakely, Ashwini S. Davison, and Gerard E. Mullin

43. Nutrition Strategies for the Treatment of IBS and the Prevention of Digestive Complaints



Ashley Koff

44. Alternative Approaches to the Patient with Inflammatory Bowel Disease



Leo Galland, Katarzyna Kines, and Gerard E. Mullin

45. Obesity



Lawrence J. Cheskin and Katrina Seidman

46. Nutrition and Colorectal Health



Mitra Rangarajan and Gerard E. Mullin

47. Liver Disease



Matthew Cave, Naeem Aslam, Christopher Kulisek, Luis S. Marsano, and Craig J. McClain

48. Integrative Approaches to Diseases of the Pancreas and Gallbladder



Vinay Chandrasekhara and Anthony N. Kalloo

49. An Integrative Approach to Gender-Specific Digestive Health Issues



Laura K. Turnbull, Gerard E. Mullin, and Sharon Dudley-Brown

50. Gastrointestinal Disorders and Eating Disorders



Carolyn Coker Ross

51. Ethical Issues in Integrative Gastroenterology



Julie Stone

52. There Is No Alternative to Evidence



Ronald L. Koretz

Index

653

CONTRIBUTORS

Naeem Aslam, MD Fellow, Department of Medicine Division of Gastroenterology and Hepatology University of Louisville School of Medicine Louisville, KY Jean-Pierre Barral, DO Director of the Department of Osteopathic Manipulation University of Paris, School of Medicine Paris, France Robert Alan Bonakdar, MD, FAAFP Director of Pain Management Scripps Center for Integrative Medicine Assistant Clinical Professor Department of Family and Preventative Medicine (Voluntary) University of California, San Diego, School of Medicine San Diego, CA David M. Brady, ND, DC, CCN, DACBN Vice Provost, Health Sciences Division Director, Human Nutrition Institute Associate Professor of Clinical Sciences University of Bridgeport Bridgeport, CT

J. Alexander Bralley, PhD Chief Executive Officer Metametrix Clinical Laboratory Duluth, GA Matthew Cave, MD Assistant Professor of Medicine Division of Gastroenterology/ Hepatology Department of Medicine University of Louisville Louisville, KY Vinay Chandrasekhara, MD Clinical Fellow Division of Gastroenterology & Hepatology Johns Hopkins University School of Medicine Baltimore, MD Sajida Chaudry, MD, MPH Family Medicine and Preventive Medicine Johns Hopkins Community Physicians Odenton, MD

xv

xvi

CONTRIBUTORS

Ann Marie Chiasson, MD, MPH, CCFP Clinical Assistant Professor of Medicine Arizona Center for Integrative Medicine University of Arizona Tucson, AZ Lawrence J. Cheskin, MD, FACP Associate Professor of Health, Behavior & Society Joint Appointment in Medicine (Gastroenterology) Director, Johns Hopkins Weight Management Center Johns Hopkins Bloomberg School of Public Health Johns Hopkins University School of Medicine Baltimore, MD Diane Clawson, DO Attending Physician Department of Psychiatry Department of Pediatrics University of New Mexico Albuquerque, NM Frederic C. Craigie, Jr., PhD Psychologist/Faculty, MaineDartmouth Family Medicine Residency Associate Professor of Community and Family Medicine Dartmouth Medical School Visiting Associate Professor Arizona Center for Integrative Medicine University of Arizona School of Medicine Augusta, Maine

Ashwini S. Davison, MD Senior Resident Department of Internal Medicine Johns Hopkins Hospital Baltimore, MD Sheila G. Dean, DSc, RD, LD, CCN, CDE Integrative Nutrition Solutions Adjunct Professor of Nutrition Science University of Tampa Palm Harbor, FL Douglas A. Drossman, MD Professor of Medicine and Psychiatry Co-Director, UNC Center for Functional GI and Motility Disorders Division of Gastroenterology and Hepatology, Department of Medicine University of North Carolina at Chapel Hill Chapel Hill, NC Sharon Dudley-Brown, PhD, FNP–BC Co-Director, Gastroenterology & Hepatology Nurse Practitioner Fellowship Program Johns Hopkins Hospital Assistant Professor Johns Hopkins University Schools of Medicine & Nursing Baltimore, MD David Durkin, DC Chiropractor Durkin Chiropractic Center Gastonia, NC

CONTRIBUTORS

Joel M. Evans, MD Assistant Clinical Professor Department of Obstetrics, Gynecology, and Women’s Health Albert Einstein College of Medicine Bronx, NY Andrew G. Franks, Jr., MD, FACP Clinical Professor of Dermatology and Medicine (Rheumatology) Director, Skin Lupus, and Connective Tissue Disease New York University School of Medicine New York, NY Gerald Friedman, MD, PhD, MS, FACP, MACG Clinical Professor of Medicine Department of Medicine, Division of Gastroenterology The Mount Sinai School of Medicine New York, NY Leo Galland, MD Director Foundation for Integrated Medicine New York, NY Peter H.R. Green, MD Professor of Clinical Medicine Celiac Disease Center Columbia University College of Physicians and Surgeons New York, NY Patrick Hanaway, MD Chief Medical Officer Genova Diagnostics Asheville, NC

xvii

Jerry Hickey, RPh Scientific Director InVite Health, Inc. New York, NY Anthony N. Kalloo, MD The Moses and Helen Golden Paulson Professor of Gastroenterology Chief, Division of Gastroenterology and Hepatology Johns Hopkins Hospital Baltimore, MD Katarzyna Kines, MS, MA, LDN, CNS, CN Holistic Nutrition Naturally, LLC Contractual Practitioner with Johns Hopkins Integrative Medicine and Digestive Center Green Spring Station, Lutherville, MD Ashley Koff, RD Founder, AshleyKoffApproved.com Ronald L. Koretz, MD Emeritus Professor of Clinical Medicine David Geffen–UCLA School of Medicine Department of Medicine Olive View–UCLA Medical Center Sylmar, CA Christopher Kulisek, MD Resident, Department of Medicine University of Louisville School of Medicine Louisville, KY

xviii CONTRIBUTORS

Sanghoon Lee, OMD, PhD, DiplAc, LAc Associate Professor of Acupuncture & Moxibustion College of Oriental Medicine WHO Collaborating Centre for Traditional Medicine East–West Medical Research Institute Kyung Hee University Seoul, South Korea Ta-Ya Lee, MSN, CRNP, MAc, LAc, MBA, MPH Johns Hopkins Community Physicians Wyman Park Internal Medicine Canton Crossing Integrative Medicine Baltimore, MD Pearl L. Lewis Founder, Maryland Chapter Crohn’s and Colitis Foundation Founder, Maryland Patient Advocacy Group Maryland Renal Advocate National Kidney Foundation of Maryland National Kidney Foundation Malignancy Advisory Board Author, Access to Care for Special Needs Populations (19 states) Ellicott City, MD Liz Lipski, PhD, CCN Director of Doctoral Studies Hawthorn University Founder of Innovative Healing Founder of Access to Health Experts Asheville, NC Richard S. Lord, PhD Chief Science Officer Metametrix Institute Duluth, GA

Tieraona Low Dog, MD Director of the Fellowship Arizona Center for Integrative Medicine Clinical Associate Professor Department of Medicine University of Arizona Tucson, AZ Dan Lukaczer, ND Associate Director of Medical Education Institute for Functional Medicine Gig Harbor, WA Loren Marks, DC, DACBN Diplomate American Clinical Board of Nutrition Integrative Assessment Technique, Founder 200 W 57 St. Ste 1010 NY Luis S. Marsano, MD Professor of Medicine Jewish Hospital Distinguished Professor of Hepatology Division of GI/Hepatology University of Louisville School of Medicine Louisville, KY Craig J. McClain, MD Professor, Departments of Medicine and Pharmacology & Toxicology Associate Vice President for Translational Research Distinguished University Scholar University of Louisville School of Medicine Louisville, KY

CONTRIBUTORS

Philip E. Memoli, DMD, FAGD, CNC Founder, Institute of Systemic Medicine and Dentistry Attending, Overlook Hospital Summit, NJ and Private Practice Berkeley Heights, NJ Anil Minocha, MD Professor of Medicine LSU Health Sciences Center Chief of Gastroenterology VA Medical Center Shreveport, LA Donna Jackson Nakazawa Author and Lecturer The Autoimmune Epidemic www.autoimmuneepidemic.com

Danna Park, MD, FAAP Medical Director Integrative Healthcare Department Mission Hospital Asheville, NC Octavia Pickett-Blakely, MD Post Doctoral Fellow Division of Gastroenterology Johns Hopkins School of Medicine Baltimore, MD Joseph Pizzorno, ND Editor-in-Chief, Integrative Medicine, A Clinician’s Journal Co-Author, Textbook of Natural Medicine President Emeritus, Bastyr University Seattle, WA Stephanie Porcaro, LMT Massage By Stephanie Baltimore, MD

Trent W. Nichols, Jr., MD Center for Digestive Disorders and Nutrition Hanover, PA

Valencia Porter, MD, MPH Director of Women’s Health The Chopra Center for Wellbeing Carlsbad, CA

Beth Nolan, LMT Massage Therapist Life Support Wellness Center Butler, NJ

S. Devi Rampertab, MD Assistant Professor of Medicine Division of Gastroenterology Penn State College of Medicine Hershey Medical Center Hershey, PA

Olafur S. Palsson, PsyD Associate Professor of Medicine Division of Gastroenterology and Hepatology Department of Medicine University of North Carolina at Chapel Hill Chapel Hill, NC

xix

Padmini D. Ranasinghe, MD, MPH Assistant Professor of Medicine Division of General Internal Medicine Johns Hopkins University School of Medicine Baltimore, MD

xx

CONTRIBUTORS

Mitra Rangarajan, MSN, ANP-BC, MPH, CDE, MS, RD Nurse Practitioner, Advanced Therapeutic Endoscopy & GI Motility Division of Gastroenterology & Hepatology Johns Hopkins University School of Medicine Baltimore, MD Carolyn Coker Ross, MD, MPH Clinical Assistant Professor of Medicine University of Arizona, Tucson, AZ Eating Disorder, Addiction Medicine and Integrative Medicine Consultant Denver, CO Martin L. Rossman, MD Clinical Instructor Department of Family and Community Medicine University of California San Francisco Medical School San Francisco, CA Anastasia Rowland-Seymour, MD Assistant Professor of Medicine Division of General Medicine Department of Internal Medicine Johns Hopkins University School of Medicine Baltimore, MD Bob Schlagal, PhD Professor Department of Language, Reading, & Exceptionalities Appalachian State University Boone, NC

Michael J. Schneider, DC, PhD Visiting Assistant Professor School of Health & Rehabilitation Sciences University of Pittsburgh Pittsburgh, PA Katrina B. Seidman, MS, RD, LDN Registered Dietician Johns Hopkins Weight Management Center Department of Health, Behavior and Society Johns Hopkins Bloomberg School of Public Health Baltimore, MD Fergus Shanahan, MD Professor and Chair, Department of Medicine Director, Alimentary Pharmabiotic Centre Cork University Hospital and University College Cork National University of Ireland David Simon, MD Medical Director, Co-Founder The Chopra Center for Wellbeing Carlsbad, CA Emily G. Singh, MD Division of Gastroenterology Scripps Clinic Carmel Valley San Diego, CA Julie Stone, MA, LLB Visiting Professor, Peninsula Medical School Universities of Exeter and Plymouth United Kingdom

CONTRIBUTORS

Kathie Madonna Swift, MS, RD Director, Food As Medicine Center for Mind Body Medicine Washington DC and Lead Nutritionist Kripalu Center for Yoga and Health Stockbridge, MA Laura K. Turnbull, BA, RNc Johns Hopkins University School of Nursing Baltimore, MD Miranda A.L. van Tilburg, PhD Assistant Professor of Medicine University of North Carolina School of Medicine Department of Gastroenterology and Hepatology UNC Center for Functional GI and Motility Disorders Chapel Hill, NC Stephan R. Weinland, PhD Assistant Professor of Medicine University of North Carolina at Chapel Hill Center for Functional GI and Motility Disorders Chapel Hill, NC Leonard B. Weinstock, MD Associate Professor of Clinical Medicine and Surgery Washington University School of Medicine Director, Specialists in Gastroenterology, LLC St. Louis, MO

xxi

Gail Wetzler, PT, EDO, BI–D Director of Physical Therapy Center for Alternative Medicine University of California, Irvine and Director of Curriculum and Program Development Barral Institute and Owner of Wetzler Integrative Physical Therapy Center Newport Beach, CA William E. Whitehead, PhD Professor of Medicine and Adjunct Professor of Obstetrics and Gynecology Co-Director of the Center for Functional GI and Motility Disorders University of North Carolina at Chapel Hill Chapel Hill, NC Yang Yang, PhD Adjunct Faculty Department of Kinesiology and Community Health University of Illinois at UrbanaChampaign and Director Center for Taiji and Qigong Studies New York, NY Savely Yurkovsky, MD Private Practice Chappaqua, NY

This page intentionally left blank

Integrative Gastroenterology

This page intentionally left blank

1 Why Integrative Gastroenterology? GERARD E. MULLIN

key concepts ■

■

■

■

■

■

■

■

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

3

Introduction

A

s gastroenterologists, internists, primary-care practitioners, nurse practitioners, or alternative providers, we need to realize that over 50% of patients with digestive disorders incorporate complementary and alternative medicine (CAM) into their treatment regimen. Studies have shown that approximately 72% of patients who utilize alternative strategies are reluctant to disclose this to their providers for fear of being stigmatized. Since our patients seek our guidance and expertise in overseeing their healthcare, it is time for us to realize that consumer demand has driven the present dynamic of patients paying out of pocket to achieve improved health and well-being by “integrating” alternative strategies into their lives. There is a body of experiential and evidence-based literature to support the utilization of these “alternative” strategies in digestive healthcare. Thus, the ongoing utilization of alternative strategies by the public, the evidence supporting its use, and the expanding groups of practitioners achieving improved health outcomes, led Dr. Andrew Weil to commission me to synthesize a comprehensive how-to guide for advising digestive disease patients, aimed at the everyday practitioner. Integrative medicine is a rapidly growing and highly credible field that seeks to integrate the best of Western scientific medicine with a broader understanding of the nature of illness, healing and wellness. Dr. Andrew Weil defines integrative medicine as a “healing-oriented medicine that takes account of the whole person (body, mind and spirit), including all aspects of lifestyle. It emphasizes the therapeutic relationship and makes use of all appropriate therapies, both conventional and alternative.” The Principles of Integrative Medicine by Dr. Andrew Weil: • A partnership between patient and practitioner in the healing process • Appropriate use of conventional and alternative methods to facilitate the body’s innate healing response • Consideration of all factors that influence health, wellness, and disease, including mind, spirit, and community, as well as body • A philosophy that neither rejects conventional medicine nor accepts alternative therapies uncritically • Recognition that good medicine should be based in good science, be inquiry driven, and be open to new paradigms • Use of natural, effective, less invasive interventions whenever possible

Why Integrative Gastroenterology? 5

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

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

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

Roots of Integrative Gastroenterology “A person whose basic emotional and physical tendencies are in balance, Whose digestive power is balanced, Whose bodily tissues, elimination functions and activities are in balance, And whose mind, senses and souls are filled with vitality, That person is said to be healthy.” Sushruta Samhita, 2000 B.C.

6 INTEGRATIVE GASTROENTEROLOGY

AYURVEDIC MEDICINE

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

TRADITIONAL CHINESE MEDICINE

Traditional Chinese medicine (TCM) was the first formalized system of health and healing in modern civilization. In Eastern philosophy, all life occurs within a circle of nature, with all things in this matrix interconnected and mutually dependent upon each other. Human beings represent a microcosm of nature and are the juncture between heaven and earth. In TCM, health and vitality are predicated upon spiritual connection, balanced living, a vegetable-based diet, proper digestion, and peace of mind. The flow of energy, or chi, is the essence of health and well-being. A blockage in the flow of chi through energy channels called meridians is the beginning of illness, and loss of adaptability is the beginning of disease. In TCM, the foods we eat are not merely nutrients but are vehicles of energy to be dispersed to our body in either a healthy or unhealthy manner, as determined by the outcome of digestion. When the digestive fire is too weak or too strong, the resultant energy imbalances create disharmony and illness. In TCM, chi is centered around the digestive tract in a ball of energy called the don tien. This virtual force field of energy circling our digestive tract is essential to health and well-being. Ayurveda and TCM principles guide the care of billions who are among the world’s healthiest people. These well-proven models of healthy living share in common sound mind, peace, wholeness and harmony, a healthy

Why Integrative Gastroenterology? 7

vegetarian-based diet, spiritual connection, and herbs for early symptoms of illness. In both systems, individuals are the sum of their diet and lifestyle choices. Proper digestion of a healthy diet is the key to a life filled with vibrant health and free of disease.

WESTERN MEDICINE

“Let food be thy medicine and let medicine be thy food.” “Leave your drugs in the chemist’s pot if you can heal the patient with food.” “Above all else, do no harm.” —Hippocrates, 450 B.C. The Western model of healthcare has been traced to Hippocrates, who is considered to be the father of medicine. As physicians, we recite the Hippocratic Oath at our medical school graduation. What I remember most, while reciting a moving self-proclamation of service to mankind by facilitating healing, is Hippocrates, as well as Sushruta Samhita and the early emperors of China, who believed that physicians are healers of the body, mind, and spirit. Th e job of the physician was to provide proper instruction of diet in the prevention and treatment of illness. Hippocrates also strongly believed that the body, mind, and spirit were inseparable in health and disease. “As man thinketh in his head, so shall his life be made.” —Hippocrates, 1450 B.C.

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

8

INTEGRATIVE GASTROENTEROLOGY

Western medicine is a very sophisticated and advanced form of healthcare for acute illness, emergencies, curable malignancies, sustaining chronic disease, and surgical miracles. When it comes to optimizing health and preventing disease, our results are inferior compared to every country in the industrialized world. For example, the United States is 41st in longevity among industrialized countries—dead last! Despite our poor results, Western-trained physicians still consider the long-standing and highly successful Eastern healing arts to be archaic and quackery, and proudly view our modern system of care to be far superior. As a profession, we perpetuate this reductionist approach more than ever before. Doctors in training are now taught that our health is merely the result of the genes that we inherited from our parents, and that health is all preprogrammed and predetermined. This view excludes the possibility that health also reflects the accumulation of the choices that we make and the circumstances around us. The reality is that our health and well-being are the result of how our environment interacts with our genes. How we were parented, whether we were breastfed, how we connect to spirit, ourselves, and others, what we eat, how we process our food and emotions, and whether our lives are balanced or toxic, all have profound influences on health. Our genes can either become our protectors and partners for wellness, or target practice for pollutants and toxins in producing illness and disease. We do make choices every day that influence the expression of our genes. Table 1.1. Comparison of Conventional, Western-Based Medicine versus Integrative Medicine Aspects of care

Conventional

Integrative

Focus

Disease detection

Disease prevention

Orientation

Doctor-centered

Patient-centered

Treatment

Drugs only

All inclusive

Healing

Drugs only

Self-healing

Empathy

Variable

Loving

Office visits

Rushed, inattentive, prescription-oriented

Open mind, open heart, healing

Doctor–Patient Relationship

Doctor-centered

Partnership

Satisfaction

Low

High

Why Integrative Gastroenterology? 9

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

The Doctor–Patient Relationship: Returning to the Roots of Medicine Digestive disease specialists are fighting to stay afloat financially by severely limiting their allotment of time to perform procedures and see patients for office visits. In the end, patients are being treated as though they are on an assembly line, rather than being present in the nurturing environment of a doctor’s office. Likewise, physicians are speeding through patient care encounters like a “rat race,” constantly fighting an uphill battle. As a measure of the modern doctor–patient relationship that has evolved in the era of Westernized managed care, a study was conducted to determine doctors’ empathy for patients. Previous work suggests that exploration and validation of patients’ concerns is associated with greater patient trust, lower healthcare costs, improved counseling, and more guideline-concordant care. The study by Dr. Ronald Epstein and colleagues included 4,800 patient surveys concerning doctor visits, and 100 covertly recorded visits by actors posing as patients. The results showed that only 15% of the doctors voiced empathy. In the study, published in the Journal of General Internal Medicine, the researchers analyzed the patient surveys and actor visits and characterized the responses by type, frequency, pattern, and communication style, and correlated them with patient satisfaction ratings. Empathy was associated with higher patient ratings of interpersonal care. “The best physicians are empathic. They show neither sympathy nor disdain. Empathy does not develop as naturally as sympathy or disdain. We must nurture this emotion, allowing it to blossom. True empathy greatly helps the doctor–patient relationship.” —Robert M. Centor, 2005 A key element to Dr. Weil’s vision of integrative medicine is for the practitioner to return to the roots of medicine by fostering partnerships with patients. We know that the stronger the doctor–patient relationship, the more powerful the healing response. This is called the placebo response by researchers, but is underutilized in today’s version of “hit and run” medicine. The restoration of

10

INTEGRATIVE GASTROENTEROLOGY

faith and trust in the treating practitioner by the patient is an essential element to healing. At Johns Hopkins, the first physician-in-charge was Sir William Osler (1849–1919), who was the father of modern medicine. In his writings and teachings, Sir William Osler emphasized humanity, compassion, observing and listening to patients with an open mind and heart, and to minimize the use of pharmaceutical medications. Following are some excerpts from many of his famous quotations. “Observe, record, tabulate, and communicate. Use your five senses. Learn to see, learn to hear, learn to feel, learn to smell, and know that by practice alone you can become expert.” “It is much more important to know what sort of a patient has a disease than what sort of a disease a patient has.” “The good physician treats the disease; the great physician treats the patient who has the disease.” “Teach young physicians to care more particularly for the individual patient than for the special features of the disease.” —Sir William Osler (1849–1919) The integrative practitioner should strive to: • Humanize healthcare: Combine old-fashioned caring with superb medical care • Prevent disease and promote health • Listen to and communicate effectively with patients and their families in order to form partnerships • Appreciate and bridge cultural differences, so that care plans are understood by their patients • Share decision making with patients and their families as partners • Emphasize the necessity of a team approach in caring for each patient • Integrate the best medical knowledge into healthcare that is accessible, patient friendly, and high quality • Act as an advocate for patients and the health needs of society • Act as a steadfast guide and source of support to patients, no matter where they choose to seek specialty care • Raise awareness that book-smart doctors can lack emotional intelligence, and appreciate how a disease affects a patient’s daily life

Sir William Osler followed in the footsteps of the ancient Greek physician, Hippocrates (460–377 B.C.). These quotations by Hippocrates reflect his

Why Integrative Gastroenterology? 11

philosophy of the body’s natural healing force and the importance of proper nutrition and exercise to good health. There is also a message to young physicians to guide the patient’s healing, that it is better to do nothing than to harm the patient. “Everyone has a doctor in him or her; we just have to help it in its work. The natural healing force within each one of us is the greatest force in getting well.” “To do nothing is sometimes a good remedy.” “Walking is man’s best medicine.” “If we could give every individual the right amount of nourishment and exercise, not too little and not too much, we would have found the safest way to health.” —Hippocrates

Conclusions Digestive diseases are responsible for a major economic burden in the United States and worldwide. Preventive care, education about the influence of diet and lifestyle on digestive disease development and treatment, and research support, all lag behind in meeting the need to correct the economic burden and to provide future generations of scientists in the digestive sciences. Given the American digestive disease epidemic, there is a need for governments to readdress this shortcoming and to review its methods of support, as well as for physicians to adopt an integrative approach to the prevention and treatment of digestive disease. “The doctor of the future will give no medicine, but will interest her or his patients in the care of the human frame, in a proper diet, and in the cause and prevention of disease.” —Thomas A. Edison, U.S. inventor (1847–1931)

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

12 INTEGRATIVE GASTROENTEROLOGY

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

2 The American Digestive Disease Epidemic GERARD E. MULLIN

key concepts ■ ■

■

■

■

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

Digestive Disease: The Cold, Hard Facts

I

n 2002, the American Gastroenterology Association (AGA) became the first physician-based organization to address the growing burden of digestive disease on the nation’s healthcare resources. Led by Dr. Robert S. Sandler, the AGA published a special report that outlined the prevalence and economic burden of digestive disease in the United States as of 1998, with financial projections to the year 2000 (Sandler, Everhart, Donowitz et al., 2002). 13

14

INTEGRATIVE GASTROENTEROLOGY

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

THE PREVALENCE OF DIGESTIVE DISEASE IN AMERICA

The NIDDK of the National Institutes of Health (NIH) is a government agency that has collected data from a variety of sources to estimate the burden of digestive disease.2 The overall prevalence of digestive diseases was reported by the NIH in 1996 to be 60 to 70 million. U.S. Government statistics of digestive disease prevalence were updated in a special report on February 02, 2009.(Everhart & Ruhl, 2009a,b,c)

There are numerous studies that analyze the burden of digestive disease in the United States. The past decade has seen a rapid expansion of individuals who suffer from chronic digestive symptoms. The prevalence of digestive disease in America has reached epidemic proportions. Based on the latest available evidence, we collected and summarized data on the prevalence of digestive disease in Tables 2.1 and 2.2. The resulting burden to the U.S economy is shown in Tables 2.3 and 2.4. Since prescription medications represent a great part of this financial burden, the costliest medications to consumers are listed in Table 2.4. 1 2

(www.aboutgerd.org) (http://digestive.niddk.nih.gov/statistics/statistics.htm)

The American Digestive Disease Epidemic 15

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

Prevalence

Prevalence

(% U.S. population)

(U.S. population

Year

Reference

4,968,809

1990

NIDDK

255,640

2004

American Cancer Society

24,980,000

2006

Levine & Ahnen (2006); Terhaar et al. (2009)

in millions)

Abdominal wall hernia 1.66 Cancer of digestive system

0.9

Colonic adenomas

30% above age 50

Celiac disease**

1.0

3,000,000

2007

Green (2006)

Clostridium difficle colitis

1.0

3,000,000

2007

Ricciardi, Rothenberger, Madoff, & Baxter (2007)

Chronic liver disease/ cirrhosis

0.15

451,710

2007

NIDDK, populationadjusted

Constipation

1.0

3,100,000

1996

Adams, Hendershot, & Marano (1999)

Diverticulosis

20

60,200,000

1969

Hughes (1969)

Diverticular disease (complicated)

0.9–2.2 4.0

2,500,000– 6,000,000 12,040,000

1996 2006

NIDDK, Duggan (2006)

Gallstones

11–22

30,000,000– 60,000,000

1999

NIDDK

Gastritis; non-ulcer dyspepsia

1.4

37,000,000

1996

Adams, Hendershot, & Marano (1999)

GERD

30–42

90,000,000– 127,000,000

2007

Singh et al. (2007); http:// www.aboutgerd. org

Helicobacter pylori infection

20–52

60,000,000– 157,000

2002

NEJM. 2003; 347:1175–1186 (Continued)

16

INTEGRATIVE GASTROENTEROLOGY

Table 2.1. (Continued) Digestive Disease

Prevalence

Prevalence

(% U.S. Population)

(U.S. Population

Year

Reference

1996

Adams, Hendershot & Marano (1999)

1980– 1998

NIDDK

2007

www.ccfa.org

in Millions)

Hemorrhoids

3.2–4.4

8,500,000

Infectious diarrhea

36.4–44.8

IBD

0.33–0.47

IBS

10–15

30–45,000,000 2007

http://www. aboutibs.org/

Lactose intolerance

10–16.7%

30–50,000,000 1994

Rusynyk & Still (2001)

Non-alcoholic fatty liver disease (NAFLD)

22–33%

Pancreatitis

0.05%

Peptic ulcer disease

135,000,000 1,000,000– 1,400,000

66,250,788– 99,376,182

2003

Angulo (2007); Suzuki & Diehl (2005)

160,000

1995

Everhart (1995)

4.90%

14,500,000

2003

NIDDK

Hepatitis A

31%

93,500,000

1998– 1994

NIDDK, NHANES (2005)

Hepatitis B

0.05–5%

1,500,000– 15,057,000

1998– 2004

NIDDK, McQuillan et al. (1999)

Hepatitis C

1.36–1.8%

4,100,000– 5,420,000

2007

NIDDK, Armstrong et al. (2006)

Hepatitis D

unknown

1990

NIDDK

Viral hepatitis

unknown; 75,000 new cases

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

The American Digestive Disease Epidemic 17

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

1985

1998

2004

1985

prevalence

prevalence

prevalence

cost

2004 cost

($millions)

($millions)

Abdominal hernias

4,741,000

4,500,000

4,968,809

2,760

6,078

Constipation

4,458,000

3,100,000

3,100,000

360

1,712

Diverticula

1,900,000

2,500,000

60,200,000

1,550

4,041

Enteric infections*

8,300,00

135,000,000

135,000,000

4,990

7,300

Enteritis (noninfectious)*

5,700,000

75,000,000

75,000,000

820

1,119

Gastritis– dyspepsia,****

2,793,000

3,700,000

3,700,000

1,130

1,269

Gallstones

956,000

20,500,000

30,000,000– 60,000,000

4,710

6,169

GERD**

546,000

53,000,000

90,000,000– 127,000,000

1,100

12,639

GI malignancy

258,000

227,700

255,560

6,080

24,148

10,360,000

8,500,000

8,500,000

830

873

IBD

2,308,000

1,081,200

1,000,000– 1,400,000

820

2,166

IBS

1,379,000

2,100,000

30,000,000– 45,000,000

400

1,007

Liver disease (chronic)**

552,000

21,950,000

108,825,788– 119,928,182

3,250

13,095

Peptic ulcer*

4,491,000

14,500,000

14,500,000

2,520

3,118

All Digestive Disease (Chronic)****

62,000,000

56,140

141,826

Hemorrhoids

60,000,000– ?????????? 70,000,000

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

18

INTEGRATIVE GASTROENTEROLOGY

Table 2.3. NIH Research Expenditures by Disease in FY 2000 Research

$$$

Diseases

(in millions)

Chronic Liver Disease and Cirrhosis

218.6

Liver Cancer

46.2

Ulcerative Colitis and Crohn’s Disease

27.0

Pancreatic Cancer

20

Gallbladder Disease

14.5

Chronic Hepatitis C

66.5

Irritable Bowel Syndrome

8.2

Peptic Ulcer Disease

12.1

Foodborne Illness

57.5

Colorectal Cancer

205.2

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

Table 2.4. All Digestive Diseases: Costliest Prescriptions Drug

Prescription

Prescription %

Retail Cost

Cost

$3,104,963,208

25.2%

number

Lansoprazole

20,898,993

15.5%

Esomerprazole

19,458,470

14.3

2,845,565,944

23.1

Pantoprazole

11,716,033

8.6

1,408,222,944

11.4

Raberprazole

8,019,431

5.9

1,135,819,908

9.2

Omeprazole

8,582,644

6.3

1,038,622,087

8.4

Mesalamine

2,448,971

1.8

468,426,719

3.8

Ranitidine

13,171,338

9.7

319,418,374

2.6

Tegaserod

1,618,699

1.2

238,030,688

1.9

Ribavirin

221,035

0.2

229,351,616

1.9

Peginterferon alfa-2a

131,001

0.1

191,754,177

1.6

49,378,593

36.4

1,351,443,116

11.0

Other TOTAL

135,735,478

100.0%

$12,331,718,182

100.0%

Reprinted with permission from Everhart JE, Ruhl CE. Gastroenterology 2009;136(4): 1134–1144.

The American Digestive Disease Epidemic 19

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

DIGESTIVE DISEASE AFFLICTS EVERY AMERICAN HOUSEHOLD

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

DIGESTIVE DISEASE: A GROWING EPIDEMIC IN OUR WESTERN WORLD

An epidemic3 is a classification of a disease that appears as new cases in a given human population, during a given period, at a rate that substantially exceeds what is “expected” based on recent experience. In 1996 the prevalence of digestive diseases was estimated to affect 60 to 70 million Americans. Digestive diseases are a silent epidemic, and the incredible number of Americans with functional digestive disorders may be an underestimate of the true U.S. prevalence. In Olmsted County, Minnesota, the reported prevalence of functional gastrointestinal disease (e.g., IBS, abdominal pain) was shown to be 42.3% in a recent study by the Mayo Clinic. (Halder et al., 2007)

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

3

(from Greek epi- upon + demos people).

20

INTEGRATIVE GASTROENTEROLOGY

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

LOSING THE DIGESTIVE DISEASE BATTLE

There is no doubt that enormous economic resources are being consumed by the burden of digestive disease. Despite the losing battle being fought by many physicians, government funding is funding is inadequately allocated to combat diseases that are affecting easily over 60 million Americans today. In 2000, NIH research expenditures for digestive disease research reached a record $676 million. The NIH spent more than 72.5% of its digestive disease budget for just two groups of conditions—liver disease ($285 million) and colorectal cancer ($205.2 million).

Certainly, colorectal cancer and liver diseases are worthy causes toward which to devote available resources. However, there are more than 40 other known digestive disease conditions that constitute the vast majority of digestive disease prevalence in America, and that deserve proportionate allocation of resources. Despite concerted efforts by the NIH to control the spread of digestive disease, its prevalence is rapidly rising. For example, celiac disease is now reported to affect 3 million Americans and is silent in 97% of those who have the disease, according to Dr. Peter Green in his book, Celiac Disease: A Hidden Epidemic (Green, 2006). The detection rate can be increased 43-fold just by instituting proper screening of all patients who have suggestive symptoms. Other emerging silent epidemics include non-alcoholic fatty liver disease and hepatitis C (Angulo, 2007). Non-alcoholic fatty liver disease (NAFLD) has been estimated to affect from 22% to 33% of Americans and is closely linked to obesity and insulin resistance as the major factors for its rapid emergence (Angulo, 2007; Suzuki & Diehl, 2005). The hepatitis C virus is known to infect 4.1 million Americans and 200 million people worldwide, resulting from person-to-person transmission (Armstrong et al., 2006). Due to the epidemic proportion of hepatitis C in the United States, a special website was established

The American Digestive Disease Epidemic 21

to educate the public and warn about its dangers.4 Both diseases are silent killers. To demonstrate the magnitude of the economic impact of constipation today, a report published in 2007 analyzed the healthcare resource utilization of Medicaid patients in California. Dr. Gurkirpral Singh and colleagues from Stanford University showed that 105,130 patients of the state’s 10 million beneficiaries (1.05%) consumed $18.9 million to treat constipation in a 15-month period of time. The total economic impact of constipation on the U.S. economy was estimated to be $54.4 billion in 2007 (Singh et al., 2007). The total economic impact to the United States economy would be $9.9 billion just to treat constipation for 18.2% of the population on Medicaid assistance.

The Singh et al. study was funded by the Novartis Pharmaceuticals Corporation of East Hanover, New Jersey. Although the report appears credible and highlights the magnitude of the problem of constipation in the United States, there is a self-serving interest for Novartis to fund this study. By showing that constipation produces an untoward economic burden on the U.S. economy, Novartis can make a strong argument to the FDA to reverse its ban on Zelnorm (touted as a magic bullet for constipation). In order to calculate the true total costs of digestive disease in 2007, the actual prevalence of disease would need to be known, along with the actual costs of prescription medications, hospitalizations, procedures, office visits, and mortality, as well as indirect costs of lost wages and productivity. In 2002, an intensive effort by the American Gastroenterology Association estimated the burden of digestive diseases on the U.S. economy (Sandler RS, 2002). Since 1998, the Consumer Price Index (CPI) has risen approximately 4% per year and the economic impact of digestive diseases today must be in excess of 40% higher when compared to 1998 statistics, totaling $141.7 billion ((Everhardt JE. 2008). In 2008, the economic burden of digestive disease appears to be much greater than reported in 1998. (Everhardt JE. 2008)We know from the IFFGD that the prevalence of the irritable bowel syndrome has risen two to three times since 1998.5 In 2003, the estimated annual direct costs for irritable bowel syndrome rose to $1.35 billion, having an estimated impact to the U.S. economy upward of $30 billion annually, excluding prescription and over-the-counter 4 5

(http://www.epidemic.org/theFacts/theEpidemic/ (http://www.aboutgerd.org/site/learning-center/congressional-testimony/2007)

22

INTEGRATIVE GASTROENTEROLOGY

medications (Leong et al., 2003; Inadomi, Fennerty & Bjorkman, 2003; Hulisz, 2004). IBS is second only to hypertension in healthcare costs in the United States annually. (Cash, Sullivan, & Barghout, 2005)

Pancreatitis, an uncommon disorder, causes more than 200,000 hospitalizations and costs between $3.6 to $6.0 billion annually (Draganov & Toskes, 2002). The American Digestive Disease Epidemic (ADDE) is wreaking havoc in the lives of many, and is costing government and industry billions of dollars annually. The most common and costly digestive conditions can be either prevented (e.g. colorectal cancer) or treated (e.g. NAFLD, GERD) with diet, lifestyle modifications, improved self-care, and a more integrative approach to healthcare.

CELIAC DISEASE

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

DIVERTICULAR DISEASE: A WORLDWIDE OR WESTERN DISEASE?

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

The American Digestive Disease Epidemic 23

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

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

COLORECTAL CANCER

Colorectal cancer is another condition in which Western diets high in saturated fat and red meat and low in fiber, compounded by sedentary lifestyles and high obesity rates, portend toward a greater susceptibility. Colorectal cancer is the most common cancer of the digestive organs, accounting for more than 60% of all digestive organ cancers and 25% of all

24

INTEGRATIVE GASTROENTEROLOGY

cancer mortality in the United States (Boyle & Ferlay, 2005). In 2004, more than 660,000 Europeans were living with a diagnosis of colon cancer. Colorectal cancer is the second most common cancer in Europe and the United States. Like diverticular disease, colon cancer is rare in Africa and Asia (except Japan). In both conditions, a high-fiber diet appears to be protective. A high-fat diet is a risk factor for the development and recurrence of colorectal cancer (Rennert, 2007). The seven Western behavioral risk factors that are associated with an increased risk for colorectal cancer are: smoking; low physical activity; low fruit and vegetable intake; high caloric intake from fat; obesity; high alcohol intake; and low intake of multivitamins (Coups, Manne, Meropol, & Weinberg, 2007).

INFLAMMATORY BOWEL DISEASE

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

GALLSTONE DISEASE

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

IRRITABLE BOWEL SYNDROME

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

The American Digestive Disease Epidemic 25

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

GASTROESOPHAGEAL REFLUX DISEASE (GERD)

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

Gallstone Disease Irritable Bowel Syndrome Gastroesophageal Reflux Disease

Conclusions Despite our affluence and economic world leadership, the United States continues to struggle with suboptimal pay for performance in healthcare outcomes, infant mortality, and life expectancy. America and Western societies continue to be sedentary, obese, consume a nutrition-poor Western-based diet, and rely solely upon pharmaceutical agents to prevent and treat disease— thus, digestive disease prevalence continues to soar. An emerging digestive

26

INTEGRATIVE GASTROENTEROLOGY

disease epidemic is damaging the physical and economic health of the United States. Lessons should be learned from the low prevalence of digestive disease in countries that adopt more nutritious diets and active lifestyles, and are less avid consumers of pharmaceutical drugs. The remainder of this book is devoted to helping those who have a digestive condition to restore their health, and to those who want to prevent alimentary tract disease and enjoy optimum health.

3 An Overview of Digestive, Sensing, and Immune Functions of the Gut PATRICK J. HANAWAY, LAURA K. TURNBULL , AND GERARD E. MULLIN

key concepts ■

■

■

■

■

■

■

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

27

Introduction

T

his chapter moves beyond the descriptive view of gut function, and serves to illustrate the systems approach to understanding the interrelationship of major gut functions. The evaluation of fundamental processes helps us to understand when, how, and if there is an imbalance within the gut, as well as how to bring it back into balance (i.e., treat it!). Thus, we have organized the chapter according to the five elements of traditional Chinese medicine, the very roots of integrative gastroenterology: • the process of digestion and absorption (EARTH/nurturance) • the selective barrier function that defines our relationship to the “outside” world (WOOD/structure) • the commensal microflora of the gut with which we are interdependent (METAL/interrelationship to the web of life) • the physiologic inflammation that is necessary to activate and maintain the immune surveillance system (FIRE/connection) • the enteric nervous system, which communicates with the rest of the body—based upon all of the above inputs. (WATER/balance).

THE GASTROINTESTINAL TRACT

The gastrointestinal tract, the tube within a tube, connects us to our environment through a dynamic interface that is larger than a doubles tennis court. Over the course of our lifetimes, we will ingest 30–40 tons of macronutrients, micronutrients, chemicals, and toxins, providing the building blocks for everything human. Disturbances in our functional ability to make the most of these nutrients have ramifications on every aspect of our being, and imbalance in the gastrointestinal system has implications that extend far beyond gastrointestinal symptoms. Thus, in nearly every clinical interaction, the clinician must be vigilant to gastrointestinal dysfunction. Classically, the role of digestion and absorption are considered the principal functions of the gastrointestinal epithelium. The quality of discernment that traditional Chinese medicine (TCM) attributes to the “small intestine official” is manifested through its ability to “separate the wheat from the chaff ” (Jarrett, 1999), but is also seen in the intertwined relationship of the innate and adaptive immune system within the gastrointestinal system. The role of diet and nutrients in the balance of the commensal flora, the role of digestion and absorption in providing proper macronutrients and micronutrients,

An Overview of Digestive, Sensing, and Immune Functions of the Gut 29

the appropriate physiologic inflammation, the development of “oral tolerance,” the production of neurochemicals within the “second brain,” and the appropriate excretion of waste, are the functions that must remain within balance to foster health and well-being. Dysfunction within the gastrointestinal system manifests in typical digestive diseases such as: gastroesophageal reflux “disease” (GERD), irritable bowel syndrome (IBS), inflammatory bowel disease (IBD; Sansonetti, 2004), nonalcoholic steatohepatitis (NASH; Angulo, 2002), and even colorectal cancer (CRC; McGarr, Ridlon, & Hylemon, 2005). It is also necessary for us to recognize that gastrointestinal dysfunction can manifest as imbalanced immunologic function, thus creating both atopic illness (Brandtzaeg, 2002), including allergy and asthma, and autoimmune dysfunction (Rook et al., 2004), including rheumatoid arthritis, Type I Diabetes Mellitus, and Hashimoto’s thyroiditis. Other diseases of immune dysregulation and gastrointestinal dysfunction now include the autism spectrum disorders.

The evolution of these diseases begins long before the presentation of symptoms; thus, the opportunity for prevention and early intervention can have tremendous impact on the burden of suffering and disease. Dietary approaches provide the most effective means of returning balance to dysfunction within the gastrointestinal system, and there are many opportunities to bring these tools to patients. However, the profound dietary changes that man has adopted over the past 10,000 years, and that have accelerated over the past 100 years, have created a discord between the nutritional input that our genetic structure has evolved to maximize, and what we are choosing to ingest (Cordain et al., 2005). This discordance creates a much more complex array of clinical opportunities for supporting the whole being to regain balance and optimal function. Diagnostic considerations include, first and foremost, an extensive health history with an exploration of the patient’s dietary inputs, as well as his or her utilization of antibiotics, laxatives, fiber, herbs, etc. In addition, one must elicit the current pattern of bowel movements including frequency, history, abdominal pain, gas, bloating, duration, and relationship of bowel elimination to meals. It is amazing how many patients consider their altered bowel movements to be normal. Western medicine does not have a defined norm of bowel movement frequency, while other forms of healing such as Ayurveda and TCM (see figure 3.1 A) view the regular functioning of the gastrointestinal tract to be a critical barometer of health and well-being, with one well-formed bowel movement per day to be the norm (Svoboda & Lade, 1988). Other diagnostic

30

INTEGRATIVE GASTROENTEROLOGY

considerations include the evaluation of stool to gather information on parameters of digestion, absorption, inflammation, infection, intestinal permeability, and altered gut flora (known as dysbiosis). Let us look more closely at the specific functional imbalances faced by clinicians, as we examine how they manifest in pathophysiology and how they can be rebalanced to optimize health.

Digestion and Absorption DIGESTION

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

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

IATROGENIC HYPOCHLORHYDRIA AND GERD

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

An Overview of Digestive, Sensing, and Immune Functions of the Gut 31

Consequences of suppressing gastric acid production include: vitamin deficiency (folate, B12), mineral deficiencies (calcium, magnesium, zinc, iron, chromium, manganese, and copper), altered bowel flora, dysbiosis, and small bowel bacterial overgrowth.

IATROGENIC HYPOCHLORHYDRIA AND SMALL INTESTINAL BACTERIAL OVERGROWTH (SIBO)

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

PANCREATIC INSUFFICIENCY

Pancreatic insufficiency is a common dysfunction that can be evaluated noninvasively. Beyond symptoms of maldigestion (belching, bloating, flatus),

32 INTEGRATIVE GASTROENTEROLOGY

there are relationships between decreased pancreatic function, osteoporosis (Moran et al., 1997), and diabetes (Hardt et al., 2000). Evaluation of pancreatic function can utilize pancreatic enzymes, such as chymotrypsin and elastase, or indirect markers, such as fecal fat. Elastase is the most sensitive marker of pancreatic insufficiency because, unlike chymotrypsin, it is not subject to bacterial degradation as it flows through the gastrointestinal tract. Treatment is simple, with pancreatic enzyme supplementation being a safe and effective therapeutic intervention to improve digestive function.

ABSORPTION

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

Barrier Function The ability of the body to be able to discern between friend and foe highlights the critical importance of the single-cell-layer gastrointestinal mucosa. This physical barrier, as large as a high school basketball court, provides the principal interface through which the body communicates with its environment. In addition to this single-cell layer, the gut microflora provide an additional barrier by competing with pathogens and producing a mucopolysaccharide matrix, known as the biofilm. Alterations in barrier function through intestinal permeability [a.k.a. “leaky gut”], changes in the microflora, and alterations in the biofilm layer can lead to immune upregulation. Permeability changes in the gut mucosa can have profound effects on anatomic and immunologic barriers to disease (Figure 3.2) (Baumgart & Dignass, 2002). Intestinal permeability can lead to increased inflammatory cytokine production, and a propagation of inflammation within the intestine (Clayburgh, Shen, & Turner, 2004). In fact, there is a great deal of evidence linking increased intestinal permeability with multiorgan system failure, systemic disease and immune dysfunction (DeMeo et al., 2002).

An Overview of Digestive, Sensing, and Immune Functions of the Gut 33

ALTERED BARRIER FUNCTION: INCREASED INTESTINAL PERMEABILITY

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

Table 3.1. Diagnoses of Altered Intestinal Permeability Intestinal permeability test interpretation

Mannitol

Lactulose

Suspect

Normal/High

High

Increased Permeability

Low

Low

Malabsorption

Low

High

Increased Permeability & Malabsorption

34

INTEGRATIVE GASTROENTEROLOGY

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

MALABSORPTION: DECREASED INTESTINAL PERMEABILITY

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

GUT FLORA

The makeup of the community of organisms that comprise the microflora of the gut is principally established during the first one to two years of life, and is maintained throughout our lives. The composition of the gut flora is indicative of our environmental exposures prenatally, intrapartum, and throughout infancy. Factors that influence the succession of gut flora from that time forward include type of delivery (Penders et al., 2006), feeding habits (Harmsen et al., 2000), gestational age, hospitalization (Björkstén, 2004), and infant antibiotic use (Teitelbaum & Walker, 2002). At birth, the digestive tract is sterile but begins to be colonized within the first few days of life. During the subsequent two years of life, the GI tract becomes home to 100 trillion commensal bacteria, fed by milk and other foods. These simple foods that stimulate the growth and maintenance of bowel flora are known as prebiotics. Cordain describes the dietary patterns most common today, and compares them with the characteristics of ancestral diets Cordain et al., 2005).There are significant alterations in glycemic load, fiber content, essential fatty acid

An Overview of Digestive, Sensing, and Immune Functions of the Gut 35

composition, pH balance and macronutrient/micronutrient composition. All of these factors have tremendous effects on the balance of the commensal flora within the gastrointestinal tract. Because nearly 70% of the immune system is localized to the digestive tract, a state of controlled physiologic inflammation, along with environmental contact with commensal bacteria, is essential for proper development of the immune system.

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

BIOFILMS

In addition to the role of individual organisms within the gastrointestinal microflora in promoting homeostasis and decreasing intestinal permeability, there is an additional interest in the collective action of these bacteria working together to form unique ecological niches, the biofilm layer. This 30-micronthick layer of “pond scum” acts to protect the intestinal lining, metabolize food remnants (especially carbohydrates), and may communicate with the immune system. In fact, it is postulated that the short-chain fatty acid (SCFA) synthesis that provides energy to the gut epithelium may also be involved in the “crosstalk” that influences the development of humoral and cell-mediated portions of the mucosal immune system. When an inflammatory process is present within the gut, the 30-micron-thick biofilm layer decreases in thickness, and there is a concomitant increase in intestinal permeability (Swidsinski et al., 2007).

36

INTEGRATIVE GASTROENTEROLOGY

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

GUT IMMUNOLOGY

The process of oral tolerance is analogous with the view of traditional Chinese medicine (TCM) regarding the “small intestine meridian.” Note that the channels of “chi” are not limited to physical properties; thus, the “sorter” (as this meridian is also known) is involved in “separating the wheat from the chaff ” through digestion and absorption, but it is also involved in the process of teaching the immune system to determine self from nonself via oral tolerance, as well as all other “sorting” functions throughout body, mind, and spirit. This phenomenon relates, deeper still, to the concept of sorting through information for decision making in which we have a “gut feeling,” and learning to trust that quality of “sorting”—even when it may not make sense. Through the process of evolution, the body has developed a number of methods to identify microbes and modulate the adaptive immune system, based upon the proper timing and presence of the bacterial stimuli. The body responds differentially to bacterial stimuli, and responds to a variety of structural components on each bacterium. The innate immune response stimulates the adaptive immune system and influences the nature of the adaptive response (Figure 3.4; see Abbas & Lichtman, 2003). The process of “oral tolerance” is an important example of this. (Brandtzaeg, 2002). Oral tolerance is mediated by regulatory T cells (Treg), which have antiinflammatory capabilities. Precursor T cells are transformed into Treg cells when antigen-presenting dendritic cells (DCs) of the gut have not been exposed to inflammation. Precursor T cells are transformed into Teffector cells (TH1 or TH2) when the DCs are mature (i.e., activated by inflammatory signals) (McGuirk & Mills, 2002). However, gut flora (like Lactobacillus) can downregulate DC maturation, thus preventing the activation of Teffector cells (Figure 3.5; see Christensen, Frøkiaer, & Pestka, 2002). The gut flora trains the innate immune system to begin to recognize “self.” There are molecules of recognition—pattern recognition receptors (PRR),

An Overview of Digestive, Sensing, and Immune Functions of the Gut 37

toll-like receptors (TLR), and pathogen-associated molecular patterns (PAMP)—that facilitate the mucosal immune system’s awareness of the bacterial environment, and determine its release of stimulating or suppressive cytokines (see figure 3.6). The epithelial mucosa is equipped with PRRs that recognize bacterial DNA from commensal bacteria and effectively modulate immune function (Jijon et al., 2004). Pathogenic bacteria will upregulate the adaptive immune system (via IL-12) within the Peyer’s patches and the mesenteric lymph nodes, inducing NF-kB activation of the inflammatory cascade Figure 3.7). Conversely, the normal gut microflora promotes immune modulation (via IL-10) and has anti-inflammatory properties (Figure 3.8 and 3.9). Disruption of gut flora disrupts oral tolerance by driving the T effector responses in the gut toward a TH1 proinflammatory response. Correction of gut flora improves oral tolerance. Thus, the immune system is dynamically educated by the presence of bacteria at the interface of the intestinal epithelium. The gut flora interacts with our innate immunity, and influences the adaptive immune response, in an important dialogue between the immune system and the environment. Commensal bacteria are also able to modulate expression of host genes involved in important intestinal functions, including nutrient absorption, mucosal stimulation, xenobiotic metabolism, and intestinal maturation (Hooper et al., 2001). Different bacteria induce different immunologic responses. Nonpathogenic bacteria also elicit different cytokine responses from epithelial cells, inducing differential effects on the gut-associated lymphoid tissue GALT and the adaptive immune system (Borruel et al., 2002).Because of this dynamic interplay between the gut flora and the GALT, the immunologic response system can be modified, based upon dietary change (in the form of prebiotics) and beneficial bacteria (in the form of probiotics). Hooper and Gordon (2001) have highlighted the effects of imbalance within this complex ecosystem. Their work has expanded our understanding of the metabolic effects of the microflora by highlighting the metabolic effects that altered gut flora can have on the development (and treatment!) of obesity. The increasing prevalence of allergy and atopy are associated with alterations of intestinal colonization, and decreased tolerance to common food proteins and inhaled allergens. Treatment with probiotics has helped to shift these symptoms back to normal (Kallomaki et al., 2003). Overall, we see that these critical environmental interactions highlight immunologic dysregulation arising from the combination of varied bacterial species (commensal and pathogenic), altered adaptive immune system activation, and multiple antigenic stimuli.

38 INTEGRATIVE GASTROENTEROLOGY

Enteric Nervous System FACTORS INVOLVED IN GUT HOMEOSTASIS

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

ROLE OF GUT MICROBIOTA

It has been long thought that disordered regulation of serotonin production played a central role in the pathogenesis of IBS (Sikander, Ranam, & Prasad, 2009). However, emerging evidence suggests that the crosstalk between the enteric nervous system (ENS) and the central nervous system (CNS) is influenced by the interplay between by-products of the gut microbiota and the enteric nerve terminals (ENTs), through the enterochromaffin cells (ECs; see Rhee, Pothoulakis, & Mayer, 2009). Thus, the enteric microbiota can directly influence the relationship between the ENS and the CNS (Figure 3.10 .). Rhee and colleagues have recently reviewed 85 articles that, in totality, suggest that the enteric microbiota maintain gut homeostasis by regulating motility, immune responses, and processing of nutrients (2009).

An Overview of Digestive, Sensing, and Immune Functions of the Gut 39

UNIDIRECTIONAL SIGNALING (BRAIN  ENTERIC)

Altered brain states, such as psychological stress, can modulate the biomass and composition of the enteric microbiota (Bailey, Lubach, & Coe, 2004). Furthermore, the enteric bacterial environment may be directly linked to the increased motility caused by stress states (resulting in shedding of the organisms). The emotional motor system (EMS) of the brain causes changes in the flora in two ways (either alone or in combination) (Holstege, Bandler, & Saper, 1996): • Directly via host enteric microbiota signaling • Indirectly via changes in the floral environment As to which populations of the enteric flora are most influenced by the EMS, reports suggest that the bacteria in biofilms that adhere to the epithelium are actually less vulnerable than luminal populations to the changes in motility and luminal contents. As a consequence, bacteria in biofilms are more involved in bidirectional signaling than luminal populations (Macfarlane & Dillon, 2007).

CNS-Related Changes in the Gut Environment PARASYMPATHETIC TONE

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

SYMPATHETIC NERVOUS SYSTEM, ENTERIC FLORA AND MUCOSAL IMMUNITY

The aforementioned biofilm is the part of the enteric flora that is adherent to the gut epithelium. Or, These bacteria influence mucosal immunity and enteric nerves differently than luminal microbes. The intestinal mucus layer is

40

INTEGRATIVE GASTROENTEROLOGY

the habitat for the biofilm. In a sympathetic dominant state, unregulated stimulation of the autonomic nervous system (ANS), or insufficient regulation by the parasympathetic nervous system, impairs proper mucus secretion, thus affecting the biofilm (Cooke, 2000). As shown in Figure 3.11 XXX., the sympathetic nervous system can moderate the mucosal immune system’s response to luminal bacteria via degranulation of mast cells, whose by-products (i.e., corticotropin-releasing factor; CRF) increase intestinal permeability, thus allowing even more nonselective antigen presentation to gut macrophages driving the process in a feed-forward manner. Under stress conditions, intestinal barrier function is weakened by a number of different mechanisms other than local release of CRF, and is reviewed elsewhere (Demaude et al., 2006).

BIDIRECTIONAL SIGNALING (BRAIN ENTERIC)

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

An Overview of Digestive, Sensing, and Immune Functions of the Gut 41

While this has been demonstrated in pathogenic bacteria, it is likely that it is also the case in commensal flora. Microbial signals can interact with afferent nerve terminals when there is compromised intestinal integrity (as in leaky gut, stress, or inflammation). As intestinal permeability increases, bacterial by-products and inflammatory mediators are able to directly access nerve endings in the mucosa.

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

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

42

INTEGRATIVE GASTROENTEROLOGY

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

4 The Intestinal Microbiota in Health and Disease: Bystanders, Guardians or Villains? FERGUS SHANAHAN

key concepts

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

■

■

■

■

■

■

Introduction

T

here is an ongoing resurgence of interest in the alimentary microbiota (flora). For basic scientists, this is being driven, in part, by improvements in technology, particularly molecular approaches for studying

43

44 INTEGRATIVE GASTROENTEROLOGY

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

Composition of the Microbiota The complexity and quantity of microbes in the alimentary tract is greatest at the orifices. The oral cavity harbors a relatively large and diverse bacterial population, whereas gastric acid restricts bacterial numbers to fewer than 103 colony-forming units (CFU)/ml of gastric contents. Along the small intestine, bacterial density increases distally with a sharp gradient across the ileocecal valve, with approximately 108 bacteria per gram of ileal contents and up to 1012 per gram of colonic contents, which comprises more than 1,000 different bacterial species (O’Hara & Shanahan, 2006; Turnbaugh et al., 2007). There is also a gradient in the composition of bacteria from mucosa to lumen. Almost all of the culturable bacteria in the ileum and the colon are obligate anaerobes, but the ratios of anaerobes to aerobes are lower at mucosal surfaces. In addition, culture-independent molecular techniques have shown that mucosaassociated bacteria differ from those recovered from feces (Zoetendal et al., 2002). In the proximal small bowel, the resident bacteria are predominantly grampositive facultative bacteria, although enterobacteria and Bacteroides also may be present. Peristalsis is the principal factor restricting bacterial numbers in the small bowel.

In the distal small bowel, the composition of the flora resembles that of the colon, with a preponderance of Gram-negative anaerobes. The most prominently represented genera in the distal bowel include Bacteroides, Clostridium, Lactobacillus, Fusobacterium, Bifidobacterium, Eubacterium, Peptococcus, and Escherichia.

The Intestinal Microbiota in Health and Disease 45

Environmental and Lifestyle Modifiers of the Microbiota Molecular profiling has shown that the microbiota is distinct in different people. Studies of twins suggest that the individuality of the human microbiota may be determined, in part, by host genetics (Zoetendal et al., 2001), but environmental variables including diet, sanitation and other lifestyle factors appear to have profound effects, particularly on early intestinal colonization (Sonnenburg, Angenent, & Gordon, 2004). Indeed, many of the elements of a modern lifestyle such as domestic hygiene, antibiotic usage, urbanization, and family size are proxy markers of microbial exposure during the early stages of life (Bernstein & Shanahan, 2008). Although the numbers and composition of the microbiota are relatively stable after infant weaning, the metabolic activity of the microbiota is continually subject to dietary and other lifestyle variables.

Techniques for Studying the Microbiota Most enteric bacteria cannot be cultured, because of a lack of selective growth media (Marchesi & Shanahan, 2007). Furthermore, because most of the indigenous bacteria are obligate anaerobes, there are logistical difficulties sampling the gut ecosystem. Therefore, molecular strategies have been devised to study bacterial nucleic acid extracted from feces or mucosal biopsy samples (Vaughan et al., 2000). The small ribosomal subunit RNA (16S rRNA in bacteria) contains highly conserved regions of base sequences that reflect an absence of evolutionary change, and that are interspersed with hypervariable regions that contain mutational changes reflecting the evolutionary divergence of different species. Sequencing of 16S rRNA permits identification and phylogenetic classification of intestinal bacteria. For rapid profiling, 16S rRNA can be amplified by polymerase chain reaction (PCR) and a profile of the mixture of hypervariable RNA fragments is achieved by variations in migration distance upon denaturing gradient gel electrophoresis. This reflects the diversity of 16S “species” in the sample. Other molecular techniques for identification of specific bacterial species are now possible because their genomic sequence has become available. Strategies include fluorescence in situ hybridization (FISH), flow cytometry

46 INTEGRATIVE GASTROENTEROLOGY

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

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

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

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

The Intestinal Microbiota in Health and Disease 47

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

Host–Microbe Communication is Reciprocal As with many other examples of interkingdom signaling (Hughes & Sperandio, 2008), host–microbe interactions in the gut are bidirectional. The apparent influence of host genetics on the composition of the commensal microbiota is supported by evidence for modulation by the immune system on the microbiota. Mucosal immune defects in different species have been associated with aberrant expansion of certain commensal organisms (Ryu et al., 2008;

48 INTEGRATIVE GASTROENTEROLOGY

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

The Microbiota is a Health Asset and Occasional Contributor to Disease The distinction between a commensal and a pathogen is often one of context. For example, the indigenous microbiota is generally a health asset, but becomes a liability in the setting of bacterial overgrowth syndromes, including C. difficile overgrowth after antibiotics. In other contexts, depending on the genetic susceptibility of the host, some but not all components of the microbiota may become contributors to the pathogenesis of disease, such as inflammatory bowel disease (Sartor, 2008). While a comprehensive review of the microbiota in different diseases is beyond the scope of this chapter, microbial alterations linked with inflammatory bowel disease have attracted particular interest. These include a reduction in fecal lactobacilli and bifidobacteria (Murch, 2001), increased adherent-invasive E. coli (AIEC; see Rhodes, 2007), increased detection of Mycobacterium avium subspec paratuberculosis (MAP; see Feller et al., 2007) and reduced bacterial diversity by metagenomic analysis (Peterson et al., 2008). The latter includes reductions in the anti-inflammatory commensal, Faecalibacterium prausnitzii (Sokol et al., 2008). Whether specific microbiota can be correlated with individual variations in the immune response is unclear, but there is evidence that this may be so (Ivanov et al., 2008).

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

The Intestinal Microbiota in Health and Disease 49

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

Metabolic Activity of the Microbiota The collective metabolic activity of the enteric microbiota is tantamount to that of a hidden organ (O’Hara & Shanahan, 2006). Coevolution with this inner biomass has several benefits for the host. In addition to the production of regulatory signals for mucosal homeostasis, the microbiota contributes metabolic properties not possessed by the host. These include biotransformation of bile acids, degradation of oxalate, breakdown of otherwise indigestible dietary components, such as plant polysaccharides, and production of shortchain fatty acids—a major energy source for colonic epithelium—from fermentable carbohydrates. Other activities include synthesis of biotin, folate, and vitamin K. Bacterial enzymes, such as azoreductase, have been exploited therapeutically to convert prodrugs, such as sulfasalazine, to active drug metabolites, such as aminosalicylate. Other examples of bacterial action on drug bioavailability include the metabolism of L-dopa to dopamine, and degradation of digoxin. In some instances, the metabolic changes induced by the enteric microbiota may not beneficial to the host. For example, bacteria may promote the production of carcinogens from dietary procarcinogens, although they probably also degrade some carcinogens (Rafter, 2003).

As alluded to earlier, the regulatory effect of the enteric microbiota on fat storage represents a compelling example of the impact of bacterial metabolism on the host (Backhed et al., 2004). Germ-free animals require a higher caloric intake to sustain a body weight similar to that of colonized animals. Thus, the microbiota of the colonized host confers a nutritional benefit. Furthermore, intestinal bacteria promote fat storage by enhancing the bioavailability of dietary monosaccharides for absorption, and also by suppressing epithelialderived, fasting-induced adipocyte factor (FIAF), which in turn releases lipoprotein lipase activity and promotes uptake of fatty acids into adipose tissue. Thus, the composition and activity of the intestinal microbiota should

50

INTEGRATIVE GASTROENTEROLOGY

be considered as a variable influenced by Western diets that may influence susceptibility to obesity. Gas production is another familiar outcome of bacterial metabolic activity. Of the five gases—N2, O2, CO2, H2, CH4—that comprise 99% of flatus, the latter three are produced by the enteric bacteria, and bacteria are the sole source of hydrogen and methane in the intestine. Hydrogen production by bacterial action on carbohydrates and, to lesser extent, on protein, normally occurs in the colon. The small bowel also becomes a site of H2 production when bacterial overgrowth occurs. Bacterial methanogens occur in the colon and produce methane from H2 and CO2, with detectable excretion in approximately 30% of humans (Levitt & Engel, 1975; Levitt, 1980). While the principal gases produced are odorless, bacterial metabolism also generates various trace and odiferous gases in flatus, such as hydrogen disulfide (Moore, Jessup, & Osborne, 1987; Suarez, Springfield, & Levitt, 1998). Qualitative and quantitative variability in gas production with diet illustrates the fluctuations in bacterial metabolic activity, despite the compositional stability of the microbiota in adulthood.

Mining the Microbiota for Novel Drug Discoveries Several predictions can be made regarding the identity of microbial-derived chemical signals suitable for mining, based on what is already known of the influence of the microbiota on host physiology and pathophysiology (see Table 4.1). Translation of these signaling molecules into bioactives or novel drugs is an exciting prospect for the future (Shanahan & Kiely, 2007). Table 4.1. Examples of Opportunities to Mine the Microbiota for Novel Therapeutics Observation

Opportunity

Isolation of novel Microbe–microbe communication ensures antibiotics (bacteriocins) stability of bacterial numbers in the gut Commensals and probiotics have anti-inflammatory effects on the host

Bacterial components or metabolites for use as anti-inflammatory drugs (e.g., lipoteichoic acid, CpG DNA)

Translation

Reference

Rea et al. Application of lacticin to treatment (2007) of pathogens such as C. difficile Evidence base for this remains to be explored and exploited

Grangette et al. (2005) Obermeie et al. (2003)

The Intestinal Microbiota in Health and Disease 51

Table 4.1. (Continued) Observation

Opportunity

Translation

Reference

Gut microbiota is required for immune maturation

Isolation of bacterialderived molecules as immunomodulatory drugs

Mazmanian Use of cell wall et al. (2005, polysaccharides as immunomodulatory 2008) drugs in IBD

Metabolic signals from the microbiota influence fat storage and composition

Manipulation of the microbiota may alter bioavailability of dietary calories

Use of food-grade organisms to modify composition of the microbiota

Backhed et al. (2004) Wall et al. (2009)

Some but not all commensals or probiotics are beneficial in irritable bowel syndrome

Some components of the microbiota may be suitable for mining for analgesic activities

An intriguing observation that awaits confirmation and exploitation

Rousseaux et al. (2007)

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

5 Alternative Laboratory Testing for Gastrointestinal Disease1 DAVID M. BRADY, J. ALEXANDER BRALLEY , RICHARD S. LORD , AND GERARD E. MULLIN

key concepts ■

■

■

■

■

1

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

Introduction

H

ealthcare practitioners who manage digestive disorders are oftentimes challenged by the limited testing that is available without referring to specialists who perform invasive procedures. The principal

1

Excerpted and adapted from Richard S. Lord and J. Alexander Bralley (Eds), Chapter 7, Gastrointestinal Function in Laboratory Evaluations for Integrative and Functional Medicine. Metametrix Institute (2008).

52

Alternative Laboratory Testing for Gastrointestinal Disease 53

difficulty is that direct sampling of intestinal contents is impractical for nongastroenterologists. Analysis of specimens such as peripheral blood, urine, and feces may give results that indirectly reflect difficulties with digestion and absorption. Due to the critical role of the gastrointestinal tract in nutrient supply, even partial answers can be of great value. Invasive procedures for observation or luminal specimen retrieval can be highly informative when performed in conjunction with noninvasive testing. This chapter will deal mainly with noninvasive laboratory evaluations of gastrointestinal function, as summarized in Table 5.1. Table 5.1. Summary of Laboratory Evaluations for Gastrointestinal Function GI Aspect

Stomach

Function

Testing

Abnormal

Intervention

Heidelberg capsule Direct pH readings

 pH

– Mucosal building protocol – Betaine HCI – Free-form amino acids (see Chapter 4, “Amino Acids”) – B-vitamins – Trace elements (see Chapter 3, “Nutrient and Toxic Elements”)

Gastric acid, Indirect Pepsin indicators

Protease

Fecal chymotrypsin

 Activity

PABA index

 Index

Plasma fatty acids

 PUFA

Fecal fats

 Fat

Fecal fatty acids

 Fatty acids Ox bile, choleretic herbs (milk thistle) and essential fatty acids

Schilling test

 Urinary B12

B12 by injection or ≥ 1,000 μg/d sublingual

LactuloseMannitol challenge

 Urinary mannitol

Mucosal restoration

Pancreas Lipase

Liver/ Gallbladder

Small intestine

Bile acid secretion

Absorption

Multiple  trace elements or amino acids

Fasting plasma Multiple low amino acids values

Pancreatic replacement enzymes (proteolytic, lipolytic and amylytic) and essential fatty acids

Essential amino acid mixtures (Continued)

54

INTEGRATIVE GASTROENTEROLOGY

Table 5.1. (Continued) GI Aspect

Colon

Immune barrier

Physical barrier

Function

Testing

Abnormal

Intervention

Food-specific IgG

Multiple elevations

Food elimination/Rotation diets

 Butyrate

Increase dietary fiber

Water Fecal butyrate resorption, or other SCFA Microbial containment Glycocalyx antigen binding Allergyantigen elimination

Serum, urinary  Foodor fecal IgA specific IgA  Total IgE Serum IgE

Regulate Serum IgG nutrient admission and restrict toxicant and Lactulosemicrobial Mannitol access challenge Normal: nutrient delivery

Microbial populations Pathogen: toxin production

 Isobutyrate Butyrate enemas

Urinary metabolic markers

HydrogenMethane breath test

Eliminate offending antigens Immune-support nutrients such as Glycerrhiza glabra (licorice) root or l-glutamine 3,000–6,000 mg daily

Many + foods Eliminate + foods by group (Rotation Diet) Add free-form amino acids and glutamine Zinc 50–100 mg/d, Bs 100–200 mg/d  Urinary Lactulose

Eliminate + foods

 Mannitol

Mucosal restoration

 Bacterial markers

Herbal or pharmaceutical antibioitics (e.g., berberine alkaloids, etc.)

 Protozoal markers

Prebiotics and probiotics with antiprotozoals

 Yeast markers

Restrict simple sugars with antifungals

 Expired gases

Herbal or pharmaceutical bacteriostatic agents

Stool microbial  Growth DNA quantititation or culture & sensitivity

Specific antibiotics

Alternative Laboratory Testing for Gastrointestinal Disease 55

The Stomach Standard medical treatments focusing on the gastrointestinal tract most often involve treating digestive symptoms by using proton pump inhibitors, which are among the most frequently prescribed medications with a myriad of potential adverse effects (see Chapter 37 by Hickey and Mullin). Stomach acid secretion is a principal line of defense against infection of the gastrointestinal (GI) tract (Giannella, Broitman, & Zamcheck, 1972). The critical function of low pH in the stomach is required to set up mineral absorption. High levels of ammonia, produced by bacterial action on amino acids, are even more directly associated with inadequate hydrochloric acid. The loss of bactericidal action and the failure to digest protein due to low stomach acid simultaneously leads to higher bacterial populations and greater availability of unassimilated amino acids for bacterial conversion. Simultaneous low levels of iron, zinc, copper, and manganese in serum, erythrocytes, or hair, is often due to gastric acid inadequacy, especially when intake of trace elements is normal.

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

HEIDELBERG CAPSULE TEST

The Heidelberg capsule test is considered to accurately assess stomach acid, though it is time-consuming for the patient, taking up to 90 minutes to complete (Wright, 1979). This type of test can give definitive answers about the adequacy of gastric acid secretion. The test uses a tiny plastic encapsulated pH probe that is swallowed by the patient. The capsule, small enough to safely pass the circuitous course of the GI tract, contains a miniature radio transmitter that continuously measures gastrointestinal pH and transmits the data to a waistband antenna connected to a bedside receiver. The pH readings are recorded for a permanent record. The capsule can either be tied to a thin string for retrieval, or swallowed untethered. The latter approach allows additional

56 INTEGRATIVE GASTROENTEROLOGY

measurements of upper intestinal pH to be gathered. After swallowing the capsule, pH readings typically start around 7.0, and then drop toward 1.0 as the capsule settles toward the stomach bottom. The patient then drinks a challenge solution consisting of concentrated sodium bicarbonate (baking soda), which has strong buffering capacity. Within half a minute, the pH will normally rise to approximately 7. If acid secretion is normal, the pH will fall again, returning to between 1.0 and 2.0 within 20 minutes. The challenge solution is given again and repeated up to four times, as long as the pH response time is less than 20 minutes. Hypochlorhydria is indicated for a patient requiring more than 20 minutes to re-acidify. With achlorhydria, the patient’s stomach secretes little acid and the pH will not fall below 4.0, even on the first challenge (Wright, 1979). Experienced technologists must administer this test, because of factors such as the timing of bicarbonate solutions that are critical for accurate, reproducible results.

ENDOSCOPIC SAMPLING

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

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

Alternative Laboratory Testing for Gastrointestinal Disease 57

FECAL CHYMOTRYPSIN TEST

The fecal chymotrypsin test is a useful noninvasive test to determine chronic pancreatic insufficiency (Henry & Steinberg, 1993). False positive results of up to 10% have been reported in normal individuals. Greater reliability for diagnosing chronic pancreatitis can be obtained by performing the fecal chymotrypsin test in combination with the bentiromide (N-benzoyl-L-tyrosyl-p-aminobenzoic acid) test (Kataoka et al., 1997). The bentiromide test measures the amount of p-aminobenzoic acid (PABA) appearing in urine following an oral bentiromide loading, indicating successful chymotrypsin cleavage at the tyrosyl peptide bond. PABA excretion rates are lower in patients with compromised pancreatic function than in healthy control subjects (Gagee et al., 1992).

FECAL PANCREATIC ELASTASE

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

FECAL FAT

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

58 INTEGRATIVE GASTROENTEROLOGY

FECAL FIBERS

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

Small Intestine INTESTINAL HYPERPERMEABILITY

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

LACTULOSE-MANNITOL INTESTINAL PERMEABILITY CHALLENGE TEST

The lactulose-mannitol protocol was developed to measure intestinal hyperpermeability for a wide range of conditions (Andre, 1986), including food sensitivities (Ventura et al., 2006), pancreatitis (Nagpal et al., 2006), Crohn’s

Alternative Laboratory Testing for Gastrointestinal Disease 59

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

Object

Amplification

Remove

Microbial overgrowth

Use bacteriostatic or mycostatic agents of sufficient strength to reduce excessive growth rates

Replace

Digestive factors

Support insufficient digestive secretory factors with oral replacements

Reinoculate

Favorable microbes

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

Repair

Tissue and immune integrity

Support the growth of healthy intestinal mucosal cells, goblet cells and immune cell responses with key nutrients

disease (D’Inca et al., 2006), and cirrhosis (Table 5.2). Lactulose-mannitol is a challenge test in which patients with suspected hyperpermeability ingest the metabolically inert sugars lactulose and mannitol. Mannitol, a monosaccharide, is passively absorbed through the intestinal mucosa. In contrast, lactulose, a disaccharide, is normally not absorbed unless the mucosal barrier is compromised. Since these sugars are not metabolized, any absorbed sugar is fully excreted in the urine within 6 hours. The urine is collected, and concentrations of the two sugars are measured. Percent absorptions are calculated using the following formula: % compound absorption = compound concentration (mg/ml) × urine volume (mL) × 100 Lactulose-Mannitol Testing Protocol • Swallow a solution of 5 g mannitol and 5 g lactulose • Collect urine for 6 hours • Assay for total lactulose and mannitol Calculate recoveriess < 14% Mannitol = Carbohydrate malabsorption > 1% Lactulosee = Disaccharide hyperpermeability In the healthy intestine, the mean absorption of mannitol is 14% of the administered dose, whereas the mean absorption of lactulose is less than 1%. The normal ratio of lactulose-mannitol recovered in urine is < 0.03. An elevated ratio indicates intestinal hyperpermeability. It is best to have the patient perform the lactulose-mannitol test twice—first in the fasting state, then again

60 INTEGRATIVE GASTROENTEROLOGY

after ingestion of a test meal (Andre et al., 1987). The lactulose-mannitol ratio was found to be an accurate predictor of relapse when measured in patients with Crohn’s disease who were clinically in remission (Wyatt et al., 1993). Recent intake of high carbohydrate meals and prolonged administration of the challenge solutions diminish responses to this test.

Mucosal Inflammation GLUTEN SENSITIVE ENTEROPATHIES

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

POLYMORPHONUCLEAR NEUTROPHIL DISORDERS

Human lactoferrin (Lf), an iron-binding glycoprotein secreted by mucosal membranes, is a major granular component of polymorphonuclear neutrophils. When these cells respond to inflammatory signals, lactoferrin is released as part of the defense mechanism. Fecal Lf is a marker of intestinal inflammation in which leukocytes infiltrate the mucosa, increasing the release of neutrophil lactoferrin. Fecal Lf has been extensively used to differentiate inflammatory bowel disease from irritable bowel syndrome (IBS) and noninflammatory bacterial infections, and it is useful for monitoring IBD treatment efficacy (D’Inca et al., 2006; Logsdon &, Mecsas, 2006; Larsen et al., 2004; Buderus et al., 2004; Kane et al., 2003; Bard et al., 2003; Greenberg et al., 2002; Vaishnavi, Bhasin, & Singh, 2000; Saitoh et al., 2000). Various other neutrophil-derived proteins, such as calprotectin (Cal), polymorphonuclear neutrophil-elastase (PMN-e), α1-antitrypsin, and lysozyme (Lys) have been shown to be reliable indicators of intestinal inflammation, and can aid in the differentiation of organic intestinal disorders (i.e., inflammatory bowel diseases (IBD), ulcerative colitis (UC), Crohn’s disease, infectious gastroenteritis, etc.) from functional intestinal disorders (i.e., IBS; see Larsen et al., 2004; Buderus et al., 2004; Kane et al., 2003; Bard et al., 2003; Gaya et al., 2005; Gearry et al., 2005; Langhorst et al., 2005; Liu et al., 2005;

Alternative Laboratory Testing for Gastrointestinal Disease 61

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

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

Microbial Population Assessment The intestinal flora is a complex ecosystem consisting of over 400 bacterial species that greatly outnumber the total number of cells making up the entire human body (Finegold, Attebery, & Sutter, 1974). These metabolically active

62

INTEGRATIVE GASTROENTEROLOGY

bacteria reside close to the absorptive mucosal surface, and are capable of a remarkable repertoire of transforming chemical reactions. Any orally taken compound, or a compound entering the intestine through the biliary tract or by secretion directly into the lumen, is a potential substrate for bacterial transformation. Anaerobic bacteria are the predominant microorganisms in the human GI tract, outnumbering aerobes by a factor of 10,000 to 1.

In health, the upper GI tract is sparsely populated with microorganisms. The vast majority of bacteria washed along with saliva from the oral cavity are destroyed in the stomach by gastric juice. The small intestine constitutes a zone of transition between the sparsely populated stomach and the luxuriant bacterial flora of the colon. In the distal ileum, the concentrations of bacteria increase to 106–107 colony-forming units per milliliter (Fuller & Perdigón, 2003). Here, Gram-negative bacteria outnumber the Gram-positive species. Beyond the ileocecal valve, the bacterial concentration increases steeply. Colonic bacteria number between 1011 and 1012 colony-forming units per milliliter of fecal material. Multiple dramatic shifts in populations of species occur between the ileocecal valve and the rectum. By the time they are passed from the body in stools, the large majority of the bacteria are no longer viable.

OPPORTUNISTIC OVERGROWTH AND DISEASE

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

THE TRANSITIONAL GUT

The microbial mass increases from levels around 1 × 105 to counts as high as 1 × 1011 in the region roughly encompassing the mid-ileum to the transverse colon.

Alternative Laboratory Testing for Gastrointestinal Disease 63

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

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

URINARY MARKERS OF BACTERIAL OVERGROWTH

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

64 INTEGRATIVE GASTROENTEROLOGY

Oral, unabsorbed antibiotics reduce indican excretion. Indican excretion is also reduced when the gut is populated with strains of Lactobacillus at levels above 105 organisms/g (Tohyama et al., 1981). Probiotics have been shown to decrease indican levels (Yoshida & Hirayama, 1984). The urine indican test may be performed after oral loading of 5 g tryptophan (Smith, 1982). Reference limits may also be set from data taken under nonloading conditions. Tryptophan loading, which can be monitored by measuring periodic levels of urinary indican, results in neuropsychiatric manifestations due to products of intestinal bacterial conversion of the amino acid (Yoshida & Hirayama, 1984). When elevations of phenol and p-cresol are included with that of indican as criteria of abnormal bacterial colonization of the small intestine, the number of false positives is reduced (Aarbakke & Schjonsby, 1976).

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

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

Alternative Laboratory Testing for Gastrointestinal Disease 65

URINARY MARKERS OF YEAST OVERGROWTH

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

The Colon: Assessing Microbes in Stool The population of the microbiota of the human GI tract is widely diverse and complex, with a high population density. All major groups of microorganisms are represented. Although they are predominately bacteria, a variety of protozoa are also present. In the colon there are over 1011 bacterial cells per gram, and over 400 different species. These bacterial cells outnumber host cells by at least a factor of 10 (Rowland, 1995). This microbial population has important influences on host physiological, nutritional, and immunological processes. In fact, this biomass should more rightly be considered a rapidly adapting, renewable organ, with considerable metabolic activity and significant influence on human health. Consequently, there is renewed and growing interest in identifying the types and activities of these gut microbes (Mackie, Sghir, & Gaskins, 1999). The normal, healthy balance in microbiota provides colonization resistance to pathogens. Since anaerobes comprise over 95% of these organisms, their analysis is of prime importance. Gut microbes might also stimulate immune responses to prevent conditions such as intestinal dysbiosis. Intestinal dysbiosis may be defined as a state of disordered microbial ecology that causes disease (Tamboli et al., 2004). Specifically, the concept of dysbiosis rests on the assumption that patterns of intestinal flora— specifically, overgrowth of some microorganisms found commonly in intestinal flora—have an impact on human health. Symptoms and conditions thought to be caused or complicated

66

INTEGRATIVE GASTROENTEROLOGY

by dysbiosis include inflammatory bowel diseases, inflammatory or autoimmune disorders, food allergy, atopic eczema, unexplained fatigue, arthritis, mental/emotional disorders in children and adults, malnutrition, and breast and colon cancer (Galland & Barrie, 1993; Hawrelak & Myers, 2004).

DIFFICULTIES IN ASSESSING INTESTINAL MICROBIOTA

Most studies of microbiota in the GI tract have used fecal samples. These do not necessarily represent the populations along the entire GI tract from stomach to rectum. Conditions and species can alter greatly along this tract, and generally run from lower to higher population densities. The stomach and proximal small intestine, with highly acid conditions and rapid flow, contain 103 to 105 bacteria per gram or milliliter of content. These are predominated by acid-tolerant lactobacilli and streptococci bacteria. The distal small intestine to the ileocecal valve usually reaches to 108 bacteria per gram or milliliter of content. The large intestine generates the highest growth, due to longer residence time, and ranges from 1010 to 1011 bacteria per gram or milliliter of content. This region generates a low redox potential, and high amount of short-chain fatty acids. Not only does the microbiota content change throughout the length of the GI tract, but there are also different microenvironments where these organisms can grow. At least four microhabitats exist: the intestinal lumen, the unstirred mucus layer that covers the epithelium, the deeper mucus layer in the crypts between villi, and the glycocalyx of the epithelial cells (Savage, 1977). Given this diverse ecological community, the question arises as to how to sample the various environments to identify populations of microbes, and ultimately understand the host–microbe interactions. This problem is an extremely difficult one, since any intervention to obtain a sample potentially disrupts the population. Fecal sampling has been used for years in microbiota assessment. But it should be understood that this sample most appropriately represents organisms growing in the lumen of the colon. In addition, > 98% of fecal bacteria will not grow in oxygen (Savage, 1977). Therefore, standard culture techniques miss the majority of organisms present.

CONVENTIONAL TECHNIQUES VERSUS NEW TECHNOLOGIES

Conventional Techniques Conventional bacteriological methods such as microscopy, culture, and identification are used for the analysis and/or quantification of the intestinal

Alternative Laboratory Testing for Gastrointestinal Disease 67

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

New Technologies DNA analysis eliminates this problem by placing the specimen in vials which contain a fixative for transport. This technique will be discussed in more detail in the next Chapter.

Microbial Metabolic Markers from Stool Testing FECAL β-GLUCURONIDASE

Bacterial β-glucuronidase is an enzyme that can effectively reverse detoxification that has taken place in the liver during the Phase II conjugation reactions. Bacterial flora may express large amounts of glycosidase enzyme activity, the principal glycosidase being β-glucuronidase. A report showing high levels of β-glucuronidase calls attention to the need to restore beneficial bacterial populations, and to the potential for greater enterohepatic circulation that can affect metabolites such as estrogen.

68

INTEGRATIVE GASTROENTEROLOGY

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

FECAL pH

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

Alternative Laboratory Testing for Gastrointestinal Disease 69

FECAL SHORT-CHAIN FATTY ACIDS (SCFAs)

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

FECAPENTAENES

Fecapentaenes are polyunsaturated ether lipids that are derived from human intestinal bacterial plasmalogens that have similar ether linkages (Van Tassell et al., 1989). Fecapentaenes cause DNA damage and mutations in human cells (Plummer et al., 1986; Gupta et al., 1984), and they are found in human feces,

70

INTEGRATIVE GASTROENTEROLOGY

where they are thought to play a role in the initiation of colorectal cancer (Schiffman et al., 1989; Kingston, Van Tassell, & Wilkins, 1990).The structures of highly mutagenic fecapentaenes have been elucidated (Hirai et al., 1985), and methods for quantification of eight specific fecapentaenes in human feces have been published (de Kok, ten Hoor, & Kleinjans, 1991; Kivits et al., 1990; Kleinjans et al., 1989). Some researchers have proposed that the widely varying ratios of two principal fecapentaenes can be traced to individual differences in intestinal flora (Baptista et al., 1984). Bacteroides have been identified as the source of fecapentaenes in a human autopsy study (Schiffman et al., 1988). With the advent of more broad species identification using 16S DNA identification techniques, there is potential for identifying more closely the organisms in the general population with a capacity for fecapentaene production.

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

6 New Molecular Techniques Revolutionize Understanding of the Influence of Gut Microbiota on Health and Disease J. ALEXANDER BRALLEY

key concepts ■

■

■

■

■

The human GI tract contains a diverse and complex ecosystem of microbiota that can exert significant influence on health. New molecular techniques now allow exploration of this ecosystem. Molecular techniques solve many of the problems of traditional culture-based microbiology. Molecular techniques significantly improve sensitivity and specificity in parasitology and bacteriology of fecal samples. Molecular techniques allow for better understanding of microbiota balance, which enhances treatment options and improves outcomes. ■

Introduction

B

acteria in the human gastrointestinal tract increase in concentration from stomach to rectum. There are up to 1012 organisms per gram of fecal material, of which approximately 95% are anaerobic. The gut microbiota cell population outnumbers the host cells by a factor of 10. In fact, the gut microbiota may be looked upon as a metabolically and physiologically adaptable, rapidly renewable organ of the body, whose function is as critical to human health as any other vital organ. 71

72 INTEGRATIVE GASTROENTEROLOGY

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

Techniques The major advantage of molecular techniques is that they can quantitatively measure the entire range of microbiota present in the human gastrointestinal tract.

New Molecular Techniques Revolutionize Understanding of the Influence

73

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

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

74

INTEGRATIVE GASTROENTEROLOGY

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

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

Drug Resistance Genes All antibiotic resistance strategies that bacteria develop are encoded in one or more genes. Drug resistance genes are readily shared among and across

New Molecular Techniques Revolutionize Understanding of the Influence 75

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

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

76

INTEGRATIVE GASTROENTEROLOGY

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

Gut Microbiota Influences on Insulin Resistance and Obesity Two predominant bacterial groups in the human GI tract are Bacteroidetes and Firmicutes. These gut microbiota significantly affect energy harvest from the diet, and energy storage in the host. Firmicutes bacteria, which include Bacillus, Clostridia, and Lactobacillus species, are very efficient at metabolizing plant polysaccharides into monosaccharides and short-chain fatty acids. These can then be absorbed by the gut and converted to more complex lipids in the liver. In addition, this group secretes a compound that results in increased activity of lipoprotein lipase in adipocytes, resulting in enhanced storage of these lipids. The Bacteroidetes group, which includes Bacteroides and Provetella species, are not as efficient in this function. While excess caloric intake is a significant factor in obesity, gut populations of microbiota that force an efficient extraction and storage of energy may play a significant role in this growing health problem. The ability to assess the balance of “fat bugs” in humans may prove to be an important advance in understanding and treating diabetes and obesity.

Recent studies have demonstrated another aspect of this intriguing story. Manipulation of the gut microbiota in mice significantly alters their glucose/ insulin response (Membrez et al., 2008). The balance of bacterial populations can actually increase levels of a bacterial lipopolysaccharide endotoxin that dysregulates the inflammatory tone, and triggers body weight gain and diabetes in mice (Cani et al., 2007). These studies demonstrate the possibility in humans that modulation of gut microbiota can ameliorate glucose tolerance by altering the expression of hepatic and intestinal genes involved in inflammation and metabolism, and change the hormonal, inflammatory, and metabolic status of the host. The ability to recognize this aspect of microbiota effects in human health has only become available through the use of molecular techniques.

New Molecular Techniques Revolutionize Understanding of the Influence

77

Ongoing studies are exploring the relationship between gut microbiota and metabolic diseases. The use of specific diets and prebiotic and probiotic therapies may significantly alter microbial balances that affect fat storage. The ability to assess the balance of these “fat bugs” in humans may prove to be an important advance in understanding and treating diabetes and obesity.

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

78 INTEGRATIVE GASTROENTEROLOGY

Table 6.1. Advantages of PCR vs. Culture • Single specimen collection vs. several • Copies a single DNA sequence of a cell over a billion times within 1 to 2 hours, allowing sensitive quantitation • Detects parasites with as few as 5 cells per/g vs. 25,000 cells per/g for microscopic techniques • 5,000 times more sensitive • Ability to ID anaerobes (majority of bacteria—95%) • No growth in transport vs. significant growth in transport • Requires only 5 to 10 bacterial cells for ID vs. 1,000 to 5,000 for culture

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

7 Principles of Integrative Gastroenterology: Systemic Signs of Underlying Digestive Dysfunction and Disease LAURA K. TURNBULL, GERARD E. MULLIN , AND LEONARD B. WEINSTOCK

key concepts ■

■

■

■

■

■

Many idiopathic syndromes overlap, and are caused by underlying gut dysfunction. Acute and chronic GI infections trigger chronic systemic diseases by several mechanisms, including small intestinal bacterial overgrowth (SIBO), inflammation, and autoimmune phenomena. SIBO underlies many poorly understood syndromes, including irritable bowel syndrome (IBS), restless legs syndrome (RLS), fibromyalgia syndrome (FMS), rosacea, and interstitial cystitis (IC). Increased intestinal permeability and inflammation are complications of SIBO. Increased intestinal permeability may explain food allergies, and the increased involvement of diseases with eosinophils and mast cells (e.g., asthma). SIBO treatment is effective treatment for IBS and SIBO-related syndromes. ■

79

Introduction

G

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

Common Extraintestinal Manifestations of GI Dysfunction

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

Genetics, Inflammation and Intestinal Permeability Altered genetic background or phenotype may result in GI dysfunction in several ways. First, specific HLA genome subtypes are found in celiac disease, and

Principles of Integrative Gastroenterology 81

result in predisposition for the disease. Furthermore, a variety of genetic markers have been found in Crohn’s disease patients, as discussed in Chapters 30 and 44 Lastly, in both celiac disease and Crohn’s disease, a genetically determined increased intestinal permeability may be a harbinger of clinical disease. Based on the phenotypic genetic makeup, the impact of various stimuli, including inflammation and dysbiosis, can lead to a variety of diseases or syndromes. Inflammation and infection of the intestinal lining can lead to increased intestinal permeability, by damaging the tight junctions of mucosal cells. The net effects are the stimulation of the inflammatory network, and activation of lymphocytes and mast cells locally and systemically. This stimulation results in the release of various cytokines, which can lead to an increase of corticotropin-releasing hormone, which can in turn affect the central nervous system (CNS), the hypothalamic-pituitary-adrenal (HPA) axis, and the peripheral nervous system. Additionally, translocation of bacteria or the lipopolysaccharides (outer covering of Gram-negative bacteria) into a damaged mucosal lining can alter the HPA axis. The complex dynamics of the emotional motor system (EMS), and the interplay of stress, cytokines, cortisol, neurological, and neuroendocrine responses, are shown in Figure 7.2.

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

82

INTEGRATIVE GASTROENTEROLOGY

Table 7.1. Incidence of Postinfectious IBS Follow-Up

Number with acute

% of patients with acute

period(s)

diarrhea

diarrhea who developed IBS

Marshall 2005

2-3 yr

1137

34

Mearin 2005

1 yr

271

10

Okhuysen 2004

6 mo

60

10

Neal 1997 & 2003

6 mo 6yr

357 192

7 7

Thornley 2000

6 mo

93

9

Gwee 1999

3 mo

100

22

McKendrick 1994

1 yr

38

31

Author

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

Principles of Integrative Gastroenterology 83

SMALL INTESTINAL BACTERIAL OVERGROWTH (SIBO)

The colon is accustomed to having trillions of coliform bacteria, but complications arise when the coliform count grows in the small intestine. There are several natural protective mechanisms that keep the small bowel bacteria at low colony counts, including the presence of stomach acid, gastrointestinal motility, digestive enzymes, mucosal immunity, and the integrity of the ileocecal valve.

To minimize bacterial counts in the small intestine (SI), one has to: • maintain physiologic gastric acid production to reduce swallowed bacteria; • control the ingestion and have proper digestion of starches (i.e., legumes) to limit the nutrition necessary for bacterial growth; • retain normal small bowel motility (as driven by the migrating motor complex in the fasting state) to sweep the bacteria toward the colon; and • preserve an intact ileocecal valve to act as a physical barrier (between the SI and colon) to prevent the reflux of stool/bacterial contents from the large intestine. These natural defenses are shown in Figure 7.3. SIBO is defined as a disruption or increase of the normal small bowel bacterial population that can result in gas, bloating, flatulence, altered bowel function, and/or malabsorption of nutrients. Bloating, diarrhea, and nutrient deficiencies are induced by excess intraluminal small intestinal bacteria, which results from: (1) fermentation of nutrients producing gas, and (2) bile salt deconjugation by bacteria, leading to fat malabsorption and subsequent steatorrhea and secretory effects, causing diarrhea. Deconjugation of the hydrophilic components decreases absorption from the loss of the water-soluble state, which is involved in fat absorption. The change in bacteria and the effect of undigested starches are shown in Figure 7.4. With chronicity, weakness and weight loss from villous atrophy, and/or malabsorption secondary to the effects of bile salt deconjugation, will become evident. Advanced cases may have peripheral edema from hypoalbuminemia

84 INTEGRATIVE GASTROENTEROLOGY

and pallor from anemia (B12 deficiency, chronic disease, and in some cases iron deficiency, for which achlorhydria is the most common explanation). In advanced stages, cachexia and other changes of vitamin and nutrient deficiency may become evident. Chronic asymptomatic SIBO can result in systemic inflammation (Lin, 2004). Circulating levels of cytokines, such as TNF-α and proinflammatory interleukins, are elevated in SIBO (Dinan et al., 2006). Recent evidence indicates that low-grade SIBO may present with virtually no GI symptoms, but may affect the body in profound ways because of the systemic inflammation it causes. This may explain many syndromes and symptoms associated with chronic fatigue syndrome, rheumatoid arthritis, fibromyalgia, interstitial cystitis, restless legs syndrome, and rosacea (Table 7.3). SIBO may also explain other syndromes due to the presence of systemic low-grade inflammation and increased intestinal permeability.

CAUSES OF SIBO

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

GASTROINTESTINAL MOTILITY AND SIBO

Neuromuscular disorders of the esophageal body, lower esophageal sphincter, stomach, and small intestine, are important in the pathophysiology of many GI and systemic disorders. Functional disorders such as IBS, GERD, and nonulcer dyspepsia are in part caused by disordered gastrointestinal motility. When small intestinal motility is disturbed, and the ability to “sweep” pathogenic organisms away from the upper gastrointestinal tract is impaired, the risk of SIBO is increased. There is a growing prevalence of SIBO in IBS patients and, as the SIBO resolves the IBS, symptoms improve. Other gastrointestinal motility disorders that can contribute to SIBO are small intestinal pseudo obstruction, scleroderma, and postsurgical states. The latter is among the most well known causes of SIBO, and is due to the decreased motility and achlorhydria after certain gastrointestinal surgical procedures

Principles of Integrative Gastroenterology 85

including, but not limited to, gastric bypass surgery and Whipple’s type surgical procedures. Additionally, gastrointestinal motility disorders, or lack of adequate production of gastric acid with subsequent ingestion of live bacteria, has been commonly recognized as contributing to SIBO (Lewis et al., 2001; Parlesak et al., 2003; Lipski, Kelly, Malhotra, & Mountford, 1992). Other classic examples of SIBO include pancreatic insufficiency, and abnormal small intestinal mucosal disorders, including celiac disease and Crohn’s disease, as shown in Table 7.2. Finally, many systemic diseases and conditions can also cause SIBO—see Tables 7.2 and 7.3 and 7.4.

Table 7.2. Common Causes of SIBO Scleroderma

Achlorhydria

Small intestinal pseudo-obstruction

Diabetes

Pancreatic insufficiency

Radiation enteritis

Jejunal diverticulosis

Immunodeficiency: CLL, IgA deficiency, T-cell deficiency

Post-surgical anatomy: Billroth, Blind-loop, ICV resection, J–pouch

Celiac and Crohn’s diseases

Table 7.3. Lesser Known Causes of SIBO Chronic renal failure

Rheumatoid arthritis

Cirrhosis

Irritable bowel syndrome

Chemotherapy

Fibromyalgia

Acromegaly

Interstitial cystitis

Hypothyroidism

Restless legs syndrome

Chronic fatigue syndrome

Rosacea

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

86

INTEGRATIVE GASTROENTEROLOGY

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

Substrate

#

Prevalence

Subjects

(%)

McCallum, 2005

Glucose

143

38.5

Lupascu, 2005

Glucose

65

30.7

Nucera, 2005

Lactulose

98

65

Walters, 2005

Lactulose

39

10

Noddin, 2005

Lactulose

20

10

Nucera, 2004

Lactulose

200

75

Pimentel, 2000–3

Lactulose

313

57, 76, 84

Weinstock, 2006

Lactulose

254

63

INTESTINAL GAS AND THE DIAGNOSIS OF SIBO

The obvious consequence of bacterial fermentation is the production of gas. The variety of gases that develop in the gut expand its diameter, causing abdominal bloating, distention, and discomfort from the triggering of stretch receptors (see Figure 7.5). This bloating is most often caused by excess hydrogen production from bacterial fermentation (King, Elia, & Hunter, 1998). Simple lactose maldigestion is well known to cause hydrogen and lactic acid production, with subsequent bloating and diarrhea. Diagnostic tests for SIBO are either direct invasive studies with bacterial cultures via nasal jejunal tubes, or indirect techniques using breath testing with either glucose or lactulose (Koshini, Dai, Lescano, & Pimentel, 2008). Hydrogen breath testing in particular is useful in identifying patients with IBS who are affected by SIBO, but other exhaled gases may have diagnostic benefit, as well (Koshini, Sun-Chuan, Lezcano, & Pimentel, 2007). Specific characteristics of each gas pose their own hazard. The production of hydrogen sulfide can cause increased nociception, as found in IBS and idiopathic constipation (IC). Excess hydrogen and methane result predominantly in bloating (as seen in IBS), while excess methane also results in altered motility, manifested primarily as constipation. Early studies of the association of methane production and altered motility looked at orocecal and whole gut transit, and found that each was significantly delayed if methane excretion occurred early on in the lactulose

Principles of Integrative Gastroenterology 87

breath test (LBT). As a result, abnormal methane production was shown to be strongly associated with constipation-predominant IBS (Pimentel et al., 2003). Methane was detected in 50 (17%) of 296 patients with IBS, compared with 2 (3%) of 78 patients with IBD (P < .01). Subsequently, a study of 87 patients showed that, of the 20 that had methane production, severity of constipation was double that of non-methane-producing IBS subjects (Chatterjee et al., 2007). A correlation was found between the degree of methane production on the breath test and the severity of constipation. Infusion of methane into the small intestine has shown that gut transit can be reduced by up to 70% (Pimentel et al., 2006). Thus, methane as a by-product of fermentation can itself slow intestinal transit.

THERAPY FOR SMALL INTESTINAL BACTERIAL OVERGROWTH

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

RIFAXIMIN THERAPY FOR SIBO

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

88

INTEGRATIVE GASTROENTEROLOGY

Table 7.5. Rifaximin Therapy for IBS-SIBO Author

Yr

Patients

Type

Efficacy

Nucera

‘04

IBS-SIBO (n=200)

Open label; Rfx 87-100% effective in + paramomycin treating SI BO by reversing 3 sugar BT’s

Lauritano

‘05

IBS-SIBO (n=90)

Dose-ranging

Dose response with Rfx

Lupascu

‘05

IBS-SIBO (n=80)

Abx comparison; open label

1 wk of Rfx vs. metro/ levoquin 12/20 vs. 14/20 H2 BT normalized

Pimentel

‘05

IBS-SIBO (n=87)

R/DB/PC

Statistical sig. vs. placebo; duration of response over 2 months for 10-day Rx

Sharara

‘06

IBS (n=70)

R/DB/PC

Statistically sig. vs. placebo

Sharara

‘06

Fx-SIBO (n=54)

R/DB/PC

Numerically diff. vs. placebo

Weinstock

‘06

IBS-SIBO (n=254)

Observational

60% mod-greatly improved

Weinstock

‘06

Fx-SIBO (n=85)

Observational

63% mod-greatly improved

reported that reversing the breath test is critical in symptom resolution (Pimentel, Chow, & Lin, 2003). Pimentel, Park, Murocha et al.’s 2006 study showed that a 10-day course of 1,200 mg/day of rifaximin resulted in 10 weeks of improvement of IBS symptoms. Patients experienced a 36% mean improvement from baseline in the severity of IBS symptoms at 10 weeks post-treatment, compared with a mean improvement of 21% among 44 patients who received placebo (P = .02). The dose of rifaximin in Sharara et al.’s study (2006) was 800 mg/day for 10 days; global symptomatic response was achieved in 41% of 37 patients, compared with 6 (18%) of 33 patients who received placebo (P = .04). After 10 days posttreatment, 10 (27%) of 37 patients in the rifaximin group maintained their symptomatic response, compared with 3 (9%) of 33 patients in the placebo group (p=0.05). In an open-label, observational study, a 10-day course of rifaximin 1,200 mg/day, as part of a comprehensive treatment regimen including tegaserod and probiotic therapy, improved IBS symptoms in 60% of 81 patients (Weinstock et al., 2006;110:A1123). Our own experience shows that effective

Principles of Integrative Gastroenterology 89

antibiotic therapy, (LBW) along with high doses of Coenzyme Q10, reduces the severity of fatigue in IBS patients with SIBO. Studies have also been done comparing the effectiveness of other antibiotics used in the treatment of SIBO compared to Rifaximin. A retrospective chart review of 98 patients with IBS who received antibiotic therapy (Yang J, Lee HR, Low K et al., 2008) showed that 58 (69%) of 84 patients who received at least one course of rifaximin experienced clinical response, compared with 9 (38%) of 24 patients who received neomycin (p<0.01) and 27 (44%) of 61 patients who received other antibiotics (e.g. amoxicillin clavulanate and doxycycline; P < .01).

COMBINATION PROMOTILITY ANTIBIOTIC THERAPY FOR SIBO

Given that disturbances in gastrointestinal motility are key to the development of SIBO (via impaired “sweeping” of bacteria in the upper digestive tract), treatment with promotility agents are paramount to the therapy of this condition. In the past, long-term tegaserod (a serotonin agonist) was given in an attempt to improve the Phase III abnormality of the migrating motor complex found in patients with IBS who have SIBO (Spiller et al., 2000). A review of IBS-SIBO patients who were treated with antibiotics and then were given tegaserod (no longer available in the United States) versus low-dose erythromycin (50mg dose acts as a stimulant to the migrating motor complex) showed that tegaserod decreased recurrence of IBS-SIBO symptoms at a rate twice that of erythromycin, and four times that of no medication after rifaximin alone (Yang J, Lee HR, Low K et al., 2008). The problems with erythromycin include the potential for abdominal cramps, interference with birth control pills, and other drug interactions including an increased risk of muscle damage when used concurrently with statin medications. Low-dose naltrexone may be used as an alternative to erythromycin. This anti-opioid can stimulate the intestine, and some emerging data suggests that it has anti-inflammatory properties, which might help repair the intestinal lining. The problems with naltrexone include general CNS stimulation (potential for jittery feelings, insomnia, and unusual dreams). It is contraindicated for people who take chronic opioids. The following are possible alternative treatments for SIBO: • Probiotics can reduce inflammation and improve permeability problems (Spiller, 2005; Resta-Lenert & Barrett, 2006; Ait-Belgnaoui et al., 2006). Specifically, bifidobacteria-based probiotics may repair small

90 INTEGRATIVE GASTROENTEROLOGY

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

Principles of Integrative Gastroenterology 91

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

Systemic Consequences of SIBO-Induced Gut Injury CHRONIC FATIGUE SYNDROME

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

92

INTEGRATIVE GASTROENTEROLOGY

RESTLESS LEGS SYNDROME (RLS)

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

THEORY FOR SIBO CAUSING RLS AND CENTRAL IRON DEFICIENCY

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

Principles of Integrative Gastroenterology 93

TREATMENT OF SECONDARY RLS

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

ANTIBIOTICS FOR RLS

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

Table 7.6. Medical Therapy for Restless Legs Syndrome Dopaminergic agents Neuroleptics Anti-seizure medications Narcotics Benzodiazepines Iron Investigational Rifaximin antibiotic therapy Magnesium Acupuncture Botox injections

94 INTEGRATIVE GASTROENTEROLOGY

for 10 days, followed by motility and probiotic therapy (Weinstock, Fern, & Duntley, 2008). The next study included patients with primary RLS who had a positive lactulose breath test for SIBO. The mean baseline IRLS score was 23.1 (Weinstock, Fern, & Duntley, 2008). Open-label treatment with rifaximin 1,200 mg/day/10 days, followed by 400 mg/every other day/20 days, resulted in a decrease in the IRLS score by 10.7 in 9 of 14 patients. Two of the five RLS nonresponders had improvement with a second course of rifaximin when combined with metronidazole, and a third patient improved when she was later diagnosed with celiac disease and placed on a gluten-free diet and iron supplementation.

ALTERNATIVE THERAPIES FOR RLS

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

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

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

Have not been reported in the literature.

Principles of Integrative Gastroenterology 95

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

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

Possible Role of SIBO and IC Pathophysiology ROLE OF FOOD ALLERGIES

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

Gut Permeability, Inflammation, and Pelvic Pain The link between chronic pelvic pain, dyspareunia, and functional digestive diseases (i.e., IBS) has been long established (Vercellini, Somigliana, Viganò et al., 2009). Since SIBO, chronic inflammation, altered HPA axis, and systemic

96

INTEGRATIVE GASTROENTEROLOGY

proinflammatory cytokines are implicated in the pathogenesis of IBS, an experimental study was undertaken to investigate the mechanism of development of pelvic pain (Rudick, Chen, Mongiu, & Klumpp, 2007). One study explored, in an animal model of IBS, whether pelvic pain could develop remotely from the original site of inflammation. These investigators confirmed that there is organ crosstalk (between the intestine and vagina), as well as modulation of pain responses by visceral inputs distinct from the inflamed site. Thus, SIBO/IBS can manifest in other organ systems distant from the site of pathology, via the common mucosal immune system (see Chapter 3).

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

ROSACEA AND DIGESTIVE DISORDERS Rosacea has been associated with gastritis and hypochlorhydria; many people have nonspecific gastrointestinal symptoms.

Helicobacter pylori The role of Helicobacter pylori has often been a subject of investigation, with studies showing conflicting results. A small study investigated ocular rosacea, and clinical and serological evidence of H. pylori infection showed significant improvement of rosacea symptoms, with ocular disease responding better than cutaneous rosacea (Daković, Vesić, Vuković et al., 2007). An older study from Poland on the treatment of H. pylori infection, in 60 patients with rosacea having erythema and flushing on the face with visible papules and pustules, was compared to 60 age and gender matched patients without any skin diseases (Szlachcic, 2002). The effect of treatment on plasma interleukin (IL-8) and tumor necrosis factor alpha (TNF-α) was also determined after 1 week of

Principles of Integrative Gastroenterology 97

omeprazole 20 mg, clarithromycin 500 mg, and metronidazole 500 mg, all twice daily. The H. pylori prevalence in rosacea patients was about 88%, compared to 65% in control patients. There was twice the incidence among rosacea patients of a more virulent form of H. pylori (cytotoxin-associated gene A [CagA] positive). After antibiotics, 51 out of 53 treated rosacea patients became Hp negative. Within 2 to 4 weeks, the symptoms of rosacea disappeared in 51 patients, markedly declined in one, and remained unchanged in one other subject. Plasma TNF-α and IL-8 were reduced significantly after the therapy in both groups of patients (72% and 65%, respectively).

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

SIBO

Italian investigators recently discovered the link between rosacea and small intestinal bacterial overgrowth (Parodi, Paolino, Greco et al., 2008). Of 113 consecutive rosacea patients, 52 had a positive breath test (versus 3 of 60 controls). After SIBO eradication by rifaximin, as determined by reversal of the breath test, cutaneous lesions cleared in 20 of 28, and greatly improved in 6 of 28 patients, whereas patients treated with placebo remained unchanged (18/20) or worsened (2/20) (P<0.001) (Figure 7.8). The patients who were given placebo were subsequently switched to rifaximin. In these patients, SIBO was eradicated in 17 of 20 cases. Fifteen of these patients had a complete resolution of rosacea. Thirteen of 16 patients with negative breath tests for SIBO remained unchanged, and this result differed from SIBO-positive cases (P<0.001). Eradication of SIBO induced an almost complete regression of their cutaneous lesions for at least 9 months. The authors of the study suggested that chronic systemic inflammation causes inflammation of the skin. Figure 7.8 shows the clinical outcome in SIBO-positive and SIBO-negative rosacea patients treated with rifaximin. 1. Myth: Syndromes are all “in your head” and are due to “stress.” 2. Restless legs syndrome is caused by central nervous system iron deficiency and altered dopamine interactions. Evidence is growing for the role of small intestinal bacterial overgrowth. 3. The real name for “leaky gut” is increased intestinal permeability.

98

INTEGRATIVE GASTROENTEROLOGY

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

8 The Skin and the Gastrointestinal Tract ANDREW G. FRANKS , JR.

key concepts ■

■

■

■

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

Introduction

T

he skin and the gastrointestinal tract are both covered or lined by epithelium, and both communicate with the external environment. Therefore, it is not surprising that diseases that primarily affect the gastrointestinal tract often have cutaneous manifestations as well. These cutaneous

99

100

INTEGRATIVE GASTROENTEROLOGY

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

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

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

Glucagonoma syndrome Bazex’s syndrome Palmar-plantar hyperkeratosis Acanthosis nigricans Gardner’s syndrome Peutz-Jeghers syndrome Cowden disease

The Neutrophilic Dermatoses and Other Benign Disorders The neutrophilic dermatoses are a spectrum encompassing four distinct diseases characterized by sterile neutrophilic cutaneous infiltrates. The etiology of these disorders is not well understood, but is thought to be related to deposition of immune complexes in dermal vessels, resulting in complement fixation and leukocytoclastic vasculitis, as well as altered neutrophilic chemotaxis. The neutrophilic dermatoses include erythema elevatum diutinum, pyoderma gangrenosum, Sneddon-Wilkinson syndrome and Sweet’s syndrome.

The Skin and the Gastrointestinal Tract 101

ERYTHEMA ELEVATUM DIUTINUM

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

PYODERMA GANGRENOSUM

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

102 INTEGRATIVE GASTROENTEROLOGY

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

SNEDDON-WILKINSON SYNDROME

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

SWEET’S SYNDROME

The combination of high fever, leukocytosis, boggy, red, painful papules and plaques with dense neutrophilic dermal infiltrates, without evidence of vasculitis on skin biopsy, is characteristic of Sweet’s syndrome, or acute febrile neutrophilic dermatosis. Soft, pea-sized papules and papulovesicles grouped within boggy violaceous plaques are very suggestive of the diagnosis. If the plaque is squeezed between the thumb and forefinger, a grey-yellow coloration may be noted within the papules. Lesions tend to occur on the extremities more so than the trunk. Sweet’s syndrome may be associated with hematological malignancy, especially acute myelogenous leukemia, as well as inflammatory bowel disease, particularly Crohn’s disease (Burrows, 1995; Mustafa & Lavizzo, 2008). The initial episode is often thought to be cellulitis or erysipelas. Patients are placed on antibiotics empirically and, as spontaneous remission

The Skin and the Gastrointestinal Tract 103

occurs, this reinforces the misdiagnosis. Patients may become secondarily infected, further causing confusion.

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

Erythema Nodosum Erythema nodosum accompanied by gastrointestinal complaints includes inflammatory bowel disease, Behcet’s disease, bacterial gastroenteritides, pancreatitis, celiac disease, and Whipple’s disease (Schwartz & Nervi, 2007). Erythema nodosum is the most common form of septal panniculitis, and the most frequent skin manifestation associated with inflammatory bowel disease. Since the development of erythema nodosum is closely related with a variety of disorders and conditions, it can serve as an important early sign of systemic disease. Aphthous stomatitis and pyoderma gangrenosum, along with erythema nodosum, are the most common skin disorders related to inflammatory bowel disease (Farhi et al., 2008). Erythema nodosum clinically presents as multiple, bilateral, painful, non-ulcerating, subcutaneous nodules that undergo characteristic color changes commencing with bright erythema, and ending in

104

INTEGRATIVE GASTROENTEROLOGY

bruise-like areas. It occurs most commonly on the extensor surface of the shins, and is less common on the thighs and arms. It usually subsides in 3 to 6 weeks without scarring or atrophy, but may be chronic.

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

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

Pancreatic Panniculitis Pancreatic panniculitis is an uncommon cutaneous eruption that is associated with disorders of the pancreas, both benign and malignant (García-Romero & Vanaclocha, 2008). The most common disorders associated with pancreatic

The Skin and the Gastrointestinal Tract 105

panniculitis are acute or chronic pancreatitis, especially the alcohol-related types, and pancreatic carcinoma. Although the underlying pancreatic pathologic conditions vary, the clinical features of pancreatic panniculitis are similar (Sagi et al., 2008.). The legs are the most commonly affected area, but the lesions can also occur on the arms, thighs, and trunk. They begin as erythematous or red-brown subcutaneous nodules, with a tendency to central softening. In the mild form, they may involute within weeks and leave an atrophic hyperpigmented scar. If the fat necrosis is severe, individual nodules may break down and ulcerate (Shehan & Kalaaji, 2005).

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

106

INTEGRATIVE GASTROENTEROLOGY

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

Malignancy-Associated Disorders GLUCAGONOMA SYNDROME

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

BAZEX’S SYNDROME

Acrokeratosis paraneoplastica (Bazex’s syndrome) is a rare paraneoplastic dermatosis characterized by psoriasiform and erythematous plaques, typically affecting hands, feet, nose, and earlobes. The condition almost exclusively affects Caucasian men older than 40 years. It is usually associated with primary

The Skin and the Gastrointestinal Tract 107

malignant neoplasms of the upper digestive tract, especially esophageal carcinoma, as well as cervical lymph node metastases from an unknown primary tumor. Other rare associations include adenocarcinoma of the stomach or uterus, anaplastic small-cell carcinoma of the lung, Hodgkin’s lymphoma transitional-cell carcinoma of the bladder, adenocarcinoma of the colon, and squamous cell carcinoma of the lower leg (Rao & Shenoi, 2004). In most cases, the skin changes precede the clinical manifestation of the underlying neoplasm. The dermatosis can be cured only by removal of the underlying carcinoma (Sator, Breier, & Gschnait, 2006).

PALMOPLANTAR KERATODERMAS

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

ACANTHOSIS NIGRICANS

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

GARDNER’S SYNDROME

Gardner’s syndrome is the association of multiple colonic and rectal polyps with sebaceous cysts and jaw osteomas (Parks, Caldemeyer, & Mirowski, 2001). The significance of this dominantly inherited condition is that the

108

INTEGRATIVE GASTROENTEROLOGY

polyps usually undergo malignant change by the fourth decade, and the extraintestinal lesions may be apparent before those in the bowel. Therefore, early detection of multiple jaw osteomas and/or multiple sebaceous cysts, particularly on the scalp, may lead to appropriate further investigation and treatment prior to malignant transformation (Basaran & Erkan, 2008). Gardner described the occurrence of familial adenomatous polyposis, with the extracolonic manifestations of desmoids, osteomas, and epidermoid cysts in the skin and the gastrointestinal tract. The number of polyps can range from no detectable polyps at colonoscopy, to more than 7,000 seen on resected specimens of bowel. The polyposis predominantly affects the left colon (Bilkay et al., 2004).

PEUTZ-JEGHERS SYNDROME

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

COWDEN SYNDROME

Cowden syndrome is an autosomal dominant disorder characterized by multiple hamartomas and a high risk of development of breast, thyroid, endometrial, and other cancers (Schrager et al., 1998). The classic features of the disease include mucocutaneous papillomatous papules and trichilemmomas on the malar area of the face (Kovich & Cohen, 2004). Most affected people develop these characteristic lesions by their early twenties. At least one of four types of skin lesions is present in nearly all cases. Facial papules are flesh-colored,

The Skin and the Gastrointestinal Tract 109

flat-topped, dry or warty 1mm to 5mm papules around the mouth, nostrils, and eyes. Oral lesions are numerous 1mm–3mm smooth white spots on the gums and palate that create a cobblestone appearance known as papillomatosis (Jornayvaz & Philippe, 2008). Acral keratoses are flesh-colored or slightly pigmented smooth or warty papules on the upper surface of hands and feet. Palmoplantar keratoses are scaly spots on the palms and soles that also may occur. Noncancerous breast and thyroid diseases are also common.

Conclusions Integrative practitioners should become aware of the various systemic manifestations of gastrointestinal disease. Dermatological conditions can precede, coincide, or occur after the underlying digestive disorder. Early recognition of dermatoses that underlie digestive health problems can lead to early diagnosis and treatment.

9 Premenstrual and Menstrual Exacerbation of IBS: An Integrative Medicine Analysis of the Bi-Directional Connection between Female Hormones and Gut Health JOEL M. EVANS

key concepts ■

■

■ ■

■

■

IBS symptoms often have premenstrual and menstrual exacerbations. Progesterone dominance in the second half of the menstrual cycle explains the observation that constipation as an IBS symptom is more frequent in reproductive-aged women than in men. Stress is proinflammatory and known to exacerbate IBS. The perimenstrual release of proinflammatory cytokines contributes to the observed increase in IBS symptoms during menstruation. Healthy gut flora and overall gut health have a direct relationship to female hormonal health. An integrative treatment plan for IBS includes normalizing hormone levels, as well as reducing stress and inflammation. ■

Introduction

W

omen have long been aware of the relationship of their menstrual cycle to nongynecologic health complaints. However, because up to 75% of women experience some recurrent premenstrual

110

Premenstrual and Menstrual Exacerbation of IBS 111

symptoms, there has been disagreement among medical authorities on whether to classify these nongynecologic health complaints as normal (physiologic) or abnormal. The premenstrual symptoms germane to IBS are the changes in bowel habits (abdominal pain, bloating, diarrhea and constipation) described by many healthy women, as well as those diagnosed with IBS.

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

EMOTIONAL FACTORS

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

However, even though stress itself increases inflammation (Miller et al., 2002), when describing the premenstrual and menstrual exacerbations of IBS it is most accurate to classify stress and emotions as contributing factors, rather than the predominant factor, to the other, more significant underlying mechanisms mentioned earlier. These mechanisms will now be discussed in further

112 INTEGRATIVE GASTROENTEROLOGY

detail, to better understand the basis for an integrative approach to premenstruation- and menstruation-exacerbated IBS.

HORMONES AND IBS

The second half, or luteal phase, of the menstrual cycle is associated with progesterone dominance relative to estrogen, with a sharp decrease of both hormones at the end of the luteal phase causing a destabilization of the endometrial lining, ending in menstruation. Because progesterone is known to have the effect of decreasing gut motility (Gonne et al., 2006), the hormonal milieu of progesterone dominance explains the clinical observation that women with IBS, as opposed to men, frequently present with constipation as the dominant IBS complaint (IBS-C).

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

INFLAMMATION AND IBS

The final mechanism to explain menstrual exacerbation of IBS is the proinflammatory state associated with menses. While all clinicians are familiar with

Premenstrual and Menstrual Exacerbation of IBS 113

the therapeutic efficacy of antiprostaglandin medications in the treatment of dysmenorrhea, further research (Wander et al., 2008) has shown that menstruation is associated with a 17% increase in C-reactive protein, a biomarker of inflammation. This shows that menstruation induces a systemic inflammatory state. Additionally, there is a documented local and systemic inflammatory cytokine release that is associated with both the tissue breakdown and progesterone withdrawal that accompanies menstruation (Critchley et al., 2001). The systemic increase in proinflammatory cytokines serves as a further explanation for the observed increase in IBS symptoms during menstruation (O’Mahony et al., 2005).

Gynecological Manifestations of IBS So far, the discussion has centered on the exacerbations of IBS that accompany the premenstrual and menstrual phases of a woman’s hormonal cycle. However, practitioners that are active in caring for women are likely to note that their patients suffering from endometriosis, chronic pelvic pain, and dysmenorrhea are more likely to also have IBS symptoms or an IBS diagnosis. In fact, one out of three women with chronic pelvic pain has IBS symptoms (Zondervan et al., 2001).

Anti-Inflammatory Therapeutic Options to Improve Gynecological Health The common underlying pathophysiologic mechanism of inflammation is the link between all of these conditions, and serves as the basis for using a broad anti-inflammatory approach (supplementing with fish oil, hops, rosemary, bromelain, turmeric, quercetin) to address both menstrual and gut symptoms (De Giorgio & Barbara, 2008). In addition, treating the underlying abnormalities in the gut—for example, by avoiding foods that create an inflammatory reaction, and supplementing with anti-inflammatory probiotics (such as Lactobacillus plantarum 299v, Lactobacillus acidophilus NCFM®, and Bifidobacterium lactis), in order to decrease gut induced inflammation—will often dramatically decrease the severity of gynecologic symptoms.

114

INTEGRATIVE GASTROENTEROLOGY

The Gut–Gynecological Axis of Health All of the preceding relationships can be summarized as showing that hormonal changes affect gut function, both directly (progesterone mediated effects) and indirectly (inflammation mediated effects). However, the relationship between the gut and female hormonal milieus is really bidirectional. In other words, it is not just that hormonal health affects gut health, but also that gut health influences hormonal health. It is crucial for practitioners treating bowel dysfunction to be aware of this bidirectionality, because by ensuring optimal gut health in their female patients, they are not only helping them lead more comfortable lives but also helping prevent and treat common estrogenrelated disorders (endometriosis, fibroid tumors, breast cancer).

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

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

Nutritional Interventions to Improve Gynecological and Gut Health Phase II detoxification of estrogen involves the attachment, or conjugation, of other compounds to enable the estrogen molecule to be excreted in the bile and then into the gut for elimination. The most important conjugation reaction for estrogen elimination is glucuronidation, whereby a glucuronide molecule is attached to estrogen to form an estrogen glucuronide. This relates to

Premenstrual and Menstrual Exacerbation of IBS 115

gut health, in that the most common reason for impaired glucuronidation (and, therefore, reduced estrogen elimination) occurs when abnormal or unhealthy gut florae are present, as they secrete an enzyme called betaglucuronidase. This enzyme cleaves the glucuronide molecule from the estrogen-glucuronide that was sent to the gut through the bile, leaving free estrogen to be reabsorbed systemically via enterohepatic recirculation. Interventions that have been shown to improve glucuronidation include a low-animal-fat diet, and supplementation with probiotics and calcium-D-glucarate (Walaszek et al., 1997). Thus, eliminating constipation and ensuring regular bowel movements in patients with IBS now has a whole new level of importance.

Conclusions In summary, the physiological mechanisms described in this chapter associated with the luteal phase of the menstrual cycle, PMS, and menstruation, explain the observed phenomenon of IBS exacerbation during those periods. The systemic inflammation associated with chronic pelvic pain and other gynecologic disorders explains the observation of increased in IBS in those patients. Lastly, the connection between gut health and estrogen elimination demonstrates the importance that gut health has in estrogen related disorders. Therefore, a truly integrative approach to managing IBS in women, in addition to therapies targeting the gut, addresses all of these additional factors. Helping women with IBS assess and normalize hormone levels, reduce systemic and gastrointestinal inflammation, ensure healthy gut flora, and identify their stressors and resolve their interpersonal conflicts, will not only improve their IBS but will also help decrease the symptoms and incidence of the disorders associated with excess estrogen, allowing women to experience healthier and happier lives. This is the true definition of a holistic approach, and is exactly what brings joy and fulfillment to the busy lives of integrative practitioners.

10 Fibromyalgia and Gastrointestinal Disorders DAVID M. BRADY AND MICHAEL J. SCHNEIDER

key concepts ■

■

■

■

■

■

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

Introduction

F

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

116

Fibromyalgia and Gastrointestinal Disorders 117

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

118 INTEGRATIVE GASTROENTEROLOGY

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

Fibromyalgia and Gastrointestinal Disorders 119

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

120 INTEGRATIVE GASTROENTEROLOGY

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

Fibromyalgia and Small Intestinal Bacterial Overgrowth Patients with FMS frequently have nonspecific bowel complaints similar to those with small intestinal bacterial overgrowth (SIBO; see Wallace & Hallegua, 2004). SIBO is a condition in which colonic aerobic and anaerobic bacteria are overrepresented in the small intestine. There is a growing body of evidence suggesting that SIBO may play a significant role in a wide range of gastrointestinal disorders, including Crohn’s disease and IBS (Funayama, Sasaki, Naito et al., 1999; Pimentel., Park, Mirocha, Kane, & Kong, 2006; Pimentel, Chow, & Lin, 2003; Sharara, Aoun, Abdul-Baki et al., 2006). Recent studies indicate that up to 84% of patients with IBS have an abnormal lactulose breath test result, suggesting small bowel bacterial overgrowth. (Pimentel et al., 2006)

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

Fibromyalgia and Gastrointestinal Disorders 121

Rome I criteria for IBS. Of 25 subjects who returned for follow-up LHBT, 11 achieved complete eradication and 14 achieved incomplete eradication of their SIBO with antibiotic therapy. Improvement in GI symptoms, including bloating, gas, diarrhea, constipation, and abdominal pain, as well as general symptoms of pain, fatigue, and sleeplessness, were also reported via follow-up patient questionnaires. Better clinical results were clearly observed with complete eradication. Antibiotics, such as neomycin, seem to improve symptoms in many subjects, but effectively eliminate SIBO in only about 25% of patients, and side effects limit their use (Pimentel et al., 2006). Rifaximin is a gutselective antibiotic with negligible systemic absorption (<0.4%), minimal side effects [similar to placebo], and broad-spectrum activity in vitro against Grampositive and Gram-negative aerobes and anaerobes. It results in effective eradication of SIBO in up to 70% of cases (Jiang & DuPont, 2005; Di Stefano, Malservisi, Veneto, Ferrieri, & Corazza, 2000). Rifaximin also has known activity against Clostridium difficile (Marchese, Salerno, Pesce, Debbia, & Schito, 2000). Traditionally, small bowel aspirate (>105 cfu/ml) has been accepted as the gold standard for SIBO diagnosis. However, breath testing and urinary markers, including cholyl-PABA and indican, have frequently been used due to their convenience and noninvasive nature. However, a systematic review by Khoshini et al. (2008) concluded that there is no well-validated test or gold standard for the diagnosis of SIBO. A better method for accurately identifying SIBO is needed, and quantitative bacterial polymerase chain reaction (PCR) may serve this role for the future. According to Khoshini, the most practical current clinical method may be a test, treat, and outcome technique. Animal models have suggested that SIBO results in bacterial translocation to mesenteric lymph nodes, and can produce systemic effects possibly mediated by Gram-negative endotoxins, which could explain the soft tissue hyperalgesia seen in some subjects labeled, incorrectly or not, with FMS (Berg, Wommack, & Deitch, 1988; Wells, Barton, Jechorek et al., 1991; Guarner, Runyon, Young et al., 1997; Nieuwenhuijs, Verheem, van DuijvenbodeBeumer et al., 1998; Lichtman, Keku, Clark et al., 1990; Lichtman, Sartor, Keku et al., 1990; Riordan, Melvor, & Williams, 1998; Maier, Wiertelak, Martin D et al., 1993; Watkins, Wiertelak, Goehler et al., 1994; Watkins, Wiertelak, Furness et al., 1994; Wiertelak, Smith, Furness et al., 1994; Kanaan, Saade, Haddad et al., 1996; Cahill, Dray, & Coderre, 1998; Walker, Dray, & Perkins, 1996a, 1996b). Lin (2004) concludes that, “The gastrointestinal and immune effects of SIBO provide a possible unifying framework for understanding frequent observations in IBS, including postprandial bloating and distension, altered motility, visceral hypersensitivity, abnormal brain–gut interaction, autonomic dysfunction and immune activation.”

122

INTEGRATIVE GASTROENTEROLOGY

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

11 Acupuncture for Digestive System SANGHOON LEE AND TA-YA LEE

key concepts ■

■

■

■

■

Acupuncture is a modality that can channel energy and blood flow to influence digestive function. Acupuncture has been shown to be beneficial for a number of gastrointestinal motility disorders. Stimulating PC6 point (located on the forearm) has been most frequently applied for nausea and vomiting. Electro-acupuncture may increase the threshold of rectal sensitivity in irritable bowel syndrome patients. Acupuncture has been shown to benefit irritable bowel syndrome and inflammatory bowel disease patients; however, sham-controlled studies have been inconsistent and lack uniformity. ■

Introduction

A

cupuncture (from Lat. acus, “needle,” and pungere, “to prick”) (Mayor, 2006) is a technique of inserting and manipulating fine needles into specific points on the body, with the aim of relieving pain, and for therapeutic purposes. According to traditional Chinese acupuncture theory, these acupuncture points lie on meridians along which qi, the vital energy, flows. There is no generally accepted anatomical or histological basis for these concepts, and modern acupuncturists tend to view them in functional rather than structural terms. Acupuncture originated in China and is most commonly associated with traditional Chinese medicine (TCM). Different types of 123

124 INTEGRATIVE GASTROENTEROLOGY

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

What Is Energy Flow? Energy, or qi, flows up and down the meridians. Sometimes the energy is blocked, deficient, excessive, or unbalanced. This throws Yin and Yang out of balance, which in turn causes illness. Acupuncture restores the balance, thus encouraging healing.

Why Needles? Acupuncture is performed using very fine needles, which are applied to promote healing. Overall, deficiencies are tonified or reinforced, and excesses will be dispersed or reduced. In addition to using needles, acupuncturists may also use heat, pressure, friction, or impulses to stimulate specific acupuncture points. Most practitioners currently use prepackaged, sterilized, one-time use, disposable needles. Electro-acupuncture is another example of a 20th century adaptation, a mix of ancient and modern technology.

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

Abdominal distention/flatulence∗ Acute and chronic pain control∗ Allergic sinusitis∗ Anesthesia for high-risk patients or patients with previous adverse responses to anesthetics Anorexia Anxiety, fright, panic∗ Arthritis/arthrosis∗ Atypical chest pain (negative workup)

Acupuncture for Digestive System 125

• Bursitis, tendinitis, carpal tunnel syndrome∗ • Certain functional gastrointestinal disorders (nausea and vomiting, esophageal spasm, hyperacidity, irritable bowel)∗ • Cervical and lumbar spine syndromes∗ • Constipation, diarrhea∗ • Cough with contraindications for narcotics • Drug detoxification∗ • Dysmenorrhea, pelvic pain∗ • Frozen shoulder∗ • Headache (migraine and tension), vertigo (Ménière’s disease), tinnitus ∗ • Idiopathic palpitations, sinus tachycardia • In fractures, assisting in pain control and edema, and enhancing healing process • Muscle spasms, tremors, tics, contractures∗ • Neuralgias (trigeminal, herpes zoster, post-herpetic pain, other) • Paresthesias∗ • Persistent hiccups∗ • Phantom pain • Plantar fasciitis∗ • Post-traumatic and postoperative ileus∗ • Selected dermatoses (urticaria, pruritus, eczema, psoriasis) • Sequelae of stroke syndrome (aphasia, hemiplegia)∗ • Seventh nerve palsy • Severe hyperthermia • Sleep disorders (Gooneratne, 2008) • Sprains and contusions • Temporomandibular joint (TMJ) syndrome, bruxism∗ • Urinary incontinence, retention (neurogenic, spastic, adverse drug effect)∗ • Weight loss (http://www.nature.com/ijo/journal/v27/n4/pdf/08022 54a.pdf

How Does Acupuncture Work? Currently there is no concrete, identifiable way to prove if acupuncture indeed works, and it is still difficult to standardize the quality and quantity of treatments since acupuncture usually has a patient-centered individualized approach. But, there are several theories that attempt to explain the benefits of treatment.

126

INTEGRATIVE GASTROENTEROLOGY

Table 11.1. The Proposed Mechanism of Action for Acupuncture Theory

Proposed mechanism of action

Augmentation of Immunity Theory

By some unknown process, acupuncture raises levels of triglycerides, specific hormones, prostaglandins, white blood counts, gamma globulins, opsonins, and overall antibody levels.

Endorphin Theory

Acupuncture stimulates the secretions of endorphins in the body (specifically, enkephalins).

Neurotransmitter Theory

Certain neurotransmitter levels (such as serotonin and noradrenaline) are affected by acupuncture.

Circulatory Theory

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

Gate Control Theory

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

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

Common, Minor Adverse Events A survey by Ernst et al. (2003) of some 400 patients receiving more than 3,500 acupuncture treatments found that the most common adverse effects from acupuncture were: • Minor bleeding after removal of the needles, seen in roughly 3% of patients. (Holding a cotton ball for about one minute over the punctured site is usually sufficient to stop the bleeding).

Acupuncture for Digestive System 127

• Hematoma, seen in about 2% of patients, which manifests as bruises. These usually go away after a few days. • Dizziness, seen in about 1% of patients. Some patients have a kind of needle phobia, which can produce dizziness and other symptoms of anxiety. Patients are usually treated lying down, in order to reduce the likelihood of fainting. The survey concluded: “Acupuncture has adverse effects, like any therapeutic approach. If it is used according to established safety rules and carefully at appropriate anatomic regions, it is a safe treatment method.”

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

Risks from Omitting Conventional Medical Care Receiving any form of alternative medical care without also receiving conventional biomedical care can be often risky, since an undiagnosed disease may go untreated and worsen. For this reason, interdisciplinary collaboration is strongly recommended.

Historical/Theoretical Basis Acupuncture as part of TCM dates back more than 2,000 years. It originates from China, but was influenced by surrounding Asian countries like Korea

128

INTEGRATIVE GASTROENTEROLOGY

and Japan. One of the earliest texts is the Yellow Emperor’s Classic of Internal Medicine, which laid out the essential theoretical foundation of TCM and acupuncture as we know it today. The text describes the fundamental theories of TCM, including Yin/Yang, the Five Elements, Meridians, Qi, Spirit, Blood, etiology of disease, pathologies, and diagnostic methods, as well as a basic knowledge concerning acupuncture points and needling techniques. The understanding of exactly how this knowledge base had come about from ancient times is still one of the underlying mysteries surrounding the development of TCM.

Technique Classical acupuncture is used to stimulate specific points in the body with very fine needles (normally 0.16 mm to 0.30 mm diameter). Many types of modified applications are available, such as acupressure, electro-acupuncture, stud, laser, magnet, etc. Traditionally, acupuncture has been applied to various gastrointestinal disorders, from short-term acute symptoms (e.g., abdominal discomfort, indigestion) to chronic disorders such as inflammatory bowel disease. In addition, many clinical trials and basic studies have been performed to verify the effectiveness of acupuncture and to investigate its mechanisms. Table 11.2. Acupuncture Effects on Gastrointestinal Function or Disorders Clinical benefits

Nausea and vomiting

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

Gastric secretion

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

Gastric motility

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

Irritable bowel syndrome

• Inconclusive. Quality of life and symptoms were improved after acupuncture compared to baseline, but no group difference with placebo or sham. (Forbes, Jackson et al., 2005; Schneider, Enck et al., 2006)

Inflammatory bowel • Acupuncture improved disease activity compared to sham; disease improved quality of life compared to baseline. (Joos, Brinkhaus et al., 2004; Joos, Wildau et al., 2006)

Acupuncture for Digestive System 129

Table 11.3. Possible Acupuncture Mechanism for Gastroenterology

Nausea and vomiting

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

Gastric secretion

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

Abdominal pain

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

Gastric and duodenal motility

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

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

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

130

INTEGRATIVE GASTROENTEROLOGY

Table 11.4. Contraindications and Precautions to Acupuncture Treatment Contraindications

Bleeding

• • • •

Platelet < 50,000/mm3 Abnormal PT, PTT Anticoagulant therapy Hemophilia

Infection

• ANC < 500 mm (Menten K, 2008) • No needles in skin lesions • Other severely immunosuppressed condition

Cardiac disorder (especially for electro-acupuncture)

• Pacemaker • Other implantable electrical device

CNS disorder

• Seizure

Allergy

• Metal allergy

Precautions

• • • • • • •

Pregnancy Unstable vital signs Unstable diabetes Sensory disorder Needle phobia Severe fatigue Severe hunger

(modified from Menten K. et al., 2008)

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

12 Ayurveda and Digestive Health DAVID SIMON AND VALENCIA PORTER

key concepts ■

■

■

■

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

General Ayurvedic Principles

A

yurveda is an ancient traditional medical system from India that emphasizes health as a balance of body, mind, and spirit. This balance can be achieved through healthy lifestyle in accordance with nature and one’s own body-mind constitution. The preventive practices of proper nutrition and exercise, nourishing relationships, good emotional health, and a regular daily routine contribute to the maintenance of health, which, according to Ayurveda, is not simply the absence of disease. Digestive health is a key principle in Ayurvedic practice. Acknowledging the multitude of functions of the digestive tract—extracting nourishment, 131

132

INTEGRATIVE GASTROENTEROLOGY

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

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

Ayurveda and Digestive Health 133

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

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

Use of Ayurvedic Herbs According to Ayurveda, three essential elements make up a healthy digestive system: digestion, assimilation, and elimination. The mind–body practices

134

INTEGRATIVE GASTROENTEROLOGY

described help to maintain all of the processes, and particular herbs may also be used to aid each of these processes.

AYURVEDIC HERBS FOR ENHANCING APPETITE AND DIGESTION

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

AYURVEDIC HERBS FOR QUIETING EXCESSIVE DIGESTIVE FIRE

Hyperacidity, heartburn, gastroesophageal reflux, and peptic ulcers are expressions of an inefficient digestive fire that is imbalanced in both location and quantity. Cooling herbs that pacify the excessive heat, and encourage a cleaner digestive fire, can help reduce heartburn and improve digestion. These include cumin, coriander, fennel, and licorice, as well as amalaki and shatavari. They are generally taken after a meal, or when the symptoms of acid indigestion are prominent. Shatavari (Asparagus racemosus), also known as Indian asparagus, is one of the prime rejuvenating herbs in Ayurveda. While particularly helpful in supporting the female reproductive system, it is also effective in relieving inflammatory conditions and in soothing irritated tissues, and has a traditional role as a digestive aid. This herb cools off an irritated digestive system that manifests as heartburn, diarrhea, or irritable bowel syndrome. In men with a history

Ayurveda and Digestive Health 135

of heartburn and indigestion after meals, shatavari was found to be as effective as metoclopramide (Dalvi, Nadkarni, & Gupta, 1990). Shatavari also has an established history as an antidiarrheal agent, although not formally studied for this purpose. In studies, shatavari has been demonstrated to have immunemodulating properties (Rege & Dahanukar, 1993; Dhuley, 1997; Thatte & Dahanukar, 1988; Rege et al., 1989). To treat digestive distress, one teaspoon in one-half cup of warm milk is taken after each meal. It mixes well with equal parts of amalaki and licorice for symptoms of heartburn or indigestion. Amalaki (Emblica officinalis), also known as Indian gooseberry, is considered the best herbal medicine for rejuvenation in Ayurveda. It is one of the richest natural sources of antioxidant vitamins, possessing almost 20 times as much vitamin C as orange juice. Used alone or in combination with many other herbs, it has wide traditional uses, including the treatment of skin diseases, lung conditions, diabetes, and indigestion. Amalaki is one of the three ingredients in triphala, the most important Ayurvedic bowel tonic. Mostly studied in the areas of cancer inhibition, lowering cholesterol, and decreasing platelet aggregation, amalaki has also traditionally been used in the treatment of heartburn, and a few scientific studies have supported this use (Chawla et al., 1982). In a clinical trial on a series of 27 patients with duodenal ulcer, and 12 with nonulcerative dyspepsia, a significant decrease in acid and pepsin secretion, with marked symptomatic relief, was found after 3 months of using amalaki (Varma et al., 1977). A recent study has shown that it has a role in mucin protection and regeneration, in the healing of ulceration related to nonsteroidal anti-inflammatory drug use (Bhattacharya et al., 2007). It also has a reputation for the treatment of liver and pancreatic conditions, and in an animal study was shown to reduce the extent of tissue damage caused by experimental pancreatitis (Thorat et al., 1995). Amalaki can be taken as the traditional rejuvenative jam, Chavan Prash, one teaspoon twice daily, either straight or mixed in juice or warm milk. Amalaki in triphala can help those with chronic constipation, as well as those with irritable bowel syndrome. Mixed with shatavari, fennel, and turmeric, it can be effective in reducing hyperacidity. To improve colon function, 1 to 2 grams daily in divided doses is recommended. Owing to its laxative qualities, amalaki should be used carefully in people with a tendency toward loose bowels. Licorice (Glycyrrhiza glabra) is another herb that has been used among many cultures, with a number of therapeutic effects. Used cautiously and with respect, licorice is a valuable healing plant, but at excessive levels it can cause potentially dangerous side effects. One of its traditional uses has been in the treatment of peptic ulcers, and animal studies have shown that licorice stimulates the production of protective mucus in the stomach lining (Nadar & Pillai, 1989). Most complications occur in people taking excessive doses of

136 INTEGRATIVE GASTROENTEROLOGY

licorice with the component glycyrrhizic acid, which causes retention of sodium and elevated blood pressure. It is advised not to take more than 100 mg of glycyrrhizic acid per day, which would be approximately 2.5 grams of dried licorice root. In addition, the German Commission E recommends limiting use to no longer than 6 weeks at a time. It is possible to obtain and use DGL (deglycyrrhizinated licorice), which contains less than 3% glycyrrhizic acid and is considered quite safe. For hyperacidity, take licorice 30 minutes before a meal or 1 hour after the meal.

AYURVEDIC HERBS FOR ENHANCING ABSORPTION

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

AYURVEDIC HERBS FOR ENCOURAGING ELIMINATION

A fiber-rich diet that includes plenty of fresh fruits, vegetables, and whole grains is the most important contributor to daily elimination. When necessary, adding fiber in the form of psyllium or flaxseed can invigorate sluggish bowels. A classic Ayurvedic formula called triphala consists of three fruits—amalaki, bibhitaki (Terminalia belerica) and haritaki (Terminalia chebula). Like psyllium, the fiber in triphala can help enhance elimination in people whose bowels are slow, and normalize bowel movements in people who tend toward loose stools. Amalaki is discussed above. Bibhitaki has a strong purgative action, and is also an excellent rejuvenative. Recent studies have also shown antiviral and lipid-lowering effects (Shaila et al., 1995; Xu et al., 1998). Haritaki is called “king of medicines” in Tibet, and recent studies have shown its promise as an antioxidant, anti-diabetic, antimicrobial, and anti-cholesterol agent (Lee et al., 2005; Gao et al., 2008; Murali et al., 2007). One animal study showed

Ayurveda and Digestive Health 137

that haritaki was comparable to metoclopramide in increasing gastric emptying (Tamhane et al., 1998). When taken in larger doses at night, triphala can be helpful in relieving constipation. Triphala can also be used as a daily rejuvenative formula, and prolonged use is safe and non-habit forming. Herbal stimulant cathartics should only be used rarely. Castor oil, cascara sagrada, senna, and aloe are the most common plant-based laxatives that act by stimulating the nerve fibers to the colon, and by causing the accumulation of salts and water in the intestines. These laxatives can cause abdominal cramping, with cascara the mildest and castor the strongest. The main problem with repeated use of these herbal stimulants is that one can become dependent on their use to stimulate bowel movements. Using these tools, to restore our digestive power to its natural state of health, supplies us with our energy and physical needs. Listening to our body–to our

Table 12.1. Ayurvedic Herbs Ayurvedic Herbs for Enhancing Digestion Ginger

Dandelion

Black pepper

Orange peel

Cayenne

Aloe vera

Wild celery seeds

Chamomile

Long pepper

Gentian

Ayurvedic Herbs for Reducing Excess Acidity Amalaki

Cumin

Shatavari

Coriander

Licorice

Fennel

Ayurvedic Herbs for Reducing Gas and Bloating Nutmeg

Basil

Wild celery seeds

Chamomile

Oregano

Long pepper

Peppermint

Thyme

Asafetida (Hing)

Lemon verbena

Coriander

Cinnamon

Cumin

Cardamom

Dill

Bay

Fennel (Continued)

138 INTEGRATIVE GASTROENTEROLOGY

Table 12.1. (Continued) Ayurvedic Herbs for Enhancing Elimination Triphala (Amalaki, Bibhitaki, Haritaki) Stimulant Cathartics: • Castor oil • Cascara sagrada • Senna Aloe (latex portion)

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

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

Ayurveda and Digestive Health 139

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

Ama-Pacifying Program 1. Follow the Body Intelligence Techniques. 2. Eliminate/reduce foods that increase ama—fried foods, heavy and oily foods, aged cheeses, meats, rich foods, and anything that is difficult to digest. 3. Stimulate your digestion with ginger tea. 4. Eat warm, freshly cooked whole foods that are light and easy to digest, such as rice, soups, lentils, freshly steamed or lightly sautéed vegetables. Table 12.2. Dietary Recommendations for your Mind-Body Constitution (adapted from Chopra, 2000) Mind–Body type

Favor

Reduce/Avoid

Vata

Warm food, moderately heavy textures Added butter and fat Salt, sour and sweet tastes Sweet fruits Soothing and satisfying foods Dairy

Cold salads, raw vegetables and greens Iced drinks Dry, salty snacks (nuts are fine in small amounts) Dried fruits Beans (except chickpeas, mung beans, pink lentils, tofu) Astringent and bitter tastes

Pitta

Cool or warm, but not steaminghot foods Moderately heavy textures Bitter, sweet and astringent tastes such as salads and legumes Less butter and added fat Milk, grains, vegetables Sweet, ripe fruits

Excessive salt, sour or spicy tastes (pickles, yogurt, sour cream, cheese, processed and fast foods) Red meat and seafood Fried foods Sour or unripe fruits Nuts and seeds (except coconut, pumpkin seeds, sunflower seeds) (Continued)

140

INTEGRATIVE GASTROENTEROLOGY

Table 12.2. (Continued) Mind–Body type

Favor

Reduce/Avoid

Kapha

Warm, light food Dry food, cooked without much water Raw fruits, vegetables, salads, legumes Pungent, bitter and astringent tastes Stimulating foods

Sweet, rich and salty foods Cold foods Dairy products (especially butter, ice cream, cheese) Oil (small amounts of corn, almond and sunflower oils Red meat and seafood Sweet and juicy vegetables and fruits

13 Osteopathic Medicine DIANE CLAWSON

key concepts ■

■

■

■

■

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

141

Introduction to Osteopathic Medicine

O

steopathic Medicine was founded in 1874 by Andrew Taylor Still, MD. In the 1800s, physicians were trained primarily through apprenticeships, and Dr. Still was no exception. The training was frequently inadequate, and the treatments of the day included bloodletting, mercury, alcohol, morphine, laxatives, and purgatives. Still watched his brother become addicted to morphine through medical treatment, and he lost three of his children to meningitis, unable to help them with the medical practices of the time. He became increasingly dissatisfied with allopathic medicine, and began to develop a method of treatment that would bring health without the often disastrous effects of the then-current practices. Still identified the musculoskeletal system as a key element of health, recognizing the importance of unobstructed circulation and innervation in maintaining health. He believed that the body has its own “pharmacy” and an innate capacity for self-healing. He stressed prevention, healthy eating, and exercise as necessary components of health. Osteopathic Medicine is based on a philosophy, of which there are four basic tenets. These are: 1. 2. 3. 4.

The body functions as a whole—mind, body, and spirit. The body is self-regulating and self-healing. Structure and function are interrelated. Rational treatment is based on the above principles.

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

Today, DOs have the same practice rights as MDs, and both are seen working together in the same hospitals, the same clinics, and the same branches of the military. This, however, was not always the case. It has been a long and arduous process to achieve equal practice rights. The American School of Osteopathy in Kirksville, Missouri, was the first school to open in 1892. In 1910, the Flexner report was published and harshly condemned both osteopathic

Osteopathic Medicine 143

and allopathic medical schools.1 As a result, all of the osteopathic schools and 122 of the MD schools were closed. During World War I, the first efforts to obtain federal recognition were undertaken so that DOs could become commissioned as military officers. Instead, the DOs were required to serve as regular soldiers, despite their medical training. In 1941, the Military Appropriations Act was passed, which allowed for recognition of DOs in the military. However, during World War II, DOs were deferred rather than drafted. The DOs were left to care for the thousands of patients left by the MDs serving in the war. This ultimately proved to be a positive development for the DOs, by enhancing the public’s view of them as full-service physicians. Finally, in 1966, DOs were accepted as physicians and surgeons in the military. The darkest days of osteopathy occurred in 1962, when there was an effort to abolish the DO licenses in California. There was a merger between the California Osteopathic Association and the California Medical Association. DOs were able to obtain an MD degree for a small fee. The degree was not recognized outside of California, but 85% of the DOs became MDs during this time. The proposed referendum was passed, and the licensing of DOs in California was discontinued. In 1974, the referendum was overturned and DOs could once again become licensed in California.

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

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

1

The Flexner Report is a book-length study of medical education in the United States and Canada, written by the professional educator, Abraham Flexner, and published in 1910 under the aegis of the Carnegie Foundation. Many aspects of the present-day American medical profession stem from the Flexner Report and its aftermath. The report (also called Carnegie Foundation Bulletin Number Four) called on American medical schools to enact higher admission and graduation standards, and to adhere strictly to the protocols of mainstream science in their teaching and research. Many American medical schools fell short of the standard advocated in the report and, subsequent to its publication, nearly half of such schools merged or were closed outright.

144 INTEGRATIVE GASTROENTEROLOGY

of the other, more traditional, forms of diagnosis and treatment, to provide comprehensive medical care to their patients.

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

Application of Osteopathic Concepts to Digestive Issues At the core of osteopathic treatment for digestive issues is a comprehensive knowledge and understanding of the segmental and autonomic innervation of the gastrointestinal tract itself. There is a reflex arc between the viscera (internal organs of the body, especially of the abdomen and thorax) and the segmentally related musculoskeletal region. (Table 13.1) When there is pathology or dysfunction, the viscera and soma become linked in a cycle of afferent and efferent impulses, which can sustain and even exacerbate the problem. With increased and prolonged visceral input, the spinal cord region becomes facilitated. As a result, there are palpatory tissue changes, joint somatic dysfunction, and tenderness to palpation in the corresponding segments on exam (Figure 13.1). The osteopathic term for this is viscerosomatic reflex. These reflexes are also responsible for what are known as “Chapman’s Reflexes.” They are defined as “a system of reflex points that present as predictable anterior and posterior fascial tissue texture abnormalities assumed to be reflections of visceral dysfunction or pathology.” (Figure 13.2.)

Table 13.1. Segmental Arrangement of the Sympathetic Chain T6

Esophagus

T6-T9

Lower Esophagus and Stomach

T6-T9 (right)

Liver and Gallbladder

T6-T9 (left)

Spleen and Pancreas

T7-T9

Small Intestine

T10-L1 (right)

Ascending and Transverse Colon

T12-L2 (left)

Descending Colon and Rectum

(Adapted from DiGiovana, 1997)

Osteopathic Medicine 145

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

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

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

14 Gastroenterology and an Integrative Chiropractic Approach LOREN MARKS AND DAVID M. DURKIN

key concepts ■ ■

■

■

■

■

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

146

A Brief History of Chiropractic

D

r. D.D. Palmer1 Dr. Daniel David (D.D.) Palmer, a Canadian-born teacher and healer, founded chiropractic in 1895. A man with a unique perspective, he was very inquisitive and determined to understand health and promote wellness by trying to work with the body’s innate life force. Dr. Palmer, having studied anatomy and physiology in his search to become a healer, had developed a very in-depth knowledge of these topics by the late 1800s and, as a result, had been using magnets to try to influence his patients’ life force. Harvey Lillard2 One day, a janitor in Dr. Palmer’s office building named Harvey Lillard, who had lost his hearing some seventeen years earlier, following feeling a “pop” in his back while in a stooped position, was working near Palmer’s office when D.D. asked the man if he could evaluate his condition. Dr. Palmer (1910) later recounted this story in The Chiropractor’s Adjuster. Palmer noticed a protrusion in the janitor’s back and asked him to lie down on a bench, at which time Dr. Palmer applied a gentle manual force to his spine, which subsequently restored his hearing following several such treatments. With this vantage point, Palmer continued studying the relationship of each spinal segment and its corresponding organ, as well as evaluating the overall health of the local townspeople and trying to relate their overall health to their spinal function. This type of study became his passion, and ultimately was the start of our present-day chiropractic profession. Dr. B.J Palmer1 D.D.’s son, B.J. Palmer, is attributed with developing the art, science, and philosophy of chiropractic. B.J. raised the standards of the chiropractic educational system, to its present doctoral level. He understood, as did physicians practicing medicine, that without knowledge of such things as microbial invasion and a continued growth in the sciences, health care would be limited. However, it has been only a decade or so that chiropractors and medical physicians have been communicating at a higher level, to help ensure an integrative

1 Pictures of D.D. Palmer and B.J. Palmer originally appeared in The Subluxation Specific ∼ The Adjustment Specific, Davenport: Palmer College of Chiropractic, 1934; Reprinted 1995. (p.2). Available at: http://www.cafeoflifepikespeak.com/tribute_DD.htm, and http://www.cafeoflife pikespeak.com/tribute_BJ.htm 2 Picture of Harvey Lillard from Chiropractic History, WikipediaOnline Encyclopedia 2008, http://en.wikipedia.org/wiki/Chiropractic_history.

148

INTEGRATIVE GASTROENTEROLOGY

healthcare model for the future. Today’s chiropractic physicians are more dedicated than ever to learning from and educating other healthcare providers, and to promoting integration of all healthcare modalities to help ensure a truly integrative medical model. An interesting point for practitioners to focus on is that all healthcare practitioners work in their chosen field for the love of their specialty, and for the benefits of contributing to the health and/or wellness of their patients. If we understand this, then it is easy to overlook some small philosophical differences, as long as the patient’s best interest is kept in focus when delivering care.

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

The Vertebral Subluxation Complex Vertebral Subluxation Complex (VSC) is a theoretical model of motion segmental dysfunction (subluxation) that incorporates the complex interaction of pathologic changes in nerve, muscle, ligamentous, vascular and connective tissues (Gatterman, 1995). These aberrations of the nervous system can result in: • Loss of sensory information:  Causing inappropriate nerve responses; and • Altered states of function in other areas of the nervous system:  Causing changes in body functions (Hughes & Rousso, 2004).

Gastroenterology and an Integrative Chiropractic Approach 149

These changes are explained with several chiropractic models, two of which will be our focus here to help us understand the link between musculoskeletal changes and an overall improvement in the global health of a patient. • Mechanical or Mechanistic  Abnormal changes in weight bearing, movement, or the spinal curves (alignment or structure). • Neurological or Vitalistic  Interference in the normal physiological function of the nervous system, affecting every tissue, organ and system in the body. Chiropractic physicians are trained to locate and treat these mal-positioned vertebrae or subluxations. Patients enter chiropractic offices daily wanting to know how this type of physical medicine can help treat, correct, and heal the host of symptoms that are talked about in chiropractic testimonies and in alternative literature. Such patients need to understand that chiropractic physicians are trained to diagnose illness, much like family physicians, but there is a difference: Chiropractic physicians primarily treat subluxations. Subluxations cause altered nerve function inducing a nerve impingement syndrome, which causes a mechanistic (alignment and structure) and a vitalistic change (altered normal function) to the exiting nerves of the spinal cord. This causes a potential alteration to all the areas that that specific nerve travels (organs, tissues, and cells) throughout the entire body. Restoring normal motion of a spinal segment can eliminate nerve impingement syndrome and restore proper function, which helps lead to a restoration of health and wellness.

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

150

INTEGRATIVE GASTROENTEROLOGY

Instruments such as the ProAdjusterTM from Sigma Instruments and ProSolutions and the Insight Subluxation StationTM from the Chiropractic Leadership Alliance have given the chiropractic profession an increased level of certainty, improving the objective data to help locate and define the degree, as well as the location of vertebral segmental dysfunction or subluxation. This, coupled with the traditional art and science of chiropractic, yields the practicing chiropractor a pool of information from which to draw upon to help reestablish the normal balance (homeostasis) of the nervous system and thus the body as a whole. If structural changes are not corrected, spinal or joint degeneration will begin and symptoms may develop and/or progress. Loss of structural integrity can cause a progression toward illness, and can even cause disease (i.e., degenerative disc disease, neuritis, neuropathy, gastritis, gastro-paresis, allergies, fatigue, sleep, various sinus conditions, colds and flu (neuro-immunology) due to the resulting nerve impingement. Structural changes are easier to identify and understand for the average patient, and for that reason is usually the focus of education in a chiropractic office. These structural changes can eventually lead to the neurological changes described in the more complicated vitalistic model of chiropractic. All types of physicians must keep in mind that a subluxation cannot be diagnosed by decreased spinal motion (hypomobility) alone, but must possess a neurological finding such as pain, weakness, and/or sensory changes. However, such changes may be difficult to detect without advanced testing like magnetic resonance imaging (MRI), electromyography (EMG) or nerve conduction velocity (NCV) tests. This is the reason many chiropractic physicians are now using more advanced instrumentation as discussed above, (ProAdjuster and Subluxation Station) to confirm their working diagnoses of subluxation. Spinal hypomobility alone would be considered only a spinal fixation, which is a precursor to subluxation but not synonymous with it. Both conditions can be treated in chiropractic offices, but the latter is more serious and includes mechanistic and vitalistic alterations. This is a common error seen when evaluating physician reports and literature on the topic of segmental dysfunction. An evolution of chiropractic has continued over the years and today’s chiropractic practices are now more geared toward total wellness than at any other time in the history of the profession. Due to the level of education available, the chiropractic educational standards, and the in-depth training of today’s chiropractors, the chiropractic profession is moving toward being trusted advisors to their patients, as opposed to treating only musculoskeletal conditions—a “wellness advisor,” if you will, that can assist patients with health issues including diet, sleep, nutritional supplementation, weight loss and stress management which support healthy lifestyle behaviors. Today’s chiropractors

Gastroenterology and an Integrative Chiropractic Approach 151

develop relationships with many medical physicians in allied fields such as orthopedic surgeons, physiatrists, neurologists and radiologists. Chiropractor’s who practice via a more holistic or wellness based model, develop relationships with all types of physicians and routinely refer to these doctors to support the overall wellness of there patients. More education and a greater focus are needed in our society on the benefits of preventative medicine and wellness care. This is a responsibility that must be embraced by all entry-level practitioners (traditional and alternative), if we are to establish a healthier society. Embracing such standards would help decrease chronic illness and human suffering. Promoting “wellness care” would decrease the practice of treating so much disease at such a huge expense to our society. Such education would allow us to help our patients understand the consequences of their lifestyle choices, reducing illness and promoting health. Wellness is a product of normal physiology and disease is a product of altered physiology. Often, delayed intervention promotes disease (longstanding altered physiology), which mandates costly allopathic intervention. If we reestablish a healthier physiological state early on, a disease that may have occurred may be prevented prior to its development, and those that do occur gain the advantage of improved and less invasive allopathic treatment. It is the opinion of the authors that the health of our society can best be obtained by all practitioners working together for the benefit of patients.

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

152

INTEGRATIVE GASTROENTEROLOGY

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

Gastroenterology and an Integrative Chiropractic Approach 153

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

Integrative Assessment Technique (IAT) – Contributing to Integration The Integrative Assessment Technique (IAT) was created by Dr. Loren Marks to establish an assessment methodology for the chiropractic profession, as well as other practitioners who wish to have a more comprehensive alternative approach bridging the three worlds of structure, emotions, and biochemistry. This muscle response technique utilizes reflexes located on the surface of the body that can be challenged by a doctor skilled in the art of this application, to read these responses and derive not only a cross-referenced capacity with known diagnostics, but also an ability to assess rapid integration of one body system over another in an attempt to derive causation. This technique is not intended to replace any known standards, but to enhance the role that integrative care can provide, while offering natural solutions where applicable. Such muscle testing has been extensively tested and validated by David Hawkins, MD, PhD, following his observation of George J. Goodheart, Jr, DC, who was

154 INTEGRATIVE GASTROENTEROLOGY

utilizing such testing in his work in the 1960s. Dr. Hawkins has written several books explaining his research, the most notable being Power Vs. Force (Hawkins, 1995). Gastroenterology is a perfect example of the benefits of an integrated mechanism. Let’s take a patient with chronic GI complaints of gas, bloating and bowel irregularities. The IAT model would begin with a thorough consultation, history, and review of any applicable studies that might have been previously performed, assuming the patient has seen either a primary care physician or gastroenterologist and continues to have unresolved complaints despite standard therapeutic intervention. The IAT model challenges the broad categories of structure, emotions, and biochemistry to identify which system is the primarily, secondary, and tertiary driver involved in contributing to disease. This prioritization is the key in identifying and allowing intervention from an etiologic perspective/paradigm. No one questions the resultant effect that patients present with, especially on an acute basis, but an example might be if mental and emotional perpetuators are the driving force of gut disturbances in a given case, and management from this vantage point will bring the patient to a quicker resolve, and if this was known with reasonable certainty before a trial of many other therapeutics, then we could accomplish improved outcomes and lower healthcare costs. Alternatively, a patient may present with a biochemical priority. Navigation through the reflexes helps to assess organ involvement, followed by various GI metabolic functions such as HCL output, biliary involvement, gut Ph, microbial overgrowth, or the presence of heavy metals, etc., as a functional medicine doctor might proceed. Here, the model allows for a unique process of reasoning, followed by diagnostic tests to confirm or rule out their presence. Chiropractic assessment of segmental dysfunction is an integral part of this process to determine if there are spinal aberrations that are either “caused by or the result of ” the metabolic imbalance in the gut (viscerosomatic response). What is so interesting is that these seemingly two worlds—a bioenergetic muscle response-testing model, and the biochemical realm of blood, urine and other diagnostic testing to validate and cross-reference its findings— have met. Without a doubt, nothing can replace the quantification of some known standards such as lipid analysis, WBC, and RBC levels. It is the rapid determination and level of integration that the IAT model purports. It seems incomprehensible in our modern scientific state that a doctor can learn the standards of IAT muscle response testing from the mapped reflexes on the surface of the skin, and accurately assess from such parameters whether a viral, bacterial, fungal, or parasitic infestation exists. Indeed, this level of accuracy is possible when one masters the fundamentals of IAT combined with one’s knowledge of biochemistry, anatomy and the

Gastroenterology and an Integrative Chiropractic Approach 155

physiologic pathways being reviewed. The application of this model is well suited to the gastrointestinal system, providing numerous avenues of proper identification, from the segmental dysfunctions that arise from viscerosomatic reactions to various states of microbial dysbiosis, inflammatory cascades, enzymatic insufficiencies and bowel toxicities that present to clinicians daily. The future belongs to those willing to lay new track, and not merely adhering to the continuance of the status quo. Integration between the various medical practitioners will ultimately be needed to accomplish this feat and reach new frontiers. A reality that is already becoming more common in today’s atmosphere, with such books and literature as this. The future of integration is bright.

15 Energy Medicine and Gastrointestinal Disorders ANN MARIE CHIASSON

key concepts ■

■

■

■

■

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

Definition and Prevalence of Energy Medicine

E

nergy Medicine is a newer term coined to refer to healing modalities that work with the underlying energy or vital force of the body: “In addition to a system of physical and chemical processes, the human being is made up of a complex system of energy” (Hurwitz, 2001). This energy system, called the energy body, biofield or subtle body, is housed within the physical body, and is considered fundamental to the functioning of the 156

Energy Medicine and Gastrointestinal Disorders

157

physical body. Energy medicine refers to any modality that affects the underlying energy or vital force of the body. The National Center for Complementary and Alternative Medicine (NCCAM) provides a comprehensive definition of energy medicine and the scope of modalities included in this paradigm. The concept that human beings are infused with a subtle form of energy has been around for 2,000 years, and has many names, “such as Qi in traditional Chinese medicine (TCM), ki in the Japanese Kampo system, doshas in Ayurvedic medicine, and elsewhere as prana, etheric energy, fohat, orgone, odic force, mana, and homeopathic resonance” (NCCAM, 2003). How the energy body and the physical body interact is described differently depending on the tradition. Energy medicine may be a resurgence of “vitalism,” or the belief that an underlying vital force exists in the body and is central to health. This concept predates Hippocrates, who espoused that the vital force was dependent on balance of the four humors. More recently, Mesmer also promoted this concept and called it magnetism. When medicine shifted to organ-based systems, with the rise of the Paris Clinics in the early 1800s, the importance of the body’s vital energy lost its importance in modern medicine. The resurgence of energy medicine is actually an integration of prior views of health and healing, with conventional medicine, and may end up augmenting our current views of health and how we treat illness.

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

158

INTEGRATIVE GASTROENTEROLOGY

The belief in an underlying vital force or subtle body is present in cultures worldwide. Ninety-four cultures have a documented concept that describes the underlying energy of the body; it is alternately characterized as spiritual healing, EM, and includes aspects of TCM, mind–body medicine, and even manual medicine therapies. Some nurses use EM, both in their usual work and as a separate modality; Healing Touch was developed by a nurse, specifically for nurses, as adjunct therapy for hospital patients. The definition of the scope of EM is up for debate. Since many EM practitioners postulate that everything is energy, one can place much of CAM within the EM paradigm. Table 15.1 gives a brief overview of some popular energy Table 15.1. Common Energy Medicine Techniques (adapted from Baggot, 1999) Technique

Theory underlying the paradigm

Acupuncture

Inserts needles or pressure to stimulate energy flow at meridian points on the body

Healing Touch

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

Homeopathy

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

Joh Rei

Detoxifies the energy body by sending universal energy to the patient from the healers hands across a short distance

Polarity Therapy

A touch therapy that balances positive and negative energy flows in the body

Qi Gong

Uses movement and laying on of hands to cultivate balanced energy flow throughout the body

Reiki

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

Sound Therapy

Uses vibration through sound to affect the energy body

Tai Chi

A series of movements and postures to stimulate and increase energy flow and restore balance

Therapeutic Touch

Transfers energy by placing the hands into the patient’s electromagnetic field around the body

Yoga

Philosophy, poses and breathing techniques to promote energy flow and balanced energy

Zero Balancing

A gentle touch and movement therapy that balances energy at the zero-point field of the body

Energy Medicine and Gastrointestinal Disorders

159

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

Anatomy, Development of Illness, and Healing The anatomy of the underlying energy field varies according to the tradition. One Qi Gong system (there are multiple of forms of Qi Gong) describes one basic energy center; the Hindu tradition introduced the chakra system, with its 7 energy centers; and TCM describes energy flows called meridians. Conceptually, the relationship between these anatomies can be seen as layers. The deepest layer is the primary energy center, the next layer houses the 7 chakras and, finally, at the interface with the organs, is the meridian system. A simple map of these layers is presented in Figure 15.1. Different EM techniques work at different layers of the biofield. For example, healing touch works at the chakra layer, while TCM works at the most superficial layer. Healers tend to perceive the energy field of the system they have been trained in, although some are able to perceive and work in multiple systems and layers. In the natural history of a disease, the energy body is postulated to be out of balance first; then pathology develops, and finally symptoms appear. Major cellular pathology develops months to years after a block in the natural flow of energy, although pain, which is also considered blocked energy, can occur right away. Factors that contribute to or cause a block include genetic or hereditary causes, outside insults, and physical or emotional trauma. Treatment is based

160

INTEGRATIVE GASTROENTEROLOGY

on transferring energy to remove blocks and to restore the body’s normal energy flow. Keeping the energy field clear, and the energy flowing, promotes health and healing (University of Arizona, 2007). Energy medicine therapies shift or change the underlying energy field of the body. The most common technique involves laying the hands on or over the patient’s body. Other techniques employ vibration, light, sound, movement, magnets, or direct current. Movement is extremely important, as it promotes energy flow. The patient can continue to “balance” himself or herself through movement or self-administered EM techniques, thus reducing the frequency of visits with an EM practitioner.

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

Energy Medicine and Gastrointestinal Disorders

161

decreased EMG during a Reiki treatment. Similar findings were demonstrated by Manville (2008) with healing touch; he reported statistically significant decreases in pretreatment versus post-treatment systolic and diastolic blood pressure, heart rate, skin conductance level, EMG, and trait anxiety.

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

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

Evidence for Energy Medicine in Gastrointestinal Disease Published studies report that the prevalence of CAM use ranges from 35% to 52% in inflammatory bowel disease patients, functional bowel disorder

162

INTEGRATIVE GASTROENTEROLOGY

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

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

Energy Medicine and Gastrointestinal Disorders

163

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

Conclusion EM techniques arise from the ancient concept of a primary vital force within the body affecting the health of the physical body. While research is limited, EM appears to be most helpful for increasing relaxation and decreasing pain and anxiety. It may also have a role in increasing sIgA levels. It can facilitate a healing relationship between practitioner and patient, which in itself is therapeutic. Women tend to seek out EM practitioners more than men, and EM may be a useful adjunct for chronic functional and inflammatory gastrointestinal disease.

16 Guided Imagery and Gastroenterology MARTIN L. ROSSMAN

key concepts ■

■

■

■

■

■

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

T

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

164

Guided Imagery and Gastroenterology 165

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

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

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

166

INTEGRATIVE GASTROENTEROLOGY

WHAT IS IMAGERY?

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

Table 16.1. Applications of Guided Imagery Relaxation training and stress reduction Pain relief Management of chronic illness and prevention of acute exacerbations Preparation for surgery and medical procedures Medication compliance and adherence issues Cancer treatment and life-threatening illnesses Terminal illnesses and end-of-life care Fertility, birthing, and delivery Grief therapy Post-traumatic stress disorder Anxiety disorders Depression

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

Guided Imagery and Gastroenterology 167

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

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

How Does Guided Imagery Work? Imagining something, especially with multiple senses, tends to create an inner experience that the brain and body react to as if the actual event were happening. A common example is sexual fantasy, which has profound influences on physiology and behavior. Since the invention of the functional MRI (fMRI), we know that when people imagine visual objects or experiences, they activate the occipital cortex, where visual information is processed. In the same way, imagining music or conversation activates the temporal cortex, and imagining movement activates the premotor cortex. Imagery activates the parts of the cortex that process real events, and sends signals to the limbic and sub-limbic structures that regulate or express emotions and physiologic responses, modulating autonomic response, endocrine response, circulation, digestion, rest and sleep cycles, and sexuality, among other functions.

168

INTEGRATIVE GASTROENTEROLOGY

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

What Are its Applications in Gastroenterology? Since imagery is a way of thinking, it has widespread applications in clinical medicine, ranging from simple relaxation techniques to preparation for procedures and surgery, treatment adherence, reducing convalescent time, changing lifestyle behaviors, and finding meaning in illness. Guided imagery is essentially a way of working with the patient, rather treating particular disease entities. However, it is especially effective in the areas listed below, which are common issues with patients with GI illness: • Relaxation Training and Stress Reduction  Imagery is the easiest way to teach relaxation: Simply invite someone to daydream themselves to a place that is beautiful and safe, where they love to be. Ask them to notice what they imagine seeing, hearing, feeling, what the temperature is like, what time of day it is, and what time of year. Their immersion in the sensory cues will elicit a relaxation response. • Pain Relief  From a safe place of relaxation (see above) invite the person to imagine something soothing, comforting, or healing coming to any areas that are uncomfortable, breathing easily and regularly while doing so. • Adapting To and Managing Chronic Illness  In a relaxed state, invite the patient to allow an image to form that represents the illness. Have him describe it, its qualities and how he feels about it. Ask him to imagine that the image can respond in a way he can understand, and facilitate an imaginary dialogue, ultimately aiming for a way they can better coexist or “help each other.” • Preparation for Surgery and Endoscopic Procedures  Many guided imagery CDs are available that lead people through relaxation and imagery, focusing on the ideal outcomes they desire.

Guided Imagery and Gastroenterology 169

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

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

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

Table 16.2. A Typical Guided Imagery Session 1. Assessment (foresight): a. Ask what symptom, illness, or thoughts the patient would like to explore. b. Ask what the patient wants to get out of the session. c. Ask patient to narrow down the problem to a short phrase or question. d. Formulate a one-sentence summary of goals. e. Obtain patient’s consent. 2. Imagery process (insight): a. Relaxation: (1) Ask how the patient best relaxes. (2) Use the patient’s best method, or teach him/her one. b. Imagine a beautiful, safe place: (Continued)

170

INTEGRATIVE GASTROENTEROLOGY

Table 16.2. (Continued) (1) “Allow yourself to imagine a comfortable and peaceful place. It might be a place that you have been before, or something that’s just coming into your imagination now. If several places come to mind, allow yourself to pick just one to explore now.” (2) Ask the patient to describe the place in regard to sensations (“What do you see, hear, smell, feel and taste? What makes you feel comfortable there?”). (3) Invite the patient to find a comfortable place to settle down. c. Imagery dialogue: (1) Invite the patient to form an image that represents the illness, symptom or issue. (2) Ask the patient to describe the image in detail. (Have him/her describe at least three things, such as appearance, character, and emotions of the image.) (3) Ask the patient to describe the qualities that the image portrays. (4) What feelings does the patient have about the image? (5) Invite the patient to express these feelings to the image and allow it to respond. (6) “Imagine that it can communicate with you in a way you can easily understand.” (7) Facilitate the imaginary conversation as needed, using “content-free” questions and suggestions such as: (a) “Do you have any questions you would like to ask the image?” (b) “How does it respond?” (c) “Ask the image what it wants from you, and let it respond.” (d) “What does it want you to know?” (e) “What does it need from you?” (f) “What does it have in common with you?” (g) “What does it have to offer you?” (h) Ask the image what it can tell you about the problem, so you can better understand. (i) Ask the image what it can tell you about the solution, so you can better understand. (j) Go back to the safe place, and return from the inner place.

Guided Imagery and Gastroenterology 171

Table 16.2. (Continued) d. When the image communicates, you might ask the patient how he/she feels about that or wants to respond, then encourage the patient to respond and let the image respond to that. Your role is to facilitate the dialogue, not provide the answers. e. If the patient appears frightened, ask whether he/she feels safe; if not, have the patient go back to the safe place, or ask what he/she needs to feel safe. 3. Evaluation (hindsight): a. Ask the patient what he/she felt was interesting or significant about the dialogue. b. Ask the patient whether he/she learned anything from or about the image and/or the symptom. c. Ask the patient whether the information changes his/her perspective, or how he/ she wants to respond. d. Ask the patient what he/she would do next with what he/she learned.

Table 16.3. Common Interactive Guided Imagery Suggestions and Questions • • • • • • • •

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

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

Is There Any Risk in Referring a Patient for Guided Imagery? The primary danger in using guided imagery to augment healing in medical situations is when it is used in lieu of appropriate medical diagnosis and/or treatment. We emphasize the necessity of an accurate diagnosis, so that the

172

INTEGRATIVE GASTROENTEROLOGY

Table 16.4. Contraindications to Guided Imagery • • • •

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

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

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

Resources GUIDED IMAGERY SELF-CARE BOOKS AND TAPES

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

Guided Imagery and Gastroenterology 173

PROFESSIONAL TRAINING AND REFERRALS

Academy for Guided Imagery www.acadgi.com Provides professional training and certification in Interactive Guided Imagery,sm and referrals to certified practitioners.

17 Hypnosis and Gastrointestinal Disorders ANASTASIA ROWLAND-SEYMOUR

key concepts ■ ■

■ ■

■

■

■

■

Hypnosis has long been used to treat chronic medical illnesses. Recent research supports the view that hypnotic suggestions effectively change aspects of the person’s physiological and neurological functions. The possible mechanism of hypnotic effects is still unclear. There is a large body of literature on the use of gut-directed hypnotherapy suggesting that hypnosis has a role in treating refractory irritable bowel syndrome. A few trials suggest that hypnosis may have a role in functional dyspepsia, and that propose a mechanism of action. Some preliminary data suggest a short-term effect of hypnosis on inflammatory markers in inflammatory bowel disease, although this data set has not been validated. More rigorous trials are required to definitively say that hypnosis produces long-lasting effects in gastrointestinal disorders. Prior studies have hinted that hypnosis may actually not be cost-prohibitive; however, trials on its cost effectiveness need to be carried out. ■

174

Introduction DEFINITION OF HYPNOSIS

T

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

POSSIBLE MECHANISMS OF HYPNOSIS

While there is general agreement that hypnosis may have clinical effects for some conditions, there are differences of opinion within the research and clinical communities about how hypnosis works. Recent research supports the view that hypnotic suggestions effectively change aspects of the person’s physiological and neurological functions. One way of thinking about hypnosis is that it changes the associations between occurrences and our perceptions of them. Some describe it as “reshuffling our mental filing cabinet.” By uncoupling associated responses or emotions from life events, one can then interpret new data differently and create new associations between events and thoughts. Researchers at Penn State have been using hypnosis as a tool to better understand the brain. They have done a number of EEG studies, looking at

176 INTEGRATIVE GASTROENTEROLOGY

pain response. One such study suggests that hypnosis can remove the emotional experience of pain, while allowing the sensory sensation to remain. Thus, one notice might notice that one was touched, but not that it hurt (Ray et al., 2002). An emerging body of literature suggests that hypnosis may cause physiologic changes in the brain. We know from studying positron emission tomography (PET) scans in people who have undergone hypnotic relaxation that they experience increased regional cerebral blood flow in the anterior cingulate cortex, the thalamus, and the midbrain. (Rainville, Hofbauer, Bushnell, Duncan & Price, 2002) Subjects who were experiencing increased mental absorption, rather than relaxation, as part of their hypnotic experience, were found to have increased regional cerebral blood flow in a distributed network predominately ranging over the prefrontal cortices. This is very similar to the patterns of activation that have been associated with tasks involving visual, auditory, and somatosensory stimulation (Rainville et al., 2002; Peyron et al., 1999). Hypnosis has long been studied in medical conditions and has been shown to have wide-ranging effects. There are studies documenting its usefulness in many illnesses, ranging from managing acute and chronic pain, decreasing presurgical anxiety, acting as sole or adjuvant analgesia during surgical procedures, promoting healing from burns, and managing nausea and vomiting, dermatologic disorders, and gastroenterologic disorders.

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

IRRITABLE BOWEL SYNDROME

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

Hypnosis and Gastrointestinal Disorders 177

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

Table 17.1. Patient Characteristics and Response to Hypnotherapy No improvement

Less symptoms

Symptom free

(n=13)

(n=9)

(n=11)

Sex

3M, 10F

2M, 7F

3M, 8F

Hypnotherapist A

6

8

3

Hypnotherapist B

7

1

8

Group Therapy

5

6

6

Individual Therapy

8

3

5

Severe symptoms at start (total symptom score ≥35)

4

5

2

Psychological Problems (GHQ score ≥5)

5∗

3

0∗

Age >50 yr

4

2

1

—

∗p<0.05 for difference between symptom-free and no-improvement groups. There were no other significant differences between response groups. Adapted from Harvey et al. (1989). Lancet, 1,424–425. Reprinted with permission.

178 INTEGRATIVE GASTROENTEROLOGY

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

Immediate group (N=15)

Time 1

Time 2

Time 3

Pretreatment

Posttreatment

4 mo follow-up

Abdominal Pain

23.9 (2.5)

12.9 (3.2)†

12.5 (3.4)†

Bloating

20.3 (3.1)

15.1 (2.7)†

11.1 (3.3)†

Proportion of hard/loose stools

0.25 (0.04)

0.10 (0.03)†

0.23 (0.05)†

3.1 (0.7)

2.3 (0.5)

2.3 (0.5)

16.00 (1.9)

16.8 (1.2)‡

10.2 (1.8)†

Bloating

13.6 (2.1)

11.67 (1.7)‡

Proportion of hard/loose stools

0.27 (0.06)

0.26 (0.06)‡

2.2 (0.4)

2.1 (0.4)

Bowel movements per day Delayed group (N=9) Abdominal Pain

Bowel movements per day

9.0 (1.48)‡ 0.8 (0.03)‡ 1.7 (0.2)

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

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

Hypnosis and Gastrointestinal Disorders 179

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

Pretreatment

Posttreatment

(mean +/-SE)

(mean +/- SE)

P

Skin conductance (μmhos)

1.45 ± 0.29

1.11 ± 0.16

NS

Skin conductance stress change (μmhos)

1.41 ± 0.18

1.01 ± 0.19

0.01

Heart rate (bpm)

66.1 ± 1.8

67.2 ± 1.9

NS

3.1 ± 1.5

4.83 ± 1.5

NS

123.6 ± 2.3

121.1 ± 2.9

NS

5.2 ± 1.5

1.4 ± 4.8

NS

70.8 ± 2.5

70.9 ± 2.4

NS

3.3 ± 1.5

3.5 ±1.0

NS

Finger skin temperature (°F)

86.7 ± 1.7

86.9 ± 1.4

NS

Finger temperature stress change (°F)

—2.2 ± 1.0

—2.1 ± 0.4

NS

Baseline EMG (μv)

4.1 ± 0.6

3.5 ± 0.5

NS

Stress-related increase in EMG (μv)

3.8 ± 1.0

3.2 ± 0.9

NS

Heart rate stress change (bpm) Systolic BP (mm Hg): Systolic BP stress change (mm Hg) Diastolic BP (mm Hg) Diastolic BP stress change (mm Hg)

Reprinted with permission from Palsson O et al. (2002). Digestive Diseases and Sciences, 47(11), 2605–2614.

possibility of a meta-analysis. Nonetheless, the authors did find that hypnosis appeared to be a safe intervention and could be tried in individuals who have failed conventional treatment for IBS. Further, they concluded that even though there was the suggestion of a beneficial effect in the short term, this finding has not been convincingly proven by high-quality studies. The suggestion of persistent long-term benefits of hypnotherapy in IBS has been noted in several studies; however, each of these studies is methodologically challenged. Only one primary-care-based study measured long-term (12 months) outcomes in a systematic method, and no benefit was found (Roberts et al., 2006).

FUNCTIONAL DYSPEPSIA

More recently, hypnosis has been looked at in the setting of functional dyspepsia. In 2002, the same Manchester group of Whorwell et al. created a threearm trial designed to explore what, if any, effect hypnosis would have on

180

INTEGRATIVE GASTROENTEROLOGY

functional dyspepsia. One arm of this trial was a hypnotherapy group, another arm was a psychotherapy plus placebo-medication group, and both were compared to standard medical therapy. There was a 59% reduction in quality of life measures, which continued to improve after treatment, reaching a 73% reduction in symptom severity at one year (Calvert et al., 2002; see Figure 17.2). Prior analyses have suggested that hypnotherapy was not economically feasible because a standard course of treatment typically requires 12 sessions with a single hypnotherapist. Others have observed, however, that once treated with hypnosis, patients with IBS often require minimal further intervention. This trial noted a statistically significant decrease in medication usage and healthcare utilization (Table 17.4). More recent functional studies have looked at possible mechanisms for hypnosis’ usefulness in GI disorders. Chiarioni et al. (2006) noted in a small trial that patients with functional dyspepsia who underwent hypnosis had a Table 17.4. Medication Use and Consultation Rate of Patients During Long-term Follow-up 40 Week follow-up Hypnotherapy

Supportive

Medical

(n = 26)

(n = 24)

(n = 29)

Number taking medication

0

20

26

% taking medication

0

81.8

89.7

PPI

0

6

15

H2 antagonists

0

8

8

Prokinetics

0

0

0

Antacids

0

4

3

Antidepressants

0

5

0

None

26

4

3

Total number of consultations median (IQR)

1 (0–2)

4 (1–10)∗

4 (0–9)∗

Number of GI consultations median (IQR)

0 (0–0)

3.5 (0–10)∗

3 (0–9)∗

NOTE. Expressed as median (interquartile range). ∗P<0.001 vs. hypnotherapy. Reprinted with permission from Department of Medical Illustration, Withington Hospital, Manchester, England. Reprinted with permission from Calvert et al. (2002). Gastroenterology, 123, 1778–1785.

Hypnosis and Gastrointestinal Disorders 181

shortened gastric emptying time as compared to cisapride and usual care. This shortened gastric emptying time was also noted in the control group of normal subjects who underwent hypnosis.

INFLAMMATORY BOWEL DISEASE

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

Conclusion There are significant data to support the use of clinical hypnosis in functional gastrointestinal disorders. Although well-designed trials are few in number, reviews suggest that hypnosis may be effective in functional disorders that are refractory to conventional medical approaches. Similarly, while there is not sufficient data to be conclusive, there is the suggestion of a possible improvement in inflammatory bowel disease. A growing body of literature details the neuroscience of hypnosis, and literature substantiates the organ-specific physiologic changes that may account for the effects of hypnosis in GI disorders. Clearly, further well-designed trials are needed to fully understand the effects that hypnosis has on gastroenterologic disorders. Additionally, it would be extremely useful to address the perceived issues of financial nonviability. Prior studies have suggested not only that self-hypnosis pays for itself in the long run by decreasing healthcare utilization, but also that accessibility can be increased, while still maintaining efficacy, with group hypnotherapy. These questions need to be answered with the help of well-designed trials.

18 Homeopathy Origins and Therapeutic Principles SAVELY YURKOVSKY

key concepts ■

■

■

■

■

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

182

Classical Homeopathy THE LAW OF SIMILARS

I

n 1796, Samuel Hahnemann, of Germany, published the paper, “A New Principle of Healing,” which he named homeopathy (Schmidt, 1988; Schmidt, 1994). The name denotes “similar disease,” based on the Greek term, homoion pathos, or the Latin term, “like cures like” (similia similibus curentur), and is referred to as “The Law of Similars.” The principle itself had been known and applied through various therapeutics, from Egyptian alchemists to Hippocrates and Paracelsus. However, both Hahnemann’s pharmacopeia and methodology were truly innovative. The remedy preparation involved serial dilutions of the original, or any substance (plant, mineral, toxicological or infectious agents, etc.), along with succussions—the parallel and repetitive mechanical impacts delivered to the solution against the bottom of a glass bottle, even far beyond Avogadro’s number, 6.02 × 1023. These remedies, then, would be administered to the sick who display symptoms similar to those elicited by the same remedies, in healthy volunteers, in the process of proving, or eliciting remedy-induced symptoms. The picture for prescribing would include not only localized pathology—e.g., headache, diarrhea, vomiting, etc.—but a very detailed qualitative analysis of these and, strangely enough, a broad range of concomitant complaints, including mental, emotional, and general symptoms nonspecific for disease, per se. Even more novel, the therapeutic rating of these other symptoms—and particularly those that were considered peculiar and seemingly unrelated to the main pathology; for example, ear itch, claustrophobia, or testicular pain in a colitis case—would often prevail over the therapeutic rating of the local disease. It was observed that the remedies that encompassed these other and especially peculiar symptoms yielded greater therapeutic success than those focused on disease, per se. The rationale for the emphasis on other and peculiar symptoms was that they were more reflective of the state of the body’s defense force on the total, complex level that the remedies aimed to stimulate in order to elicit more specific and intense response of that defense force against any morbid factors behind an illness. This approach was deemed to be based on the law of totality and was referred to as classical homeopathy. Another unique property of homoeopathy has been formulated as Hering’s Law of Cure, summed up by Constantine Hering in the nineteenth century (Treuherz, 2005). It is based on countless clinical observations that in any set

184

INTEGRATIVE GASTROENTEROLOGY

of pathologies, in order for true healing to take place, the pathology in the course of the therapeutic process must move in a downward anatomical direction from head to toe, from inside out, and in reverse order of the time of onset of pathological symptoms. The first two rules underscore a priority in protecting more physiologically important organs, while the third rule implies the process of peeling off morbid layers of disease in the corresponding chronological order of their original aggregation. It is of interest that the latter rule is deemed to be placebo-proof since, in the majority of cases and only upon the return of old and often forgotten symptoms by patients, did the patients make their homeopaths aware of those symptoms’ past existence. On the whole, neglect of Hering’s Law via mere suppression of local pathological symptoms, without cure through conventional or alternative means, has been observed to be followed by progressive disease with the passage of time. This sequence was encountered particularly in cases with suppressed bodily discharges, either via skin, respiratory, gastrointestinal, or urogenital outlets. More impartial evidence for the confirmation of this tenet is based on the successful experiences of homeopathic treatment where regression of chronic diseases was followed by the return of the original suppressed discharges, or other old symptoms. This phenomenon presupposes the existence of some property of cellular memory in the tissues in relation to unresolved pathogenic layers, accrued over time. Homeopathy also seeks to address a person’s inherited systemic weaknesses through the prescription of certain constitutional or miasmatic remedies. It has been observed that these were often followed by copious discharges or skin outbreaks, as if some underlying morbid agents were indeed being released while, in their wake, progress in health would ensue. This is the main reason why homeopathy favors centrifugal therapeutic action versus a centripetal, suppressive one.

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

Homeopathy Origins and Therapeutic Principles

185

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

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

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

186

INTEGRATIVE GASTROENTEROLOGY

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

Samples of Remedies and their Prescribing Keynotes for Common Gastrointestinal Ailments Constipation (Kratz, 2001) • Bryonia alba • Calcarea Carbonica • Lycopodium clavatum Diarrhea (Lilienthal, 1996) • • • •

Aloe socotrina Argentum Nitricum Arsenicum Album Bryonia alba

Homeopathy Origins and Therapeutic Principles

• • • •

187

Hyoscyamus niger Oxalicum acidum Podophyllum peltatum Zincum Metallicum

Gallbladder Disorders (Kruzel, 1988) • • • •

Berberis vulgaris Calcarea carbonica Carduus marianus Chelidonium majus

Nausea and Vomiting • • • • • • • • •

Cocculus Indicus Crotalus Horridus Glonoinum Ipecacuanha (Cephaëlis ipecacuanha) Kreosotum Nux Vomica (Strychnos nux vomica) Rhus Toxicodendron Tabacum (Nicotiana tabacum) Zincum metallicum

Summary Since its inception, homeopathy has remained a poorly understood medical system. The main arguments: the remedies defy accepted chemistry rules, utilize implausible therapeutic principles based on the law of similars, treats morbid stressors via near or identical morbid stressors, or via an approach of totality by addressing seemingly unrelated symptoms. However, mounting evidence from multidisciplinary sciences over recent decades continues to yield copious supporting data on behalf of the tenets of homeopathy. Among these are laws of complexity applicable to living systems, information and chaos theories (Bellavite & Signorini, 2002; Bell & Koithan, 2006), the phenomena of quantum physics (Smith, 1998; Wolkowski, 1994) and cellular memories (Miller, 1978; the discovery of DNA and related disease predispositions, and even the theory of evolution, which emphasizes adaptation of species to stressors via exposure to the identical stressors (Darwin, 1859). Not surprisingly, The Law of Similars has been in extensive use in conventional medicine through such practices as vaccinations, allergy desensitization, and botulin administration in neurological diseases. Another example,

188

INTEGRATIVE GASTROENTEROLOGY

the newly emerging field of psychoneuroimmunology, has substantiated— via experiments involving the peptide systemic network—interconnections among multiple systems and their functions as including those of emotions and nervous systems, as well as endocrine and immune systems (Pert, 1997). Modern technologies using spectral analysis obtained with the Raman laser, infrared absorbance, and nuclear magnetic resonance (NMR), have all confirmed the difference in emission patterns between homeopathic remedies and a placebo. In addition, each homeopathic remedy was found to exhibit a unique NMR emission pattern. Furthermore, substances that were both diluted and succussed to 30X potency, according to the full homeopathic method, exhibited a specific band pattern in their emission spectra that was absent when the substances were merely diluted but not succussed. (Barros et al., 1984; Smith & Boericke, 1966; Young, 1975; Lasne et al., 1989; Smith & Boericke, 1968; Sacks, 1983; Demangeat et al., 1992). All this evidence does supports the scientific foundation of homeopathy and provides a safe and at times cost-effective option to patients and practitioners for a number of gastrointestinal tract ailments.

19 Massage for Digestive Health STEPHANIE PORCARO AND GERARD E. MULLIN

key concepts ■ ■ ■ ■

Massage can calm patients with underlying anxiety disorders. Massage can influence gastrointestinal physiology. There is data to support its use for patients who are constipated. Contraindications to massage exist, and practitioners need to be aware of the potential risks and benefits of massage. ■

A Brief History of the Benefits of Massage

M

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

189

190

INTEGRATIVE GASTROENTEROLOGY

Benefits of Massage that May Improve Digestive Illness • • • • • • •

Relieves stress and promotes an overall feeling of relaxation Alleviates pain and tension Decreases inflammation Improves circulation Improves and strengthens immune system Reduces anxiety and promotes an overall feeling of well-being Increases body awareness (Takeda et al., 2008; Lee, 2006)

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

Anxiety Arthritis Chronic and acute pain Circulatory problems Depression Fibromyalgia Headaches Sleep disorders Stress

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

Massage for Digestive Health 191

Gastric motility has also been shown to improve in preterm neonates after abdominal massage. Compared with preterm neonates receiving sham massage, those receiving massage therapy exhibited greater weight gain and increased vagal tone and gastric motility during, and immediately after, treatment. Gastric motility and vagal tone during massage therapy were significantly related to weight gain. Postoperative motility has been shown to improve after acupressure massage (Chen et al., 2003; Daletskaia, Ekisenina, & Lorie, 1988). Thermovibromassage of the right hypochondrium area, for biliary dyskinesia, has been reported to promote normalization of biliary system motility (Matveeva, Kuz’menko, & Kirillova, 1997). Remission persisted for 6 to 8 months in patients with biliary dyskinesia. Thus, massage may in part reset enteric nervous system electromyographic rhythms, as suggested by human and animal studies (Koizumi, Sato, & Terui, 1980; Liu et al., 2005). Abdominal massage to relieve constipation is a palliative type of care that used to be a commonly practiced therapy. Massage to promote movement of fecal wastage has been well documented and should be considered in patients with functional constipation (Di Lorenzo, Ordein, & Hyman, 1993; Culbert & Banez, 2007; Harrington & Haskvitz, 2006; Preece, 2002; Ernst, 1999; Jeon, & Jung, 2005; Kim et al., 2005). One study showed massage to provide a benefit for relief of symptoms of irritable bowel syndrome (Bosseckert, 1982).

Massage and the Digestive Tract Technique for Patients Abdominal massage relaxes and tones the organs, muscles, and fascia of the abdomen, while providing overall relaxation and stress relief. Abdominal massage is effective and fast. Some people feel the urge to eliminate during or just after the massage itself, when well hydrated. In this section, we assume that individuals are working with a partner, although most techniques described can be performed during self-massage. The abdominal area is highly sensitive. Approach it with respect and positive intention. Begin with a gentle opening hold, slowly bringing your hand down to rest in the center of your partner’s abdomen just below the navel. Allow your partner to become comfortable with the sensation of being touched there. Encourage deep, relaxed breathing during the massage. Open the area with slow stretches between the floating ribs and iliac crest, reaching for the side of the body opposite you and pulling up and toward the navel in a sweeping motion. This technique addresses the obliques and transverse abdominis. Next, effleurage the rectus abdominis in a sweeping motion, creating clockwise

192

INTEGRATIVE GASTROENTEROLOGY

circles with your hands around the center of the abdomen. Abdominal massage always proceeds in a clockwise motion, reinforcing the clockwise passage of waste through the large intestine. Working in a counterclockwise direction may harm the intestines and intensify existing fecal impaction. Now that the superficial abdominal tissue is relaxed, it is possible to perform intestinal massage. Please refer to the diagram (Figure 19.1) for assistance with the anatomy. Depending on the size of the individual, and whether he or she is constipated and remains relaxed during the session, you may actually feel the intestines themselves. Even if you do not palpate the structures, work in the area where they are located, with the intention of massaging them. Start at the upper left-hand quadrant of the abdomen just below the ribcage. Sink in deeply and travel with circular friction, 2 to 4 inches down the line between the navel and the anterior superior iliac spine (the pointy part of the front of the hip). Repeat 2 to 5 times. Next move across to the right ribcage area and sink into the tissue, massaging across the transverse colon to the left side. Avoid deep pressure over the fascia of the midline of the body, which you will cross while massaging the transverse colon. Repeat 2 to 5 times. Now move to the area between the right anterior hip and navel, and massage up the ascending colon with circular friction. Repeat 2 to 5 times. Put the three parts of the massage together—starting again at the ascending colon, moving to the transverse and to the descending—in one fluid motion. Imagine your hands pushing out the waste for elimination. Return back to the lower right abdomen, at the point between the navel and the hipbone. This locates the ileocecal valve (ICV). Gently push down at this point to feel the valve and the connection between the small and large intestine. Then massage up an inch toward the left shoulder, palpating the ICV. If this area is sore or uncomfortable, the valve flap may be stuck open. When this occurs, waste backs up into the small intestine, causing small intestinal bacterial overgrowth. Repeat the massage, starting at the ileocecal valve, continuing to use small clockwise circles overlapping the entire pattern as before. Each circle or pass, after that, allows the circular massage to close in around the navel. Finish the massage by placing your hand flat over the abdomen. Turn your whole hand—flat, and with equal pressure on the fingers and heel of the hand—in a clockwise direction. This is calming and reinforces the direction of the deeper work. There are many massage therapy modalities that focus on core work and digestive health. For further exploration, see videos available on the Internet, on Maya Abdominal Massage, Ayurvedic, and Tuina.

Massage for Digestive Health 193

Abdominal Massage Don’ts • Abdominal massage should not be done if a person has inflammation of the uterus, bladder, ovaries, or fallopian tubes. • Abdominal massage should not be done if a person has stones in the kidneys, bladder or gallbladder, or ulcers of the stomach or intestines. • Abdominal massage should not be done after a heavy meal. • The bladder should be emptied before the massage. • Since blood pressure increases during abdominal manipulation, patients with hypertension should avoid abdominal massage. • Massage should also be avoided in cases where there has been recent bleeding in the lungs, stomach, or the brain.

20 Mindfulness Based Stress Reduction for Health and Diseases PADMINI D. RANASINGHE

key concepts ■

■

■

■

■

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

Introduction: Stress and Health

S

tress is a complex phenomenon that occurs in humans, with multiple sequences of events affecting short-term to long-term health, ranging from endocrine to neuronal systems. Within seconds following a stress-causing stimulus, catecholamines from the sympathetic nervous system 194

Mindfulness Based Stress Reduction for Health and Diseases

195

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

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

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

196

INTEGRATIVE GASTROENTEROLOGY

Mindfulness meditation is a reflective practice followed by various Buddhist traditions.

This chapter describes some of the evidence available in the literature of the use of MBSR practices in healthy adults and populations with certain clinical conditions. MBSR has been studied and shown some benefits in conditions, such as chronic pain, cancer, psychiatric conditions, and some chronic diseases. Physiological changes follow any sustained activity. MBSR and mindfulness meditation are known to produce physiological and anatomical changes in bodily systems over time, some of the changes are in the cardiovascular system, respiratory system, neurological system, endocrine system and immune system. A decrease in cardiac pre-ejection period, increase in cardiac output, and decrease in diastolic blood pressure (BP) were observed during mindfulness meditation (Ditto et al., 2006).

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

MBSR in Practice MBSR has been used in various patient populations and healthy adults to promote physical, social, and psychological health. MBSR techniques may help a broad range of individuals to cope with clinical and nonclinical problems, and

Mindfulness Based Stress Reduction for Health and Diseases

197

are shown to be effective as an interventions in a variety of healthcare settings (Praissman, 2008; Grossman, Niemann et al., 2004; Williams, Kolar et al., 2001). In some healthcare settings MBSR technique has been taught in weekly group sessions, usually lasting 8 to 10 weeks with video-assisted homework assignments. Other adapted methodologies also have been used in research settings. Group mindfulness meditation techniques have been shown to be beneficial immediately, as well as one year after intervention, in several physical, psychological and social parameters (Reibel et al., 2001). It has been shown that MBSR may be effectively taught by video-conferencing in patients with chronic pain (Gardner-Nix et al., 2008).

HEALTHY ADULTS

Most MBSR-related studies were conducted among healthy adults. Mindfulness meditation has been shown to play a role in cognitive flexibility, stress reduction, increased relaxation, and decreased overall psychological symptoms, while promoting an overall sense of control in adult volunteers (Agee et al., 2009; Moore & Malinowski, 2009; Astin, 1997). Experienced meditators showed increasing introception awareness and heartbeat detection (Khalsa et al., 2008). MBSR has been shown to improve sleep quality, improve night-time symptoms of insomnia and decrease pre-sleep arousal, sleep effort and dysfunctional sleep-related cognition (Klatt et al., 2008; Winbush et al., 2007; Ong et al., 2008).

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

198

INTEGRATIVE GASTROENTEROLOGY

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

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

CANCER

For oncology patients, MBSR is gaining recognition as a credible and beneficial intervention to be incorporated in to the treatment. A review study has shown that the patients with cancer who received MBSR training had a positive change on psychological functioning, stress reduction and increased coping skills and well-being (Ott et al., 2006). Cancer patients who participated in an MBSR program had increased quality of life, less stress, and fewer physical symptoms (Kieviet-Stijnen et al., 2008). Another review article found a potential benefit for MBSR in cancer patients for sleep, mood, and reduction in stress (Smith, Richardson et al., 2005). In a small study, cancer patients who underwent hematopoietic stem cell transplant showed a statistically significant decrease in heart and respiratory

Mindfulness Based Stress Reduction for Health and Diseases

199

rates, and improvements in physical and psychological symptoms immediately before and after each MBSR session suggesting potential benefits and feasibility of MBSR in hospitalized cancer patients (Bauer-Wu et al., 2008). Similarly studies involving breast and prostate cancer patients showed that an MBSR program was resulted in positive benefits, such as increased quality of life and sleep, decreased stress symptoms and cortisol level, as well as immune patterns consistent with less stress and mood disturbance, and decreased blood pressure (Carlson, Speca et al., 2004, 2007; Carlson & Garland, 2005). MBSR may also have positive effects on the quality of sleep in breast cancer patients whose sleep disturbances were associated with stress (Shapiro, Bootzin et al., 2003). Studies have also shown psychological benefits for MBSR in patients diagnosed with cancer.

A randomized, controlled clinical trial showed that patients diagnosed with breast cancer had lower depression scores, less anxiety, and less fear of recurrence, in addition to improved energy and physical function after MBSR intervention (Lengacher, Johnson-Mallard et al., 2009). MBSR programs have been shown to reduce mood disturbance and symptoms of stress, and increase well-being and the ability to handle stress in adult patients with various cancers (Carlson, Ursuliak et al., 2001; Speca, Carlson et al., 2000). A meta-analysis has shown that MBSR has the potential to improve psychosocial adjustment to the disease in cancer patients (Ledesma & Kumano 2008). Some other benefits of 8 weeks of MBSR in patients diagnosed with breast cancer include an increase in serum immune markers: regained peripheral blood mononuclear cell NK cell activity (NKCA) and IFN-gamma production, decreased IL-4, IL-6, and IL-10 production, and decreased plasma cortisol levels, in addition to improved quality of life and coping (Witek-Janusek et al., 2008). In patients with breast and prostate cancer who received MBSR training, had decreased in pro-inflammatory immune cells and cytokines steadily over 1 year In addition to improving symptoms stress, quality of life and mood and they concluded that these shifts in immune parameters are associated with the resolution of depressive symptoms (Carlson, Speca et al., 2003).

PSYCHIATRIC CONDITIONS

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

200

INTEGRATIVE GASTROENTEROLOGY

In one study, 28 patients with chronic recurrent depression with protracted course and current symptoms of depression were randomized to receive mindfulness-based cognitive therapy or usual treatment. There was a decrease in symptoms from severe to mild levels of depression in patients who were assigned to the mindfulness-based cognitive therapy group (Barnhofer et al., 2009). Mindfulness has been shown to be beneficial in relapse prevention in patients with depression after adjusting for other variables at 12 months follow-up (Michalak et al., 2008). Small study with 11 participants with generalized anxiety disorder who received 8 week mindfulness-based cognitive therapy showed that there was a significant reduction in anxiety, depressive symptoms, and worry, from baseline to end of intervention (Evans, Ferrando et al., 2008). Eight week MBSR practice as an intervention has been shown to decrease perceived stress and vital exhaustion, and is strongly associated with positive affect and quality of life and well-being in adult patients with distress from the community and mindfulness mediated effect on stress and quality of life (Nyklicek & Kuijpers, 2008;) Another study of 174 adults in a clinical mindfuleness progam has shown that 8 week MBSR had increased mindfulness, wellbeing and decreased stress. This imporvement was singinifantly related to the time spent on MBSR related activities and minfulness was found to be a mediator for some outcomes. (Carmody & Baer, 2008). It also has been shown that patients with chronic physiological and psychological stress would benefit from an 8-week MBSR program to improve their well-being and quality of life (Majumdar et al., 2002). In a study involving both cognitive behavioral therapy (CBT) and MBSR, for patients with DSM-IV generalized social anxiety disorder receiving CBT showed a greater improvement in social anxiety disorder related symptoms than MBSR group, but an equally comparable improvement was recorded in mood, disability and quality of life from both interventions. (Koszycki et al., 2007). Three-year follow-up study of patients with anxiety has shown that there were long-term benefits of mindfulness meditation in the treatment of anxiety disorder (Miller et al., 1995). Kabat-Zinn et al. (1992) have shown that MBSR with group mindfulness meditation training is beneficial in reducing symptoms of anxiety and panic and to maintain those low levels in patient with generalized anxiety disorder. It has been shown in small studies that MBSR-related techniques may also be beneficial in treating other psychiatric conditions like obsessive-compulsive disorder and ADHD in adults—possibly by letting go, and improving behavioral and neurocognitive impairment, respectively (Hanstede et al., 2008; Zylowska, Ackerman et al., 2008). A small study has shown that patients with bipolar disorder who received mindfulness-based cognitive therapy did better

Mindfulness Based Stress Reduction for Health and Diseases

201

with anxiety symptoms specific to bipolar disorder than those who did not receive it (Williams, Alatiq et al., 2008). There appear to be some promising results with MBSR techniques for younger women with bulimia nervosa and and women with sexual dysfunction (Proulx, 2008; Brotto, Basson et al., 2008). A study of patients, 1-year after mild to moderate brain injuries, who received MBSR showed an improvement in quality of life, cognitive affect, domain of Beck Depression Inventory, and positive distress inventory of SCL90R (Bedard et al., 2003).

OTHER CHRONIC DISEASES

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

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

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

Congestive Heart Failure Prospective cohort study of heart failure (NYHA 11) patients who underwent a MBSR program in addition to medications had a lower anxiety score,

202 INTEGRATIVE GASTROENTEROLOGY

less depression, and improved symptoms as measured by Kansas City Cardiomyopathy questionnaire symptom scale and clinical scale, but there was no treatment effect on death/rehospitalization at one year (Sullivan et al., 2009).

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

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

HEALTHCARE UTILIZATION

There is some evidence to suggest that MBSR interventions may decrease healthcare utilization and chronic care visits in addition to improving selfesteem and decreasing medical and psychological symptoms, in an inner-city English and Spanish speaking population (Roth & Stanley, 2002; Roth & Creaser, 1997).

Mindfulness Based Stress Reduction for Health and Diseases

203

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

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

204

INTEGRATIVE GASTROENTEROLOGY

(Gaylord S.A. Whitehead W et al., and David Kearney) Finally although there is a lack of studies favoring the use of MBSR in the prevention and treatment of digestive disturbances and other chronic diseases, practitioners may educate patients about its potential benefits, given the lack of adverse effects.

21 Naturopathic Medicine and Digestion JOSEPH PIZZORNO

key concepts ■

■

■

■

■

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

Naturopathic Medicine

N

aturopathic medicine is a distinct system of health-oriented medicine that stresses promotion of health, prevention of disease, support for the body’s own healing systems, patient education, and selfresponsibility. However, naturopathic medicine symbolizes more than simply a healthcare system; it is a way of life. Unlike most other healthcare systems, naturopathy is not identified with any particular therapy, but rather a way of thinking about life, health, and disease. It is defined not by the therapies it uses, but by the philosophical principles that guide the practitioner. 205

206

INTEGRATIVE GASTROENTEROLOGY

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

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

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

7 NATUROPATHIC GUIDELINES 1. 2. 3. 4. 5.

Reestablish the basis for health. Stimulate the vital force. Tonify and nourish weakened systems. Correct structural integrity. Prescribe specific substances and modalities for specific conditions and biochemical pathways (e.g., botanicals, nutrients, acupuncture, homeopathy, hydrotherapy, counseling). 6. Prescribe pharmaceutical substances. 7. Use radiation, chemotherapy, and surgery.

Naturopathic Medicine and Digestion 207

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

A Physiological Systems Approach to Healing While the foundation of patient care is education and counseling in diet and lifestyle, much of naturopathic intervention centers on normalizing system function.

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

Dealing with the disorders of the digestive system is an excellent way to demonstrate the applications of the principles of naturopathic medicine. The old naturopathic adage, “disease begins in the bowel,” which sounded quaint to new students 35 years ago, is now recognized as wise clinical insight. The GI system is the primary gateway by which the external environment interacts with the body (Sult, 2006). The basic physiology of digestion and absorption is well understood, although digestive disturbances remain unresolved in a significant portion of the population. Viewing digestion as a physiological process, the food must be broken into its components by mechanical homogenization and chemical breakdown, followed by absorption of the smaller carbohydrates, lipids, proteins, vitamins, minerals, and other nutrients, through a variety of passive and active processes. In addition to the digestion and absorption of food, the GI tract must also defend against pathogens and toxins that we are exposed to on a continuous basis. It has a number of protective mechanisms, including a low pH in the stomach, coverage of the complete GI tract with a mucus layer, a diverse array of immune cells that lie beneath this mucus layer, and the presence of

208 INTEGRATIVE GASTROENTEROLOGY

commensal microbes that abundantly colonize the GI tract (Zoetendal, RajilicStojanovic, & de Vos, 2008). There are many ways in which one or more of these critical processes can break down. Rather than focus on what specific digestive disease a patient may have, the naturopath instead focuses on restoring normal function of all digestive processes.

Restoring Physiological Function The largest survey of GI symptoms to date (Camilleri et al., 2005) found an overall prevalence of at least one upper GI symptom (during the previous 3 months) of 45% those surveyed (including heartburn, early satiety, loss of appetite and postprandial fullness). A smaller survey of Canadian adults found a prevalence of lower GI symptoms of 5.2% (abdominal pain/bloating, constipation, diarrhea) (Hunt et al., 2007). More recent studies in the United States suggest bloating is as common as 19% to 21% among U.S. adults (Jiang et al., 2008; Tuteja et al., 2008) In as many as half of the symptomatic patients seen by gastroenterologists, a cause (i.e., disease) is not found, and they are often given a diagnosis of unclear etiology, such as functional dyspepsia or irritable bowel syndrome (IBS). (Geeraerts & Tack, 2008)

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

Naturopathic Medicine and Digestion 209

excessive bowel permeability, imbalanced microbial flora, malabsorption, reduced bile salt secretion, overgrowth of bacteria in the small bowel, food intolerance/allergy, etc.

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

DIAGNOSIS

• Laboratory diagnosis. Heidelberg pH capsule gastric analysis, gastric tube, serum pepsinogen I (S-PGI) and serum gastrin-17 (S-G-17). • Clinical diagnosis. High predictability factors include the H. pylori infection, use of antacids, H2 blockers and proton-pump inhibitors (PPIs), and pernicious anemia. Medium predictability factors include age greater than 60, acne rosacea, and rheumatoid arthritis. Lower predictability factors include nausea, abdominal gas, belching, constipation, chronic diarrhea, dyspepsia, weak/cracked/peeling fingernails, osteoporosis, asthma, gastric ulcer, and decreased ferritin.

CAUSES

Acid Secretion-Suppressing Drugs. The use of acid-suppressing drugs has increased the incidence of problems associated with the stomach. For example, a study of nearly 1,700 cases of C. difficile infection and acid suppression found that the adjusted rate ratio of infection was 2.9 for the use of PPIs, and 2.0 with H2 receptor antagonists (Dial et al., 2005). The frequency of B12 deficiency

210 INTEGRATIVE GASTROENTEROLOGY

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

INTERVENTION

The basic clinical strategy is as follows: 1. Stop acid secretion-inhibiting drugs if they are being used, and instead treat the causes of the GERD. 2. Eradicate the H. pylori; make conditions inhospitable for its return. 3. Stimulate regeneration of the gastric mucosa and parietal cells. 4. If HCl production has not returned, stimulate with herbal bitters. 5. If still no HCl production, emulate with oral supplementation. H. pylori. A recent study found that eradication of H. pylori was associated with a return to normal gastric acidity (Kato et al., 2008). This is supported by an earlier study, monitoring pepsinogens and gastrin, in 172 patients that underwent eradication therapy; at 12–15 months the results were comparable to those without previous infection (Ohkusa et al., 2004). The most reliable

Naturopathic Medicine and Digestion 211

intervention is with triple drug therapy (two antibiotics and an H2 inhibitor); see Chapter 39 by Minocha. Effective natural therapies include: • Concurrent Lactobacillus GG supplementation makes standard drug therapy more effective, and reduces adverse drug reactions (Armuzzi et al., 2001). • Vitamin C at 5 g/d for 4 weeks eliminates H. pylori in 30%, and longterm (5-year) use inhibits H. pylori growth and reverses gastric atrophy as measured by pepsinogen secretion (Zhang, Wakisaka, Maeda, & Yamamoto, 1997; Sasazuki et al., 2003). • Curcuma longa has great potential, as it is both bactericidal to H. pylori and, in an animal model, decreases the inflammation associated with the infection (De et al., 2009). Human research is, however, limited. One study concluded that since curcumin only eradicated H. pylori in 12% of the participants, it was not successful. However, treatment was only 7 days in duration and combined with other nutrients. The patients showed significant improvement in dyspeptic symptoms and reduction in serological signs of gastric inflammation 2 months after the end of the short therapy (Di Mario et al., 2007). The inhibition of H. pylori and anti-inflammatory effects may help explain curcumin’s anti-gastric cancer effects (Cheng et al., 2001). Deglycyrrhizinated licorice (DGL). The flavonoids found in Glycyrrihiza glabra impair H. pylori growth (including antibiotic-resistant strains; see Fukai et al., 2002). It has a long history of use in the successful treatment of gastric ulcers (Doll et al., 1962), and has been shown to stimulate regeneration of the gastric mucosa (van Marle, Aarsen, Lind, & van Weeren-Kramer, 1981). Glycyrrhizin is removed to allow long-term use, as it can cause pseudohyperaldosteronism. Acid secretion-suppression drugs. Rather than treat symptoms, deal instead with the causes of GERD. While these drugs in the short run decrease symptoms and may prevent sequelae, the long-term effects of maldigestion, impaired B12 absorption, etc., are serious and underappreciated (see Chapter 37). Herbal bitters. Herbal bitters (sometimes known as Swedish bitters) have a centuries-old tradition of use for digestive disorders. While they are claimed to increase stomach acid secretion, there is actually no apparent objective research. In fact, some constituents of bitters, such as aloe, have actually been shown to suppress gastric acid secretion, although it does protect the gastric mucosa (Yusuf, Agunu, & Diana, 2004).

212

INTEGRATIVE GASTROENTEROLOGY

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

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

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

Naturopathic Medicine and Digestion 213

DIAGNOSIS

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

CAUSES

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

214 INTEGRATIVE GASTROENTEROLOGY

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

INTERVENTION

1. Eliminate contributing factors. Although not always causative, patients should avoid alcohol and smoking, particularly those with chronic pancreatitis. Additionally, avoidance of gluten in those with celiac disease may improve the pancreatic insufficiency in some cases (Carroccio et al., 1991). 2. Pancreatic enzyme replacement. Complete replacement should include proteolytic enzymes, lipase, as well as enzymes that digest carbohydrate. The supplement should be taken during or immediately after meals for the greatest efficacy (Domínguez-Muñoz et al., 2005). 3. Correct related nutrient deficiencies. Fat soluble vitamins, (A, D, E, and K) are likely to be deficient in patients with poor pancreatic exocrine function, along with essential fatty acids (Peretti et al., 2005; Dodge &Turck, 2006). 4. Potential therapies. Although clinical research is lacking, melatonin appears to have an important role in pancreatic function. The concentration of melatonin in the GI tract is 10 to 100 times higher than in the plasma, and the total amount of melatonin is around 400 times higher than the amount of melatonin in the pineal gland (Bubenik, 2008). Melatonin has been shown to have some protective function for the pancreas, and to strongly stimulate pancreatic amylase secretion (Jaworek et al., 2007).

INCREASED INTESTINAL PERMEABILITY

Abnormal permeability refers to a measurable increase in flux of small watersoluble compounds across the paracellular pathway of the small intestine.

Naturopathic Medicine and Digestion 215

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

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

DIAGNOSIS

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

CAUSES

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

216

INTEGRATIVE GASTROENTEROLOGY

INTERVENTION

The strategy to facilitate repair of the damaged intestinal mucosa entails 3 steps: 1. Stop the damage. 2. Reestablish a healthy microbial flora. 3. Stimulate regeneration. The intestinal mucosa is damaged by allergenic foods, commonly consumed chemicals such as alcohol, NSAIDs and some food additives, cytotoxic drugs, and toxic microbial flora. Food allergy/intolerance. A recent trial found that, in subjects with adverse reactions to food, the severity of clinical symptoms correlated with the degree of intestinal permeability, as measured by lactulose/mannitol (Ventura, Polimeno, & Amoruso, 2006). An immune-mediated reaction to foods can cause increased intestinal permeability, as is well documented in celiac disease, and proper treatment results in restoration of intestinal integrity (Vilela et al., 2008). The basic approach is to determine and eliminate the foods that induce an immunological reaction. Unfortunately, there is no gold standard to achieve this. The author prefers challenge testing. Once the worst allergenic foods are eliminated, a 4-day rotation diet is recommended until proper digestive function is reestablished and the intestines healed. Surprisingly, this may take only a few weeks. However, this does not mean the allergenic foods can be immediately reintroduced, and some patients appear to have a lifelong reaction to some foods. Bowel microbial flora. The increased permeability caused by bacterial and viral infections is well known. Less well appreciated is the chronic subclinical inflammation and intestinal damage caused by commensal microbial agents that do not cause overt infection (Tlaskalová-Hogenová, 2004).55 Also underappreciated are the diverse roles a healthy microbial balance plays in the maintenance of healthy digestion, as well as disease prevention. These include the production of essential vitamins and cofactors, cidal activity against pathogenic bacteria, enhancement of intestinal barrier function through modulation of cytoskeletal and tight junctional protein phosphorylation, metabolism of toxins, reduction of GI inflammation, and help maintaining immune homeostasis within the gut-associated lymphoid tissues (GALT; see Ng, Hart & Kamm, 2009).

Naturopathic Medicine and Digestion 217

The clinical approach is to use low-toxicity antimicrobial agents to kill the unwanted bacteria and to then reseed with preferred strains. This author has seen considerable success using Hydrastis canadensis (goldenseal), which has been shown to be active against many of the undesirable intestinal microflora (Scazzocchio, Cometa, Tomassini, & Palmery, 2001). Many probiotics and prebiotics have been used to reseed the intestines.8 One of the most researched strains is Lactobacillus rhamnosus (Hawrelak, 2006). Probiotics that support Bifidobacteria spp. growth include fructooligosaccharides (asparagus, onion, leek, garlic, artichoke, Jerusalem artichoke, chicory root); galactooligosaccharides (cow’s milk, yogurt, human milk); xylooligosaccharides (oats); and galactosyl lactose (human milk). Lactobacillus spp. are supported by β-glucooligomers (oats) and raffinose (legumes, beets). Cabbage juice and glutamine. More than 50 years ago, daily consumption of 1 quart of cabbage juice was found to repair gastric ulcers, which was confirmed radiologically (Cheney, 1949). Follow-up research unofficially dubbed the unknown factor in cabbage juice “vitamin U” (Cheney, Waxler, & Miller, 1956). This factor was later determined to be glutamine, and subsequent research (with a few exceptions) has clearly documented the efficacy of 500 mg three times a day in repairing a damaged intestinal mucosal barrier (Li et al., 2006). Several other natural agents have been shown to decrease excessive gastrointestinal permeability, including quercetin, glutathione, omega-3 fatty acids, and Aloe vera (Rosella, Sinclair, & Gibson, 2000; Lash, Hagen, & Jones, 1986; Kim et al., 2005). • High predictability factors include IBS, Type 1 diabetes, migraine, celiac disease and food allergies. • Medium predictability factors include Type 2 diabetes, inflammatory bowel disease, use of ibuprofen, indomethacin, naproxen or aspirin, Giardia, Blastocystis hominis, Entamoeba histolytica, Candida albicans, atopic dermatitis, psoriasis, asthma, hypochlorhydria, abdominal bloating, aphthous stomatitis, and chronic stress. • Lower probability factors include taking Vioxx or Feldene, and essential fatty acid deficiency.

Conclusion Disorders of digestive function are surprisingly common, and often aggravated by conventional drug interventions. These disorders not only cause signs and symptoms of digestive distress, but they also cause a diverse range of

218

INTEGRATIVE GASTROENTEROLOGY

systemic diseases from chronic nutrient deficiencies, increased production and transport of inflammatory mediators, immune complex deposition from food allergies, and absorption of toxins from aberrant microbial flora. Restoration of normal digestive function not only relieves symptoms, but often results in widespread improvement in health and decreased disease burden. Finally, as amply demonstrated in the example of vitamin D deficiency secondary to subclinical pancreatic exocrine deficiency, nutrient deficiencies can occur with digestive dysfunctions that are not clinically overt. This requires a high level of clinical awareness of the many ways digestion become disordered.

22 Taiji, Qigong, and Digestive Health YANG YANG AND BOB SCHLAGAL

key concepts ■

■

■

■

■

■

Research points to the value of exercise and diet in maintaining digestive health. Research supports a role for stress reduction techniques in limiting digestive distress. Carefully conducted studies of tai chi verify a cascade of exercise and stress reduction benefits stemming from its practice. Focus on two core components of tai chi practice, form and Qigong, appears to produce the greatest health and stress reduction benefits. Carefully conducted scientific studies have verified many of the benefits of tai chi that have long been claimed by practitioners. Tai chi’s focus on deep relaxation and gentle exercise promotes improved everyday physical functioning, and should assist in regulating the brain–gut axis. ■

Stress Reduction and Exercise

F

unctional GI disorders are extremely common in the general population. They are not caused by the kinds of organic diseases readily assessed by standard diagnostic procedures (x-rays, blood tests and the like). Instead, these diseases present themselves as abnormally functioning digestive tracts, and are identified by process of elimination and reported symptoms of distress. The most common of these is the irritable bowel syndrome. 219

220

INTEGRATIVE GASTROENTEROLOGY

Experts estimate that 50% to 80% of those suffering from abnormal functioning of the GI tract do not seek medical help and, instead, use over-thecounter prescriptions and/or a variety of complementary and alternative therapies (Mullin, Pickett-Blakely & Clarke, 2008).1 The Foundation of the American Gastroenterological Association, among many other medical associations, makes a variety of nonmedical recommendations for maintaining GI tract health. These include recommendations about diet, but also stress reduction and regular exercise.

The presence or absence of stress and/or physical fitness is seen to play a role in the onset, mitigation, or prevention of GI disorder symptoms. Stress is known to produce wearing effects on the immune, circulatory, and nervous systems. By contrast, deep relaxation has been shown to produce benefits in these systems (Barnes, Treiber, & Davis, 2001; Carlson, Speca, Pate, & Faris, 2007; Jones & Heymen, 2008; Kjaer, Bertelsen, Piccini et al., 2002; Sakakibara,Takeuchi, & Hayano, 1994; Travis & Wallace, 1999; Young & Taylor, 1998). 2,3,4,5,6,7,8. Training in some form of stress reduction tends to produce not only benefits to these systems, but also assists in preparing individuals to encounter stresses at a lower level of anxious arousal. This can assist in improving symptoms and in managing digestive distress (Keefer & Blanchard, 2001; Toner, 2005).9,10

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

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

Taiji, Qigong, and Digestive Health 221

Components of Tai Chi Practice Tai chi (also known as t’ai chi chuan, taiji, or taijiquan) is an ancient Chinese martial art that has long been associated with health promotion. It is practiced in slow, even, and relaxed movements, with an emphasis on diaphragmatic breathing and the goal of circulating energy efficiently and thoroughly throughout the body. It also emphasizes stable, relaxed postures and dynamic balance. Carefully conducted scientific studies have verified many of the benefits of tai chi that have long been claimed by practitioners. These include positive effects on blood pressure, oxygen uptake, cardiovascular fitness, bone density, strength, balance, and agility, as well as improved immune function and enhanced self-efficacy (Yang & Grubisich, 2008; Yang, 2005; Yang et al., under review) To date, there appear to be no studies of tai chi exercise in relation to GI health, though this is also one of the benefits that Chinese masters have long believed results from this practice. Training the mind–body connection (by combining exercise and meditation) is the heart of traditional tai chi training.

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

QIGONG

Qigong, however, holds an equal if not more central role. Qigong (energy cultivation) is exercised through both static and dynamic methods. Static Qigong includes standing, sitting, and lying-down meditation. Standing involves holding specific postures and relaxing into a calm, meditative state. This is one of the ways that tai chi players cultivate the deep relaxation and strong natural structures that are to be used while executing form practice. Although holding a particular posture can be initially somewhat demanding, the muscles are

222 INTEGRATIVE GASTROENTEROLOGY

progressively loosened and the mind is settled on the dantian, the area that radiates from the naval upward to the lower ribs and downward to the pelvic floor. (The dantian is understood to be the center for cultivating and storing energy). In this way, breathing relaxes, deepens, and becomes diaphragmatic. It is through practice in this way that qi (internal energy) is cultivated. With continued exercise, one can enter a state of great calm during static Qigong. (Sitting and lying-down meditation are also central, and used to attain deep calm and relaxation). An old saying (taiji tai he) holds that “peacefulness is a requisite of tai chi” (Yang & Grubisich, 2008). It is also said (Qì gōng néng qū bìng, yuán yóu zài sōng jìng) that “relaxation and tranquility/quietness are the reasons why Qigong can heal you” (Yang & Grubisich, 2008). Lastly, it is often said (Yào bŭ bù rú shí bŭ, shí bŭ bù rú qì bŭ, qì bŭ bù rú shén bŭ), “To improve your health, medicine is not as good as food/nutrition; food/nutrition is not as good as Qi(gong); Qi(gong) is not as good as spiritual nourishment” (Yang & Grubisich, 2008). The “spiritual” component—an important facet of stress reduction—is nurtured in tai chi during static Qigong through the use of positive and tranquil imagery.

DYNAMIC QIGONG

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

Taiji, Qigong, and Digestive Health 223

TAI CHI FORM

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

IMPROVING BRAIN-GUT FUNCTION THROUGH TAI CHI

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

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

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

224

INTEGRATIVE GASTROENTEROLOGY

Table 22.1. Mayo Clinic Summary of Tai Chi’s Empirically Supported Health Benefits • • • • • • • •

Reducing anxiety and depression Improving balance, flexibility and muscle strength Improving sleep quality Lowering blood pressure Improving cardiovascular fitness in older adults Relieving chronic pain Increasing energy, endurance and agility Improving overall feelings of well-being

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

Conclusion No carefully controlled scientific studies have yet examined the effect of a traditional tai chi curriculum on the mitigation of functional GI disorders. Nonetheless, it is our experience that integrating Western medical approaches with Eastern methods of health cultivation, like tai chi, holds significant potential for improved regulation of the brain–gut axis. This belief has been shared by generations of tai chi practitioners based on sustained anecdotal evidence. (Yang & Grubisich, 2008) Further, tai chi offers an approach to a variety of health issues, has no undesirable side effects, is cost effective, and has comparatively low post-intervention dropout rates. (Yang et al., 2008)

23 Digestive Health and Reiki Energy BETH NOLAN

key concepts ■

■

■

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

R

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

225

226 INTEGRATIVE GASTROENTEROLOGY

Reiki Reiki is the Japanese term for universal life energy, a visible and palpable energy that infuses and permeates all living forms (Usui & Petter 2003; Bohm, 1980; Zukav, 1989). Reiki as a healing technique is an energy-based touch therapy that allows life force energy, or chi, to recharge, realign, and rebalance the human energy fields (Honervogt, 1998). Similar to other touch therapies, such as therapeutic touch and healing touch, Reiki involves the use of energy directed by the practitioner’s hands to strengthen the recipient’s ability to heal. It also involves a mind–body connection. Reiki is an ancient energetic healing practice believed to have originated thousands of years ago in the Tibetan sutras, and then lost. It was rediscovered in the 1800s by Dr. Mikao Usui, a Japanese monk (Zukav, 1989). Nurses and others have observed that Reiki may have relaxation and stress-management benefits, and may lessen pain and promote inner healing. However, there is little empirical evidence to show just how it works (Miles & True, 2003; Bullock, 1997; Nield-Anderson & Ameling, 2000). Within the last 10 years, the use of Reiki has increased among nurses, physicians, and rehabilitation therapists, and is practiced in hospitals, hospice care, emergency departments, psychiatric settings, nursing homes, operating rooms, family practice, and many other settings (Barnett & Chambers, 1996). A review of the medical literature fails to produce any published evidence that Reiki can benefit digestive health or disease. However, studies of its ability to reduce stress, rebalance the autonomic nervous system, relieve acute and chronic pain, and ameliorate anxiety and depression have been published (Shiflett, Nayak, Champa, Miles, & Agostinelli, 2002; Wardell & Engebretson, 2001; Olson, Hanson, & Michaud, 2003; Mackay, Hansen, & McFarlane, 2004). Functional digestive disorders (IBS, non-ulcer dyspepsia, non-cardiac chest pain, etc.) and inflammatory bowel disease are chronic illnesses characterized by acute and chronic pain, stress-provoking flares, frequent psychopathology, and improvement of intestinal symptoms in response to mind–body therapies. Thus, Reiki, which has been shown to improve these core imbalances of pain and dysfunction, is likely to benefit patients with many digestive illnesses.

24 Self-Care Journaling for Digestive Health DANNA M. PARK

key concepts ■

■

■

■

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

Self-Care Journaling: Theory

J

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

227

228 INTEGRATIVE GASTROENTEROLOGY

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

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

Self-Care Journaling for Digestive Health 229

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

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

230 INTEGRATIVE GASTROENTEROLOGY

Table 24.1. Patient Handout Using journaling to aid digestive health

What Is Journaling? Journaling is the process of writing about times in our lives that were stressful or traumatic. It provides an avenue for the expression of thoughts and memories that may have been internalized. These repressed emotions can often lead to a worsening of physical symptoms. William Boyd, a pathologist at the turn of the 19th century, described this process well; he wrote, “The sorrow that hath no vent in tears, may make other organs weep.” Journaling is one type of therapy that can be used to aid this process. How Does It Work? Studies have found that if we express feelings about a time in our lives that was very traumatic or stressful, our immune function strengthens, we become more relaxed, and our health may improve. Writing about these processes helps us organize our thoughts and create closure to an event that the mind has a tendency to want to suppress or hide. This can be done in the privacy of your home and requires only pen and paper. Does Anybody Need to Read It? No. You can share your writings with others if you desire, but no one needs to read what you write. The most benefit comes from writing the document, and the words can be thrown away if you desire. In fact, some people find that burning or destroying the document can add ceremony to the process. Letting the wind carry away the smoke can act as a positive metaphor that helps them let go, forgive, and heal. Others prefer to keep their writings private, so they can look back on them and see how they have grown from the events. Are There any Side Effects or Things I Should Be Aware Of? Recalling stressful memories can make you feel uncomfortable for a few days. If this were not the case, the body would not use so much energy trying to repress them. The benefits of journaling become most apparent weeks to months after writing. This process can bring back into mind some frightening events for which you may need the help of a licensed counselor. Please notify your medical practitioner if you develop feelings that would benefit from further discussion. This is often the first step toward creating an environment that will promote healing from within. How Is It Done? There are many different ways to express emotions. Journaling is simple and inexpensive, and can be done independently. It would be beneficial to keep a regular journal to write about events that bring anger, grief, or joy. But if that is unlikely, and you just want to deal with a specific event or see whether this technique will help your condition, follow these steps:

Self-Care Journaling for Digestive Health 231

Table 24.1. (Continued) Using journaling to aid digestive health

1. Find a quiet place where you will not be disturbed. 2. Using pen, pencil, or computer, write about an upsetting or troubling experience in your life, something that has affected you deeply and that you have not discussed at length with others. 3. First describe the event in detail. Write about the situation, surroundings, and sensations that you remember. 4. Then describe your deepest feelings about the event. Let go and allow your emotions to run freely in your writing. Describe how you felt about the event then, and how you feel now. 5. Write continuously. Do not worry about grammar, spelling or sentence structure. If you come to a “block,” simply repeat what you have already written. 6. Before finishing, write about what you may have learned or how you may have grown from the event. 7. Write for 20 minutes for at least 4 days. You can write about different events, or reflect on the same one each day. 8. If the process proves helpful, consider keeping a journal regularly. How Can I Learn More? An excellent resource for more information on this subject can be found in Opening Up: The Healing Power of Expressing Emotions by James Pennebaker (Guilford Press, 1997). There is also a comprehensive web site on the subject: www.journaltherapy.com This article was published in Integrative Medicine, Second Edition. David Rakel, Chapter 98, page 1043. Copyright Elsevier 2007.

25 Spirituality FREDERIC C. CRAIGIE , JR.

key concepts ■

■

■

■

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

S

pirituality frames a broad and central aspect of human experience having to do with meaning and purpose, life force, and enlivening and sustaining relationships with spirit. (Craigie, 2010) Former Surgeon General C. Everett Koop, for instance, has defined spirituality as “the vital center of a person; that which is held sacred.” (Koop, 1994) Spirituality is not synonymous with religion. For some people, “the vital center” and “sacredness” are expressed in the context of religious traditions and communities; for other people, spirituality is a more personal journey, or one that is not aligned with a particular religious faith. There has been lively interest in the interface of spirituality with medicine (e.g., Levin, 2001) and with integrative medicine (Craigie, Silverman & Maizes, 2007) in recent years. The emerging literature suggests that spirituality is important in healthcare for a variety of reasons. First, the spirituality of 232

Spirituality 233

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

Spiritual Care in Integrative Medicine Spiritual care begins with compassionate presence (Puchalski, 2004), and with the ways compassion and healing intention are embodied in the clinician. (Craigie, 2010) A family physician describes this well: “Before I go in a room, I stand briefly outside the door, feet flat on the floor, and remind myself why I want to be there for the patient I am about to see.” (Interview notes from Craigie and Hobbs, 1999) Healthcare practitioners may pursue many approaches, such as meditation, prayer, affirmations, and devotional or inspirational readings, to cultivate a spirit of compassion, mindfulness, and healing intention as they move through their days.

234 INTEGRATIVE GASTROENTEROLOGY

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

Spirituality 235

of a range of practices and pursuits as they speak with patients, and may make their own suggestions. Examples include mindfulness and meditative practices (Kabat-Zinn, 2005), rituals, ceremonies and sacraments (Hammerschlag & Silverman, 1997), participation in religious or spiritual communities, service or volunteer work, and creating or journeying to sacred places.

Summary Spiritual beliefs and practices are strongly associated with well-being and health. Clinicians incorporate spirituality in healthcare by cultivating their own centeredness, intention, and compassionate presence with patients. Clinicians also support patients’ spiritual resources by encouraging patients to express the values and activities that are “vital and sacred” in their lives. While spirituality in medicine is not defined by specific techniques, there are often particular practices, such as meditation, prayer, forgiveness, devotional reading, and community gatherings that draw upon patients’ spirituality as a healing force. Chaplains and other spiritual care specialists can often be very helpful clinical partners when patients are particularly distressed and burdened by spiritual issues.

26 What Patients Want from Their Doctors DONNA JACKSON NAKAZAWA

A

fter my book, The Autoimmune Epidemic, came out, I heard from thousands of people from every conceivable background who suffered from a wide range of diseases. In conversations and emails, they shared with me their experiences of illness and treatment, their hopes, disappointments, and lessons gleaned. At the heart of each of their stories is the tale of a patient’s relationship with his or her doctor and how it helped—or hindered—the patient’s journey toward wellness. Their stories, along with the experiences of patients I interviewed while researching The Autoimmune Epidemic, and my own decade-long journey as a patient in the American medical system, have taught me what American patients want—and desperately need—from their doctors. Patients love to tell “doctor stories”; the good, the bad, and the unfortunate. Often, those suffering from illness want to tell me stories about the first doctor who really (finally) listened to them, that compassionate healer who went the unexpected extra mile to help solve the mystery of their illness. They want to share the tale of the practitioner who gave them a clear message of hope—a conviction that they could be well—which became a mantra that settled somewhere in their psyche and played a part in nudging them toward recovery. But, more often, the stories they tell me are about doctors who didn’t listen, or didn’t seem to care, or dismissed them as malingerers; practitioners whose obvious condescension still rankles them to this day. This concern with what makes a good doctor isn’t surprising when you consider recent statistics that 133 million Americans suffer from a chronic disease, be it heart disease, cancer, severe back pain, arthritis, autoimmunity, or a plague of other challenging ailments that derail normal life. These chronically ill patients often traipse from one healthcare professional to the next in search of answers and relief—a process that can take years. Indeed, the average autoimmune disease patient, of whom there are now 24 million in the United States alone, sees four doctors over four years before receiving a proper diagnosis. This search for a good doctor can be emotionally arduous. Recent surveys 236

What Patients Want from Their Doctors 237

conducted by the American Autoimmune Related Diseases Association reveal that 45% of patients with diagnosed autoimmune diseases were told that they were hypochondriacs at some point in their medical care. Increasingly, patients who feel they need more than what traditional medicine can offer go “off the reservation,” seeking help from holistic and alternative healthcare specialists as well. Whether a patient seeks the help of traditional or alternative/complimentary practitioners (or, as a majority of patients now do, both) all “healer stories” really contain the same key themes. If the good healthcare practitioner were a recipe, the four integral ingredients would be these: 1) Compassion. Patients know whether healthcare professionals have it or they don’t. Doctors who express compassion for their patients’ pain and circumstances stand out immediately. I know a well-known transverse myelitis and multiple sclerosis specialist at a major medical institute who, when he diagnoses a patient, feels so deeply for them that he always hands them his cell phone number, because he knows there will be “dark moments” where they will have “sudden, urgent questions” that can’t wait for the next clinic visit. And I have heard his voice crack when he talks about the loss of a young patient he could not save. Another physician revealed the strength of his character when, after diagnosing me with Guillain Barre Syndrome, a disease in which the body becomes increasingly paralyzed degree by steady degree, he sat with me in a small, white exam room at Johns Hopkins, talking with me quietly for an hour and a half, while my mother and husband rushed to arrange admission to the hospital, collected my bags from home, and arranged for child care. He stayed with me, he said, because he didn’t want me to wait alone after the devastating news he’d just delivered—even though nurses were rapping on the exam room door, and his patient waiting room was near to overflowing, and it no doubt meant he would go home much later that night to his family than he might like. He is a very decent man, a good man, and the numerous patients I know who see him use those words to describe him whenever they mention his name. On the other hand, there are doctors and practitioners who make it clear that you are taking up too much or their time, or wearing their patience thin with your illness—mentally placing you, perhaps unconsciously, somewhere in the category of the famous Freudian hysterics (especially if you are a woman). They don’t respect their patients. I can’t help but think of the story of one young woman, now president of a large advocacy group for autoimmune disease, who was in her early 30s when she began suffering from severe muscle fatigue and disabling weakness. Her doctor, whom she’d seen eight times, was unable to come up with a diagnosis. “We’ve given you every test known to man but an autopsy,” he said. “Would you like one of those, too?” She was later

238

INTEGRATIVE GASTROENTEROLOGY

diagnosed with myasthenia gravis by a doctor who took time to understand the complex portrait presented by her symptoms and lab work. I recall, in my own health tribulations, seeing a doctor who, despite my history of severe autoimmune issues, paralysis, and other complications, yelled at me in his office: “Yesterday you came in here saying you were nauseated, and now today you say you have diarrhea! Make up your mind, which one is it?” The next day I ended up in the emergency room and was hospitalized. While I was there I was treated by a GI specialist who came into my hospital room on several different occasions at the end of the day and sat down, his briefcase on his lap, to talk to me about pursuing wellness strategies outside the box. The hospital by that hour was growing quiet and dark, he had already seen me earlier in the day during the requisite rounds, and his day was now done. Yet, he had enough compassion for a mom with two young children to take time to educate me about how to approach my GI problems more holistically—advice which, over the next two years, would lead to turning around my GI symptoms. Of course, delivering compassion means building time into the patient–doctor relationship to allow for that extra, meaningful exchange—a conundrum in a healthcare climate that has shaved the average doctor’s visit down to a mere matter of minutes. I would bet that a doctor who has been consistently stripped of time has also been stripped of compassion. The question healthcare professionals need to ask themselves is this: which type of practitioner would you prefer to see? The one who gives you their cell number, or sits with you after a tough diagnosis, or the one who speaks to you disrespectfully or impatiently? Granted, most practitioners fall somewhere in between, but patients search hard and long for the former, and never forget them when they are lucky enough to find them. Compassionate doctors emerge as central figures when patients share their healing stories. 2) A Deep and Growing Fund of Knowledge. Of course, compassion alone hardly makes for a good healer. If a healthcare specialist doesn’t possess a deep fund of knowledge—and the curiosity to constantly keep abreast in their field to extend their acumen—all the compassion they can muster can’t make up for what they just don’t know. One woman consulted three local doctors, several times each, over eight months; they all missed her multiple sclerosis. She then saw a university hospital specialist who suspected MS in the first visit, ordered a series of tests, and diagnosed her disease that same week. “Why didn’t those other three doctors even know enough to suspect MS?” she asks. Another young woman described suffering from severe thirst, dizziness, fatigue, and a 20-pound weight loss over three weeks, but the doctor she was seeing dismissed her complaints and told her, “You just need to gain some weight. Go have a banana split and you’ll be fine.” A few hours after that appointment, a friend found her in a near-diabetic coma on her sofa and rushed her to the

What Patients Want from Their Doctors 239

emergency room, where she was diagnosed with Type 1 diabetes. “How did he miss it, given the state I was in?” she asks. These stories become the doctorwho-didn’t-get-it lore that patients so often vent about with each other. But patients also share positive stories about practitioners who, although they may not have ready-made answers, commit time and energy to solve their patient’s case. One patient suffering from severe fatigue and poor appetite for half a year told me of his relief in finding such a doctor. He had already been to two doctors who “couldn’t find anything” (one of whom handed him antidepressants). A third physician confessed that he, too, was perplexed, but he took a different approach. He put his hand on his patient’s shoulder and reassured him, “I don’t know what’s causing this, but I promise you we’re going to figure this out together.” It took several weeks and much diligence to determine that he was suffering from an uncommon parasite infection. Likewise, another patient talks about meeting a doctor who surprised and moved her by asking her to “start by telling me about the last time you were well.” This patient confesses, “No one had ever asked me anything like that before.” Indeed, this doctor’s narrative approach to obtaining her patient’s medical history was just the first of many ways in which she showed her commitment to helping this patient toward recovery. 3) Open to Complementary Approaches. In a healthcare world in which the majority of patients now use alternative medicine, it’s a given that patients want physicians whose fund of knowledge includes being well-versed in complementary medicine. Patients seek doctors who are able to offer advice on food as medicine, safe supplements, exercise, stress management, and who are willing to move beyond disease labels to delve into what combination of factors may lead to a patient to falling ill in the first place. But this kind of physician can be tough to find. Hundreds of patients (including many with inflammatory bowel disease, a disease whose course is known to be influenced by diet) have told me that the physician or specialist they see never mentions diet or supplements to them at all. Yet, by working with a nutritionist whom they seek out, or by researching the role of nutrition in their ailments on their own, they are able to help turn their disease around. When patients find the rare physician who competently blends Western and complementary approaches, they stick with them, and they refer other patients to them as well. One young woman with rheumatoid arthritis told me about her relief in finding a doctor who not only helped her sort out the side effects among her choices of medications, he also emailed her recent groundbreaking studies to convince her to make dietary changes that would improve her health. Patients today take a proactive role in their own wellness journeys—and they view allopathic physicians who rely solely on drugs as being out of touch with the growing data that exists on how lifestyle factors

240

INTEGRATIVE GASTROENTEROLOGY

impact one’s well-being. Of course, office visits that allow time for discussions of diet and lifestyle, as well as writing prescriptions, take longer—and patients are choosing healthcare practitioners who have built that buffer time into their patient schedule. 4) A Champion of Hope. Patients seek healthcare specialists who avoid focusing on negative outcomes and referring to diseases as “degenerative” or “progressive,” and who, instead, offer as part of their Rx the conviction that their patient can and will have a hopeful, positive outcome. Indeed, patients love to tell stories about how their practitioners’ encouraging statements of hope and healing, statements that emphasize the miracles the human body is capable of, often become the patient’s own inner affirmation that they can and will be well. One woman’s doctor told her, during a particularly difficult time in her battle with cancer, “You are going to beat this and you are going to live a totally normal life.” This doctor couldn’t know that to be true, but by saying it with conviction, she helped her patient to believe it too, and might just have helped to save her patient’s life. At least her patient—ten years later—believes that her doctor’s faith helped to pull her through. In my own health history, this certainly has been the case. The neurologist who sat beside me those long hours after diagnosing me with Guillain Barre later saw me through a repeat episode of the disease. The second time Guillain Barre strikes (and it is rare for it to strike twice) it is much more damaging. It took me five months to learn to walk unaided again. During this time, several other neurologists at the hospital where I was being treated made it clear that they were dubious that I would ever regain my mobility. I asked my neurologist, “Why are they all warning me to prepare for the worst?” He shook his head. “Don’t listen to that,” he said. “I’m your doctor and I know you. Patients have recovered and been able to walk again after having Guillain Barre twice. I know you. They don’t know you. And I know that if it can be done, if it is possible, then you will do it.” Could he have known, as he said these words, that his reply would stay with me day in, day out, that long, hard summer, as I spent hours in grueling physical therapy, first learning to walk to the door of my bedroom, then finally—five months later—down the steps and out the door? Healthcare professionals who offer up compassion, a deep fund of knowledge of both Western and complementary treatments, and a heartfelt prescription for hope, facilitate better patient outcomes. But that’s not the only good news. In my work, I also talk to and hear from numerous doctors and healthcare practitioners who tell me that when they offer this “recipe” to their patients, their lives as healers become imbued with greater meaning, and their own work lives are all the more joyful and rewarding.

27 The Value of Support Groups PEARL L. LEWIS AND GERARD E. MULLIN with a foreword by Bernie Siegel

key concepts ■

■

■ ■

■

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

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

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

241

242

INTEGRATIVE GASTROENTEROLOGY

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

Overview Illness represents an imbalance between the individual and society, and requires participation of the patient’s family and community members to restore balance. In many ancient traditions (e.g., Celtic, Native American Indian), community members contribute to the healing of the sick. In Western medicine, these traditions are often substituted with isolation and separation of the sick from society, resulting in concomitant depression, disability, and despair. However, groups of patients have rallied by organizing support systems that work in concert with special-interest medical societies (e.g., Crohn’s and Colitis Foundation of America). The concept of group support in the healing practice of Western medicine evolved from the success of Alcoholics Anonymous in the 1930s. Today, support group members provide each other with various types of help for a particular shared, usually burdensome, illness. The help may take the form of providing and evaluating relevant information, relating personal experiences, listening to and accepting others’ encounters, providing sympathetic understanding, and establishing social networks. A support group may also work to inform the public or engage in advocacy. A variety of studies support the idea that social isolation is associated with adverse health outcomes and that self-expression, education, and sense of community can lower levels of stress hormones, improve quality of life, and enhance immune function (Gordon, 2006). Key studies are summarized below: 1. All-Cause Mortality. Social isolation itself has been identified as an independent major risk factor for all causes of mortality (House, Landis, & Umberson, 1988). Being well integrated socially reduces allcause, age-adjusted mortality by twofold—about as much as having low versus high serum cholesterol levels or being a nonsmoker (House, Landis, & Umberson, 1998).

The Value of Support Groups 243

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

244

INTEGRATIVE GASTROENTEROLOGY

1. Connection in the Community (Egolf, Lasker, Wolf, & Potvin, 1992). A 50-year observational study followed the health of residents of the towns of Roseto, Bangor, and Nazereth, Pennsylvania. In the 1930s and 1940s, it was noted that the town of Roseto had a significantly lower rate of acute myocardial infarctions (MIs) than its neighboring communities, despite equal prevalence of diabetes, obesity, and highfat diet in the three towns. During the follow-up in the 1970s, the rates of MI and overall mortality substantially increased in Roseto, but not the other towns. When health behaviors were analyzed, there were still no significant differences in the three communities as to smoking, weight, diet, diabetes, or other risk factors. What had changed, however, was the social structure of Roseto, whose close family ties and community practices (mainly religious) in the 1930s and 1940s began to disintegrate in the late 1960s. At the same time, the rates of MI and mortality began to rise. This is the longest of multiple studies of communities that show a clear relationship between community activity, social structure, and the rates of disease. It also points toward the role of community practice and its effect on disease prevalence. 2. Support Group Connection as Intervention: Benefits of Support Groups. During the last 30 years, researchers have shown great interest in the phenomenon of social support, particularly in the context of health. Prior work has found that those with high quantity or quality of social networks have a decreased risk of mortality, compared with those who have low quantity or quality of social relationships, even after statistically controlling for baseline health status (Westaway, Seager, Rheeder, & Van Zyl, 2005). In fact, social isolation itself has been identified as an independent major risk factor for all-cause mortality (Fischer Aggarwal, Liao, & Mosca, 2008). Current research has focused on expanding several areas of knowledge in this field. These include social support influences on morbidity, mortality, and quality of life in chronic disease populations, understanding the mechanisms responsible for such associations, and understanding how we might apply such findings to design relevant interventions. In researching the topic of the value of social support in various chronic diseases, we found that support was valuable, no matter what the disease. One study demonstrated that: (1) socio-emotional and tangible support were the underlying dimensions of social support; (2) socio-emotional support is an important determinant of health and well-being; and (3) social support is beneficial for one aspect of diabetes mellitus management, namely, blood pressure control (Eisenberger, Taylor, Gable, Hilmert, & Lieberman, 2007).

The Value of Support Groups 245

In an ethnically diverse population, emotional social support was linked to higher high-density lipoprotein cholesterol levels, through increased physical activity and wine intake, suggesting possible mechanisms through which social support may reduce cardiovascular disease risk (Shepp, Chase, & Rawls, 1999). 1. Key studies in which a psychosocial “connection” intervention altered disease outcomes for diseases not generally considered psychosomatic diseases: Metastatic Breast Cancer (Spiegel, Bloom, Kraemer, & Gottheil, 1989). In this study, women with metastatic breast cancer attended a weekly 90-minute group support session for one year. Follow-up occurred over 5 years. The initial hypothesis was that group support would help these women adjust to their disease, as well as help with anxiety, depression, and other psychosocial issues. The outcomes supported this hypothesis. A more dramatic and surprising outcome was that the group-support patients lived twice as long as the control group (18 months versus 9 months on average). Malignant Melanoma (Fawzi, Fawzi, & Hyun, 1993). In this study, patients who had undergone local resection of malignant melanoma were placed in a 6-week support group. They were then followed for 5 to 6 years. No other intervention was used. There were 13 recurrences and 10 deaths in the control group, compared with 7 recurrences and 3 deaths in the support group, results that were statistically significant.The Ornish program for reversing heart disease (Ornish et al., 1983, 1990, 1998; Ornish, 1998). This series of studies has followed up to 477 patients. The intervention includes a low-fat vegetarian diet, exercise, yoga, and group support. These trials have had remarkable success in reversing CAD and diminishing adverse events, procedures, and cost of care. Individuals in groups that bond well and interact well in their group sessions tend to have greater improvements on subsequent angiograms, and fewer adverse outcomes than those in groups that become dysfunctional. The group model of intentional connectedness is clearly one of the most powerful tools we have to combat illness-related depression and anxiety. It is also one of the most potent effectors of behavioral change, as documented in chemical dependency programs. Even venting itself appears to impact the outcome of illness (Spiegel, 1999). The above studies (and others) show that group support significantly affects the clinical course of a person with an illness. 2. The healing physiology of support group connection: underlying mechanisms.

246

INTEGRATIVE GASTROENTEROLOGY

It is well established that a lack of social support constitutes a major risk factor for morbidity and mortality, comparable to risk factors such as smoking, obesity, and high blood pressure. Although it has been hypothesized that social support may benefit health by reducing physiological reactivity to stressors, the mechanisms underlying this process remain unclear. Cormier (2005) reported that individuals who interacted regularly with supportive individuals across a 10-day period showed diminished cortisol reactivity to a social stressor. Moreover, greater social support and diminished cortisol responses were associated with decreased activity in the dorsal anterior cingulate cortex (dACC) and Brodmann’s area (BA) 8, regions previously associated with the distress of social separation. Lastly, individual differences in dACC and BA 8 reactivity mediated the relationship between high daily social support and low cortisol reactivity, such that supported individuals showed reduced neurocognitive reactivity to social stressors, which in turn was associated with reduced neuroendocrine stress responses. This study is the first to investigate the neural underpinnings of the social support–health relationship, and provides evidence that social support may ultimately benefit health by diminishing neural and physiological reactivity to social stressors. Other mechanisms may explain the health benefits of support group connection. Intentional connection (group support), interpersonal connection (marriage, friendship, and pets), and community connection (participation in church groups and social groups), have all been shown to decrease life stress. Life stress is internally mediated through the release of catecholamines, cortisol (if chronic), and probably other neurohormonal mechanisms. Social isolation is associated with elevated catecholamines and cortisol. Catecholamines and cortisol contribute directly to disease susceptibility through the following mechanisms: increased blood pressure, increased blood viscosity, increased platelet adhesion, increased endovascular reactivity and endothelial inflammation, increased production and release of proinflammatory cytokines. For example, IL-6 has been found to be inversely associated with social integration in men (Loucks et al., 2006). Social support predicted lower stimulated levels of IL-8, IL-6, and tumor necrosis factor (TNF-α) (Marsland, Sathanoori, Muldoon, & Manuck, 2007). Immunologic Mechanisms (Kiecolt-Glaser & Glaser, 1993). The healing benefits of group support connections occur through immunologic mechanisms as well. Cortisol suppresses immune function. Group support has been shown to be effective in the treatment of autoimmune diseases. Psychosocial factors have been shown to affect the susceptibility to, or the progression of, autoimmune diseases, infection, and cancer. Immunologic reactivity is altered by stress. Findings for people under stress include: decreased NK cell activity Gamma interferon levels decreased by 90 percent, decreased T-cell responsiveness, decreased immune responsiveness, increased

The Value of Support Groups 247

upper respiratory infections. Social connection for caregivers was correlated directly with immune function. The most convincing research backing the use of support groups appears in Current Opinion in Psychiatry (Remblin & Unchino, 2008). The researchers postulate that the acts of giving and receiving support have unique pathways to stress reduction: Giving is mediated by increased efficacy, leading to lower stress, while receiving support has a direct effect on stress. Taken together, studies such as these suggest that there is something potentially unique about the act of giving support. It may be that people experience positive affect while helping others, which may improve their health. Or it may be that benefits occur in the context of a high-quality relationship in which one feels valued and can reciprocate by providing support. In isolation, there is no hope; without hope, life can be bleak. By referring your patient to a support group, and participating with a support group yourself, you can give your patient the most valuable of gifts—one that complements and assures compliance with your medical treatment.

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

From Where I Stand: Pearl Lewis Chronic digestive disease brings with it, besides physical symptoms, a host of psychological and emotional issues that can have negative effects on one’s family life, education, and progress in the work force. The path to a correct diagnosis is often long. During this time, the patient may be told his or her condition is either stress-related or “all in your head.” As a result, painful

248

INTEGRATIVE GASTROENTEROLOGY

symptoms such as depression, anxiety, and isolation can dash one’s hopes for the future. In the most severe cases, income from work is replaced by Social Security Disability; health benefits are replaced by Medicare—after a 24-month waiting period without access to healthcare.

Group Support Related Specifically to Digestive Disease1 Most people are familiar with the Crohn’s and Colitis Foundation of America. This organization has existed since the 1970s and has provided education, support, and research funds for Crohn’s disease and ulcerative colitis. During the last several decades, however, there has been a proliferation of support groups for almost every digestive disease (refer to the list in the appendix). One of the newest members of the digestive healthcare team originated at a 550-bed tertiary care center in the Southeast, which created an interactive, educational patient and family support group for people with pancreatitis. No previous support groups for this population could be located in the United States, even though pancreatitis may progress to include chronic pain, frequent hospitalizations or emergency room visits, narcotic dependence, and depression. The group used a partnership model as a basis for helping empower patients and their family members to have more understanding of, adaptation to, and participation in the treatment choices and responsibility for managing symptoms of their chronic illness. Facilitated by a multidisciplinary team, this is the first group of its kind in the United States and was enthusiastically received by those who participated. “Abundant research supports the premise that social support facilitates patient well-being and contributes to health and health promotion through interpersonal interactions,” write Klytta and Wiltz (2007). “Gastroenterology nurses are well positioned to facilitate improved outcomes in patients with chronic hepatitis C virus by initiating interventions designed to enhance existing sources of social support or to promote new ones. Development of psychosocial interventions, such as support groups, aimed at maintaining or fostering social support, may improve health outcomes and promote a higher healthrelated quality of life for persons living with chronic hepatitis C virus.” Whether one has irritable bowel syndrome, hepatitis A, B, or C, clostrodium difficile, gluten intolerance, celiac sprue, or an ostomy, there are support groups for it online or located in a town nearby.

1

See Directory of Digestive Diseases Organizations for Patients in Appendix B.

The Value of Support Groups 249

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

250 INTEGRATIVE GASTROENTEROLOGY

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

28 Overview of Visceral Manipulation for the Integrative Gastroenterologist JEAN-PIERRE BARRAL AND GAIL WETZLER

key concepts ■ ■

■

■

■

An organ in good health has physiologic motion. The interrelationship of structure and function among the internal organs is interdependent. Mobilizing the organs increases proprioceptive communication in the body and enhances internal mechanisms for better health. Research demonstrates that the beneficial effects of visceral manipulation are due to the return of normal organ mobility and pressure, rather than the return of normal anatomical position. Current evidence suggests that during functional gastrointestinal disease, organs lose their mobility and inherent tissue motions. Visceral manipulation is the primary modality used to explore these fixations, and restore heir natural rhythm and motion for better function. ■

What Is Visceral Manipulation?

V

isceral Manipulation (VM) is a manual therapy consisting of gentle yet specifically placed manual forces that encourage normal mobility, vascularity, tone, pressure, and inherent tissue motion of organs, their connective tissues, and their relationship to other areas of the body where physiologic motion has been impaired. The central premise of VM is that an organ in good health requires physiologic motion (Barral, & Mercier, 1988). 251

252

INTEGRATIVE GASTROENTEROLOGY

Table 28.1. Visceral Manipulation (VM) Parameters Visceral Manipulation is a modality concerned with the 3-dimensional dynamics of organ biomechanics and how they relate to the body (including connective tissue structures, vascular, nervous, and musculoskeletal systems). Visceral Manipulation Parameters: • Are derived from the concept that good health is not a state, but a search for equilibrium. • Healthy organs have an axis of motion in which mobility and motility are the same. • Structure and function are interrelated. Movement and function are interdependent. • Movement within the organs, such as secretions, absorption, blood and lymph circulation, peristalsis, respiration, nutrition and immune mechanisms, creates physiological efficiency.

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

Overview of Visceral Manipulation for the Integrative Gastroenterologist 253

TABLE 28.2. Influences of Visceral Mobility Central nervous system

Voluntary movement of musculoskeletal system

Autonomic Nervous System

Diaphragm motion Peristalsis Reflex activity in the CNS and PNS

Articulations

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

Pressures

Subatmospheric Tugor Gravity

as mobility, deformation, compressibility, viscoelastic compliance, elongation, and organ secretion of fluids (Stone, 2007). The goal of mobilizing the organs is to facilitate their ability to move when stimulated by central nervous system (CNS), autonomic nervous system (ANS) or enteric nervous system (ENS) activity, and to respond to fluid dynamics (Table 28.3; see Stone, 2007; Barral, 1989; Allison, Dhillon, Lewis and Pounder, 1998). Further research on how manual therapy affects the ANS is currently being conducted at the University of North Texas Health Science Center (Osteopathic Research Center, 2008). Three major processes have been identified as being potentially influenced by manual therapy (Barral, 1988): (a) repair process, (b) fluid flow dynamics, and (c) adaptation process (length; see Lederman, 2005) Table 28.3. The Goals of Visceral Manipulation Treatment 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

Restore functional mobility Restore motility Restore soft tissue elasticity Restore fluid exchange Restore pressure systems between the cavities and inside the organs Restore physiologic function Relieve pain Resolve the mechanical link compensation Restore proprioceptive communication Restore local and systemic responsiveness Restore viscerosomatic relationship Restore visceral-emotional relationship (Barral, 1988; Stone, 2007)

254 INTEGRATIVE GASTROENTEROLOGY

Clinical Relevance INFLAMMATORY BOWEL DISEASE

It is our expert opinion that many functional digestive disorders have vascular origins. Manual treatment of the mesenteries that house blood vessels is necessary to improve functional digestive illness. Since these membranes are highly reflexogenic, if they contain abnormal tension, vasoconstriction may result (Barral, 1989). The literature reports that inflammatory bowel disease is associated with vasomotor instability, congestive regional lymph nodes, mucosal ulcerations/scarring, inflammation of the intestinal wall, and abnormal tonus and extensibility of the colon (Pounder, 1998; Hudson et al., 1992; Sankey et al., 1993). The entire gut should be treated because it can lose elasticity easily, create multiple adhesions, and go into more frequent spasm with ANS and vagus nerve influences (Table 28.4.).

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

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

Table 28.4. Treatment Considerations for Inflammatory Bowel Disease 1. 2. 3. 4. 5. 6. 7. 8.

Intestinal function depends on diaphragmatic mobility and intestinal peristalsis Hepatic and splenic flexures are suspended from the diaphragm Transverse colon is subject to diaphragm attraction Greater omentum as it links the stomach to the transverse colon and connects laterally on the diaphragm Dysfunctional sphincters disrupt the pressure differentials Vagus Nerve and ANS techniques for abnormal tonus and peristalsis Influence of urogenital system restrictions Colon, duodenum and jejunoileum mobility and motility

Overview of Visceral Manipulation for the Integrative Gastroenterologist 255

and ultimately to the parietal peritoneum, causing a mechanical chain of fascial pain (Steer et al., 2003). The fascial coverings of organs limit expansion and increase internal pressure, which further compromises the neural tissue. The pain pathways barrage the area of synapse within the cord, promoting viscerosomatic disorders. In IBS, it is important to know how to manipulate the colon at junctions and sharp angles (flexures), as these are areas of lesser circulation where there can be risk of ischemia and inflammation (Steer et al., 2003; Barral & Mercier, 1988).

DYSPEPSIA

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

GERD When reflux occurs due to a dysfunctional hiatal zone, the visceral practitioner will evaluate for the dominant mechanical cause of the symptoms (Table 28.5). The manual technique for gastric ptosis, or loss of elasticity in the organ ligaments, has been checked several times with fluoroscopy. These studies showed the pyloric antrum had moved upward by as much as 5 cm. (Dr Searge Cohen) Manipulations of the hiatus can facilitate resolution of gastroesophageal reflux disease (GERD; see Michallet, 1989). (17)

256

INTEGRATIVE GASTROENTEROLOGY

Table 28.5. Structural Causes of GERD That Can Be Addressed by VM • • • • • • • • •

R/O cervical or brachial plexus problems that can provoke phrenic nerve irritation Diaphragmatic hypertonicity Thoracic or abdominal scarring Esophagus/stomach immobility Fascial restrictions of surrounding tissues/organs Gastrophrenic ligament and upper fundus restrictions T5, T6 viscerosomatic restrictions T12–L3 spinal mechanical restrictions Gastric ptosis (loss of elasticity in the organ ligaments)

Experiments • Alain Crobier, DO, J.P. Barral, DO. (2007–2008). Effects of manual therapy on the vascular system of 200 different people using the Doppler for pretreatment and post-treatment evaluations. Dissections • During 1970–1974, more than 100 cadavers were dissected with Dr. Barral and Professor Arnaud in Grenoble, France, to better understand anatomy and its interrelationships. Video • Visceral Manipulation by Jean Pierre Barral, 2005, Coproduction of Eastland Press, Inc., and the Verlag fuer Ganzheitliche Medizin, Dr. Erich Wuehr, GmbH Website • www.barralinstitute.com

SUMMARY

Based on the central premise that organs in good health require physiologic motion, mobilizing the viscera can be beneficial in the treatment of internal organ dysfunction. We have treated more than 104,000 patients with visceral manipulation, providing us with expert evidence and real-life clinical experience. We firmly believe that manipulations should be precise, with the goal of a whole-body response and for the achievement of homeostasis. Visceral manipulation should be considered as part of an integrative approach to digestive disorders.

29 Probiotics in the Prevention and Treatment of Gastrointestinal Disease GERALD FRIEDMAN

key concepts ■

■

■

■

■

■

Probiotics are “live microbial feed supplements that beneficially affect the host animal by improving its intestinal microbial balance.” Prebiotics are “non-digestible food ingredients that beneficially affect the host by selectively stimulating the growth and/or activity of one or a limited number of bacteria in the colon.” Clinical situations where probiotics may play a role in the alleviation of disease include lactose intolerance, infantile necrotizing enterocolitis, antibiotic-associated diarrhea and clostridium difficile colitis, irritable bowel syndrome, traveler’s diarrhea, ulcerative colitis, Crohn’s disease, bacterial overgrowth syndromes, colon carcinoma, food allergy, and gut-origin septicemia. There are a limited number of well-regarded, randomized, placebo-controlled, double-blind trials on the effects of probiotics on antibiotic-associated diarrhea, pouchitis, and irritable bowel syndrome. Probiotics appear to be most efficacious in the prophylaxis of disease, and as maintenance therapy. Probiotics are derived from “normal” commensal bacteria and, as such, are generally safe for short-term use. Caution should be used with severely immune-compromised subjects, patients with central vein catheters, and patients with valve replacements. Future research using single-strain or multi-strain probiotics in humans will provide further supporting evidence for the value of probiotics. ■

257

Introduction

P

robiotics have been in vogue intermittently since the turn of the century, when Eli Metchnikoff received the Nobel Prize for observations on the value of lactic acid-producing bacteria in enhancing health and longevity (Metchnikoff, 1910). Presently, there is renewed interest in the contributions of commensal bacteria to human health. Major advances in defining the quality, quantity, and physiologic activity of the intestinal microbiota were enabled by the conversion of culture-based techniques to genetic analysis. Now, DNA sequences can define the profiles and functions of microorganisms inhabiting the GI tract (Schloss & Handelsman, 2005). To better understand the critical value of commensal microbiota, it is important to know the nature, number, anatomic distribution, and development of these hollowtract bacteria.

Commensal Bacteria The adult human intestinal tract contains approximately 100 trillion microbial organisms known as microbiota (Backhed et al., 2005). These essentially anaerobic organisms contain more than 500 species. The longitudinal distribution of intestinal microorganisms increases in density, progressing from the small bowel to the colon. In the duodenum and jejunum, aerobes and facultative anaerobes contain 103 to 105 organisms/gram luminal contents. The terminal ileum contains approximately 107 to 108 organisms/gram luminal contents, and the colon contains 1010 to 1011 organisms/gram luminal contents (Berg, 1996). The microbiota benefit the host by performing metabolic functions, including energy-producing fermentation of malabsorbed carbohydrates, producing short-chain fatty acids, adding to trophic action on the epithelium, producing vitamins (B vitamins and vitamin K), and playing a pivotal role in the development of the immune system.

Development of Intestinal Microbiota The initial manner of acquisition of intestinal microbiota affects the rate and the nature of the development of the immune system. The host genotype and birth environment are important in determining populations of intestinal organisms (Palmer et al., 2007). Fetuses are sterile in utero. Vaginal delivery

Probiotics in the Prevention and Treatment of Gastrointestinal Disease

259

allows infant exposure to maternal bacteria; the longer the birth process, the greater the exposure. Infants born by Cesarean delivery acquire bacteria by nonvaginal maternal exposure, as well as isolates transferred by nursing staff, other infants, air, and equipment. Following birth, oral and cutaneous bacteria from the mother are mechanically transferred to the infant by suckling, kissing, and caressing. Breastfeeding exposes the infant to bacteria, especially bifidobacteria from milk ducts, nipple, and surrounding skin. Breast milk contains antimicrobial and growth factors that stimulate the development and maturation of the intestinal mucosa (Mackie, Sghir, & Gaskins, 1999). Infants born by Cesarean section may experience a delay in the development of a full complement of commensal bacteria. Some suggest that this delay presents an opportunity for the development of certain allergic-related illnesses such as atopic dermatitis, allergic bronchitis, and certain autoimmune diseases. After introduction of solid food, by the first two years of life, the bacterial profiles of breastfed and formula-fed infants are similar to those of adults.

Definitions of Probiotics, Prebiotics, and Synbiotics Probiotics are “live microbial feed supplements that beneficially affect the host animal by improving its intestinal microbial balance” (Fuller, 1989). Prebiotics are “non-digestible food ingredients that beneficially affect the host by selectively stimulating the growth and/or activity of one or a limited number of bacteria in the colon” (Gibson & Roberfroid, 1995). Examples of prebiotics include fructooligosaccharides, inulin and psyllium. “Synbiotics” is the term used when a product contains both probiotics and prebiotics.

How Do Probiotics Act? Most probiotics are obtained from normal human commensal bacteria. Predominant species include lactobacilli, bifidobacteria, E. coli and Streptomyces. The exception is a yeast, Saccharomyces boulardii, obtained from the lychee plant. Experimental data gleaned from actions of single-strain and multi-strain bacteria reveal three groups of biologic effects of probiotics. The first includes modulation of the immune system, by increasing total and specific IgA secretion, downregulation of T-cell responsiveness, alteration of cytokine profiles, and induction of oral tolerance. The second group includes enhancement of intestinal barrier function by increasing mucous production, promoting tight cellular junctions and epithelial restitution. Third, probiotics prevent invasion of pathologic bacteria by bacteriocin production, prevent

260

INTEGRATIVE GASTROENTEROLOGY

adhesion of pathologic organisms, increase colonizing resistance, and decrease luminal pH through the formation of organic acids (Fedorak & Madsen, 2004).

Clinical Applications of Probiotics Clinical situations in which probiotics play a role in the alleviation of disease include: 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

Lactose intolerance Infantile necrotizing enterocolitis Antibiotic-associated diarrhea and Clostridium difficile colitis Irritable bowel syndrome Traveler’s diarrhea Inflammatory bowel diseases, including Crohn’s disease, ulcerative colitis, and pouchitis Bacterial overgrowth syndromes Colon carcinoma Food allergy Gut-origin septicemia

A brief review of selected clinical applications follows. The review includes a description of the clinical entity, the rationale for the use of probiotics, and an analysis of available clinical trials supporting its use.

Lactose Intolerance Lactose intolerance is a problem worldwide, its prevalence varying from 7% to 20% among Caucasians, 50% among Hispanics, 75% among Africans and African-Americans, and more than 90% in Asian populations. Clinical symptoms include diarrhea, abdominal pain, and flatulence following the ingestion of milk or milk products. The reduced amount of lactase enzyme in the glycocalyx of the proximal small bowel fails to hydrolyze lactose to glucose and galactose. As a result, the poorly absorbed lactose passes into the colon where it is metabolized by colonic microbiota, producing short-chain fatty acids and an excess of hydrogen, methane, and carbon dioxide gases, resulting in the symptom complex noted above. Symptoms vary based upon the dose of lactose ingested, and the concomitant dilutional effect of the accompanying meal. Treatment involves reducing lactose intake, using enzyme substitutes

Probiotics in the Prevention and Treatment of Gastrointestinal Disease

261

(e.g. Lactaid tablets), or probiotics (He et al., 2008). In my personal experience, combining a probiotic (Lactobacillus GG) and a prebiotic (fructooligosaccharide) effectively ameliorates symptoms of patients with hydrogen-breath-test proven lactose intolerance (Friedman, 2008).

Necrotizing Enterocolitis Necrotizing enterocolitis is the most common gastrointestinal emergency in neonates, particularly affecting premature infants, with an increased risk for males and black infants. Clinically, infants present with gastrointestinal and systemic signs including feeding intolerance, delayed gastric emptying, abdominal tenderness and distention, occult or gross blood in the stool, lethargy, and respiratory distress. Treatment consists of bowel decompression, broad-spectrum antibiotics, and careful monitoring. Up to 20% to 40% of patients may require surgery. Probiotics reduce the risk of necrotizing enterocolitis, reduce the risk of death, and shorten time to full feeds (Deshpande, Rao, & Patole, 2007).

Irritable Bowel Syndrome Irritable bowel syndrome is one of the most common syndromes seen by primary care physicians and gastroenterologists, with a prevalence of 10% to 15%. It is characterized by chronic, intermittent, and recurring abdominal pain in association with altered bowel function (diarrhea, constipation, or alternating diarrhea and constipation) occurring longer than three to six months. Symptoms are more common among young to middle-aged females; female to male ratio 2:1. Etiological factors include psychologic and stress features, altered gut motility and hypersensitivity, dysregulation of gut-based serotonin, altered immune function, postinfectious bowel dysfunction, and bacterial overgrowth. Predominant complaints of most patients with IBS involve “gas syndromes,” increased flatulence, abdominal distention, and bloating. Increased gas production is related to fermentation of malabsorbed carbohydrates, swallowed air, delayed small bowel and/or colonic motor function, or altered bacterial flora. A unifying framework for understanding irritable bowel syndrome has been offered by Dr. Henry Lin (2004), who identifies distal small bowel bacterial overgrowth as its central feature. This model then accounts for both intestinal and extraintestinal IBS symptoms. Further support is given to small intestine bacterial overgrowth (SIBO) in a subset of patients with IBS (Pimentel, Chow, & Lin, 2000), and evidence exists that IBS

262 INTEGRATIVE GASTROENTEROLOGY

symptoms can be ameliorated with poorly absorbed antibiotics (Pimentel, Chow, & Lin, 2003). Indeed, there are some physicians who use a nonabsorbable antibiotic (rifaximin) as therapy for IBS patients suspected of SIBO (Pimentel et al., 2006).

Postinfectious Irritable Bowel Syndrome (PI-IBS) Patients experiencing infectious diarrhea may be predisposed to IBS symptoms. Postinfectious IBS develops in 3% to 30% of individuals following bacterial or viral gastroenteritis. Major risk factors include the severity of the initial illness, female gender, prior anxiety/depression, and other psychological factors (Spiller & Campbell, 2006). Symptoms may be sustained by immunologic factors (Dupont, 2007). Various histologic changes include increased intraepithelial and lamina propria lymphocytes, as well as increased intestinal permeability. Cytokine profiles reveal increased expression of interleukin (IL)-1b, a proinflammatory cytokine. Treatment and prognosis are similar to that of other IBS patients. Special attention should be given to the elimination of nutrients that contribute to the patient’s symptoms (reduction of lactose, sorbitol, fructose). Antidiarrheals for diarrhea, bulk laxatives for constipation, low-dose anticholinergics, or selected antidepressant medications for abdominal pain or cramps should be used.

Probiotics and Irritable Bowel Syndrome The goal of probiotic therapy is to beneficially alter the microbial flora by ameliorating the symptom complex associated with IBS. More than 15 randomized, double-blind studies of probiotics have been published, using single or multiple bacterial strains. These studies generally reveal methodologic design limitations, lack of comparative standardizations, variations in dosages, lack of dose-response curves, different durations of study, and use of small patient numbers (Borowiec & Fedorak, 2007; Guslandi, 2007; Jonkers & Stockbrugger, 2007; Camilleri, 2006). However, it is apparent from these studies that the symptoms in common—flatulence, bloating, distention, abdominal pain, and altered bowel function, as measured by patient’s global assessment—are completely or partially ameliorated. Thus, in concert with Dr. Lin’s assessment noted previously, it is this author’s belief that the commensal bacteria remain a central focus. Probiotics can replace the diminished concentrations of lactobacilli and bifidobacteria noted in IBS patients, thus counteracting the proinflammatory cytokines interleukin-12 (IL-12.) Abnormal colonic fermentation

Probiotics in the Prevention and Treatment of Gastrointestinal Disease

263

(King, Elia, & Hunter, 1998) may be ameliorated, reducing the short-chain fatty acid contractile propulsive activity. Increased deconjugation of bile acids by lactobacilli and bifidobacteria can reduce the bile acid load, and diminish colonic mucosal secretion, which contribute to diarrheal symptoms. Two randomized controlled studies deserve mention: one with a single strain probiotic, and the other a multi-strain. A four-week, multicenter study with a large number of female IBS patients used Bifidobacteria infantis compared to placebo in a dose-ranging study. Statistical improvement was demonstrated in composite global symptom scores and bloating (Whorwell et al., 2006). This author’s four-week, multicenter randomized placebo-controlled study used a multi-strain probiotic (Lactobacillus acidophilus LA-5, Bifidobacterium BB-12, Lactobacillus paracasei CRL-431 and Streptococcus thermophilus STY-31), with diarrhea as the primary end point, and demonstrated statistical reduction of diarrheal episodes, as well as decreased bloating (Friedman & Biancone, 2008).

Traveler’s Diarrhea Interest in traveler’s diarrhea is prompted by the frequency of global vacations and business travel. Highest risk areas (>30%) are Mexico, South and Central America, Asia, and Africa. The most common causative bacterial organism is enterotoxigenic E. coli (ETEC). The possible progression of this illness to postinfectious IBS is a matter of concern. Dupont has summarized recommendations for prevention and treatment. 1. Bismuth subsalicylate, (2.1 g/day–two tablets with meals and at bedtime): 65% effective 2. Levofloxacin, one 500 mg tablet once daily: 80% effective 3. Rifaximin, one 400 mg tablet twice daily: 75% effective 4. Probiotics, Lactobacillus GG, one capsule twice daily: 40% effective (Hilton et al., 1997)

Antibiotic-Associated Diarrhea (AAD) Antibiotic-associated diarrhea occurs in 5% to 25% of patients receiving antibiotics, with increased risk in the aged, immunosuppressed, and GI surgery patients. AAD extends hospital stays by 8 to 20 days, causes higher medical care costs, and places patients at higher risk for acquiring other nosocomial infections. Agents most likely to cause diarrhea include cephalosporins, clindamycin,

264

INTEGRATIVE GASTROENTEROLOGY

and broad-spectrum penicillins. Antibiotics alter epithelial barrier defense, allowing insurgence of pathogens. Clostridium dificile is the most severe form of AAD, and accounts for 15% to 25% of hospital cases. This is a toxin-mediated illness with characteristic clinical and pathologic features (Bartlett, 2002). Diagnosis is confirmed by assay of toxins A & B. Probiotics prevent mucosal barrier disruption and restore normal commensal bacteria. Saccharomyces boulardii has been effective in reducing AAD, and as adjunctive therapy for C. difficile infection (McFarland, 2006). Mechanisms of action include inactivation of toxins A & B, stimulation of host immune system, and trophic effects on intestinal mucosa (Buts & Bernasconi, 2005). The dosage is 250 mg twice daily for prevention, and four times daily to prevent recurrent C. difficile colitis, in concert with either metronidazole or vancomycin. Lactobacillus GG has been extensively studied as effective treatment of acute diarrhea in infants and children, dosage being one capsule twice daily. This Gram-positive rod has powerful adhesive properties, modulates antigen transport, augments immune responses, and increases IgA secretion (Doron, Snydman, & Gorbach, 2005).

Inflammatory Bowel Diseases Causative elements of inflammatory bowel diseases are genetic predisposition, altered immune response, environmental factors (diet, smoking, stress), and commensal bacteria. Commensal bacteria have been implicated in the pathogenesis of IBD because the areas of inflammation involved have a high density of luminal bacterial organisms, the continuity of the fecal stream is linked with disease activity, surgical interruption of the stream results in diminished inflammatory activity, and restoration results in renewed inflammation. These concepts have been supported by the creation of a colitis-like disease in genetically altered animals, in which colitis only occurs when microbiota are added to the germ-free animal. Pouchitis is a nonspecific inflammation of the ileal reservoir following ileal pouch–anal anastomosis for ulcerative colitis. Approximately half of all pouch patients experience inflammation at some time after the operation. There are diminished amounts of lactobacilli and bifidobacteria in the pouch contents. Most patients respond to antibiotic therapy (metronidazole or ciprofloxacin). Recurrent or refractory inflammation occurs in 10% to 15% of patients. After suppression of the inflammation with antibiotics, maintenance therapy is needed. Probiotics have been successfully used in place of further antibiotic therapy. Probiotic treatment of pouchitis was the first major randomized controlled trial for IBD demonstrating prophylactic

Probiotics in the Prevention and Treatment of Gastrointestinal Disease

265

efficacy for recurrent disease (Gionchetti et al., 2000). Gionchetti et al., randomized 40 patients and compared 20 patients on VSL3 (3 g twice daily; four strains of Lactobacillus [casei, plantarum, acidophilus, and delbruckii subsp bulgarius]; three strains of Bifidobacterium [longum, breve, and infantis]; and one strain of Streptococcus [salivarius subsp thermophilus]) with 20 patients on placebo for nine months. In the VSL3 group three (15%) patients relapsed compared with 20 (100%) in the placebo group (P=0.001). Within four months after discontinuation of therapy, 100% of responding patients relapsed. All of the responding patients on VSL3 showed an increase in the concentrations of lactobacilli and bifidobacteria. Two years later, a similar study confirmed these results (Mimura et al., 2004). Administering 6 g/day immediately after operation as a prophylactic to pouch patients for one year prevented recurrent pouchitis in 90% of subjects, compared to 60% recurrence on placebo (Gionchetti et al., 2003).

Ulcerative Colitis Ulcerative colitis is a mucosal inflammatory disease that may affect the rectum (proctitis), rectosigmoid (proctosigmoiditis), extend to the splenic flexure (left-sided colitis), or involve the entire colon (pancolitis). Most human trials have assessed the efficacy of probiotics on sustaining remission following suppression by anti-inflammatory agents (steroids, immunosuppressive agents, biologic agents, mesalamine). The reason for treating quiescent disease rather than active colitis is related to rapid passage of the probiotic through the GI tract secondary to diarrhea, disallowing adequate time for nidation and proliferation of the probiotic. Open label studies using much larger doses of probiotics have shown some success. Equivalency studies, comparing remission rates of E. coli Nissle strain 1917 with mesalamine, have been reported (Kruis et al., 1997; Rembacken et al., 1999). These studies are interesting, but not persuasive. In an open label, two-center trial by Fedorak and Madsen (2004), 30 patients with mild to moderate ulcerative colitis who failed mesalamine therapy were treated with VSL3 (1 x 1012 CFU daily) for 4 months with a remission rate of 63%. Another open label study using Saccharomyces boulardii treated 25 mild to moderate colitis patients who failed mesalamine therapy (Guslandi, Giollo, & Testoni, 2003). These investigators used 750 mg daily for one month, with a response rate of 68%. In summary, the use of probiotics in both the acute phase and maintenance of ulcerative colitis are suggestive, but inconclusive. Large, randomized, double-blind, placebo controlled trials are needed.

266

INTEGRATIVE GASTROENTEROLOGY

Crohn’s Disease Crohn’s disease is a chronic inflammatory bowel disease that can affect any part of the GI tract from mouth to anus, with a predominance of small bowel and colonic involvement. Pathologically, it is transmural, affecting mucosa, submucosa, muscularis and serosal surfaces. Crohn’s disease trials are divided into three areas: (1) treatment of acute, active disease; (2) maintenance after medically induced remission; and (3) maintenance after surgically induced remission. There are no randomized, controlled trials of patients with acute, active Crohn’s disease. In the maintenance phase of medically induced remission, a double-blind study by Malchow (1997) with 28 patients, randomized to receive E. coli Nissle l917 compared to placebo for one year, revealed a relapse rate of 30% in the E. coli group compared to 70% in the placebo group. An open label maintenance study by Guslandi et al. (2003) compared Saccharomyces boulardi 1000 mg/day + mesalamine 2 g/day with mesalamine 3 g/day for six months. The remission rate was 94% with the former and 38% with the latter. A randomized, controlled trial of maintenance after surgical resection by Campieri et al. (2000) treated 40 patients for one year, comparing rifaximin l.8 g/day for 3 months followed by VSL3 for 9 months with mesalamine 4 g/day. Endoscopic remission was noted in 80% versus 60% of patients on mesalamine alone. Overall, published results do not support the use of probiotics in the treatment of active Crohn’s disease, or as maintenance therapy for medical or surgically induced remission.

Safety Issues The safety of the microbes traditionally used as probiotics has been confirmed through experience. The use of non-sporing LAB in fermented foods is widespread. There have been reports associating LAB and S. boulardii with clinical infection in immunosuppressed, severely debilitated patients (Gasser, 1994; Schlegel, Lemerle, & Geslin, 1998). Probiotics should not be used in severely immunocompromised patients, patients with synthetic valves, or patients with indwelling central venous catheters (Hennequin et al., 2000). Capsules should not be broken in patients’ rooms for use in enteral tube feedings.

Probiotics in the Prevention and Treatment of Gastrointestinal Disease

267

Summary In the past decade there has been a dramatic resurgence of interest in commensal bacteria related to improved genetic analysis of intestinal microbiota. These bacteria benefit the host by performing metabolic functions, including energy-producing fermentation of malabsorbed carbohydrates that produce short-chain fatty acids, adding to trophic action on the epithelium, producing vitamins, and playing a pivotal role in the development of the immune system. Probiotics are live microbial feed supplements that beneficially affect the host animal by improving its intestinal microbial balance. Selected clinical studies demonstrate that probiotics play a role in the alleviation of such illnesses as lactose intolerance, infantile necrotizing enterocolitis, AAD and C. difficile colitis, IBS, traveler’s diarrhea, IBD, and pouchitis. There are a limited number of well-regarded, randomized, placebo-controlled double blind trials available. Such trials have focused on pouchitis, AAD, and IBS. Future research using single strain and multi-strain probiotics in humans and animals will provide further supporting evidence regarding the value of probiotics.

30 The Role of Nutritional Genomics and Functional Medicine in the Management of Crohn’s Disease SHEILA G. DEAN AND KATHIE M. SWIFT

key concepts ■

■

■

■

■

Diet and nutritional intervention for gastrointestinal health may be personalized to the individual’s genetic uniqueness. Multiple risks have been identified that can increase the risk for Crohn’s disease; however, research strongly supports genetic susceptibility and a leaky gut as predisposing factors. Functional clinical tests to assess intestinal inflammation, such as fecal calprotectin, are useful diagnostic tools. Certain nutrients such as antioxidants and polyphenols can provide protection of the gut mucosa, and functional foods, including prebiotics and probiotics, support function of the gut immune system. A “4R” GI restoration program that involves removing toxic substances, replacing digestive factors, reinoculating with commensal bacteria, and regenerating the GI integrity, may have significant impact in inflammatory bowel disease, and merits further study. ■

268

Introduction to Nutritional Genomics

N

utritional genomics is an emerging field that is now defined as the interface between genes and nutrition. It addresses the concept of one’s biochemical and genetic uniqueness, and how this interaction then gives rise to outward, physical traits known as the phenotype. While nutritional genomics continues to develop, the groundwork was established over 50 years ago by pioneers such as Linus Pauling and Roger Williams. Dr. Pauling, Nobel Prize winner for Chemistry in 1954, and Peace in 1962, was already teaching about the importance of nutrients in modulating physiological processes at the biomolecular level (Pauling, The Roots of Molecular Medicine). Roger Williams is credited with developing the concept of biochemical individuality, and has been described as having “contributed to the evolution of the understanding of the molecular origin of disease” and advanced the concept of genotrophic disease (Williams, 1998). The catalyst for the development of present-day nutritional genomics has been the Human Genome Project, a multinational undertaking that began in 1990. While there were a number of goals, the primary goal was to identify the nucleotide sequence of the human DNA. However, the specific goals have changed over time, since the Human Genome Project was completed in 2003, earlier than expected. Current research is focused on identifying the total number of genes, their chromosomal location, and their function (Human Genome Project Information, 2007). Why is this important to the healthcare team? One reason may be because the impact of the Human Genome Project has created new information that is expected to alter the approach to risk assessment of nutritional issues. However, in order for the digestive healthcare practitioner’s evolving role in the application of nutritional genomics to clinical practice to occur effectively, it will require a deepened understanding of genomics and gene–diet interactions. (Kozma, 2003). Individual gene variants called SNPs (single nucleotide polymorphisms) result in differential response to environmental factors including diet.

Fogg-Johnson and Kaput (2003) explain that some of the new information of the Human Genome Project is surfacing in areas that are not totally predictable. Through the Human Genome Project, it has been discovered that

270 INTEGRATIVE GASTROENTEROLOGY

individual gene variations exist, and are referred to as single nucleotide polymorphisms (SNPs, pronounced “snips”). These SNPs result in differential response to environmental factors, such as diet. The science of how naturally occurring chemicals in foods alter expression of genetic information at the molecular level, and how this affects the individual phenotype, is the essence of what nutritional genomics scientists seek to uncover (Fogg-Johnson & Kaput, 2003). An understanding of genomics and gene–diet interactions will impact the delivery of personalized clinical nutrition practices.

Diet, lifestyle, and environment have significant influence on the way an individual can metabolize specific substances based upon his or her genetic uniqueness. These discoveries have opened the door for the future of molecular medicine, and the development of a personalized medicine that recognizes aspects of gene–diet–environment interactions and their roles in individual disease causation, and the design of specific intervention programs. The takeaway from these concepts is that one size does not fit all. Diet and nutritional intervention must be personalized to the genetic characteristics of the individual. Gastrointestinal health is particularly important to achieving optimal nutrition and affords several examples of how diet and genes interface and how the field of nutritional genomics can assist the healthcare team in maximizing nutrition care interventions for the individual. The GI tract functions as a selective barrier between the internal and external environment and the intestinal microflora plays an active role in maintaining gut integrity.

The Healthy Gut Gastrointestinal health affords several examples of how nutritional genomics can maximize nutrition care intervention.

The gastrointestinal (GI) tract is the second-largest body surface area. The condition of this organ’s microflora is essential to optimal health. The healthy intestinal wall is coated with hundreds of different species of microorganisms,

The Role of Nutritional Genomics and Functional Medicine 271

both beneficial and pathogenic bacteria, numbering in the trillions (Whitney, Cataldo, & Rolfes, 1998). This rich protective coating of microorganisms acts in concert with the physical barrier provided by the cells lining the intestinal tract, and other factors, to provide the body with important filter-like protection. So, in addition to digesting, absorbing, and eliminating food substances and nutrients, the normal GI tract functions as a critical semipermeable (selective) barrier between the internal and external environment. This prevents toxic, antigenic, or pathogenic molecules or microorganisms from entering the bloodstream. Ultimately, the importance of the intestinal microflora and, more specifically, its composition, in physiological and pathophysiological processes in the human GI tract, is becoming more evident (Jones, 2005).

Inflammatory Bowel Disease Inflammatory bowel disease (IBD) is a critical and chronic disorder of the intestines. Generally, its complications can be severe, widespread, and very painful. Crohn’s disease and ulcerative colitis (UC) are two forms of IBD. As researchers try to understand its long-unknown etiology, there does not appear to be one precise cause of Crohn’s disease. However, it is clear that Crohn’s disease is relapsing in nature, and it affects all layers of the intestines from mouth to anus. In comparison, UC is generally limited to the large bowel and does not necessarily affect all layers of the intestine.

Risk Factors Crohn’s disease and ulcerative colitis are two forms of inflammatory bowel disease (IBD) with multiple etiologies including genetic susceptibility.

There are several risk factors (see Table 30.1) for Crohn’s disease, which range from adult appendectomy to the use of various substances, including nicotine (Somerville, Logan, Edmond, & Langman, 1984; Cottone, Rosselli, Orlando, Oliva & Puleo1994; Lindberg, Jarnerot, & Huitfeldt, 1992), oral contraceptives, antibiotics, and nonsteroidal anti-inflammatory agents (NSAIDs). Even second-hand smoke exposure has been shown to increase risk for developing CD (Lashner, Shaheen, Hanauer, & Kirschner, 1993; Persson et al., 1990). Other demographic factors, such as economic, educational, geographic, and occupational status, can increase the risk of developing CD (Sonnenberg et al., 1991). Despite these risk factors, Ferguson (Ferguson, L., Shelling, A. N.,

272

INTEGRATIVE GASTROENTEROLOGY

Table 30.1. Risk Factors for Crohn’s Disease • Genetics • Medications: oral contraceptive agents, antibiotics, nonsteroidal anti-inflammatory agents (NSAIDs) • Diet • Stress • Socioeconomics • History of eczema

Browning, B. L., Huebner, C., & Petermann, I 2007) explains that “IBD is considered a genetic disease,” as approximately 20% of people with one form of IBD have a blood relative also with IBD, and 58% of monozygotic twins share the disease as compared to 4% of dizygotic twins (Jess et al., 2005; Halfvarson et al., 2005). Other factors that appeared to increase disease risk were history of eczema and consumption of a low-fiber diet (Bartel et al., 2008) Research has demonstrated that stress can be a contributing factor in Crohn’s disease. Crohn’s disease is characterized by increased intestinal permeability, and extensive animal research has shown stress significantly influences intestinal permeability (Hollander, 1999). Furthermore, psychological stress, anxiety, depression, and altered quality of life are likely to influence further Crohn’s disease activity following a relapse (Mittermaier et al., 2004).

The Immune–Inflammatory Connection The gastrointestinal tract contains trillions of bacteria that are, ideally, in homeostasis with the host immune system (MacDonald, 2005). The gut contains most of the immune cells in the body, and engages in attacking harmful pathogens while leaving symbiotic bacteria largely unscathed (Rescigno & Chieppa, 2005). Th1 & Th2 cells are important regulators of the gastrointestinal immune system and Th1/Th2 balance plays an important role in gut mucosal integrity.

One theory of immune regulation involves homeostasis between T-helper 1 (Th1) proinflammatory and T-helper 2 (Th2) anti-inflammatory activity (Kidd, 2003). “Th1” and “Th2” cells are “important regulators of the class of immune response.” (Kidd, 2003) Alterations in the host gastrointestinal flora can have a significant influence on the Th1/Th2 balance of the gastrointestinal immune

The Role of Nutritional Genomics and Functional Medicine 273

system (gut-associated lymphoid tissue, or GALT; see Mazmanian et al., 2005). Sometimes referred to as systemic versus organ-specific immune responses, respectively, balance of Th1/Th2 cytokines produced by the mucosa-associated lymphoreticular system (MALT) and the GALT plays a role in the stabilization of mucosal surfaces in the gut (Neurath et al., 2002). Mullin et al. (1996) were the first to elucidate the predominance of Th1 responses in the intestinal mucosa of Crohn’s disease patients. These mucosal surfaces have multiple tasks that include absorption, macromolecule transfer, and intestinal barrier and secretory functions. Large mucosal surfaces, such as the 300 square meters found in the human intestinal tract, are continuously exposed to millions of potentially harmful antigens from the environment, food, and intestinal microbes. The mucosal surfaces possess a unique immune system that tightly controls the balance between responsiveness and nonresponsiveness. Loss of this immunological recognition of “friend versus foe” in the gut can result in activation of the inflammatory process (Rescigno & Chieppa, 2005). There is growing evidence that chronic inflammatory disorders in the mucosa, such as IBD, are due to the dysregulation of the mucosal immune system, leading to a Th1-dominant inflammatory reaction and impairment of the barrier function of the gut (Neurath et al., 2002). The Th1–Th2 immune response paradigm hypothesizes hypotheses that, under the influence of a variety of factors including the cytokines, interleukin 4 (IL-4) and IL-12, naive T-cells can mature into one of two phenotypes, Th1 or Th2, that counter-regulate each other. This model illustrates that, in most circumstances, interaction between Th1 and Th2 cells is more complex than originally thought. These cell types probably represent extreme examples of a spectrum of phenotypes, and it is possible that a cell is not committed irrevocably to one phenotype (see Figure 30.1).

Genes/Gene Variants Associated With IBD—What Do We Know? Knowing the genes and gene variants associated with IBD can be useful for the practitioner, once it is understood what genes are involved and how their variations are related to underlying mechanisms of IBD pathogenesis. Furthermore, evidence-based nutrition intervention can be used to modulate genetic expression, which can ultimately affect phenotypic outcome of the individual. While IBD appears to be of polygenic etiology, research strongly supports the assumption that susceptibility to IBD, especially Crohn’s disease, is inherited. It also indicates that IBD is not inherited as a Mendelian trait, but rather

274 INTEGRATIVE GASTROENTEROLOGY

Table 30.2. Susceptibility Genes Associated with IBD Name of the gene

Gene abbreviation

Gene variants

Areas genes affect

(discussed in this review)

Affects bacterial recognition of the intestinal wall

Caspase-activated recruitment domain 15/nucleotide oligomerization domain 2

CARD15/NOD2

Autophagy-related 16-like 1

ATG16L1

Affects bacterial recognition of the intestinal wall

Human beta defensins B2, B3 and B4

HBD-2, HBD-3 and HBD-4

Affects bacterial recognition of the intestinal wall

• Arg702Trp • Gly908Arg • 1007finsC or c.3020insC

Major histocompatibility MHC complex

Affects immune response

Interleukin-23 receptor

IL23R

Affects immune response

Toll-like receptors

TLRs

Affects immune response

Sodium dependent organic cation transporters

SLC22A4/ SLC22A5 (also called OCTN1/ OCTN2)

ATP-binding cassette subfamily B member 1

ABCB1

Drosophila discs large homologue 5

DLG5

• SLC22A4 1672 C>T Affects mucosal • SLC22A5 -207 G>C transport or polarity of the intestinal wall Affects mucosal transport or polarity of the intestinal wall • • • • • •

DLG5 113G>A P.P1371Q P.G1066G Rs2289308 DLG_e26 P.D1507D

Affects mucosal transport or polarity of the intestinal wall

The Role of Nutritional Genomics and Functional Medicine 275

has a complex genetic basis, with many contributing genes and at least nine susceptibility loci identified (Neurath et al., 2002; Chamaillard et al., 2006). Table 30.2 is a classification of the susceptibility genes, their variants, and affected areas (Hampe et al., 2001; Hugot et al., 2001; Chamaillard et al., 2006; Schreiber et al., 2005; Ogura et al., 2001; Peltekova et al., 2004; Stoll et al., 2004; Cho, 2006; Buning et al., 2006). IBD has a complex genetic basis with many contributing susceptibility genes and gene variants.

This chapter is focused specifically on three IBD-associated genes that appear to identify major susceptibility loci for Crohn’s disease: (1) CARD15/ NOD2; (2) DLG5; and (3) SLC22A4/A5 (OCTN1/OCTN2).

Gene Variants and Their Potential Impact on IBD Pathogenesis CARD 15/NOD2. Alterations in this gene have been associated with a defective bacterial signal that leads to NF-κB overexpression and subsequent excessive immune response, which can lead to chronic gut inflammation in susceptible individuals. DLG5. Variations in this gene seem to predispose individuals to what has been coined “leaky gut syndrome,” thus allowing for intestinal permeability and integrity dysfunction. SLC22A4/SCL22A5 (OCTN1/OCTN2). Functional polymorphisms decreasing OCTN activity and/or expression have been associated with chronic inflammation, and contribute to CD/IBD pathogenesis. Specifically, this may be due to reduced carnitine transport function, resulting in impaired fatty acid metabolism in the gut, and toxic bacterial metabolites generated due to reduced ability for proper clearance of bacterial byproducts.

CARD15/NOD2: associated with exaggerated immune response DLG 5: associated with increased intestinal permeability SLC22A4/SCL22A5 (OCTN1/OCTN2): associated with impaired fatty acid metabolism and reduced clearance of toxic bacterial byproducts

276

INTEGRATIVE GASTROENTEROLOGY

Current Medical Management Conventional pharmacological treatment has been directed toward suppressing inflammation, and antibiotics for lowering bacterial antigenic drive to the overactive mucosal immune system. Typical drugs (see Table 30.3) used to treat Crohn’s include aminosalicylates (such as sulfasalazine and mesalamine), corticosteroids (such as prednisone and budesonide), immunosuppressive agents (such as azathioprine, 6-mercaptopurine, methotrexate), and antibiotics (Baumgart & Sandborn, 2007). More recently, anti-TNF-alpha monoclonal antibodies, such as infliximab and related drugs (Remicade®, Enbrel®, Humira®), are being prescribed, since tumor necrosis factor appears to play a significant role in the pathogenesis of Crohn’s disease (Bamias et al., 2003; Braegger et al., 1992). Antidepressants are typically offered for assisting with stress management, as stress can also aggravate Crohn’s disease symptoms (Lerebours et al., 2007). Unfortunately, medications used in the therapy of IBD often contribute to the development of many nutrient deficiencies (see Table 30.4). For example, sulfasalazine produces folate malabsorption, by competitive inhibition of the jejunal folate conjugate enzyme (Hoffbrand et al., 1968). Corticosteroids suppress small intestinal calcium absorption and increase urinary calcium excretion. Cholestyramine (which is sometimes used in patients who have undergone

Table 30.3. Pharmaceuticals Used in the Management of Crohn’s Disease Aminosalicylates

Sulfasalazine

Corticosteroids

mesalamine prednisone budesonide

Immunosuppressants

azathioprine 6-mercaptopurine methotrexate

Anti-TNF-alpha monoclonal antibodies

Remicade® Enbrel® Humira®

The Role of Nutritional Genomics and Functional Medicine 277

Table 30.4. Drug-Induced Nutrient Deficiency and Potential Mechanisms Drug

Nutrient depleted

Potential mechanism

Sulfasalazine

Folic acid

competitive inhibition of the jejunal folate conjugate enzyme

Corticosteroids

Calcium

suppresses small intestinal absorption and increase urinary excretion

Cholestyramine

Fat, calcium, and fat-soluble vitamin deficiencies

used in those who have undergone post-ileal resection in Crohn’s disease to prevent diarrhea

Sulfasalazine

Water and fat-soluble vitamins

may cause nausea, vomiting, and dyspepsia

5-aminosalicylic acid

Water and fat-soluble vitamins

metronidazole

Water and fat-soluble vitamins

post-ileal resection in Crohn’s disease to prevent diarrhea) produces fat, calcium, and fat-soluble vitamin deficiencies. Sulfasalazine, 5-aminosalicylic acid, and metronidazole may cause nausea, vomiting, and dyspepsia, which frequently lead to decreased nutrient intake (Riley et al., 1988; Singleton et al., 1970).

Nutritional Management

Drug-induced nutrient depletion is a common side effect of commonly prescribed medications for IBD.

Elemental diets, elimination diets, omega-3 fish oils, high-fiber, low-fiber, high-protein, low-residue diets, and bland diets have all been used in one form or another as part of the nutritional management of IBD, and are reviewed in Chapter 44 (Ferguson, L., Shelling, A. N., Browning, B. L. et al., 2007; Ferguson, L. R., Shelling, A. N., Lauren, D. et al., 2007; Han et al., 1999; O’Sullivan & O’Morain, 2006; Hodges, 2005). However, nutritional protocols have been inconsistent, despite growing research on IBD. Until recently, theories on nutritional management of IBD have been somewhat disunified.

278

INTEGRATIVE GASTROENTEROLOGY

Functional Clinical Tests Genetic testing, along with functional assays, such as intestinal permeability, can be useful in identification and treatment of IBD.

A major task of the intestine is to form a defensive barrier to prevent absorption of damaging substances from the external environment. This protective function of the intestinal mucosa is called permeability. Ample evidence indicates that permeability is increased in most patients with Crohn’s disease, and in 10% to 20% of their clinically healthy relatives (Secondulfo, M. de Magistris, L., Fiandra, R., Caserta L & Belletta M 2001). The major determinant of the rate of intestinal permeability is the opening or closure of the tight junctions between enterocytes in the paracellular space. A combination of functional clinical testing that includes an intestinal permeability assessment, combined with genetic testing (e.g., screening for CARD15/NOD2, DLG5, etc.), could prove to be a prudent way to identify those at risk of IBD. Increased intestinal permeability is common Crohn’s disease patients and 10%–20% of their healthy relatives.

Because the increase in intestinal permeability in Crohn’s disease could be caused by the inflammation itself, or by some predisposing genetic abnormality, permeability in patients and their healthy relatives have also been studied (Hollander, 1988) Approximately 10% to 20% of healthy relatives of patients with Crohn’s disease also have an abnormal increase in intestinal permeability (Hollander et al., 1986; Katz et al., 1989; May et al., 1993). These observations link genetic abnormalities and a leaky gut, which predisposes an individual to the development of Crohn’s disease (Hollander, 1988; Hollander, 1993). Clearly, a genetic predisposition could not be the only abnormality; rather, the presence of specific, as yet unknown, antigens in luminal contents or infectious agents, as well as possible abnormalities in the intestinal immune responses, are presumed to be additional factors in the genesis of the disease. The “leaky gut” explanation ties together the influence of luminal antigens and an abnormal immune reactivity, and offers a unifying concept that explains the interaction between luminal factors and the immune system (Hollander, 1994). Conducting a fecal calprotectin evaluation is one type of test for measuring intestinal inflammation (Teahon, Roseth, Foster, & Bjarnason, 1997; Tibble, Sigthorsson, & Bjarnason, 1999). Calprotectin is a calcium-binding protein

The Role of Nutritional Genomics and Functional Medicine 279

found in the following types of white blood cells: neutrophilic granulocytes, monocytes, and macrophages (Teahon et al., 1997). Calprotectin resists metabolic degradation and can be measured in the feces. The fecal calprotectin test makes use of the fact that the release of calprotectin in the stool is associated with damage to the GI mucosa, and increased inflammatory processes (Tibble et al., 1999).

Nutritional Influences in IBD Buddington and Weiher (1999) proposed that, in managing functional gastrointestinal disorders, the GI system should be viewed as a flow system or “river.” The GI tract is a complex ecological system that flows from top to bottom and requires an optimum environment, which is influenced by nourishment to create the appropriate “ecology” within the small and large intestines. Fecal calprotectin is a functional measure of damage to the GI mucosa, and resultant inflammatory processes.

A variety of nutrients have been found to be deficient in Crohn’s disease patients (See Table 30.5). Table 30.5. Malnutrition in Individuals with Crohn’s Disease (adapted from Mullin, 2009) Deficiency

Percentage of individuals

Treatment

with Crohn’s disease with nutrient deficiency

Negative Nitrogen Balance

69%

Adequate energy and protein

Vitamin B12

48%

1000 mcg/d x 7 then Q mo

Folate

67%

1 mg/d

Vitamin A

11%

5,000–25,000 IU/d

Vitamin D3

75%

5,000–25,000 IU/d

Calcium

13%

1,000–1,200 mg/d

Potassium

5–20%

Variable

Iron

39%

Fe Gluconate 300 mg TID

Zinc

50%

Zn Sulfate 200 mg daily or BID

280

INTEGRATIVE GASTROENTEROLOGY

The GI system can be viewed as a complex ecological system that flows like a river and is influenced by its environment.

Causes include: • • • •

Malabsorption in the small intestine Increased nutrient need because of disease activity Low nutrient intake Nutrient loss due to chronic diarrhea or increased transit time or effect of medications

Nutrient deficiencies are common in Crohn’s disease, due to: • Malabsorption • Compromised dietary intake • Disease activity • Chronic diarrhea • Increased nutrient losses • Medications

One study examining multiple nutrient deficiencies found 85% of 279 Crohn’s disease patients had deficiencies. Nutrients most frequently found deficient were iron, calcium, zinc, protein, vitamin B12, and folate (Rath et al., 1998). It has recently been suggested that certain protective nutrients and functional foods can provide protection of the gut mucosa from the CARD15/ NOD2-related Th1-dominant inflammatory reactions (Duggan et al., 2002). The amino acids glutamine and arginine, and the essential micronutrients vitamin A, zinc, vitamin E, and the B vitamin, pantothenic acid, are among these protective nutrients. Evidence indicates that chronic IBD is associated with elevated oxidative stress in the intestinal mucosa, with increased levels of reactive oxygen species and protein carbonyls in tissues, along with other markers of free radical injury (Lih-Brody, 1996; Ding et al., 2007). Therefore, supplementation with antioxidants, including ascorbic acid, tocopherol, and food flavonoids like quercetin (found in apples) and epicatechin gallate (from green tea) may be beneficial. Shapiro et al. (2007) discuss the addition of polyphenols to nutritional formulas to improve the outcome of patients with IBD. Five polyphenols in particular have shown, in animal and human studies, (Shapiro et al., 2007; Gupta et al., 1997; Gupta et al., 2001; Gerhardt et al., 2001; Gautam et al., 2007; Camacho-Barquero et al., 2007; Kurup et al., 2007; Sharma et al., 2007; Holt et al., 2005; Hanai et al., 2006) to have benefit in IBD

The Role of Nutritional Genomics and Functional Medicine 281

by reducing inflammation associated with variations of the CARD15/NOD2 and SLC22A4/A5 genes: • • • • •

Boswellia Curcumin Epigallocatechin Quercetin Resveratrol

Prebiotics and probiotics are also important substances that support proper function of the GALT and lead to the repair phase of gastrointestinal restoration (Duggan et al., 2002). Free radical injury, and increased oxidative stress in the intestinal mucosa, warrants a diet rich in antioxidants, along with concomitant nutrient supplementation.

Functional medicine seeks to understand the antecedents, triggers, and mediators underlying dysfunction.

Putting it all Together with the Functional Medicine “4RTM” GI Restoration Program There is a growing awareness that understanding the etiology at the genetic– molecular–environmental level may be just as important, if not more important, than disease classification. “Functional Medicine”—an evidence-based systems biology approach—addresses this concept of underlying etiology and root cause solutions, and is now being encouraged by the National Institutes of Health under the new program NIH Roadmap, a route to accelerate medical discoveries that will improve health (OPASI, 2007). In essence, functional medicine assessment is concerned with understanding the antecedents, triggers, and mediators of dysfunction that give rise to molecular imbalances underlying the signs and symptoms of disease (Jones, 2005). The following is a brief adaptation of the “4RTM GI Restoration Program” pioneered by the Institute for Functional Medicine for the management of gut dysfunction and chronic disease. (Jones, 2005; Liska & Lukaczar, 2001). It is a conceptual framework within which to target therapies aimed at improving GI function.

282 INTEGRATIVE GASTROENTEROLOGY

The 4R GI Restoration Program is a functional medicine GPS to assist the practitioner in targeting therapies to improve GI function, and includes: • Remove (offending foods, toxins, infections, stress) • Replace (enzymes and other digestive factors) • Reinoculate (probiotics) • Regenerate or Repair (healing nutrients)

1. REMOVE  What does this patient need to have removed for healthy GI function? Remove focuses on eliminating pathogenic bacteria, viruses, fungi, parasites, and other environmentally derived toxic substances from the GI tract. Dietary modification is important, since foods to which a patient is intolerant or allergic can exacerbate GI dysfunction, and stimulate immune and inflammatory responses systemically. Because Crohn’s disease is characterized by elevations in anti-Saccharomyces cerevisiae (brewer’s yeast) antibodies in up to 60% of cases (Vermeire & Rutgeerts, 2004), eliminating foods with yeast may prove to be therapeutic. Β-glucuronidase is a marker for fecal putrefaction associated with increased risk of the adverse effects of colonic fermentation by bacteria. Interestingly, reduction of β-glucuronidase in the stool was a favorable outcome observed with rice bran supplementation, but not with wheat bran (Gestel et al., 1994). 2. REPLACE  What does this patient need to have replaced to support normal GI function? Replace refers to the replenishment of enzymes and other digestive factors lacking, or in limited supply, in an individual’s GI environment. GI enzymes that may need to be replaced include proteases, lipases, and saccharidases normally secreted by cells of the GI tract or by the pancreas. Other digestive factors that may require replenishment include betaine hydrochloride and intrinsic factor, normally produced by parietal cells in the stomach wall (Griffin et al., 1989). Regenerate (Repair) nutrients may include: • L-Glutamine • Fish Oils (EPA/DHA) • Zinc carnosine

The Role of Nutritional Genomics and Functional Medicine 283

3. REINOCULATE  What does this patient need to support or reestablish a healthy balance of microflora? Reinoculate refers to the reintroduction of desirable bacteria, or probiotics, into the intestine to reestablish microflora balance and to limit proliferation of pathogenic bacteria, candida, and microbes associated with variation in the CARD15/NOD2 gene. Probiotics serve a variety of functions in the GI tract: they synthesize various vitamins, produce short-chain fatty acids necessary for colonic cell growth and function, degrade toxins, prevent colonization by pathogens, improve epithelial and mucosal barrier function, and alter immune regulation via stimulation of secretory IgA or reduction in TNF-alpha (Faber, 2001; Johnston, 2001; Malin, Suomalainen, Saxelin, Isolauri. 1996; Borreul Carol & Casellas2002, Plain & Hotz, 1993). 4. REGENERATE (also referred to as the REPAIR phase)  What does this patient need to support the healing of the gastric and mucosal layer? Regenerate refers to providing support for the healing and regeneration of the GI mucosa. Part of the support for healing comes from removing insults that continually reinjure or irritate the mucosa, and promoting healthy microflora. Zinc carnosine is a chelate compound consisting of a zinc ion and L-carnosine, a dipeptide of beta-alanine and L-histidine. Studies have demonstrated that zinc carnosine promotes wound-healing action, has an antioxidant effect in the GI system, and seems to have anti-Helicobacter pylori activity (Lee et al., 2000, Mahmood et al., 2007). Supplementation with omega-3 fatty acid-rich oil (3.24 gm of EPA and 2.16 gm of DHA daily) lowered the inflammatory response associated with variation of the CARD15/NOD2 and SLC22A4/A5 genes (decreased rectal levels of leukotriene B4), and improved remission in patients with IBD (Belluzi et al., 1996). L-glutamine supplementation has also been found useful as part of a repair and regenerate program to restore GI mucosal integrity associated with the variation in the DLG5 gene (Souba, 1990). A fifth “R” has recently been added (Functional Medicine Clinical Series, 2006): 5. RELIEVE Relieve addresses acute discomfort in patients while treating the underlying conditions. Lavender oil has been used as an upper GI antispasmodic

284

INTEGRATIVE GASTROENTEROLOGY

(Blumenthal, 2003), while chamomile flower extract and peppermint leaf oil have been studied as lower GI antispasmodics (O’Hara et al., 1998). Additionally, Chinese licorice root, tienchi ginseng root, and astragalus root may have a role in addressing heartburn and mild indigestion (Blumenthal, 2003. Promoting gastrointestinal health through this type of program may have significant effects, not only on localized intestinal inflammatory risk, but also on systemic inflammatory processes associated with the loss of intestinal mucosal integrity. A fifth R for Relieve addresses easing the discomfort with herbs, such as lavender oil, chamomile flower extract, peppermint leaf oil, and Chinese herbs.

Future Strategies The application of nutritional genomics can create a better understanding of IBD pathology, and has focused attention on the interaction between genetic factors and bacteria within the gut. Increasing scientific evidence supports the notion that IBD results from a genetic predisposition to abnormal interaction with an environmental stimulant—most probably, part of the normal luminal bacterial flora—which, in turn, leads to excessive immune activation and chronic inflammation. There are many putative bioactive molecules being identified that can help modulate genetic expression of inflammation; however, many of these components still need to be tested further with in vivo animal models of human disease. In the past decade, nutrition research has undergone a shift in focus from epidemiology and physiology to molecular biology and genetics. This shift has resulted in a growing realization that we cannot understand the effects of nutrition on health and disease without determining how nutrients act at the molecular level. Muller and Kersten (2003) pointed out that “there has been a growing recognition that both macronutrients and micronutrients can be potent dietary signals that influence the metabolic programming of cells and have an important role in the control of homeostasis.” As a result, adequately trained health professionals who possess an authentic and experienced understanding of the interconnectedness of the biological systems in the human body, as well as the common underlying mechanisms that cut across many diseases, syndromes, conditions, and organ systems, will be required to interpret and communicate this information both to the public and with regulatory officials, to responsibly develop, apply, and progress this new field.

The Role of Nutritional Genomics and Functional Medicine 285

Additionally, this solid background and training will allow for far more personalized preventative care that incorporates a client-centered approach, tailored to the patients’ unique needs. Nutrition-focused practitioners are at a pivotal point in the history of their practice. Kauwell (2003) recently stated, “Armed with the findings of the Human Genome Project and related research, dietetics practitioners will have the potential to implement more efficient and effective nutrition intervention strategies aimed at preventing and delaying the progression of common chronic diseases.” Vay Liang W. Go explains in a 2005 article that “with the advent of the postgenomic era, biological and medical research and clinical practice [have] witnessed an explosion in strategies and goals. This eventually will revolutionize the classical practice of nutrition from the current evidence-based medicine towards genomic-based medicine” (Go et al., 2005). But this very explosion can be part of the barrier to realizing the vision for healthcare professionals. Clinicians today must contend, as never before, with a massive amount of information emerging from the scientific literature. One thing that can be done now, to move this vision ahead, will be the unbiased utilization of the already created and available organizational architecture of information that moves beyond the well-established “silos” of organ system medicine. For example, the effects of chronic inflammation on one organ system do not necessarily stop there. The inflammatory process can operate throughout the patient entirely, affecting multiple systems including the brain, the immune system, and the endocrine system. Utilizing this type of “functional medicine” approach will allow for a more precise and clear evaluation, formulation, and integration of all the information at our disposal, to create a systematic and effective nutrition care plan for our patients that can potentially alter the trajectory of their health status forever.

Conclusion The emerging field of nutritional genomics, defined as the interface between genes and nutrition, is credited with debunking the concept that “one size fits all” as it relates to nutritional management of chronic disease, including inflammatory bowel disease (IBD). Crohn’s disease, a subcategory of IBD, contributes to significant morbidity, particularly in industrialized nations. It is characterized by chronic inflammation and ulceration that can occur in any portion of the intestinal tract. A number of factors contribute to its etiopathogenesis, including genetic, microbial, inflammatory, immune, and permeability abnormalities. Several susceptibility genes have been associated with IBD;

286

INTEGRATIVE GASTROENTEROLOGY

however, this review focused specifically on three IBD-associated genes that appear to identify major susceptibility loci for Crohn’s disease: (1) CARD15/ NOD2, (2) DLG5, and (3) SLC22A4/A5 (OCTN1/OCTN2). Variations of these genes and their potential impact on IBD pathogenesis are discussed. Nutritional management, including the use of various functional clinical tests, nutritional influences in IBD and a functional medicine systems biology approach referred to as the 4R™ Gastrointestinal (GI) Restoration Program weredescribed. The 4R™ approach, “Remove, Replace, Reinoculate, Regenerate” provides a framework in which to focus clinical assessment and intervention. Future strategies including a discussion of the evolving role of the registered dietitian as a vital clinician in the integrated healthcare team were offered.

31 Functional Foods for Digestive Health and Disease ELIZABETH LIPSKI

key concepts ■

■ ■

■

■

Diet affects GI health: Food can be inflammatory; food can be healing. The Standard American Diet (SAD) accelerates chronic disease. Probiotics, prebiotics and fiber help restore balance in the GI tract. The Elimination Diet can become a useful tool to reduce gut inflammation in digestive conditions. Functional foods can facilitate and restore digestive health and well-being. ■

Introduction

F

ood is our most intimate contact with our external environment. Each day we put several pounds of food into our mouth. (Amber Waves 2005). The body must read and react to the food as friend or foe, which is why fully two-thirds of our immune system is located in the digestive system. Increased intestinal absorption and dysbiosis can lead to systemic illness and symptomatology and have been well-covered previously in this text. As discussed in Chapter 30), food is information that elicits a genetic and cellular response.

287

288

INTEGRATIVE GASTROENTEROLOGY

Food can be inflammatory and anti-inflammatory. In our Western culture, much of the food that is commonly eaten is inflammatory. In a recent issue of the Journal of the American College of Cardiology, Guiliano et al state: “Dietary patterns high in refined starches, sugar, and saturated and transfatty acids, poor in natural antioxidants and fiber from fruits, vegetables, and whole grains, and poor in omega-3 fatty acids may cause an activation of the innate immune system, most likely by an excessive production of proinflammatory cytokines associated with a reduced production of anti-inflammatory cytokines.”(Giugliano, Ceriello et al., 2006) For example, processed foods contain denatured fatty acids, which lead to a build-up of arachidonic acid and omega-6 fatty acids and a deficit of omega-3 fatty acids. A high omega-6-to-3 ratio commonly increases production of arachidonic acid and the resulting inflammatory PGE2 prostaglandins. For further details, see The Omnivore’s Dilemma by Michael Pollan (2007). This chapter will discuss the inflammatory nature of the standard American diet, use of elimination diets to reduce digestive and systemic inflammation, and use of specific foods to protect the gastrointestinal system.

NUTRITION AND DIGESTIVE WELL-BEING

Appropriate nutrition is critical for digestive well-being. In the Surgeon General’s Report on Nutrition and Health (Koop, 1988), diet was reported to play an important role in 5 out of the 10 leading causes of death. Although no digestive illness is listed in the top 10, the digestive system serves to transport nutrients to each cell of the body. If cells cannot assimilate adequate nutrients, virtually any illness or condition can occur. This makes the process of digestion critical for overall health and well-being. Although there is a growing public interest in nutrition, whole foods, and food quality, nutrition is a topic rarely discussed except peripherally in the physician’s office. Food diaries are seldom used as part of an initial medical history, even though they are an essential part of understanding a patient’s overall health.

THE STANDARD AMERICAN DIET IS INFLAMMATORY AND LOW IN NUTRIENTS

Dietary patterns have changed dramatically during the last decade. The current standard American dietary pattern is high in refined starches, sugar, and

Functional Foods for Digestive Health and Disease

289

saturated and trans fats, poor in natural antioxidants and fiber from fruits, vegetables, and whole grains, and poor in omega-3 fatty acids. This may lead to (Figure 31.1): • activation of the innate immune system • excessive production of proinflammatory cytokines • reduced production of anti-inflammatory cytokines Disappearance data indicates that Americans are eating 523 calories more each day than in 1970 (Amber Waves 2005). It’s no wonder that we are increasingly obese. Our foods are mainly processed, and each time a food is processed it loses essential nutrients. The definition of a nutrient is that it is essential for life; chronic deficiencies lead to changes in all body systems. Americans eat 20.4 of their calories as refined grains, yet only 3.5 as whole grains. When grains are refined, they lose 58.1 of 19 vitamins and minerals they contain (see Appendix C). Refined sugars, such as high-fructose corn syrup and white sugar, comprise an additional 18.6 of our caloric intake, at an average of 141 pounds per year, or 6.2 oz. per day (United States Economic Research Service Food Consumption, 2007). Refined vegetable oils make up another 17.6, and alcohol 1.4. The damaged and nutritionally depleted omega-6 fatty acids and oils used in processed foods increase levels of arachidonic acid and inflammatory cytokines, which help promote inflammatory gut conditions such as Crohn’s disease. Worse, potatoes as French fries are the vegetable most commonly eaten by toddlers over 15 months of age. In 2004, soft drinks were the third most commonly consumed food among American children ages 2 to 5, with cookies and French fries ranking sixth and seventh, respectively (Demory-Luce, 2004) No wonder rates of childhood obesity and other diseases are rapidly increasing. All told, the typical American eats 58 of his or her total calories as highsugar, highly processed, nutritionally depleted, inflammatory foods (Cordain et al., 2005). The film “Supersize Me” increased public awareness about the inflammatory nature of processed fast food and its overconsumption. A Swedish study (Kechagias et al., 2008) replicated the movie’s results. An intervention group of 18 people with an average age of 26.6 were asked to eat at least two fast food meals per day for 28 days. The goal was to double their regular caloric intake, increase total body weight by 5 to 15, and follow a sedentary lifestyle of not more than 5,000 steps per day. Thirteen of the subjects (72.2) had pathological increased levels of the liver enzyme alanine aminotransferase ALT; 23 had steatohepatitis; and 13 had fatty liver. In most subjects, these elevations occurred during the first week. One man was dismissed in the third week due to increased ALT of 447 (normal is 0 to 40).

290

INTEGRATIVE GASTROENTEROLOGY

This study is relevant to the eating habits of many Americans, including children. An estimated 26.5 of Americans eat at fast food restaurants, which contributes one-third of their total caloric intake. Fast foods have lower levels of vitamin A, carotenoids, vitamin C, magnesium, fruits, and vegetables (Bowman & Vinyard, 2004). Fifteen percent of adults in the United States have nonalcoholic fatty liver disease, and 50 of adults with diabetes or hyperlipidemia have hepatic steatosis (Pitt, 2007). A 2006 study at the University of San Diego School of Medicine looked at autopsies of 742 children and teens who had died due to accidents, homicide, or suicide. Based on their results, the researchers estimate that 10 of children in San Diego County have steatohepatitis. High-fructose corn syrup and end-stage glycation products have been implicated in steatohepatitis (Thuy et al., 2008).

Use of the Elimination Diet Approximately 3 of children and 1 of adults have IgE mediated food allergies. Peanut allergies alone doubled from 1997 to 2002 (Sicherer, MuñozFurlong & Sampson, 2003). One person in three changes their diet to adapt for what they consider to be food allergies, although the true incidence of such allergies is estimated to be around 5 (Cordain et al., 2005). The majority of the people who believe that they have food allergies likely have food hypersensitivities or food intolerances instead. Seventy percent of the world’s population is considered to be lactose intolerant, for example; others have fructose intolerance. In addition people can have other negative reations to substances in food such as: Food hypersensitivity reactions (IgG, IgG4, IgM, IgA), lectins, tyramines (found in cheese, caffeine, coffee, chocolate), complement reactions, sulfate reactions (due to impaired sulfation pathways), inability to handle phenols, oxalates, food dyes, food additives, or other possible food substances. In my clinical experience as a nutritionist, it is common for symptomatic patients who test negative for celiac disease to respond positively to a glutenfree diet. Although research on gluten intolerance is nearly nonexistent, one can hypothesize that damage from gluten-containing grains is on a continuum, with celiac disease at the far end of the spectrum. When working with someone with gastrointestinal (or rheumatological, autoimmune, or respiratory) illness, it can be useful to begin with a lowantigen, low-inflammation diet (Sköldstam. 1986; Sköldstam & Magnusson, 1991; Kjeldsen-Kragh, Haugen et al., 1994; Kjeldsen-Kragh, Hvatum et al., 1995). Working with a “clean slate” can clear myriad symptoms by reducing total load, enhancing detoxification pathways, and reducing inflammatory cytokines. It’s simple and cost-effective.

Functional Foods for Digestive Health and Disease

291

Research on elimination diets has been promising, One meta-analysis reports that the only effective dietary strategy for ulcerative colitis is the elimination diet, but this observation was based upon one study (Galandi & Allgaier, 2002) Fasting has been well-researched in rheumatoid arthritis (Muller, de Toledo, & Resch, 2001) There is an increasing number of controlled studies on elevations in IgG antibodies and the use of elimination diets for a variety of GI issues. Research substantiates use of IgG and IgE testing in irritable bowel, atopy, and other digestive and systemic conditions. In a study by Atkinson, 150 patients who had IgG food antibody testing were randomized to receive either an appropriate elimination diet or a sham diet. After 3 months, there was a 24 reduction in symptoms in the study group (Atkinson, Sheldon, Shaath, & Whorwell, 2004). A similar study was done in China: IgG antibodies for 14 common foods were tested in 55 people with diarrhea-dominant IBS, 32 people with constipation-dominant IBS, and 18 normal controls. Sixty-three percent of subjects with diarrhea-dominant IBS and 43.8 of subjects with constipationdominant IBS had positive IgG food antibodies. Both groups had more positive food antibodies than controls. After adhering to individualized eliminated diets for 2 months, a total of 65.7 of people reported either complete improvement (31.4) or remarkable improvement (34.3; see Yang & Li, 2007). Zar, Kumar, and Benson (2001) report that elevations of IgG antibodies in subjects with IBS. Drisko et al. (2006) investigated food intolerance using Rome II criteria, in 20 patients with IBS who had failed standard care. IgG and IgE food and mold panels, comprehensive stool analysis, and small bowel bacterial overgrowth were assessed. Subjects filled out quality of life questionnaires and complied with elimination diets based on IgE and IgG testing results. They were also given probiotics. Testing was repeated at 6 months, with follow up at 12 months. In subjects who had significant responses to the diet, 100 had baseline abnormalities in IgG and IgE antibody levels. There were significant improvements in stool frequency and quality of life. At baseline, 100 of subjects had imbalances in beneficial and dysbiotic flora. At 6 months, there was a trend toward normalization of beneficial bacteria, with no change in dysbiosis. At one year, there was continued adherence to the food rotation diet and minimal issues with IBS. There is much anecdotal evidence for use of the Specific Carbohydrate Diet, which was popularized by Elaine Gottschall Ph.D. in Breaking the Vicious Cycle, in GI disorders, especially in Crohn’s disease. Unfortunately no controlled studies have been done on the Specific Carbohydrate diet. This diet is entirely grain-free and limits disaccharides from starchy vegetables as well. (www.scdiet.com)

292 INTEGRATIVE GASTROENTEROLOGY

Table 31. Case1 Sidebar. Case History:

• 48-year-old male, Caucasian • Weight: 245 lbs. Height: 6’1” • Current Medical Diagnoses • IBS • Osteoarthritis • Depression • Hypertension • High cholesterol • Eczema • Obesity (BMI of 32) • Allergies • Current Medications • Wellbutrin XL • Benicar HCT • Topical steroid ointment • Aspirin • Previously had been on Lipitor • Primary Complaints: • Constant GI cramps for 2 to 3 days; sharp pains are relieved with diarrhea, which lasts 2 to 3 days • Occurs several times a month • Abdominal bloating • BM: At least three times daily • Secondary Complaints: • Lower back: fairly consistent low-grade pain, with flare-ups sending pain to hips and legs • Muscle inflammation, difficult to grip without pain. • Constant pain in hands and feet.

Functional Foods for Digestive Health and Disease

293

Table 31. (Continued) Case History:

• Eczema • Allergies/stuffy nose: cats, dust, pollen, molds • Depression • Low energy level • Caffeine necessary to jump start • Legs swollen by the end of the day • History/Family History • Life-long GI issues—remembers several times a year as a child recurrent abdominal pain (RAP) and diarrhea. • Asthma as a child at age 10 • Brothers also had asthma • Had stomach ulcer as a child • No significant family history noted • Prior Testing • Upper GI: negative • Endoscopy: negative except for hiatal hernia • Colonoscopy: negative • Food Diary • Breakfast: fruit, cereal (oat, rice or corn), soy or rice milk, coffee, sometimes fruit juice • Lunch: fruit, beans & rice, or Garden burger with veggie slices and bread, mustard. • Dinner: beans and rice, vegetable (yams, broccoli, kale, green beans), fish, pasta, bread, and margarine • Removed meat and dairy from diet a few weeks ago. This was a drastic change • Initial Treatment Plan: • IgG and IgE food sensitivity/allergy testing • Ask physician to run Celiac Panel (IgG, trans-glutaminase, endomysial, anti-gliaden) • In the meantime, begin Elimination Diet plan for 2 weeks • Replace potassium (99 mg), calcium (400 mg), and magnesium (200 mg) lost to hydrochlorothiazide. (continued)

294

INTEGRATIVE GASTROENTEROLOGY

Table 31. (Continued) Case History:

• Two-Week Recheck • Celiac testing: negative • Carefully followed elimination diet, which consisted of fruits, vegetables, poultry, fish, rice, olive oil, salt, pepper, herbs, spices • Lost 8 pounds • No gut pain, cramping, or diarrhea • No hand, foot, leg or hip pain • Played fiddle at a concert for 3 hours • Depression has lifted • Has not started calcium, magnesium, or potassium. • Nasal congestion has cleared. • Continue with diet. Just sent blood to lab IgG/IgE. • Four-Week Recheck • IgG and IgE results indicate gluten, dairy, and egg intolerance. Eliminated eggs from diet. • Experiencing continued well-being. • Six-Week Recheck • More improvement without eggs in diet • Has lost 18 pounds • No arthritis • No IBS symptoms • Off Wellbutrin • Has good energy, not relying on caffeine • No improvement with eczema • Hyper-sensitive to gluten • Resistant to further testing or taking any supplements • Three-Month Recheck • Continues to feel great. “I never realized I’d actually feel younger.”

Functional Foods for Digestive Health and Disease

295

Table 31. (Continued) Case History:

• Found Belgian beers without gluten • Lost 30 pounds • Energy level is high • No IBS/No arthritis/No depression • Stopped ALL Medications • Eczema changing slowly • Extreme sensitivity to gluten • Resistant to further testing or taking any supplements • One-year Recheck • Still on the diet • Feeling great! • Off of all medications • Cholesterol and blood pressure improved • Eczema not cleared • Gums are healthier than ever • Still sensitive to gluten • Seems more sensitive to dairy than before • Hay fever and allergies are diminished • Resistant to further testing, nutritional supplements, or any other intervention

The Functional Foods Simply stated, a functional food is a food that confers one or more specific physiological benefits that reduce risk of disease. A food or spice may be considered to be a functional food in its natural state. Functional foods are often manufactured foods that contain specific nutraceutical ingredients. These are often also called “medical foods.”

296

INTEGRATIVE GASTROENTEROLOGY

MEDICAL FOODS

• There are two types of medical foods that can be effective for many people, when working with gastrointestinal issues: those designed to upregulate liver detoxification, and those designed to support GI function. • Currently one nutraceutical manufacturer produces a product that is specifically designed to support gastrointestinal function. This product is based on a low-allergy, high-amylase rice flour, plus amino acids, vitamins and minerals, and gut supportive nutrients, such as zinc, L-glutamine, panthothenic acid, and fructooligosaccharides (FOS). There are no specific case studies or published clinical research on this product. • Most nutraceutical companies have a medical food product designed to upregulate phase I and phase II liver detoxification pathways (see Figure 31.3). • Phase I nutrients include riboflavin, niacin, pyridoxine, folic acid, vitamin B12, glutathione, branched-chain amino acids, flavonoids, and phospholipids. Nutrients included to assist with the reactive oxygen intermediates include carotenes, vitamins C and E, selenium, copper, zinc, manganese, coenzyme Q10, thiols, bioflavonoids, silymarin and pycnogenol. • Phase II nutrients include the amino acids: glycine, taurine, glutamine, ornithine and arginine. Cysteine and N-acetylcysteine are also used as methylation cofactors.

PROBIOTICS AND PREBIOTICS IN FOOD

Probiotics and prebiotics are increasingly being added to foods, primarily cultured dairy products. For an extensive review of probiotics, see Chapter 29, by Gerald Friedman. There is a simultaneous resurgence in the popularity of probiotic-laden fermented and cultured foods that have been used in traditional diets.

Health Benefits of Prebiotics and Probiotics: • have a positive influence on immune development • improve colonic integrity

Functional Foods for Digestive Health and Disease

297

• regulate local and systemic immune function • decrease incidence and duration of infections in the intestinal tract, urinary tract, vagina, and respiratory system • downregulate allergic response • improve digestion • regulate gut transit and stool regularity • increase lactose tolerance • improve elimination • prevention or regulation of diarrhea induced by antibiotics, rotovirus, and lactose intolerance • reduce concentration of cancer-promoting enzymes and/or putrefactive (bacterial) metabolites in the gut • have beneficial effects on inflammation in diseases of the gastrointestinal system • prevent or alleviate atopic disease and allergies in infants • beneficial effects on cholesterol, ischemic heart disease, autoimmune disease, and oral health are less well documented • regulate appetite through leptin and ghrelin • manufacture vitamins B1, B2, B3, B5, B6, B12, and K • metabolic control of nutrients: glycemic control, cholesterol, amino acids (Hanaway 2010, Lipski 2004, Liska, 2006; de Vrese & Schrezenmeir, 2008; de Vrese, 2008)

Prebiotics are insoluble fibers that selectively stimulate the growth and/or activity of probiotics in the intestines. They are nondigestible food carbohydrates, and are often called resistant starch, soluble fiber, nonstarch polysaccharides, and soluble oligosaccharides that promote the growth or activity of a limited number of bacterial species for the benefit of host health and help optimize microbiotica health and function (Douglas & Sanders, 2008). They include fructans, inulin and fructooligosaccharides, arabinogalactans (larch), and soy oligosaccharides (Plummer, Quilt, & Crockett, 2003; Liska & Bland, 2006). Prebiotics pass undigested through the stomach and small intestine and are subsequently completely fermented in the colon by microflora, primarily Bifidobacteria species, producing short-chain fatty acids (acetic acid, butyric acid, and propionic acid). Characteristics of Prebiotics: • change in composition of short-chain fatty acids • differential stimulation of probiotic bacteria in the colon

298

INTEGRATIVE GASTROENTEROLOGY

• promote growth of Bifidobacteria and lactobacilli • increased fecal weight • mild reduction in luminal colon pH • decrease in nitrogenous end-products • increased expression of binding proteins or active carriers associated with mineral absorption • discourage growth of clostridial species • normalize bowel function (Hanaway, 2010, Douglas & Sanders, 2008) For a list of best food sources of prebiotics, see Appendix X.

Traditional populations have all had fermented foods and/or cultured dairy products in their native diet. Koreans ate a variety of pickled vegetables. Europeans made sauerkraut and pickles. Eskimos fermented fish by burying it for months. Worldwide, dairy products were fermented into cheese and cultured milks such as yogurt and kefir. In many cultures, grains were fermented to create sourdough breads. Fermenting and culturing foods enhances their digestibility, can improve nutritional content (increased B complex, decreased mineral-binding phytates), and decrease toxicity (as in cassava or poi). Di Cagno and colleagues (2003, 2004, 2005) have reported that traditionally fermented sourdough bread and pasta have been well-tolerated by people with celiac disease. Probiotics (as discussed in Chapter 4) are defined as living microorganisms that, when consumed in adequate amounts, confer a health symbiotic benefit to the host (Douglas & Sanders, 2008). The most well researched bacterial species are Lactobacilli and Bifidobacteria, and a yeast called Saccharomyces boulardii.

Probiotic rich foods: • cultured dairy products (yogurt, kefir) • sauerkraut • kim chee • miso • natto • tempeh • poi • natural soda beverages (kvoss, ginger beer) • fermented grains (gruel, sourdough bread)

Functional Foods for Digestive Health and Disease

299

FIBER TO REGULATE GI FUNCTION

Prebiotics, discussed above, are one type of beneficial dietary fiber that specifically enhances digestive function. Dietary fiber refers to a group of plant polysaccharides that are not digested or absorbed. Examples of dietary fiber include prebiotics, cellulose, hemicelluloses, pectins, beta-glucans and gums. Soluble fiber dissolves and/or swells when it is added to water; some soluble fibers can hold up to 20 times their weight in fluid. Insoluble fibers do not dissolve or absorb fluids. For example, oatmeal that sits in water overnight will swell and partially dissolve; a carrot will not change. Foods generally are composed of a blend of soluble and insoluble fibers. Most grains and vegetables contain mainly insoluble fibers. Soluble fibers have been shown to lower serum cholesterol levels, and add bulk to and soften stools. Insoluble fibers are bulking agents, and help with peristalsis and bowel transit time. Further categories of fibers include those that hold water and form a gel-like consistency, and those that are fermentable fibers. Gel-like fibers aid in peristalsis and increase bulk of the stools. Fibers that are fermented by Bifidobacteria in the large intestine become short-chained fatty acids that are the essential energy and maintenance source for colonic mucosal cells (Liska et al., 2004; Jones, 2006; McGuire & Beerman, 2007). Dennis Burkitt, father of the fiber theory, believed that people in Africa who ate traditional diets had few modern chronic diseases yet the same people living in cities developed them. He reported that the average weight of a Western daily bowel movement was about 3.5 oz (100 grams); people who ate traditional diets had stools that weighed at least 1 pound daily. It is recommended that we consume 20 to 35 grams of fiber daily, yet the average American gets only about 14 to 15 grams daily. The average worldwide fiber intake is in the 50 to 75 grams per day range. Fiber plays an important role in both phase I and phase II liver detoxification pathways.(Liska et al., 2004; Jones, 2006; McGuire & Beerman, 2007) Studies in mice show upregulation of cytochrome P450 and glucuronidation pathways. Foods high in dietary fiber include legumes, fruits, vegetables, nuts, seeds and whole grains. People should increase dietary fiber gradually to prevent flatulence and bloating.

Polyphenols in Digestive Health Polyphenols are phytochemicals that are found in food substances produced from plants. They are different from essential micronutrients in that a

300

INTEGRATIVE GASTROENTEROLOGY

Table 31.1. Fiber Chart Soluble Fiber

Insoluble Fiber

Benefits • Lowers cholesterol levels • Regulates glucose • Regulates pH balance in the intestines • Binds bile acids • Regulates phase 1 and 2 liver detoxification

Benefits • Promotes peristalsis and bowel regularity • Provides substrate for Bifidobacteria to produce butyrate and other short- chain fatty acids in colon • Improves IBS • Increases satiety • Cancer protective • May reduce risk of diverticulosis

Food Sources • Apple pulp • Barley • Beans • Bran (oat and rice) • Carrots • Citrus fruits • Flaxseed • Peas • Potatoes • Psyllium seeds • Oats • Oranges • Rice • Soy • Strawberries

Food Sources • Apple skin • Beets • Bran (wheat, corn) • Brussels sprouts • Carrots • Cauliflower • Fruit skin • Green beans • Green leafy vegetables • Nuts • Root vegetables • Seeds • Turnips • Whole grains such as wheat and rye

deficiency state has not been identified for them; nevertheless, these chemicals are believed to play a biologically active role and have been shown to act as potential immunomodulators (Clarke, Mullin et al., 2008). Polyphenols are found in colorful foods, such as fruits, tea, coffee, and to a lesser extent, vegetables, grains and legumes. Common polyphenols include isoflavones, gallic acid, catechins, flavanones, flavonols, flavonoids, stilbenes, tannins and quercetin (Manach, Williamson, Morand, Scalbert, & Rémésy 2005; alsosee Appendix C for Polyphenols in Food chart.) On average, Americans consume about one gram of polylphenols, phenols, and tannins daily, in ranges from 100 mg to more than 2 grams. More than 95 of these substances reach the colon and are fermented by colonic bacteria (Parkar, Stevenson, & Skinner, 2008). Polyphenols have established antioxidant, anti-cancer, and anti-inflammatory effects on the digestive system and throughout the body. A growing

Functional Foods for Digestive Health and Disease

301

body of research indicates that they also have regulatory effects on cell signaling pathways, and help to regulate energy metabolism and GI health. (Stevenson & Hurst, 2007)

Demulcent Foods Herbalists use the word “demulcent” to describe any substance that soothes inflamed mucous membranes. A wide variety of foods have demulcent effects on the digestive system, including fenugreek, flax, ghee, and oat gruel. The following foods appear to enhance digestive function and improve overall well-being:

GREEN BANANAS/PLANTAINS

It has been observed that specific varieties of “green bananas” (just barely ripe) and plantains (bananas of the Musa species) have anti-ulcer effects. Several studies in rats have attempted to elucidate the physiological benefits of bananas. Green bananas have been reported to increase mucosal tolerance to stomach acids (Rao, 1991; Best, 1984), and plantains have been reported to stimulate the growth of gastric mucosa (Rao, 1991). Unripe bananas also contain protease inhibitors, which may play a role in curing stomach ulcers (Rao, 1991). Other researchers have isolated a substance called leucocyanidin, which prevents aspirin-induced ulcers in rats.

BONE BROTHS

It is instinctive to bring chicken soup or beef consume to someone who is ailing. Bone broths are alkaline and mineral rich. They have been found to contain gelatin, free amino acids, calcium, glycinate, proline, phosphorus, hyaluronic acid, chondroitin sulfate, magnesium, potassium, sulfate and fluoride. In 1985, Dr. Erich Cohn, of the Medical Polyclinic of the University of Bonn, recommended bone broths for catarrh, which is now known as irritable bowel syndrome. He also recommended a concentrated calf ’s foot broth for more serious digestive disorders. Gelatin was reported to balance both deficiencies and excesses of hydrochloric acid. Traditionally, gelatin was believed to act as a demulcent, soothing the gastrointestinal tract. In 1908, a researcher named C. A. Herter suggested that the

302 INTEGRATIVE GASTROENTEROLOGY

gelatin in bone broths helped reduce carbohydrate fermentation due to gastrointestinal bacterial infections, now called fermentation dysbiosis. He stated that: “The use of gelatin as a foodstuff in bacterial infections of the intestinal tract has never received the attention it deserves. The physician is not infrequently confronted with a dietetic problem which consists in endeavoring to maintain nutrition under conditions where no combination of the ordinary proteins with fats and carbohydrates suffices to maintain a fair state of nutrition. The difficulty which most frequently arises is that every attempt to use carbohydrate food is followed by fermentative disturbances of an acute or subacute nature which delay recovery or even favor an existing infection to the point of threatening life. A great desideratum, therefore, is a food which, while readily undergoing absorption, shall furnish a supply of caloric energy and which at the same time shall be exempt from ordinary fermentative decomposition. Such a food exists in gelatin.” (Daniel, 2003) Bone broths are simple to prepare. The key is to use a few tablespoons of either lemon juice or vinegar to help pull more nutrients from the alkaline bones.

Bone Broth Recipe • Take the bones from poultry, beef, lamb, shellfish, or whole chicken or whole fish (remove meat after it has cooked for about 1 hour) • Cover with water and add: • 1 to 2 tbsp. of lemon juice or vinegar • 1 to 2 tsp. salt • ½ tsp. pepper • Carrots, onions, and celery • Parsley, sage, rosemary, thyme, and bay leaf • Cook between 4 and 24 hours on the stove, or in a crockpot on low • Remove bones and skim off fat

CABBAGE JUICE

There is a strong evidence-based tradition for the use of cabbage juice in people with peptic ulcers, diabetes, cirrhosis, cancer, and arthritis (Miron, Hancianu, Aprotosoaie, Gacea, & Stanescu, 2006). Its efficacy may be due to immunomodulary polysaccharide compounds found in cabbage. Cabbage juice contains glutamine, methionine and sulforaphanes.

Functional Foods for Digestive Health and Disease

303

The original research was conducted by Garnett Cheney at Stanford University Medical School from 1949 to 1952 (Cheyney, 1949) In a study of 181 patients, Cheney reports that cabbage juice helped decrease pain and led to improvement on X-rays. More than 80 of patients were symptom-free in 1 week, and two-thirds reported improvement within 4 days. Other studies followed, with researchers typically recommending 1 quart of cabbage juice daily for 7 to 10 days. Most subjects experienced relief within the first few days (Doll & Pygot, 1954; Strehler & Hunziker, 1954, Klimov, 1961; Trusov, Belosludtsev, Pevchikh, & Shinkareva, 1964; Dunaevskiĭ, Migunova, Rozka, & Chibisova, 1970; Zhgun & Aloiants, 1971). More recently, sulforaphanes have demonstrated effects against H. pylori and gastric cancers. This particular study used sulforaphanes from broccoli and broccoli sprouts, but cabbage also has high levels of sulforaphanes (Fahey et al., 2002). Dosage: 1 quart fresh, green cabbage juice daily for 7 to 10 days in divided doses. The taste can be intense, so people will probably be more compliant if it is diluted with other fresh vegetable juices.

GINGER

Ginger is one of the most widely used culinary spices. Its best-studied active ingredient, gingerol, has the following characteristics: • • • • • • • • •

Antiemetic Antitussive Bile stimulating Cancer protective Cardiotonic Hepatoprotective Hypertensive Prostaglandin suppressive Sedative

(al Somall, Coley, Molan, & Hancock, 1994; Schulick, 1994) Ginger itself: • inhibits proinflammatory cytokines: IL-12,TNF-alpha; IL-1-beta, MCP-1, and RANTES • suppresses inducible NOS and COX-2 synthesis • inhibits platelet aggregation and thromboxane synthesis in vitro (Alt. Med.Review, 2003; Tripathi, Maier, Bruch, & Kittur, 2007)

304

INTEGRATIVE GASTROENTEROLOGY

For the digestive system, research focus has focused mainly on ginger’s use in reducing morning sickness of pregnancy and post-surgical nausea and vomiting (Chaiyakunapruk, Kitikannakorn, Nathisuwan, Leeprakobboon, & Leelasettagool, 2006). While the exact mechanism of action is unclear, ginger seems to inhibit serotonin receptors and to have anti-emetic effects on the GI and neurological systems, anti-spasmodic effects and carminative effects (Alt. Med. Review, 2003; White, 2007). Ginger can be used fresh, dried, or as an extract. It can be added in cooking or used as a tea, in ginger ale or ginger beer, or as crystallized ginger.

HONEY

Honey has long been used worldwide for its medicinal effects on wound healing, infection, and digestive issues. Researchers in New Zealand studied 345 honey sources and found that antibacterial activity varied greatly, depending on plant sources. Honey from manuka flowers (Leptospermum scoparium) had the highest level of antibiotic activity. In an in vitro study, it was determined that manuka honey had a strong inhibitory effect on H. pylori. The researchers found that the minimum inhibitory dosage of manuka honey could be achieved with 2.5 ml (½ tsp.) taken prior to a meal. This would be tolerable and perhaps enjoyable for the average person, and is a low-cost, low-side-effect option to standard therapy (al Somall et al., 1994). Another group looked at chemically induced ulcerative colitis in rats. They compared honey, glucose, fructose, sucrose and maltose mixtures that were administered orally and rectally once daily for 4 days. On the third day, a 3 acetic acid solution was used to induce colitis. Biopsies were taken on day 4. Honey protected against acetic-acid-induced colonic damage. At dosages of 5 gram/kg there was almost 100 protection. There was no protection with any of the other sugars used (Mahgoub, el-Medany, Hagar, & Sabah, 2002). Dosage: 1 tsp. daily

PEPPER

Black pepper is one of the most commonly used spices. Several benefits to the GI system are attributed to piperine, one of the active ingredients in pepper. Piperine has been reported to stimulate pancreatic enzymes, reduce bowel transit time, and enhance digestion (Srinivasan, 2007). It has an inhibitory influence on drug biotransformation reactions in the liver, strongly

Functional Foods for Digestive Health and Disease

305

inhibiting hepatic and intestinal aryl hydrocarbon hydrolase and UDPglucoronyltransferase. It has also been shown in vitro to have antioxidant effects.

PEPPERMINT

Peppermint oil has long been used as a flavoring and relaxes smooth muscle in the digestive tract. Although no studies have been conducted on peppermint-leaf tea, there is much research on the use of peppermint oil. Enteric-coated peppermint oil has been well-researched in children and adults for its beneficial effect on irritable bowel syndrome, non-ulcer dyspepsia, and colonic spasm. Two studies have found it to be of benefit in reducing spasm during barium enema and possibly colonoscopy (Kligler & Chaudhary, 2007).

INDIAN SPICES

Use of spices not only makes food taste better, but simultaneously enhances digestion. Fennel, fenugreek, cumin, cardamom, and coriander seeds are provided by Indian restaurants for this purpose. Fennel tea has been a standard of care in Europe for colicky and fussy babies. A review article by Platel and Srinivasin (2004) discusses the digestive actions of spices and herbs used in Indian cooking. They report that spices stimulate digestive function primarily through increased bile production and secretion. Various spices also increase production and secretion of pancreatic lipases and amylases, and affect alkaline phosphatase. The same researchers report rat studies that show bowel transit time was shortened by the ingestion of most herbs and spices. This shortening did not affect growth rates or produce diarrhea. Shortened bowel transit time has been associated with a decreased risk of colon cancer.

TURMERIC (CURCUMA LONGATA)

Turmeric, a member of the ginger family, is one of the primary antiinflammatory substances used in traditional Indian and Hawaiian medicine. Much research has been done on the anti-inflammatory effects of turmeric, and especially on one active component, curcumin.

306

INTEGRATIVE GASTROENTEROLOGY

Table 31.2. Digestive Stimulation from Spices Pancreatic

Lipase activity

Significantly > activity

Stimulated > of at

amylases >

> up to 80%

of disaccharides:

least one disaccharase phosphatase

sucrase, lactase, and

enzyme

Alkaline

maltase. Effects most pronounced when consumed on a regular basis

• Ginger • Curcumin • Curcumin

• Coriander > nearly 300 • Onion

• Ginger • Ajowan • Fennel • Cumin Asafetida • Curcumin • Capsaicin (from cayenne) • Piperine (from black pepper)

• Increased: • Onion • White coriander • Decreased: • Coriander • Fenugreek • Mint • Mustard • Asafetida

Adapted from Platel & Srinivasan, ; Indian J Med Res, , –. Review Article: Digestive stimulant action of spices: A myth or reality?

Turmeric has the following reported effects: • • • • •

inhibits inflammation antioxidant effects anti-microbial effect hepatoprotective cancer protective

The studied mechanisms of action of curcumin include: • • • • •

inhibits TNF-alpha inhibits arachidonic acid production cortisone-like inhibitory action on phospholipases a potent inhibitor of transcription factor NF-kappa B antioxidant activity (Alternative Medicine Review, 2001).

Dosage: Take either 1 finger-sized piece of fresh turmeric twice daily or 1 tbsp. dried turmeric daily. If using fresh turmeric, place in blender with juice or water. If using dried turmeric, mix into foods such as salad dressings,

Functional Foods for Digestive Health and Disease

307

grains, juice or tea. Some people enjoy simply mixing it with honey and adding it to tea.

UMEBOSHI PLUMS

Umeboshi plums are a traditional condiment used throughout Japan, Korea and China for their health benefits. The ume plum is picked unripe, dried in the sun, then pickled in a brine of sea salt and shiso leaves. The net result is a highly alkaline, naturally fermented pickle that is rich in enzymes and probiotics. Researchers have found it to have antioxidant and antibiotic properties. It has been used traditionally for hangovers, liver support, detoxification, nausea, as an appetite stimulant, for skin diseases such as eczema, and for bad breath, dysentery, typhoid, and paratyphoid (Kuleshnyk, 2008). Umeboshi plums can be eaten in many ways. They are used as a condiment on vegetables or rice. The plums are very salty, but can be eaten whole from the jar. Umeboshi vinegars are also available for use in salad dressings or on rice or other grains. Whole plums or umeboshi paste can also be drunk as a tea. Just let them steep in boiled water for 5 minutes, then drink. This is a very restorative tonic.

WHEATGRASS JUICE

Wheatgrass has been claimed to benefit many conditions, but there has been only one good study on the use of wheatgrass juice for digestive diseases. Scandinavian researchers (Ben-Arye E 2002) studied 23 people with active distal ulcerative colitis who consumed either wheatgrass juice (two-thirds of an ounce to begin with, and increasing to 3.5 oz. daily) or placebo for one month. There was significant improvement in overall disease activity; sigmoidoscopy showed improvement in 78 of people drinking wheatgrass juice, compared to 30 of people on placebo; 33 experienced nausea, while 41 reported an increase in vitality. Other researchers have linked wheatgrass juice to reduced need for blood transfusions in thalassemia (Marawaha, Bansal, Kaur, & Trehan, 2004), and a pilot study reports reduced myelotoxicity in women receiving chemotherapy for breast cancer. Wheatgrass juice can induce nausea, perhaps by acting as a powerful cholagogue and activator of liver detoxification, a side effect that is often too strong for many people. Wheatgrass can be grown in a tray in the kitchen and then juiced with a special wheatgrass juicer. Wheatgrass juice can also be purchased at most

308

INTEGRATIVE GASTROENTEROLOGY

natural food stores. Begin with small amounts and titrate up to prevent possible nausea.

Conclusion Eating whole foods rather than packaged foods can significantly enhance GI function. There is a growing body of research on the use of customized diets to optimize function. When GI dysfunction occurs, it may be useful to clear the board and begin with a modified fast or elimination diet. In clinical practice, use of a 2- to 3-day food diary on an initial visit can be one of your most useful diagnostic tools. Probiotics, prebiotics, fiber, and polyphenols contribute to a well-balanced microbiota. It is the life in foods that gives us life: Think colors. Think fresh. Think about how your ancestors ate and move toward a more traditional diet, which will in turn move you toward optimal health.

32 The Role of Herbal Medicine in Integrative Gastroenterology TIERAONA LOW DOG Of the history of medicine the average person is likely to know only the tall tales of supposedly nonsensical treatments such as phlebotomy, poultices and purges… Such flippant rejection of many millennia of accumulated knowledge has its price, as does the rejection of traditional medicines from foreign cultures. Ignorance of the past has never been a firm foundation for the present. —Robert and Michele Root-Bernstein, Honey, Mud, Maggots and Other Medical Marvels

key concepts ■

■

■

Many functional gastrointestinal disorders are not effectively managed with conventional medications. A number of botanicals show promise in the field of gastroenterology, particularly when used within an integrative approach. ■ Ginger rhizome is an effective antiemetic and prokinetic. ■ Enteric-coated peppermint oil effectively treats irritable bowel syndrome. ■ Artichoke leaf is a reliable choleretic. ■ Berberine-rich plants have broad antimicrobial activity against numerous gut pathogens. ■ Turmeric is a potent anti-inflammatory in inflammatory bowel disease and potential chemopreventive agent in colorectal cancer. ■ Silymarin is an effective hepatic protectant against druginduced damage. Clinicians should inquire about patient use of all dietary supplements, including botanicals, and document in the medical chart. 309

■

Report adverse events from dietary supplements to FDA Medwatch and/or your local poison control center. ■

Herbal Medicine and Gastrointestinal Disorders

S

ince specific disorders are covered in depth throughout this text, this chapter will explore in broad terms the physiological action of plants that are utilized in the treatment of gastrointestinal disorders. Gastrointestinal complaints rank among the most frequent reasons for primary care visits in the United States. Direct costs are in excess of $85 billion annually (Sandler et al., 2002), with an additional $20 billion in indirect costs due to days off work (Mullin et al., 2008). Many of these complaints fall into the category of functional gastrointestinal disorders, a group of conditions— such as irritable bowel syndrome (IBS), GERD, chronic constipation or diarrhea—for which no structural or biochemical cause can be found. A metaanalysis of 53 studies published in 1996 concluded that, due to methodological flaws, there are no proven effective therapies for the treatment of non-ulcer dyspepsia (Veldhuyzen van Zanten et al., 1996), making many of these conditions of maldigestion amenable to the use of herbal medicine. In addition, herbal therapies are being explored for their beneficial effects in inflammatory bowel disease (IBD), as hepatoprotectants and for their potential to reduce gastric and colorectal cancer. While this chapter will focus on the use of botanicals, it should be implicitly understood that the use of these remedies must exist within a framework that includes appropriate diagnosis and holistic treatment; e.g., dietary recommendations, mind–body therapies, manual medicine, or other approaches that may promote wellness and healing in the patient. For the specific integrative management of irritable bowel syndrome, GERD, inflammatory bowel disease, etc., please see the appropriate chapters within the text.

Introduction to Herbal Medicine Herbal medicine, also referred to as phytotherapy or botanical medicine, is the use of plants, plant parts, and preparations made from them for therapeutic and/or preventive purposes. Herbal medicine gave rise to the modern sciences of botany, pharmacy, perfumery, and chemistry. Some of our most useful and beneficial

The Role of Herbal Medicine in Integrative Gastroenterology 311

drugs originate from plants, including aspirin (salicylic acid derivates derived from willow bark and meadowsweet), quinine (from cinchona bark), digoxin (from foxglove) and morphine (from opium poppy). Through isolating the potent actives in these plants, pharmaceutical products can be produced with a consistent and uniform composition. Indeed, one primary drug discovery model has been the identification, isolation, and production of single active compounds. These active compounds can then be researched, patented, and sold as drugs. While there are drugs that are made directly from plant material, these isolated compounds are not considered herbal medicines in the classic sense. In the traditional practice of herbal medicine, the plants and plant parts are themselves considered medicinally functioning wholes. They are chemically complex mixtures, and the entire plant, or part, is considered the “active.” Refinement of knowledge, tradition, and the preparations themselves are not stagnant, however, and the field continues to evolve alongside our scientific studies. Milk thistle (Silybum marianum) has been used to treat a variety of conditions over the centuries. Its common name, “milk” thistle, is a reminder that the seeds have been valued as a lactagogue, or an agent that can help stimulate the production of breast milk. References to its use for liver and other digestive disorders can be found over the past several hundred years. In 1830, silymarin, a group of flavones, were isolated and extracted from the seeds. An antidote for Amanita phalloides (deathcap mushroom) poisoning was later developed from these compounds. From the broad to the narrow, from crude plant to highly refined extract, the field of herbal medicine continues to grow and flourish. Unfortunately, there has been little financial incentive to study herbal medicines that can be easily grown in the garden or harvested in the wild, or to study products for which there is no type of protection for manufacturers. Nor has there been a way for consumers to distinguish clinically tested products from the myriad “me-too” products in the marketplace that piggyback off other companies’ research. And, all too often, the research that is undertaken is focused on the use of one particular herb for one specific condition, even though most experienced herbal practitioners individualize their prescriptions based upon the unique characteristics of the patient. Herbal mixtures are often preferred over single herbs, as they are thought to offer greater efficacy and, to some degree, greater safety. Multi-herb formulations may have additive, or synergistic, effects and secondary herbs can be included to modify potential side effects from the primary herb. For example, an anthraquinonebased herbal laxative (e.g., senna, cascara sagrada) often causes intestinal griping, which can be reduced or eliminated by adding gut antispasmodics (e.g., fennel, ginger). Given the number of traditional medical systems that utilize herbal formulations, the focus on single herb preparations may be a critical shortcoming in botanical research, though monotherapy is probably

312

INTEGRATIVE GASTROENTEROLOGY

the best approach for the clinician who is just starting to use herbs in his or her practice. Getting to know each herb in this way allows the practitioner to gain greater familiarity and expertise with its use.

Quality of Botanical Products Given the dizzying array of herbal products, it is understandable that both consumers and healthcare professionals have difficulty navigating the supplement marketplace. Consumers look down the aisle and ask, “Which product should I take? What dose? Will it interact with my medications? Does it work? Is it safe?” In addition to questions of efficacy and safety inherent to the plant, there are also concerns about the quality of dietary supplements in general, and botanical products in particular, as the media and professional literature are filled with reports of product adulteration and contamination, as well as variation between what is printed on the label and what is actually in the bottle. Though not a significant problem with products manufactured in the United States, cases of heavy metal poisoning (e.g., mercury, lead, and arsenic) from Chinese, Indian, Arabic, and African traditional remedies have been reported, and testing has demonstrated that a number of these products contain unacceptable levels of arsenic, lead, mercury, and cadmium (Cooper et al., 2007; Obi et al., 2006; Saper et al., 2004). While many manufacturers produce high-quality botanical products, the unscrupulous and/or incompetent have, unfortunately, tarnished the industry, making it relatively difficult for consumers or practitioners to distinguish the good companies from the bad. With the passage of the new good manufacturing guidelines (GMP) by the Food and Drug Administration (FDA) in June of 2007, concerns of contamination, adulteration, and poor quality will hopefully become less of an issue in the future. The inspection of dietary supplement manufacturers by the FDA will increase in 2009, when companies will be required to come into compliance with the new guidelines. A number of companies will in all likelihood not be able to meet the stringent requirements for supply chain management and traceability. The burden on manufacturers, however, should actually help the industry in the long run, as consumers will become more confident in the products they purchase, and healthcare providers will be more comfortable making supplement recommendations.

Safety Overall, most of the herbs in general commerce in the United States have a relatively good safety profile when used appropriately and manufactured to

The Role of Herbal Medicine in Integrative Gastroenterology 313

high-quality standards. As more concentrated herbal products are introduced into the marketplace, many of which will be taken for extended periods of time, new questions of safety will undoubtedly arise. The chronic use of certain herbs (e.g., comfrey, chaparral, licorice) can cause hepatic, renal, or electrolyte abnormalities. Like any chemically active substance, whether an herb is safe or toxic depends upon the dose, type of product, and the underlying constitution of the patient.

The concomitant use of botanical remedies with prescription or over-thecounter medications may lead to adverse interactions, especially in elders and those with diminished renal or hepatic function.

A national survey noted that 16 of prescription drug users also reported taking one or more herbals/supplements within the prior week (Kaufman et al., 2002). It is imperative that clinicians dialogue with patients about their use of botanical medicines and other dietary supplements, to help prevent potentially dangerous herb–drug interactions. There are a wide variety of herbal practices and products available in the United States, which makes generalizations difficult; however, by asking a few open-ended questions, clinicians should be able to assess the patient’s beliefs, cultural practices, and use of botanical remedies: • When you were growing up did you, or your family, ever use any medicinal plants or herbal remedies to improve your health or treat an illness? • How do you use herbs or herbal remedies in your home? • Are you taking any herbs or herbal medicines now? If so, what are you trying to treat, and do you think the herbs are working? Document all patient responses in the medical chart and be alert for potential adverse effects and herb–drug interactions, as well as therapeutic benefit.

If you suspect a possible adverse effect, report it to FDA Medwatch at www. fda.gov/medwatch. Another excellent resource is to contact your local poison control centers; the new nationwide toll-free number in the U.S. for poison control is 800-222-1222.

314

INTEGRATIVE GASTROENTEROLOGY

Herbal Actions When examining botanicals it is useful to start with a basic understanding of how they work. In some cases, scientific research has identified key compounds within the plant that account for its physiological effects; in other cases, there are multiple compounds working in harmony that account for the overall therapeutic effect, making the hunt for an “active compound” futile at best. More than 2,000 years ago, anticholinergic plants such as Atropa belladonna were used to treat painful gastrointestinal spasm, even though the tropane alkaloids atropine, hyoscyamine, and scopolamine would not be isolated for many centuries. Practitioners observed the physiologic action of these plants and were able to use them effectively in their patients, even in the absence of isolating specific compounds or having a detailed understanding of cellular physiology. Thus, this section is a blending of traditional wisdom and modern science, observation and reductionism. It is beyond the scope of this chapter to address all herbal actions; it will focus only on those commonly considered when addressing GI disorders.

ANTIEMETIC

The most potent antiemetic plants are those containing the anticholinergic tropane alkaloids hyoscamine, scopolamine and/or atropine. The dominant plants in this category include belladonna (Atropa belladonna), jimson weed (Datura stramonium) and henbane (Hyoscyamus niger). Scopolamine patches have been widely used to reduce postoperative nausea and vomiting, as well as motion sickness; however, these plants and their isolated alkaloids are associated with considerable side effects and are not generally used by practicing herbalists today. A mild, yet effective, antiemetic is ginger (Zingiber officinale). While commonly referred to as “ginger root” it is actually a rhizome, or underground stem. Ginger is a popular home remedy for dyspepsia and has been clinically studied for hyperemesis gravidarum, motion sickness, and chemotherapyinduced nausea and vomiting. A meta-analysis of randomized controlled trials favored ginger over placebo for relief of nausea and vomiting in general (Ernst & Pittler, 2000), while a review of six randomized controlled trials specifically addressing nausea and vomiting of pregnancy found 1.0–1.5 grams/day of dried ginger more effective than placebo (Borrelli et al., 2005a). The way in which ginger acts as an anti-emetic is not completely understood. One class of antiemetics used in conventional medicine is the 5-hydroxytryptamine (5-HT) antagonists, such as ondansetron, that work

The Role of Herbal Medicine in Integrative Gastroenterology 315

specifically on 5-HT3. Several components of ginger; 6-gingerol, 6-shogaol and galanolactone, have shown anti-5-HT activity with galanolactone acting as a competitive antagonist at ileal 5-HT3 receptors (Huang et al., 1991). Cisplatin, one of our most emetogenic chemotherapeutic agents, inhibits gastric-emptying, which is thought to be the primary reason it causes nausea. Both the acetone extract of ginger and ginger juice effectively reverse cisplatininduced delay in gastric emptying. The reversal produced by ginger acetone extract was similar to the effect seen with ondansetron, while ginger juice at oral doses of 2 and 4 ml/kg, was superior to the drug (Sharma & Gupta, 1998). A study in 24 healthy human volunteers found that 1,200 mg of dried ginger accelerated gastric emptying and stimulated antral contractions greater than placebo (Wu et al., 2008). Note: dried rhizome is a more potent antiemetic than fresh.

Because of ginger’s prokinetic and antiemetic activity, it is often included in formulations for gastroparesis, which can present with signs and symptoms such as heartburn, gastroesophageal reflux, early satiety, abdominal bloating, and nausea and/or vomiting several hours after eating a meal. The dose is typically one gram dried rhizome, taken 15 to 20 minutes after meals. Another excellent prokinetic herb is corydalis (Corydalis ambigua), a plant related to the opium poppy. It has been used in traditional Chinese medicine for centuries as a sedative and to relieve abdominal pain. The combination of corydalis root and pharbitis seed (Pharbitis nil. or P. purpurea) significantly accelerated gastric emptying, and restored delayed gastric emptying caused by apomorphine and cisplatin, up to almost normal levels in animal models (Lee, 2008).

ANTI-INFLAMMATORY

There are numerous botanicals with anti-inflammatory activity, and since all orally ingested herbs pass directly through the gut, many are useful for relieving gastrointestinal irritation and inflammation. Research demonstrates that botanicals reduce inflammation through a variety of mechanisms including mediation of cytokine secretion, histamine release, immunoglobulin secretion, lymphocyte proliferation, and cytotoxic activity (Plaeger, 2003). Compounds with potent anti-inflammatory activity particularly relevant to the GI tract include curcumin (turmeric), gingerols and shogaols (ginger), glycyrrhizin (licorice), alpha-bisabolol and azulenes (chamomile), resveratrol (red grapes), tea polyphenols (tea), silymarin (milk thistle), boswellic acids (boswellia) and

316 INTEGRATIVE GASTROENTEROLOGY

withanolides (ashwagandha; see Khanna et al., 2007). Green tea polyphenol extracts (Abboud, 2008; Mazzon, Muià, & Paola, 2005) and resveratrol (Martín, 2006, 2004) attenuate intestinal injury in animal models of experimental colitis. Animal data and small pilot studies in humans indicate that Boswellia serrata extracts may be of some benefit in collagenous colitis, ulcerative colitis and Crohn’s disease (Madisch, Miehlke, & Eichele, 2007, Ammon, 2006). Ashwagandha (Withania somnifera) reduces gastric acidity and ulceration in animal models of stress induced ulcer (Bhatnagar, Sisodia, & Bhatnagar, 2005). The gastro-protectant effects of licorice root (Glycrrhiza glabra, G. uralensis) have been known for centuries. Research has shown licorice to be a useful anti-ulcer agent as effective as H2 blockers (Aly, 2005). Compounds in licorice increase local prostaglandin levels that promote mucus secretion and cell proliferation in the stomach (Baker, 1994).

Prolonged use of licorice at doses higher than 1 gram per day can lead to pseudoaldosteronism. A special preparation, deglycyrrhizinated licorice (DGL), has had the glycyrrhizin removed and may be taken without concern. I find DGL to be very effective for managing GERD and for helping patients wean slowly off proton-pump inhibitors. The usual dosage is 760 mg, chewed, taken 20 minutes before meals for 4 to 6 weeks and then as needed.

It is turmeric (Curcuma longa), or more often the isolated polyphenoic compounds collectively referred to as curcumin, that is being heavily researched these days. There are numerous Phase I and II studies evaluating the effectiveness of curcumin alone, or in combination with other compounds, for a wide range of conditions including colorectal cancer, pancreatic cancer, multiple myeloma, Alzheimer’s disease, psoriasis, IBD, IBS, familial adenomatous polyposis (FAP), oral lichen planus, and rheumatoid arthritis (clinicaltrials.gov). Curcumin has a range of molecular targets that contribute to its overall pharmacological effects, such as modulating the activation of various transcription factors and regulating the expression of inflammatory enzymes, cytokines, adhesion molecules and cell survival proteins. As curcumin is poorly absorbed from the gut, much of its therapeutic benefit is concentrated in the GI tract. Studies show that doses of 760 mg to 2.0 grams per day of curcumin are beneficial for improving symptoms or preventing relapse in patients with ulcerative colitis and Crohn’s disease (Holt, Katz, & Kirshoff, 2005; Hanai et al., 2006). Curcumin is also a highly promising chemopreventive agent. The combination of 480 mg of curcumin and 20 mg of quercetin taken orally three

The Role of Herbal Medicine in Integrative Gastroenterology 317

times a day reduced the number and size of ileal and rectal adenomas in patients with FAP (Cruz-Correa et al., 2006). The average daily intake of turmeric in India is approximately 2 to 2.5 grams/ day, which corresponds to an intake of 60 to 100 mg of daily dietary curcumin (Goel, Jhurani, & Aggarwal, 2008). Phase I clinical trials demonstrate that curcumin is safe at doses as high as 12 grams/day (Anand, 2007). While many practitioners recommend turmeric over the isolated or concentrated curcuminoids, it is important to note that the medicinal doses used in many clinical trials would require the consumption of more than 25 grams per day of turmeric!

When two grams of curcumin was given orally to healthy humans, serum curcumin levels were either very low or undetectable. Concomitant administration of piperine, a primary alkaloid in black pepper, increased bioavailability by 2000% (Shoba et al., 1998). Interestingly, black pepper has been traditionally added to many herbal preparations to enhance absorption and increase the effectiveness of the formulation. To concentrate curcumin in the gut, it is best to take a non-lipid preparation without piperine on an empty stomach or 1 to 2 hours after eating.

ANTIMICROBIAL

Plants contain multiple constituents: phenols, quinones, flavones, tannins, terpenoids and alkaloids, with antibacterial, antiprotozoal and antiviral activity (Cowan, 1999). Botanical antimicrobials that are safe, effective, and inexpensive may have significant global health implications in areas endemic with infectious diarrhea, and may expand our arsenal against Helicobacter pylori. Many common spices have antimicrobial activity. Turmeric, ginger, chili, and cumin are bactericidal to Helicobacter pylori, and turmeric reduces adhesion of the bacterium to the stomach mucosa (O’Mahony et al., 2005). Berberinecontaining plants, such as goldenseal (Hydrastis canadensis), barberry (Berberis vulgaris), Oregon grape root (Mahonia aquifolium) and goldthread (Coptis sinensis), have been traditionally used to treat gastritis and infectious diarrhea. Crude methanol extracts of goldenseal root and rhizomes are highly active against multiple strains of H. pylori (Mahady et al., 2003). Berberine inhibits the growth of Giardia lamblia, Entamoeba histolytica, Trichomonas vaginalis, and Leishmania donovani (Kaneda, Tanaka, & Saw, 1990). Berberine reduces intestinal secretion of water and electrolytes induced by cholera toxin, and directly inhibits some V. cholera and E. coli enterotoxins, significantly reducing smooth muscle contraction and intestinal motility (Akhter, 1979).

318 INTEGRATIVE GASTROENTEROLOGY

I have successfully treated a number of patients with Entamoeba histolytica who failed multiple rounds of metronidazole with both goldenseal and Oregon grape root. All berberine-rich plants taste bad; better compliance will be achieved with encapsulated products. I generally recommend 1,000 mg of Oregon grape root three times daily for 14-30 days.

Allium vegetables, particularly garlic (Allium sativum), exhibit broad antimicrobial activity against many organisms. Louis Pasteur documented the antibacterial activity of garlic in 1858, while Albert Schweitzer reportedly relied upon it to treat amoebic dysentery. Modern research confirms that garlic is active against a number of diarrhea-causing bacterium, including Salmonella and Escherichia coli O15 (Adler, 2002). It is also active against Entamoeba histolytica and Giardia lamblia, major sources of gastrointestinal infection worldwide (Ankri, 1999; Harris et al., 2000). When the garlic clove is crushed, the odorless amino acid alliin is metabolized by the enzyme alliinase, to yield allicin and other thiosulfinates that are the source of garlic’s characteristic odor. The thiosulfinates and other secondary metabolites are thought to be responsible for garlic’s antimicrobial activity (Yoshida et al., 1999). Though low heat does not appear to destroy the antimicrobial effects of garlic—one study found the antibacterial activity of garlic stable at 100° C, or 212° F (Sasaki et al., 1999)—raw garlic preparations are probably the best choice. In addition to its antimicrobial effects, there is a body of evidence suggesting that garlic is protective to the GI mucosa. Multiple studies confirm that aged garlic extracts prevent or reduce the gastrointestinal toxicity that can result from administration of methotrexate (Li et al., 2008, Horie et al., 2006, Yüncü, Eralp, & Celik, 2006), while a systematic review found an inverse relationship between raw and cooked garlic consumption and colorectal cancer risk (Ngo, 2007).

ANTISPASMODIC

Antispasmodic plants with specific affinity for the GI tract include hops (Humulus lupulus), valerian (Valeriana officinalis; V. wallachii), wild yam (Dioscorea villosa), bogbean (Menyanthes trifoliata), chamomile (Matricaria recutita), and lemon balm (Melissa officinalis). Chamomile is commonly used to alleviate minor abdominal pain in children and elders, as it is mild in action and low in adverse effects. Animal data confirm the antispasmodic activity of both aqueous and ethanolic extracts of chamomile, with fractions being similar or superior to papervine, a known smooth muscle relaxant (McKay &

The Role of Herbal Medicine in Integrative Gastroenterology 319

Blumberg, 2006). Valerian, though primarily known as a mild sedative or calmative, has been shown to reduce small bowel contractions in animal studies (Gilani et al., 2005), and is often included in IBS formulations for those with anxiety or nervousness. Wild yam was traditionally referred to as “colic” root, a nod to its historical use in crampy intestinal pain. One of the most popular gut remedies for alleviating intestinal gas and abdominal cramps is peppermint (Mentha x piperita). Peppermint oil significantly prolongs orocecal transit time (Goerg, 2003) and directly inhibits smooth muscle contractions by interacting with calcium channels (Hills & Aaronson 1991). The active compounds in peppermint oil, menthol and menthone, are highly fat-soluble and rapidly absorbed from the proximal gut. Thus, enteric-coated sustained release peppermint oil capsules are the ideal formulation for IBS, particularly diarrhea dominant. Peppermint oil is often found in combination with caraway seed oil. Caraway seed oil inhibits smooth muscle contraction (Al-Essa 2010) and both peppermint and caraway oils inhibit gallbladder emptying (Goerg, 2003). A review of four randomized clinical trials found the fixed combination of peppermint and caraway oil to have effects of similar or greater magnitude when compared with conventional therapies used in dyspepsia, as well as a very good safety profile (Thompson Coon & Ernst, 2002). Interestingly, caraway may be protective against colon carcinogenesis (Deeptha et al., 2006), as well as having lipid- and triglyceride-lowering effects (Lemhadri et al., 2006). There are a number of high-quality peppermint oil capsules in the marketplace. The dose is 0.2 ml enteric-coated softgel capsule taken 3 times per day, 30 minutes before meals. If this causes heartburn or anal burning, instruct the patient to take with food. Iberogast® is a proprietary blend of nine herbs (chamomile, lemon balm, caraway, peppermint, clown’s mustard (Iberis amara), and others) that has demonstrated beneficial effects in cases of functional dyspepsia and irritable bowel syndrome (Rosch 2006). It has a pleasant taste and is suitable for both children and adults, though it contains 31% alcohol. It should be noted that the mixture contains small amounts of greater celandine (Chelidonium majus), which may induce hepatotoxicity at high doses. However, this blend has been used for more than 40 years in Europe with good postmarketing surveillance safety data, even in pediatrics.

BITTERS

Bitter-tasting herbs have been used for millennia as digestive aids. The bitter taste stimulates a sensory response in the tongue, which in turn increases the

320 INTEGRATIVE GASTROENTEROLOGY

production of gastric acid and primes the exocrine pancreas. Bitters are generally taken 20 minutes before the main meal for those who experience symptoms such as bloating, gas, sluggish stools, and a sense of fullness after eating. Some of the most commonly used bitter herbs include artichoke (Cynara scolymus), dandelion root (Taraxacum officinale), gentian (Gentiana lutea), hops, and bitter orange peel (Citrus aurantium). Dandelion is a well-known bitter digestant with anti-inflammatory and prebiotic activity (Schütz, 2006). While the leaves are predominantly employed as a diuretic, the roots are used in cases of habitual constipation, sluggish digestion, bloating after meals, and poor appetite. Bitter orange peel is often included in small amounts in herbal formulations as a flavoring agent, and also a mild bitter and carminative.

Angostura bitters, a proprietary product available in the liquor section of most grocery stores, is a classic bitter aperitif, taken before meals to aid digestion. There are numerous other proprietary bitters for sale. I often recommend Gallexier Herbal Bitters by Floradix, as it does not contain any alcohol or the laxative herbs found in some blends. The small amount of bitter orange peel in digestive formulations is quite safe—but be aware that many weight-loss products contain very concentrated forms of the herb, standardized for high synephrine content.

CARMINATIVES

Carminatives are herbs that relieve bloating and intestinal gas. These plants are often rich in volatile oils that relax the GI smooth muscle; thus, they are also referred to as gut antispasmodics. Carminatives are usually included in herbal laxative formulations to reduce the abdominal cramping that can occur with both bulk-forming and stimulant laxatives. The vast majority of carminatives fall into the spice/culinary herb category. Aniseed, cinnamon, fennel, dill, caraway, and peppermint are classic examples. Fennel is used to relieve digestive complaints in young children, as it is mild tasting and well tolerated. Two small studies have shown that fennel emulsion (Alexandrovich, 2003) and fennel tea, in combination with chamomile and lemon balm (Savino et al., 2005), improves infantile colic. Peppermint, fennel, or anise can be made into a pleasant afterdinner tea (tisane), or the East Indian tradition of chewing fennel seeds after the meal is also effective for relieving bloating and gas. Herbal digestifs have a longstanding tradition of use in Europe for improving digestion. Classic examples include Anisette and Crème de Menthe. Generally, one tablespoon is taken alone or diluted in water after the meal.

The Role of Herbal Medicine in Integrative Gastroenterology 321

CHOLERETICS/CHOLAGOGUES/DIGESTANTS

Choleretics increase the production of bile by the liver, cholagogues stimulate the contraction and release of bile from the gallbladder, and digestant is a general term used to describe those remedies that act on the gallbladder and exocrine pancreas. All three of these terms are used somewhat interchangeably in herbal medicine. Many spices and culinary herbs fall under this category, as gastric secretions are stimulated by their aroma and pungent taste. Ginger, coriander, cumin, turmeric, chili, and peppercorn increase pancreatic lipase and amylase activity (Platel & Srinivasan, 1996), as well as bile volume and bile acid secretion, improving the digestion of dietary fats and carbohydrates (Platel et al., 2002). Ginger, chili, and peppercorn dramatically enhance pancreatic trypsin, enhancing the digestion of protein. A premiere choleretic/cholagogue is globe artichoke leaf (Cynara scolymus), considered a specific for digestive disorders in traditional herbal medicine, especially those accompanied by flatulence, abdominal pain, bloating, and poor digestion of fats. Artichoke leaf is a potent choleretic and cholagogue (Speroni, 2003) and the enhanced biliary cholesterol excretion (Saenz Rodriguez 2002) likely contributes to its clinically documented lipid-lowering effects. Interestingly, globe artichoke is a member of the milk thistle family and also a source of the hepatoprotectant compound silymarin, the cold-pressed seed oil yielding up to 85. Artichoke and yarrow are also potent choleretics.

DEMULCENTS

Demulcents soothe and protect irritated tissues. These herbs are typically rich in mucopolysaccharides that become “slimy” when they come in contact with water. These compounds are destroyed by high alcohol content, so are best prepared as teas. Demulcents are used to alleviate irritation of the mouth, throat, esophagus, stomach, and bowels. Marshmallow (Althaea officinalis) and slippery elm bark (Ulmus rubra) are classic demulcents. The British Herbal Compendium recognizes the use of marshmallow root or leaf in cases of duodenal ulceration, ulcerative colitis, and enteritis. The inner bark of slippery elm (Ulmus fulva, U. rubra) has been used as a food and medicine for centuries, and was an official drug in the United States Pharmacopeia from 1820 to 1936. Native Americans and early settlers made a nutritious gruel from the inner bark, in a fashion similar to oatmeal. The polysaccharide-rich mucilage found within the bark is an effective cough

322

INTEGRATIVE GASTROENTEROLOGY

suppressant, soothes a sore throat, and helps to heal the mucosa of the gastrointestinal tract. Indications listed in the British Herbal Compendium for slippery elm bark include “inflammations and ulcerations of the gastrointestinal tract, such as oesophagitis, gastritis, colitis, gastric or duodenal ulcers; diarrhoea” (Bradley 1992). Though there are virtually no modern studies on slippery elm, the FDA has approved slippery elm as a safe nonprescription product for demulcent use. Demulcents are usually taken at least one hour after prescription medications to prevent interference with absorption. There are slippery elm lozenges, flavored and unflavored, as well as medicinal teas readily available at most natural grocery stores. You can make your own by taking 1 tsp. of the powdered bark, adding 1 to 2 tbsp. water and making into a paste. Then add 2 cups boiling water. Let steep for 10 minutes. Pour off the liquid and add a pinch of cinnamon, nutmeg, or pumpkin pie spice. It’s great for soothing a sore throat, easing a cough, or relieving occasional heartburn.

HEPATICS

Hepatics generally refer to herbs that have a beneficial effect upon the liver. The prime examples include milk thistle (Silybum marianum), katuka (Picrorrhiza kurroa), artichoke (Cynara scolymus) and phyllanthus (Phyllanthus amarus). The most rigorous research has focused on the beneficial effects of milk thistle. The seeds of milk thistle have been used for more than 2,000 years as a treatment for liver and biliary disorders. Modern studies on the flavonolignans collectively referred to as silymarin have demonstrated hepatoprotection from various substances including alcohol, acetaminophen, and the toxins from Amanita phalloides, or deathcap mushroom. The main effects of silymarin are the membrane stabilizing and antioxidant effects, which can assist in liver cell regeneration, decrease inflammation and inhibit fibrogenesis in the liver. These results have been established by experimental and clinical trials. A systematic review and meta-analysis concluded that the use of silymarin is reasonable in Amanita phalloides poisoning, alcoholic liver disease (as an addition to abstinence) and Child’s A cirrhosis (Saller, 2008). A recent study using intravenous silymarin in combination with ribivarin demonstrated rapid suppression of hepatitis C viremia (Biermer, 2009). Together, these and other data suggest that silymarin may be used for its antiviral effects in future clinical trials for hepatitis C. The flavonolignan silibinin competitively antagonizes toxins from binding to liver cell membrane receptors in mushroom poisoning and other hepatotoxic

The Role of Herbal Medicine in Integrative Gastroenterology 323

exposures. Administration of silibinin up to 48 hours after mushroom ingestion appears to be effective for preventing severe liver damage. The dose of silibinin: IV 20 to 50 mg/kg/d. Interestingly, while widely available in other countries, this IV form of milk thistle is not presently available in the United States. In addition to hepatic protection, animal studies suggest that silymarin may protect against chemotherapy-induced renal toxicity from cisplatin (Bokemeyer et al., 1996) and adriamycin (El-Shitany 2008) and that silymarin administered prior to radiation acts as a renal protectant (Ramadan et al., 2002).

Milk thistle is a fantastic example of an herb that may offer a real benefit in today’s modern world as it can offer hepatoprotection from environmental, toxin- and drug-induced damage. Silymarin appears to offer both liver and renal protection in patients undergoing chemotherapy or radiation. It is reassuring that in vivo studies demonstrate that oral administration of silymarin does not inhibit CYP3A4 (Fuhr 2007), however in vivo pharmacokinetic studies are lacking at this time for other CYP enzyme systems and intravenous administration likely has a different profile. Typical dose for silymarin is 420-760 mg silymarin per day, taken in three divided doses. Higher doses may be necessary based upon emerging evidence.

LAXATIVES

Laxatives stimulate the intestines, causing the body to eliminate waste. The primary types of plant laxatives include fiber or bulk, stimulants or cathartics, and stool softeners. Bulk-forming laxatives are indigestible, hydrophilic substances that absorb water, forming a bulky, emollient gel that distends the colon and promotes peristalsis. Psyllium seed and husks are prototypical of the category, though they often take up to four weeks for patients to notice a significant improvement in bowel function. Encouraging patients to drink herbal teas of ginger, fennel, or caraway can help ease the abdominal distension and gas that often accompanies initial increases in fiber intake. Flaxseed (Linum usitatissimum) is another bulk-forming laxative, containing both soluble and insoluble fiber, which can be used to ease constipation and may also help reduce the risk of colon cancer when consumed regularly in the diet (Bommareddy et al., 2006). This nutty flavored seed is also rich in alpha linolenic acid, an omega 3-fatty acid, and is a good source of magnesium. Grind flax seeds in a coffee grinder to enhance their digestibility and nutritional value. Take 1 to 2 tbsp. two times per day to improve regularity. Each tablespoon contains 2.2 grams of fiber, 1.6 grams of protein, and 1,800 mg of omega-3 fat.

324 INTEGRATIVE GASTROENTEROLOGY

While little known in the United States, a common Ayurvedic remedy for constipation is Triphala, made from the dried fruits of three medicinal plants: Terminalia chebula, Terminalia belerica and Phyllanthus embelica. I have had tremendous success using it for those with constipation dominant irritable bowel syndrome, as well as elders and children with hard, dry stools. Take 1 to 2 grams per day for 5 to 7 days, and increase to 3 to 4 grams per day if needed. Triphala is not habit forming and is available in capsules or powders that can easily be mixed with food or in beverages.

Many stimulant laxatives and cathartics are derived from plants rich in bitter anthraquinone glycosides, such as cascara sagrada (Rhamnus purshiana), senna (Cassia angustifolia), aloe latex (Aloe spp) and turkey rhubarb (Rheum palmatum). The anthraquinone glycosides are metabolized slowly by gut microflora, resulting in a period of 8 to 10 hours between ingestion and evacuation of stool. Concerns regarding the relationship of anthraquinone laxative use and colon cancer, or the belief that chronic use causes structural or functional impairment of enteric nerves or intestinal smooth muscle, are inconclusive at best (Borrelli et al., 2005b; Wald, 2003; Nusko et al., 1997). For patients who fail to respond to bulk or osmotic laxatives, these plants represent a reasonable alternative. Many herbalists contraindicate the use of stimulant laxatives during pregnancy, but when bulk-forming laxatives are ineffective, senna is considered safe (Prather, 2004).

Conclusion Herbalists consider a well-functioning GI system to be the foundation of health. Proton pump inhibitors, antacids, and NSAIDs, while of great benefit, are used far too often and can have devastating effects on the gut long term. In herbal medicine, the mantra is remove, repair and restore. Remove foods and other substances that are disruptive to the integrity of the gut (e.g., food allergens, drugs, tobacco, etc.). Repair the gut through a wholesome diet rich in plant fiber, appropriate use of botanicals that have anti-inflammatory and demulcent activity, and supplements such as glutamine that nourish the colonic tissue. Restore both motility and healthy microflora by adding fermented foods, prebiotics, probiotics, dietary fiber, and by using prokinetic agents as needed. When reviewing the history and contemporary research, it is clear that herbal medicines have played, and continue to play, a significant role in treating

The Role of Herbal Medicine in Integrative Gastroenterology 325

disease and improving health. Given the vast number of botanicals that have yet to be explored for their medicinal effects, it is likely that plants will continue to contribute to our understanding and management of gastrointestinal disease. However, there remains much work to be done from “bench to bedside” to determine which botanicals are most efficacious and how they are best used in clinical practice. While this text cites the clinical trials that are being conducted on herbal medicines for various GI disorders, the research literature reflects only a very small percentage of plants that have potential benefit, and there is definitely a need for more rigorous and creative research in this area.

33 Brief Review of Mind–Body Medicine in Gastroenterology Practice MIRANDA A.L. VAN TILBURG, STEPHAN R. WEINLAND, AND OLAFUR S. PALSSON

key concepts ■

■

■

■

■

Mind–body medicine recognizes that illness symptoms and behaviors cannot be completely explained by biological processes alone, but only from the interaction between biological and psychosocial processes. Both psychosocial and biological aspects are important targets for therapy. Practicing mind–body medicine means, first and foremost, that physicians elicit information from the patient about his/her illness beliefs and expectations for treatment. Behavioral and cognitive interventions for functional gastrointestinal disorders comprise a range of therapeutic modalities (cognitive-behavioral therapy, hypnotherapy, biofeedback, guided imagery, relaxation training) that have at their core a therapeutic relationship and an understanding of the mind– body connection. Behavioral and cognitive treatments aimed at reducing gastrointestinal symptoms have proven effectiveness for the treatment of highly prevalent conditions like IBS and functional dyspepsia. ■

T

he dualistic model, common in medical practice, characterizes patient symptoms as either of organic or functional origin, with little understanding of relational aspects between the two. This view has been propagated through medical education and persists in clinical practice and

326

Brief Review of Mind–Body Medicine in Gastroenterology Practice 327

research. Patients are often categorized as either having “biomedical” or “psychosocial” difficulties and are treated accordingly (Drossman, 1998) However, it is increasingly recognized that this type of medicine is insufficient in treating many bodily ailments. Mind–body medicine, on the other hand, recognizes that illness symptoms and behaviors cannot be completely explained by biological processes alone, but only by understanding the interaction between biological and psychosocial processes. Therefore, both biological and psychosocial processes are addressed in medical care. The application of the mind– body approach to medicine and gastroenterological illness has gained increased prominence since George Engel first introduced the biopsychosocial model of illness (Engel, 1977). Nowadays, the U. S. National Institutes of Health describes mind–body medicine as a field that views health care providers as “catalysts and guides” in the process of health promotion, and diseases as “opportunity for personal growth and transformation” (NCCAM, 2008). This change in view of medicine away from having biological focus to a more experiential one that feels awkward to many practitioners. However, a change in name or direction does not mean that the scientific method is not applicable to studies of mind–body relationships and treatments. Indeed, empirical validation is critically important when considering newer treatments. In this chapter, we will briefly review mind–body medicine in gastroenterology practice. Few areas of medicine demonstrate clearer connections between mind and body as those seen in gastroenterology. Lay terms of experiencing “butterflies in the stomach” in the presence of anxiety or “not having the stomach” to face a situation are just some of the ways that an understanding of a brain–gut connection is communicated (Read, 1993). Although mind–body medicine can be and is practiced across all areas of gastroenterology, it has gained the most acceptance for the treatment of functional gastrointestinal disorders because of the large literature supporting its use.

Physician–Patient Relationship Mind–body medicine starts in the physician’s office. Working with patients experiencing GI difficulties in practice can be difficult when the disorders have a “functional” presentation. Standard care for functional GI disorders by physicians and other medical professionals is aimed primarily at psychosocial aspects, such as reassurance and advice on diet/exercise/stress, and only secondarily at pharmacological and other biomedical approaches (Whitehead et al., 2004). Since most patients believe in a biomedical approach to illness, this type of treatment may not be easily accepted. Many physicians experience difficulty in working with patients who present with increasingly complex

328

INTEGRATIVE GASTROENTEROLOGY

disorders as one moves up the care hierarchy. Mitchell and Drossman (1987) have found that patients with irritable bowel syndrome, a typical “functional” GI illness, make up 12 of primary care issues and up to 28 of gastroenterology practice. Patient–physician interactions can play a significant role in the benefit/detriment experienced by GI patients in working with clinicians. Drossman and colleagues have extensively written on the use of effective physician-patient communications in functional gastrointestinal disorders (for example see (Drossman, 1997)) (Drossman, 2009) Here, we will briefly describe some important aspects.

Practicing mind–body medicine means, first and foremost, that physicians elicit information from the patient about his/her illness beliefs and expectations for treatment. This involves understanding not only the symptoms, but the life context within which the symptoms developed. The patient’s worries and concerns must also be identified and addressed.

A common fear often elicited from the patient is that of having an underlying cancer. Quickly dismissing the concern by stating that “nothing is seriously wrong” may not be reassuring to the patient, particularly if the concerns have not been properly addressed through proper diagnostic testing. A quick dismissal may lead the patient to believe that the physician is incompetent, or that “it must be in my head.” When a diagnosis is made, it is helpful to explain to the patient that the symptoms are occurring within a biopsychosocial construct; i.e., with the integration of biological and psychosocial processes in their illness and disease. Also, many patients have never been told what they suffer from, and providing a positive diagnosis (e.g., of IBS) and then explaining the physiological basis for the symptoms can be very empowering. A physician needs to communicate that (s)he is rather confident, based on the current findings, that the patient suffers from a functional disorder, but will stay vigilant for changes that require future testing. This approach emphasizes continuation of care, and understanding of the patient’s concern while limiting ordering unnecessary tests. Furthermore, many patients feel unable to deal with their symptoms, and therefore relinquish control of their symptoms to the physician. With any chronic illness, no matter what the cause, self-management is a crucial aspect of medical care. Therefore, patients and physicians should negotiate shared responsibility of care. Ideally, patients should accept a primary role in their care, while physicians need to be available for support and advice.

Brief Review of Mind–Body Medicine in Gastroenterology Practice 329

The presence of a physical or sexual abuse history in patients is often dismissed or not adequately assessed in GI practice; however, an appropriate understanding of such a history and its effects on mind–body connections is critically important in patient care.

In a study published in 1990, Drossman and colleagues reported that up to 50 of patients in a tertiary care setting have a history of physical or sexual abuse, though only 11.4 of the physicians were aware of this history (Drossman et al., 1990). The association between abuse and gastrointestinal symptoms has also been found in children (Van Tilburg et al., 2010). Later work showed that an abuse history has profound effects on health status in patients with functional or structural diagnoses in terms of quality of life, health care utilization, symptom severity, or even risk of having surgery (Drossman et al., Lesserman, Toomey, Hu 1996) Recent literature has shown a relationship between a history of physical or sexual abuse and central upregulation of pain-reporting centers in the brain (Drossman, 2005). For a comprehensive examination of ways this issue can be identified and addressed during the course of the biopsychosocial interview, readers are directed to a more comprehensive review (Chang & Drossman, 2002). Standard medical care may not be sufficient for most patients. We have found, for example, in a study of 1,665 patients with functional bowel disorders seen in a U.S. health maintenance organization (Whitehead et al., 2004), that only 22 of patients had a larger than 50 reduction on a global bowel symptom index six months after a doctor visit for their bowel symptoms, and only 51 of patients judged their symptoms to be at least somewhat better at that time. Similarly, Thompson et al. (1997) reported that less than half of IBS patients in primary care are satisfied with the care they have received. This finding is echoed by a recent study of almost 2,000 patients in an Internet survey (Drossman. Morris, Schnek, Hu, Norton, Weinland, Dalton, Leserman., 2008). About a third of patients pursue alternatives to regular medical care, such as herbal medicine, massage therapy, and yoga (van Tilburg et al., 2008).

Patients who do not respond to medical therapy and/or have comorbid psychiatric disorders may benefit from behavioral therapy such as cognitivebehavioral treatment, hypnosis, or biofeedback.

330

INTEGRATIVE GASTROENTEROLOGY

Both clinical care and behavioral interventions should be integrated. In medical communities, it is advisable to at least identify a psychologist who is familiar with treating patients who have functional GI disorders, and who can be closely connected with the ongoing medical care. Ideally psychologists are part of the clinical program and are seeing patients in the same clinical setting. This helps to bridge the gap between medical and psychological care, and allows for a more unified biopsychosocial approach. There is a wealth of evidence to show that behavioral treatments are effective in treating functional gastrointestinal disorders. It must be kept in mind that these treatments typically involve specific behavioral intervention modalities applied on top of the behavioral and cognitive interventions (e.g., soliciting and challenging erroneous beliefs, such as a fear of cancer) routinely provided in standard medical care.

Behavioral and Cognitive Therapies for Functional Gastrointestinal Disorders Behavioral and cognitive interventions for functional gastrointestinal disorders comprise a range of therapeutic modalities that have at their core a therapeutic relationship and understanding of the mind–body connection. Psychologists and other licensed practitioners working in behavioral medicine or clinical health psychology have a range of therapeutic modalities and options that have been shown to be effective in managing GI illness (Lackner et al., 2004). From these options, a mounting level of evidence for efficacy has been found in utilizing cognitive-behavioral therapy (CBT), biofeedback, hypnosis/guided imagery, and relaxation training.

COGNITIVE-BEHAVIOR THERAPY

CBT is a form of semi-structured psychotherapy that is usually conducted individually as a course of 8–12 weekly treatment sessions. The therapist aims to help patients to overcome distorted and negative thinking patterns that amplify physical symptoms or adversely affect life functioning as well as psychological well-being. Therapy tasks commonly include: increasing awareness of the association between stressors, thoughts, and symptoms; examining and correcting irrational beliefs; countering automatic negative thoughts; and identifying and adopting alternative, more adaptive coping strategies to handle challenging life situations and deal with bowel symptoms.

Brief Review of Mind–Body Medicine in Gastroenterology Practice 331

CBT has been most extensively used in IBS. There are several controlled and uncontrolled trials studying its effectiveness for treating IBS. In a review of the literature Toner (2005) concluded that there is some support for CBT in improving symptoms associated with irritable bowel syndrome (IBS), but many studies have important shortcomings, making it hard to draw firm conclusions. Drossman and colleagues (2003) have completed the largest and methodologically most rigorous trial in the history of behavioral treatments for GI conditions—treating 431 women with functional bowel disorders, most of whom met Rome criteria for IBS—in a randomized, placebo-controlled, multicenter study. These investigators compared a 12-week cognitive-behavior therapy to the same amount of education intervention. They found that cognitive-behavior therapy resulted in treatment response rate that was almost twice as high (70 versus 37) compared to the education control intervention. In order to increase access to CBT, low-cost self-administered treatments are being developed as a first-line psychological intervention for IBS. Initial results are promising. In two studies, GI symptoms were decreased as compared to waitlist control, while self-administered CBT was comparable to standard CBT (Lackner et al., 2008; Sanders, Blanchard, & Sykes, 2007).

BIOFEEDBACK

Biofeedback is a treatment method that uses recordings of specific physiological parameters, such as muscle tension or intraluminal gut pressure, to provide patients with moment-to-moment feedback of their physiological activity, which can help them to learn to regulate physiological activity that is related to the targeted symptoms. Patients are asked to repeatedly make attempts at deliberate control over the targeted physiological processes while observing the response in their body, and in that way to gradually gain control through successive approximation. Biofeedback has been successfully used for chronic constipation due to pelvic floor dyssynergia (PFD) and fecal incontinence (Heymen et al. 2007, 2009). Biofeedback for PFD is directed at teaching patients to relax their pelvic floor muscles while simultaneously applying downward intra-abdominal pressure to generate propulsive force (Valsalva maneuver). This is done with the aid of visual or auditory feedback to the patients from either electromyography sensors measuring electric activity in the external anal sphincter, an anal canal pressure sensor device, or both of these in combination. This training is sometimes combined with practice in defecating a water-filled balloon.

332

INTEGRATIVE GASTROENTEROLOGY

Biofeedback for fecal incontinence is aimed at enhancing or restoring the key functions that maintain stool continence. Continence depends on adequate rectal sensation to detect distention of the rectum, as well as on the capability to synchronously contract the external anal sphincter in response to the reflexive inhibition of the internal anal sphincter that occurs when the rectum fills. Three types of biofeedback to ameliorate fecal incontinence problems are: (1) coordination training, where patients are taught to coordinate or synchronize contractions of the pelvic floor muscles; (2) strength training, which trains patients to contract the external anal sphincter to prevent leakage from the bowel; and (3) sensory training to diminishing rectal distensions without muscle contractions. A large research literature has accumulated over decades on the outcomes of these two gastrointestinal biofeedback applications. (Palsson et al., 2004, Chiarioni et al., 2008, Heymen et al., 2003, Heymen et al., 2001).

A 2004 systematic review of the world literature (Palsson, Heymen, & Whitehead, 2004) found 74 published prospective studies of biofeedback treatment for functional anorectal disorders, making biofeedback the most investigated of all behavioral treatment modalities for gastrointestinal disorders. A recent systematic review concludes that biofeedback helps about 75% of fecal incontinence and 70% of patients with PFD constipation (Chiarioni & Whitehead, 2008).

HYPNOSIS AND GUIDED IMAGERY

Hypnosis is a form of therapy that makes use of a special mental state of narrowed focus of attention and heightened mental receptivity to suggestion (hypnotic state), and achieves its therapeutic effects through therapeutic suggestions and imagery given by the therapist to patients in this facilitative state. Most of the work on hypnosis for gastrointestinal disorders has, until recently, focused on irritable bowel syndrome. More than 20 published studies have assessed the therapeutic utility of this mode of treatment for IBS, including six controlled studies. Although most of the trials of hypnosis for IBS have been small, and they have been variable in quality, recent systematic reviews examining this entire body of literature (Gholamrezaei, Ardestani, & Emami, 2006; Whitehead, 2006; Wilson et al., 2006) have generally concluded that hypnosis is an effective treatment for IBS, as evidenced in nearly universally positive outcomes and high success rate. An analysis provided in the review by Whitehead (2006) found that the median success rate of this treatment

Brief Review of Mind–Body Medicine in Gastroenterology Practice 333

modality for IBS across all formal trials was 86, that bowel symptoms were generally reduced by more than half after treatment, and that the therapeutic effects commonly lasted one or more years. Recent randomized controlled trials have shown hypnotherapy to be equally effective for the treatment of dyspepsia (Calvert et al., 2002), noncardiac chest pain (Jones et al., 2006) and for functional abdominal pain in children (Vlieger et al., 2007; Weydert et al., 2006; Van Tilburg et al). Hypnosis is a highly specialized form of therapy, and one of the limitations to wide availability has been the dearth of therapists in many locations that provide this form of treatment, as well as unfamiliarity of most therapists who use such methods with how to apply them for treating gastrointestinal disorders. However, a couple of innovations led by our research group are brightening the prospects for wide application of this treatment modality. One of these is the development and distribution of a fully scripted hypnosis protocol for IBS that therapists can easily follow verbatim, making it much easier to use (Palsson, 2006). A second innovation is to develop home treatment programs to make this treatment entirely self-administered. A pilot study (Palsson, Whitehead, & Turner, 2003) of a home therapy version of the scripted North Carolina Protocol, delivered via audio CDs, found that overall IBS severity was twice as likely to show reduction of at least 50 after six months than a comparison group receiving standard medical care (53 versus 26 of patients). Similarly, a controlled study by van Tilburg et al. (2009) of 30 children ages 7–15, testing a two-month home treatment of self-hypnosis, delivered on CDs, found that children’s abdominal pain symptoms improved substantially more after guided imagery compared to children receiving standard medical care.

RELAXATION TRAINING

Because functional GI symptoms are widely recognized to be associated with heightened stress, relaxation training and meditation are sometimes applied in their treatment to combat the physical aspects of stress. Such training can take a variety of forms. Common techniques include progressive muscle relaxation, autogenic training, or meditation. However, they all have in common that the goal is to reduce sympathetic arousal (stress response) and create physiological changes associated with physical relaxation that can have beneficial effects on gastrointestinal symptoms. Relaxation training has often been applied as a component of multimodal treatments, in published studies of treatment of gastrointestinal disorders. For example, it is a common complement to cognitive therapy or hypnosis treatment. However, it has been studied as the main or sole therapeutic ingredient in four controlled studies, and found effective in

334 INTEGRATIVE GASTROENTEROLOGY

most of these trials (Shaw et al., 1991; Voirol & Hipolito, 1987; Keefer & Blanchard, 2001) except for one, which is likely underpowered (Boyce et al., 2003).

LIMITATIONS

In spite of the numerous impressive studies discussed above, demonstrating the advantage of cognitive and behavioral treatments over standard medical care or other comparison groups, use of these treatments is still an exception rather than the rule—even when patients are unresponsive to standard management. Although standard medical care fails to give adequate relief to 4 out of every 5 patients, behavioral treatment is only offered or suggested to 10 of patients (Whitehead et al., 2004). This disconnect can be explained by several factors. First, in a healthcare climate highly concerned with containing skyrocketing costs, physicians and third-party gatekeepers may consider behavioral treatments to be a luxury for functional GI problems. Physicians who take time to develop a supportive relationship with their patients aren’t being reimbursed for the extra time they spend with the patient, and mental health programs are severely underfunded. In view of long-term data in functional dyspepsia (Calvert et al., 2002) and irritable bowel syndrome (Gonsalkorale et al., 2003), it is almost certainly an erroneous view that behavioral treatments are a luxury. When the cumulative benefits associated with years of reduced medication and healthcare needs, and lessened disability following behavioral treatments, become further documented in multiple studies, offering such treatments to patients who are unresponsive to conventional medical care might become a required standard of care to contain costs and maximize positive outcomes. Secondly, there is an art to referral. Patients may perceive the referral as a sign that their physician thinks they are “crazy.” Only about 30 of IBS patients have confidence in the referral by their physician to a mental health provider (van Tilburg et al., 2008). Lack of confidence may lead to failure to follow up on the referral, and/or discontinuing the treatment early. An important aspect in referral is to present these treatments in a way that is acceptable to patients. For example, CBT can be offered as a way to learn management strategies to better anticipate and respond effectively to episodes when they occur. In addition referral to CBT should be accompanied by reassurance that referral complements the medical treatment, and does not mean the physician believes the symptoms are “all in your head.” It is important to stress that CBT has been found to effect IBS symptoms, independent of changes in patient’s psychological distress (Lackner et al., 2007).

Brief Review of Mind–Body Medicine in Gastroenterology Practice 335

Only those patients who are open to behavioral treatments should be referred to a mental health provider. Otherwise, it is unlikely that the patient will follow up on their physician’s advice (and even if they do. it is unlikely to be successful), while uniformly pushing a treatment may damage the very important physician–patient relationship.

Thirdly, there is an enormous shortage of qualified therapists. In a system that prepares most mental health providers for the treatment of mental disorders, very few will know how to approach behavioral treatment of medical disorders. It is important to make sure that the patient is referred to a therapist who understands functional gastrointestinal disorders. In many areas, no such therapist may be around. Some centers, such as ours, have recruited and trained our own psychologists who operate as part of a treatment team that includes medical doctors, physician assistants, and nurses. Others have developed close relationships with therapists in the catchment area. The lack of availability of suitably specialized therapists, and the cost of therapy, hinder widespread use of these treatments. Creative methods to minimize these hurdles could greatly increase the use of behavioral treatments. With that aim in mind, our group at UNC-Chapel Hill has begun testing of a home-treatment hypnosis program delivered via audio CDs and facilitated by Internet-mediated symptom monitoring. The first pilot results have been promising (Palsson, Whitehead, & Turner, 2003; Van Tilburg et al 2009), although response rate is lower than in our face-to-face therapy studies. Similarly, Lackner and colleagues in New York have reported encouraging results from a self-administered CBT program for IBS (Lackner et al., 2008). New treatment modalities like these offer promise for the widespread use of behavioral treatments in FGIDs.

Conclusions Adopting a mind–body medicine approach to the care of functional gastrointestinal disorders is important. As no organic cause can be found to treat with medical therapy, psychosocial aspects become an important target for therapy. Physicians can deliver effective care when developing a good relationship with their patients. But for many patients, additional treatment is required. Behavioral and cognitive treatments aimed at reducing gastrointestinal symptoms have proven effectiveness for the treatment of highly prevalent conditions like IBS, chronic constipation and functional dyspepsia. Adding behavioral

336 INTEGRATIVE GASTROENTEROLOGY

treatments to standard medical care can potentially reduce overall GI symptom severity by more than half, provide long-lasting therapeutic benefit, benefit treatment refractory patients, and reduce healthcare utilization substantially, while having no serious side effects. The current level of evidence suggests it is time to start regarding behavioral treatments as serious and responsible options in routine care for functional GI patients with moderate or severe symptoms.

34 Mind-Body Medicine in Digestive Disease DOUGLAS A. DROSSMAN AND WILLIAM E. WHITEHEAD

key concepts ■

■

■

■

■

The UNC Center for Functional GI and Motility Disorders has a 15-year history in the biopsychosocial knowledge and care of patients with functional gastrointestinal and motility disorders, with initiatives in the area of research, patient care, training, and patient education: The clinical program provides multidisciplinary, patientcentered care involving gastroenterologists, physiologists, psychologists, and physician assistants. Emphasis in clinical training is placed on advanced interview methods and relationship building to maximize an effective provider–patient interaction, and on the use of newer gutdirected and psychopharmaceutical agents. The research program is internationally recognized in the areas of psychosocial and psychophysiological investigation, epidemiology, and treatment of functional gastrointestinal and motility disorders. On-site training is provided to students, trainees, and established clinicians and investigators to help them gain advanced skills in research and patient care. ■

337

Introduction

T

he practice of gastroenterology has changed from a patient-based quality-of-care model to a business model with emphasis on income generation. This has occurred with the use of endoscopy and related procedures, along with brief, disease-focused clinic visits. (Drossman, 2004) Furthermore, training in the care of patients with functional gastrointestinal disorders (FGIDs) is limited and at times deemphasized, because FGIDs are considered “second class” (Drossman, 2005b), thus reducing motivation for clinical practice. (Drossman, 2001) Nevertheless, people with FGIDs comprise the largest segment of patients seen in gastroenterology practice (Russo et al., 1999). These patients tend to believe that their care is unsatisfactory and their needs are unmet (Drossman et al., 2008a). With regard to research, the greatest interest and support for federal funding is in basic and translational research; the goal is to understand the basic mechanisms of disease, with the intent to cure and ultimately benefit the patient. However, this research emphasis does not help patients with chronic functional GI disorders. Furthermore, with the decreasing availability of NIH funds, success in obtaining and sustaining research related to pathophysiological mechanisms of the FGIDs, and the proper care of patients, has been challenging and discouraging at best. In the face of these realities, the UNC Center for Functional GI and Motility Disorders has continued to promote and successfully sustain a quality-based model of patient care, a biopsychosocial model of research, and state- of-theart training in the FGIDs. The center has maintained its supremacy in providing new scientific knowledge to the field, innovative training opportunities for physicians and investigators, and optimal service to our patients. This chapter will review the history and philosophy of the center, and the ways in which its goals have been accomplished.

Brief Overview of the Center The UNC Center for Functional GI and Motility Disorders (www.med.unc. edu/ibs) was established in 1994, when Dr. William Whitehead moved from Johns Hopkins University and joined Dr. Douglas Drossman at the University of North Carolina Division of Digestive Diseases. Prior to that, Dr. Drossman had an active clinical practice in irritable bowel syndrome (IBS) and the

Mind-Body Medicine in Digestive Disease 339

functional GI and motility disorders, as well as a biopsychosocial research program related to clinical and psychosocial outcomes in the FGIDs. (Drossman, 1998a) Dr. Whitehead, who had established a research and biofeedback treatment program for motility disorders at Johns Hopkins with Dr. Marvin Schuster, was recruited to set up what has become a world-class motility program at UNC. Drossman and Whitehead combined their skills and expertise in an effort to establish a research and clinical program that was committed to the field of functional GI and motility disorders. The Center’s mission (to advance the biopsychosocial understanding and treatment of functional gastrointestinal and motility disorders through an integrated approach to patient care, research, training and education) was implemented through four areas of activity: (1) Patient Care – to offer state-of-the-art evaluation and treatment for the full range of functional GI and motility disorders; (2) Research – to conduct studies on the physiological and psychosocial mechanisms underlying functional GI and motility disorders, their impact on quality of life and health outcomes, and their treatment; (3) Training – to provide multidisciplinary training and education in clinical and research skills with an emphasis on patient-centered care and advanced research methods; and (4) Patient Education – to provide helpful and up-to-date information through seminars and workshops, as well as printed materials, videos, and the Internet.

Structure of the Center One of the most unique features of the new center was Drs. Drossman and Whitehead’s shared responsibility as co-directors. This collaboration between two senior academicians has sustained the program for more than 15 years. Dr. Drossman coordinates the clinical activities, Dr. Whitehead established the motility program, and both have active research programs with independent and shared federal, foundation, and pharmaceutical support. In addition, several new faculty and investigators have joined the center and established their own research careers and clinical programs. The center also has developed collaborations with dozens of investigators worldwide; established a clinical program to implement multidisciplinary care; recruited an administrative staff to coordinate day-to-day activities including visiting scholars, media development, website maintenance, and the production of teaching tools; and established data management and biometry cores to provide advanced clinical and website-based research and data analysis.

340

INTEGRATIVE GASTROENTEROLOGY

Clinical Program The Functional GI and Motility Disorders Clinic is a tertiary care referral site for patients with difficult-to-diagnose functional GI and motility disorders, who present with challenging management issues. A team of gastroenterologists, psychologists, physician assistants, gastroenterology fellows, and visitors in training or on sabbatical, work together to provide a unique multidisciplinary approach that integrates medical, physiological, and psychological factors in the evaluation and treatment of patients. Emphasis is placed on a patient-centered diagnostic interview, with the goal of establishing an effective physician–patient relationship; state-of-the-art physiological and clinical investigations including endoscopy, breath H2, and motility testing; and psychological assessment and pharmacological treatments using the most advanced agents. The clinical program provides several therapeutic initiatives: 1. Establishment of an Effective Physician-Patient Relationship. The basis for optimal treatment rests in establishing an effective physician– patient relationship (Drossman, 2007a). Borrowing from the work of George Engel (Morgan & Engel, 1969) and Karl Rogers (Rogers, 1980), we view the presenting symptoms in the context of the patient’s illness beliefs. From that point, the clinician applies his or her medical knowledge to develop an optimal negotiated treatment plan, along with provision for continuity of care. An example of the ways in which an effective therapeutic relationship can be established is shown in Table 34.1. 2. State of the Art Pharmacological Treatments. At UNC, the FGID clinicians are thoroughly familiar with the full range of pharmacological treatments for the FGIDs, including the newer psychopharmacological agents used to treat visceral hypersensitivity and comorbid conditions. The use of advanced treatment approaches requires proper preparation; the method at the UNC Center is shown in Table 34.2. In addition, the UNC Center is continually involved with providing new investigative agents as part of Phase II and III studies, and then offering them to patients. 3. Biofeedback. Certain FGIDs—including pelvic floor dyssynergia, fecal incontinence, and levator syndrome—are amenable to biofeedback treatment. In fact, our clinicians and researchers have in many cases published the seminal literature in this area of investigation. The center also has a dedicated Pelvic Floor Biofeedback Clinic. 4. Psychological Treatments. Our psychologists are skilled in the full range of psychological interventions, including cognitive-behavioral therapy, stress management, relaxation therapy, and hypnosis.

Mind-Body Medicine in Digestive Disease 341

Table 34.1. Behaviors that Affect Physician-Patient Relationship Behavior

Facilitates

Inhibits

Clinical environment

Private, comfortable

Noisy, physical barriers

Eye contact

Frequent

Infrequent or constant

Body posture

Direct, open, relaxed

Body turned, arms folded

Head nodding

Helpful if well timed

Infrequent, excessive

Body proximity

Close enough to touch

Too close or too distant

Facial expression

Interest, empathy, understanding

Preoccupation, boredom disapproval

Touching

Helpful when used to communicate empathy

Insincere if not appropriate or properly timed

Open-ended to generate hypotheses

Rigid or stereotyped style

Closed-ended to test hypotheses

Multiple-choice or leading questions (“You didn’t . . . ?”)

Use of patient’s words

Use of unfamiliar words

Fewer questions and interruptions

More

Nonjudgmental

Judgmental

Follows lead of patient’s earlier responses

Follows preset agenda or style

Use a narrative thread

HPI -> PMH -> ROS -> Psych

Appropriate silence

Frequent interruptions

Appropriate reassurance

Premature or unwarranted reassurance

Elicits psychosocial data in a sensitive and skillful manner

Ignores psychosocial data or uses “probes”

Nonverbal

Verbal Question forms

Question style

(Adapted from Drossman and Chang, )

342 INTEGRATIVE GASTROENTEROLOGY

Table 34.2. Management of FGIDs with Psychopharmacological Agents 1. Choice of the agent based on: • The specific symptom treated • The side-effect profile • The cost of the drug • Previous experiences and preferences with psychotropic agents • Coexisting psychiatric conditions targeted 2. Initiating treatment • Negotiate treatment plan. • Consider previous drugs that worked. • Start with a low dose (e.g. 25 mg/day of TCA). 3. Continuing treatment: • Escalate dose by 25%–50% every 1–2 weeks to receive therapeutic effect with least possible dose. • Watch for side effects – Counsel that most of them disappear in 1–2 weeks. If not, try to continue same or lower dose from same class before switching to a different class. • Follow up within 1st week and then within 2–3 weeks to ensure adherence. • Gauge treatment benefit with improvement in coping, daily function, QOL, and emotional state. • If a poor initial response: • Re-address patient concerns • Switch to a different class • Consider combination therapies (eg. SSRI+TCA, pharmacological and psychological treatment). • If needed, obtain psychiatry consultation for pharmacotherapy. • Increase doses up to full psychiatric doses if patient can tolerate before discontinuing. • If there is no benefit in 6–8 weeks on higher doses, alternate strategies (e.g., adding psychological treatment or referral) should be sought. • Depending upon the response and side effects, another agent with different mechanism of action can be added to augment treatment efficacy and minimize side effects. 4. Stopping treatment: Continue treatment at minimum effective doses for 6–12 months. Long term therapy may be warranted for some patients. Gradual taper to prevent withdrawal symptoms. (Adapted from Grover & Drossman, )

Mind-Body Medicine in Digestive Disease 343

Research Program The UNC Center has been a leader in research on the functional GI and motility disorders since its inception. Our seminal contributions to the field include the following. (See Appendix D for details). • Diagnostic criteria: The center’s co-directors have made major contributions to the development and validation of reliable diagnostic criteria for the functional GI and motility disorders through their research, including factor analysis studies (Whitehead et al., 1990a; Whitehead et al., 1998a; Whitehead et al., 2003a), epidemiological surveys (Drossman et al., 1993), validation studies (Whitehead, 2006) and their leadership of the Rome Foundation. The Rome Criteria have been a major impetus to scientific discovery by enabling investigators to select more homogenous groups of patients and communicate replicable findings. Dr. Drossman has served as the President of the Rome Foundation from its inception, and Dr. Whitehead has served on the Board of Directors. • Pathophysiological mechanisms of IBS: Research by Center investigators has established the key role of visceral hypersensitivity and motility in the symptoms of IBS (Whitehead et al., 1990c; Dorn et al., 2007; Kanazawa et al., 2008b), and the CNS mechanisms that mediate visceral pain sensitivity. (Ringel et al., 2003a; Ringel et al., 2008) • Psychosocial contribution to the development of IBS: With NIH support, UNC Center faculty and investigators have identified and documented the key role played by sexual and physical abuse in the development of IBS. (Drossman et al., 1990; Leserman et al., 1996b) They have also articulated a model for understanding the ways in which psychosocial and biological factors interact to produce the symptoms of IBS and other functional GI disorders. (Drossman, 1998b) • Psychological treatment of IBS: The Center has carried out the largest NIH-funded randomized, controlled trial of the treatment of painful functional bowel disorders with cognitive-behavior therapy and antidepressants. (Drossman et al., 2003b) We also developed a scripted protocol for hypnotherapy (the “North Carolina model”) that is used throughout the world. In addition, we are pioneers in the investigation of psychotropic drug treatment for IBS and the FGIDs.

344

INTEGRATIVE GASTROENTEROLOGY

• Biofeedback treatment of pelvic floor disorders: We described pathophysiological mechanisms for fecal incontinence (Chiarioni et al., 2002a) and dyssynergic defecation (Chiarioni et al., 2005b), and carried out randomized, controlled trials (Chiarioni et al., 2006b; Heymen et al., 2007a) to show that biofeedback is the treatment of choice for these disorders. • Outcome assessment: We have developed widely used questionnaires for assessing symptom severity (Drossman et al., 1995; Drossman et al., 2000c), sexual abuse (Leserman et al., 1997a), impact on quality of life (Drossman et al., 2000b; Drossman et al., 2007a), and comorbidity (Palsson et al., 2002). • Brain imaging: Center investigators have published studies, initially with PET and later fMRI imaging, from a hypothesis-driven perspective, looking to understand the role of psychosocial factors and, in particular, sexual and physical abuse on anterior cingulate activation. (Ringel et al., 2008; Ringel et al., 2004; Ringel et al., 2003b; Drossman et al., 2003a; Drossman, 2005a) This provides a possible mechanism for understanding the role of stress factors on pain threshold via cingulate activation. • Pharmaceutical trials: Through our research (Whitehead et al., 2006b), leadership positions in the Rome Foundation (Irvine et al., 2006), and consultations to industry, we have shaped the guidelines for conducting pharmaceutical trials. In addition, our broad involvement with current and emerging pharmaceutical agents permits the availability of several Phase II and III treatment trials in which our patients may participate.

RESEARCH TEAM

The center’s research program currently includes 14 faculty investigators within the UNC Division of Gastroenterology and Hepatology (including 6 who are principal investigators for NIH grants), plus four fellows or visiting scientists on site. These investigators are supported by four research coordinators, three physician assistants who participate in research, two research nurses, and 12 research assistants. We also have a large number of collaborators in other departments and schools within UNC, and an extensive network of investigators at other institutions (see Figure 34.1).

Mind-Body Medicine in Digestive Disease 345

Center investigators have received a number of national and international honors and awards, including: two Janssen Clinical Investigator Awards, the AGA Fiterman Award in Clinical Research, the AGA Education Award, the AGA Mentor Scholars Award, two FBGRG Senior Investigator Awards, an FBGRG junior investigator award, and two senior IFFGD Awards for Research Excellence. The center’s co-directors also serve on national review panels. Dr. Drossman was on the Council of the National Center for Complementary and Alternative Medicine, the NIDDK Digestive Diseases Commission, and the Institute of Medicine Committee on Gulf War and Health: Physiologic, Psychologic, and Psychosocial Effects of DeploymentRelated Stress. He chairs the program committee and the research awards committee for the IFFGD. Dr. Whitehead serves on the Data Safety and Monitoring Board for the NIDDK Gastroparesis Research Network, and is a co-investigator on the NICHD Pelvic Floor Disorders Network. He is a member of the NIH BMIO Review Panel, and chairs the Rome Foundation Research Committee. Research support for the center has come chiefly from the NIH (approximately 60). Center investigators currently hold an R24 Mind–Body Infrastructure grant, two RO1s, two R23s and an R21, in addition to support they receive as co-investigators on grants by their collaborators outside the center. This support from the NIH is supplemented by several investigatorinitiated research contracts with pharmaceutical companies for outcomes research unrelated to drug approval (for example, estimating the impact of FGIDs on quality of life and health economics).

RESEARCH INFRASTRUCTURE

Currently, the center is supported by an R24 Mind–Body Medicine infrastructure grant, which funds a number of cores that support the research of our investigators. These cores are as follows: • Research Administration Core, which provides a registry of research participants and staff support for recruiting research subjects, assistance with the recruitment of Hispanic and other minority subjects, and a team of research coordinators. • Biometry Core, which provides consultation on experimental design and statistical analysis, questionnaire and data entry forms, and data management schemes. For selected studies, this core provides actual data management and data analysis. • Data Acquisition and Technology Applications Core, which provides technical support for automated data entry (scan-able questionnaires,

346

INTEGRATIVE GASTROENTEROLOGY

Internet-based questionnaires and surveys), creation of websites for study management, and maintenance of a secure server, which serves as a reservoir for databases. • Education and Dissemination Core, which maintains a website to educate patients and healthcare providers and disseminate research findings, prepares posters, slides, and brochures for center investigators, and publishes a quarterly newsletter. • Seed Grant Core, which provides one-year grants of $37,500 to new investigators to collect pilot data for grant submissions. This program has been highly successful, in that six of the first nine seed grant recipients have obtained independent NIH funding related to their seed grants (two RO1s, two R21s, one R23s, and a supplement to an R24).

International Activities The center is represented nationally and internationally through a network not only of research activities (see above) but also in leadership positions. As noted, Dr. Drossman is President and Dr. Whitehead on the Board of Directors of the Rome Foundation, the organizational responsible for standardization in diagnosis in the FGIDs. Center investigators are actively involved on the advisory boards of pharmaceutical companies, NIH, FDA, and the International Foundation for Functional GI Disorders, have held leadership positions in the Functional Brain-Gut Research Group, have served as associate editors for Gastroenterology, and are editors or on editorial boards for Gastroenterology, Internal Medicine, and Psychosomatic Medicine. The center is frequently highlighted by the media in newspapers and magazines, and several videos, radio, and TV shows have been produced on site.

Academic Training and Public Education A major commitment of the center is to provide onsite training not only for our GI fellows but for visitors from around the world. The Visiting Scholars Program provides an opportunity for faculty, investigators, and clinicians from other institutions to visit the center for a few days to several weeks. The Visiting Scientists Program hosts faculty and investigators for sabbaticals and extended stays for one to two years. In this capacity, the visitors spend enough time to return to their home institution and establish independent research careers, or set up their own clinical programs in the FGIDs. There are several components to the training program:

Mind-Body Medicine in Digestive Disease 347

1. Mentored Learning. Trainees work in an individually structured relationship with one or more faculty mentors, who provide ongoing support and feedback to their work. Guidelines developed by the center for providing this mentored learning are available (Drossman, 2007b). The senior investigators at the center have independently established research careers with NIH funding, and are able supervise trainees in all aspects of research, including project development, grant writing, ongoing project administrative support, abstract and manuscript preparation, and presentation skills. Clinicians are offered the opportunity to observe our clinical staff in the care of patients seen in the clinic (with patient permission). With proper credentialing, they are able to independently work with patients in a preceptorship arrangement. 2. Training Seminars. We hold a weekly clinical case conference, where patients seen by the clinicians are presented and discussed among the entire clinical staff to provide new insights into diagnostic and therapeutic approaches. In addition, the center hosts a monthly psychosocial skills seminar, with GI fellows and clinicians outside the division, to facilitate learning about patient care. This includes live patient interviews and discussions, videotaped learning sessions on the medical interview, role plays, and small group learning. There is also a monthly interdisciplinary Anorectal Motility Case Conference, in which gastroenterology, radiology, surgery and urogynecology staff discuss the diagnosis of patients with complex pelvic floor disorders and plan optimal treatment approaches. 3. Public Education. The center’s education programs target patients and their families and friends, healthcare professionals at all levels, and the public at large. The center promotes increased awareness and understanding of the FGIDs through a biennial all-day patient symposium, printed materials, videos, and its website (www.med.unc. edu/ibs). Many of these programs have won national recognition, including the Freddy Award and the Communicator Award, and have been shown on TV and webcasts on major networks.

Concluding Comments In the current healthcare environment that emphasizes procedures over time spent with patients, the UNC Center has been able to sustain a patientcentered biopsychosocial model of care that is quality based and effective. Furthermore, with federal research emphasis on biomedical research, and

348

INTEGRATIVE GASTROENTEROLOGY

shrinking research funding, we have successfully maintained a broad and comprehensive NIH-funded research portfolio that has helped to move the field forward. We have also been successful in communicating our clinical and research agenda to other healthcare providers and investigators around the world. Hopefully this effort will ultimately help our patients with functional GI and motility disorders.

35 Yoga and Digestive Health SAJIDA CHAUDRY AND BETH NOLAN

key points ■

■

■

■

Yoga is a means to experience consciousness and harmony with the world. Yoga and ayurveda are sister sciences—both believe in the inseparable nature of the mind, body and spirit. Patanjali’s eight limbs of yoga include yama, niyama, asana, pranayama, pratyahara, dharana, dhyana and Samadhi. Yoga poses and breathwork for digestive health enhance relaxation and reduce sympathetic nervous system stimulation. ■

Introduction Evenness of the mind is called yoga. —Bhagavad Gita Yoga is believed to have two meanings, union and discipline. Yoga comes from the Sanskrit work “yuj” which means to join together. The root is similar to the work yoke, which also means to bond together. At its very core, yoga brings together the individual self (jiva—our physical body) and the cosmic or universal self (atman—the entire universe) to form a single unity. Yoga is the vehicle to achieve consciousness, to transcend the ego–personality and to experience Unity. In this state of Unity, there is no inner conflict and complete harmony with the world.

349

350

INTEGRATIVE GASTROENTEROLOGY

The practice of yoga can be dated back to the third millennium BCE. Patanjali, the Indian sage, wrote the Yoga Sutras around 200 CE in the form of 195 organized and codified terse aphorisms. Thus, classical yoga emerged. Yoga and ayurveda are considered to be sister sciences—both believe in the inseparable nature of the mind, body and spirit and both view the body as channels of energy (nadis) that can result in disease if blocked. Kapha, pitta and vata imbalances affect the entire body including the gastrointestinal system. Balancing doshas (see ayurvedic section) is fundamental to both yoga and ayurveda. Yoga is divided into eight stages, know as Patanjali’s eight limbs of yoga: 1. 2. 3. 4. 5.

Yama - universal moral commandments Niyama - self-purification by discipline Asana - posture Pranayama - rhythmic control of the breath Pratyahara - withdrawal and freedom of the mind from the senses and the exterior world 6. Dharana - concentration 7. Dhyana - meditation 8. Samadhi - state of bliss or super-consciousness where the individual merges with the universal spirit Yoga as practiced in the West focuses mainly on asana, poses named after animals, but really yoga intends for integration of the mind, body and spirit through all of the above stages. The yogic path involves body and mind purification, asana preparing the body for meditation and samadhi.

Yoga and Digestive Health In terms of gastrointestinal health, yoga allows relaxation, balancing the physiological effects of stress. Reduction in skeletal muscle tension decreases sympathetic system stimulation and subjective tension and may improve gut motility (Drossman, 2003). Relaxation training includes imagery, breathwork, meditation and biofeedback—all components of yoga. Gastrointestinal disorders such as irritable bowel syndrome involve enhanced motility and visceral hypersensitivity associated with brain–gut dysfunction. With its meditative approach, yoga helps with changing the relationship to stress, and the actual postures bring awareness of the body with gentle physical activity. Yoga has been compared in a small randomized, controlled trial to standard drugs (loperamide) in diarrhea-predominant IBS. Both have

Yoga and Digestive Health 351

been shown to work at 2-month follow-up, with yoga having the additional benefit of increased parasympathetic activity (Taneja et al., 2004). The yoga intervention group consisted of a set of 12 asanas (e.g., Vajrasana, Shashankasana, Ushtrasana, Marjariasana, Padhastasana, Dhanurasana, Trikonasana in two variations, Pawanmuktasana and Paschimottanasana), along with Surya Nadi pranayama (right-nostril breathing) two times a day for 2 months. Other studies have looked at pranayama (yogic breathing), asanas (yoga postures) and meditation and have concluded that yoga may be a beneficial, low-risk, economical addition to the treatment of illnesses that can worsen gastrointestinal health such as stress, anxiety and depression (Brown & Gerbarg, 2005). Yoga teaches us how to breathe deeply and fully. Breathing this way brings the natural functions of the organs into balance, especially the eliminatory organs. The diaphragm and the lungs expand and contract, thus massaging the internal organs. In the case of weak abdominals, the digestive and eliminatory functions are weakened as well. The diaphragm is connected to some of the abdominal muscles via connective tissue. If the muscles are weak, a full, deep breath is limited. Yoga postures using the complete three-part breath can strengthen the abdominal wall and the digestive organs, supporting good health and vitality. In terms of gastrointestinal health, yoga allows relaxation, balancing the physiological effects of stress. Reduction in skeletal muscle tension decreases sympathetic system stimulation and subjective tension, and may improve gut motility.

Yoga Postures for Patients with Digestive Illness A compassionate approach to one’s body is essential. There is no benefit if there is pain. The goal is to find relaxation in the body and mind through breathing deeply and fully in the postures.

There are numerous yoga postures that address digestive health. Five will be covered here. These five are easy and simple enough for any patient to practice. All postures can be modified to accommodate any physical limitations by using pillows, bolsters, and even chairs. Good advice to health practitioners is to consider experimenting with the poses themselves, to understand them experientially. To achieve the greatest benefit from each of these postures, patients will need at least 10 to 15 complete yogic breaths per pose. If at any

352 INTEGRATIVE GASTROENTEROLOGY

time your patient is uncomfortable, recommend readjusting the body, or ask your patient to take himself or herself completely out of the posture to rest. Then ask your patient to consider returning to the posture and attempting to challenge themselves again. Usually, anyone with digestive problems feels discomfort and agitation. Starting with Viparta Karani (legs up the wall) calms the nervous system and the mind, bringing focus to the breath deep in the lower abdomen. The height of the bolster supporting the hips will vary according to the severity of the discomfort. In the case of irritable bowel syndrome (IBS), it is best to use a folded blanket—about an inch high—so as not to over-stretch the abdominal walls and intestines, which would cause more irritation. The idea is to bring calmness to the intestines and to one’s breathing. Due to its supportive nature, this posture can be recommended with a hold for 10 to 15 minutes. Once your patient has been in Viparta Karani, and his or her body, mind, and breath are calmer, a forward bend series will help massage and encourage the elimination process. Patients can assume the Dandasana (staff pose) by engaging their muscles and breathing the full three-part breath. This posture can tone the abdominal organs, lift sagging abdominal walls, improve digestion, and reduce heartburn and gas. The Janu Sirasana (head to knee pose) has the ability to massage the ascending colon when the right leg is extended out first, and the descending colon when the left leg is extended. This posture can be recommended with a strap to create a more vigorous massage, or with a chair or bolster. This supports the head and arms for a more restorative effect. After your patient has completed this pose on both sides, ask them to return to Dandasana and to prepare for Paschimottanasana (full forward bend). As in the last posture, this position can be very active and engaging for patients by using their hands or strap to fully work the posture, and by bolstering their head and upper body with pillows and or a chair. The key to any of these variations is to ask patients to keep the full three-part breath, expanding and contracting to massage the organs from the inside out. After this pose, ask patients to return to Dandasana with 3–5 breaths, and roll down to their backs, resting in Savasana (relaxation or corpse pose). If there is any lower back pain or discomfort, ask patients to bend their knees and bring them toward the chest. Patients can gently roll around to relieve any discomfort, and then return to Savasana. If there is still discomfort, then patients may rest with a pillow under their knees, or keep their knees bent and feet flat on the floor. Encourage focus on the three-part breath. Resting between postures or a series of postures allows your patient’s body to integrate and feel the benefits as they rest. Marichyasana (spinal twist) is a great benefit to the body as a whole. By twisting the spine, they are affecting

Yoga and Digestive Health 353

the nervous system, which increases energy levels and massages the organs under the rib cage. This improves the functions of the liver, spleen, pancreas, kidneys, and intestines. Spinal twist also has the ability to realign the spine, allowing the nerve impulses to flow and respond more efficiently. Spinal twists should be done with caution. Avoid recommending them if the patient has diarrhea, dysentery, insomnia, or migraines. Variations of spinal twist can be recommended; these are done while lying down, practicing knee-down twist or the traditional twist with one leg bent and the other extended, or by twisting with crossed legs.

Advasana (Reversed Corpse or Relaxation Pose) The next series of postures start in Advasana—the opposite of Savasana—lying flat on the stomach. Ask your patient to turn his or her head to one side or the other to get an even stretch in the neck while breathing the three-part breath. This allows the stomach and/or diaphragm to expand and press into the floor with each breath. Allow the exhalation to relax the patient into the floor. To deepen the massage of the digestive tract, place hands or fists under the stomach and continue breathing. Recommend that the patient always be gentle, never causing pain or discomfort. A compassionate approach to one’s body is essential. There is no benefit if there is pain. The goal is to find relaxation in the body and mind through breathing deeply and fully.

36 Integrative Approaches to Abdominal Pain ROBERT A. BONAKDAR AND EMILY G. SINGH

key concepts ■

■

■

■

1

Patients with chronic abdominal pain deserve a biopsychosocial approach (Figure 36.1) to their condition, including a thorough evaluation of organic causes as well as focus on psychological state, family dynamics, and coping strategies. Use of standardized tools (Irritable Bowel Syndrome Symptom Severity Score, Brief Pain Inventory) is encouraged to enhance global understanding and monitoring. The most common cause of abdominal pain, especially recurrent pain in children, is irritable bowel syndrome (IBS). In addition to currently approved medications, an evidenceguided approach should be utilized to recommend or consider the following treatments on an individual basis: ■ Mind–Body Therapies ■ Reassurance and education ■ Cognitive-behavioral therapy (CBT) for IBS, number needed to treat (NNT) of 21 ■ Biofeedback, especially for pain associated with pelvic floor dyssynergia (PFD)/functional constipation ■ Hypnosis, especially gut-directed hypnotherapy, trial in patients who fail standard medical therapy, ■ Biologically Based Therapies ■ Dietary counseling by a qualified practitioner for optimizing dietary intake ■ Peppermint oil for IBS, NNT of 2.5 ■ Probiotics for IBS, NNT of 8.9

Number Needed to Treat (NNT): Defines the number of subjects needed to be treated to have a successful outcome versus control treatment.

354

Fiber for IBS, NNT of 11 Alternate Medical Systems/Energy-Based Treatments ■ Acupuncture for IBS, trial in patients who fail standard medical therapy ■ Herbal medicine and dietary interventions from a traditional Chinese medicine, Tibetan Ayurvedic, or naturopathic perspective for IBS ■ Transcutaneous electrical nerve stimulation (TENS) used on acupoints for IBS or pain related for functional dyspepsia In some cases, a formally structured multidisciplinary program may need to be initiated for optimal management. ■

■

■

■

INTRODUCTION

A

bdominal pain, especially of a chronic, functional nature, can be a complex, difficult-to-treat condition requiring global assessment and individualized care options. As described below, the most common cause of abdominal pain, especially in children, is irritable bowel syndrome (IBS). Unfortunately, as noted in most the recent meta-analysis of available drug treatments in the setting of IBS currently, options are not optimal, with global assessment and treatment required: “The evidence for efficacy of drug therapies for IBS is weak. Although there is evidence of benefit for antispasmodic drugs for abdominal pain and global assessment of symptoms, it is unclear whether anti-spasmodic subgroups are individually effective. There is no clear evidence of benefit for antidepressants or bulking agents. The physician should be aware that global assessment is a construct containing various dimensions. For each individual, these will have a different weighting and treatment should be aimed at the most debilitating symptom.” (Quartero et al., 2005) In this setting, it is not surprising that many patients consider the use of non-pharmacological (NP) and complementary and alternative medicine (CAM) for pain and symptom management. Chapter 37 will provide an overview of these treatment options including prevalence, patient rationale for utilization, and clinical efficacy. Most importantly, as many of these choices are

356

INTEGRATIVE GASTROENTEROLOGY

accessed without the input of a clinician, the chapter aims to provide guidance regarding the discussion and coordination of care for these treatments.

OVERVIEW AND IMPACT

Chronic abdominal pain is defined as pain that has been symptomatic for three months or more. In addition, pain may be categorized as organic or functional (absence of anatomic abnormality, inflammation, or tissue damage). Various diagnoses fit into the category of functional gastrointestinal disorders, as noted Table 36.1 (Guthrie & Thompson, 2002). In some cases, a diagnosis may fit into more than one category. For example, IBS, which will be the main discussion point in this chapter, is typically defined as a functional bowel disorder. However, more recent evidence demonstrates potential inflammatory and infectious etiologies that may explain at least a portion of IBS cases (Alonso & Santos, 2009). IBS appears to be one of the most common causes of chronic or recurrent abdominal pain. Irritable bowel syndrome affects 10 to 15 of the North American population, and thus is comparable in incidence to other chronic conditions such as asthma, coronary heart disease, diabetes, hypertension, and migraine (Cash, Sullivan, & Barghout, 2005; American College of Gastroenterology, 2002). Even though IBS accounts for nearly 3 of general practitioner consultations, only a quarter of those with IBS actually seek medical treatment for their symptoms (Thompson et al., 2000; Drossman & Thompson, 1992). Thus, on average, an IBS sufferer has symptoms for 10 years before diagnosis (International Foundation for Functional Gastrointestinal Disorders, 2002). For many reasons, IBS has the ability to create a substantial financial and quality-of-life burden on the patient and society (American Table 36.1. Categories for Functional Gastrointestinal Disorders • Functional dyspepsia • Ulcer-like dyspepsia • Dysmotility-like dyspepsia • Unspecified dyspepsia • Functional diarrhea • Functional constipation • Irritable bowel syndrome • Functional abdominal bloating • Unspecified functional bowel disorder • Functional abdominal pain syndrome • Unspecified functional abdominal pain (Reprinted with permission from Guthrie &Thompson (2002) BMJ, 325(7366), 701–703).

Integrative Approaches to Abdominal Pain 357

Gastroenterological Association, 2004; Frank et al., 2002). Estimates place combined direct and indirect costs of IBS at nearly $30 billion a year (Cash, Sullivan, & Barghout, 2005). Because of the significant use of healthcare resources, and indirect costs including absenteeism and loss of productivity, the estimated cost of IBS appears to be greater than that of conditions including asthma or migraine, and comparable with hypertension and congestive heart failure. Additionally, chronic abdominal pain is well recognized to have detrimental effects on quality of life, which may be more difficult to delineate (Cash, Sullivan, & Barghout, 2005; Hahn et al., 1999).

OVERVIEW OF INTEGRATIVE OPTIONS *

Non-pharmacological and CAM treatments include a vast array of choices for the abdominal pain patient. The definitions of these treatments vary and are constantly being updated. Non-pharmacological treatments are typically defined as options that are not prescription medications. However, several options that have been nonprescription options in the past, such as omega-3 oils and B vitamins, are now available in formulations requiring a prescription. In addition, several options, such as S-adenosyl methionine (SAMe), which are nonprescription in the United States, may require prescriptions outside the United States. Similarly, CAM was previously defined as treatments not included in medical school training. Currently, more than 60 of the nation’s allopathic medical schools are providing some level of instruction on CAM (Wetzel, Eisenberg, & Kaptchuk, 1998). More recently, CAM has been defined by the National Institutes of Health Center for Complementary and Alternative Medicine (NCCAM) as treatments or medical systems that are not typically incorporated in conventional treatment recommendations. This definition has evolved to include integrative medicine, which is the practice of incorporating selected evidence-based CAM options into mainstream practice. The NCCAM system classifies CAM into categories that are helpful for discussion. Currently, there is no consensus and large overlap in the use of these terms. For this chapter, the non-pharmacological and CAM treatments reviewed will be referred to collectively as NP/CAM options. An overview of NP/CAM options categorized under NCCAM headings is noted in Table 36.2.

PREVALENCE OF NP/CAM USE *

NP/CAM use is quite common, especially in those suffering from pain. CAM usage was reported in approximately one-third of the United States population

358

INTEGRATIVE GASTROENTEROLOGY

Table 36.2. Overview of Non-pharmacological and Complementary and Alternative Medicine (CAM) Treatments Category Overview

Examples

1. Alternative Medical Systems Systems of care based on unifying health paradigms, which may incorporate individual treatments including those noted in the categories below.

Traditional Chinese Medicine Ayurveda Naturopathy Homeopathy

2. Mind–Body Interventions Diverse techniques that utilized cognitive, behavioral, and movement therapies in order to modify and increase awareness between mental and physiological functioning

Biofeedback Meditation Yoga Exercise, various Tai chi/qi gong Creative therapies (art, music or dance) Relaxation

3. Biologically Based Therapies Therapies that modify nutrient intake, either through dietary intervention or supplementation

Dietary modification (dietary elimination, fasting, or specific dietary regimen) Dietary Supplements: Herbal supplements (white willow bark) Non-herbal supplements (glucosamine), vitamins (vitamin D), minerals (selenium)

4. Manipulative and Body-Based Methods Techniques that utilize manipulation, movement, and/or stretching of one or more parts of the body

Chiropractic manipulation Osteopathic manipulation Manual and massage therapy

5. Energy Therapies (biofield therapies) Techniques that involve the application of human or nonhuman energy fields

Acupuncture Qi gong Healing Touch Therapeutic touch

Adapted from What Is CAM? http://nccam.nih.gov/health/whatiscam/

Hypnosis Visualization Guided imagery Cognitivebehavioral therapies Group support Autogenic training Spirituality

Integrative Approaches to Abdominal Pain 359

in 1990, and increased to 42 by 1997. At that point, this represented 628 million office visits and $27 million spent on CAM services, which far exceeded total out-of-pocket expenditure and office visits (328 million) for conventional primary care providers in the same year. A follow-up analysis demonstrated that approximately one-third of the visits to CAM providers were for the treatment of pain (Wolsko et al., 2003).

A more recent analysis of CAM use by the NIH found that a majority of the top 10 reasons for CAM use were related to pain complaints, with abdominal pain in the top 10 in 2002 and top 15 in 2007. (Barnes et al., 2002; Barnes, Bloom, & Nahin, 2007).

PREDICTORS AND PATTERNS OF USE *

Several surveys have demonstrated that approximately half or more of IBS sufferers use CAM. In one survey of 413 GI clinic patients (61 IBS, 22 functional dyspepsia [FD], 17 gastroesophageal reflux disorder [GERD]), a total of 181 users of CAM were identified, or 44 of the group. The use of CAM was most frequent for IBS (51 IBS, 36 FD, 27 GERD). The most frequently utilized treatments were herbal medicines.

Predictors of CAM use were diagnosis with IBS, history of abdominal surgery, emergency room visits, disabilities and prescription of benzodiazepines and 3 or more medical visits for gastrointestinal tract disorders within the previous year. (Carmona-Sánchez & Tostado-Fernández, 2005).

In another survey examining the acceptability of various—mostly NP/ CAM—treatments for IBS, Harris and Roberts (2008) found a number of reasons for non-use, including dislike or disbelief in the treatment modality, as well as insufficient knowledge. The proportion of patients finding various treatments for IBS acceptable is noted in Table 36.3. In a multicenter pediatric survey, Vlieger et al. (2008) compared CAM use in patients with functional and organic gastrointestinal diseases. The overall prevalence of CAM use was 37.6 and, as expected, use was higher in patients with functional disorders than organic disorders (25.3 versus 17.2). Predictors of CAM use included less than satisfactory or adverse effects of conventionally prescribed medications, school absenteeism, and age 11 years

360

INTEGRATIVE GASTROENTEROLOGY

Table 36.3. Proportion of Patients Finding Various Treatments for IBS Acceptable Tablets 83.9% Diet change 81.6% Yoga 76.6% Stomach cream 67.6% Homeopathy 64.8% Heat pad 63.7% Hypnotherapy 63.7% Acupuncture 59.0% Suppository 57.4% (adapted from Harris and Roberts, 2008)

or below. Interestingly, 93 of the parents considered it important for pediatricians to be involved in CAM research, and 51 of were willing to participate in CAM research trials. Those who utilize CAM for IBS may share characteristics with the general CAM user, which may be important for the clinician to keep in mind. Namely, CAM users are more likely to be women with higher levels of education and income. Those using CAM have health values, beliefs, and coping systems that are also quite important to keep in mind. Those who are involved in “active coping behaviors,” which includes physical activity and particular diets, tend to view CAM use in a similar manner (Astin, 1998). Additionally, patients with a more “holistic outlook” wish to utilize complementary methods that take their viewpoint into consideration (Furnham & Bhagrath, 1993). There has been speculation that CAM use signals dissatisfaction with conventional care. One survey found that rheumatology patients with more medical skepticism had a higher likelihood of utilizing a CAM provider. This finding was especially true for abdominal pain patients (Callahan et al., 2008). However, the more likely scenario is that of CAM as an adjunct to conventional care. In fact, dissatisfaction with conventional care did not predict use of CAM in a previous survey, and less than 5 of CAM users did so in isolation from conventional care. Most CAM users state that their motivation for CAM use is that it provides them more control over their health care, and up to 80 report benefit from its use a previous survey (Astin, 1998).

Integrative Approaches to Abdominal Pain 361

CAM users have been noted to have more frequent relationships with a primary care physician, have regular physician follow-up, and good compliance with recommended preventative health behaviors such as regular mammography. Thus, what may be termed “medical skepticism” may in fact be an active coping behavior attempting to identify and incorporate potentially helpful treatments. As discussed below, the coordination of these efforts by a medical provider is quite important to help maximize treatment utility. (Astin et al., 2000).

Approach to the Patient* Regardless of their experience or particular beliefs about CAM, clinicians have an ethical obligation to discuss treatment alternatives with their abdominal pain patients. This is quite pertinent in the abdominal pain population that has an especially high use of NP/CAM. In this setting, it is especially important to have an open, nonjudgmental discussion about all treatments being considered or utilized, in order to provide full and optimal coordination of care. Unfortunately, the interaction between patients and clinicians regarding CAM use is often suboptimal. This situation is linked to several factors noted below, including the patient’s and clinician’s CAM knowledge base, level of discussion, and management strategies such as charting and follow-up. Several strategies and pertinent resources are reviewed to help optimize the approach to the abdominal pain patient.

KNOWLEDGE BASE*

The knowledge base of the average clinician and consumer regarding NP/ CAM, including popular areas such as dietary supplements, is suboptimal. Physician surveys have found that physicians may have an insufficient general understanding of commonly utilized supplements, as well as their safety, regulation, and interaction profiles (Ashar, Rice, & Sisson, 2007; Kemper, Gardiner, Gobble, & Woods, 2006). Similarly, consumers and patients tend to have misconceptions regarding product claims and efficacy. As pointed out by a previous Harris Poll, the majority of consumers believe that the government ensures a higher level of safety and regulation than actually exists (Harris Interactive, 2002). These misconceptions, as well as biased or anecdotal information found on some health websites and advertising, may create a scenario of decreased

362

INTEGRATIVE GASTROENTEROLOGY

perceived need for clinician guidance regarding CAM (Washington, Fanciullo, Sorensen, & Baird, 2008).

Discussion* The level of discussion regarding NP/CAM that occurs in the average pain consultation can be quite minimal. This is exemplified by the example of an editorial from the journal Pain, entitled “Food and Pain: Should we be more interested in what our patients eat?” The average pain clinician does not spend significant time discussing diet in general, or as an intervention. The reasons for this may include lack of training and resources and more comfort prescribing other interventions, including medication (Bell, 2007; Smith, 2004). The level of discussion regarding CAM, specifically, may be even more deficient.

Surveys have found that in approximately 70% of encounters there was no discussion of CAM use, and that neither the patient nor clinician introduced the topic. More concerning is the fact that if a patient is hospitalized by a specialist, CAM use is not identified up to 88% of the time. It is important to understand why patients may not discuss CAM use. (Wold et al., 2007; Azaz-Livshits et al., 2002).

Surveys indicate that factors including anticipation of a negative clinician response, as well as belief that the clinician will not provide useful information, motivated non-discussion (Adler et al., 1999). However, most important may be clinician inquiry, because patients demonstrate a willingness to disclose supplement use, but only if asked by a clinician (Hansrud et al., 1999). Unfortunately, a recent survey of physicians found that few felt comfortable discussing CAM with their patients. One of the major reasons for this lack of comfort was related to a need for improved knowledge base regarding CAM (84 of responders). It is theorized that with improved education and knowledge base about CAM, physicians may be more willing to discuss and counsel patients (Corbin-Winslow et al., 2002).

INVOLVING THE FAMILY

To most successfully understand and treat abdominal pain, it is imperative to view the condition and coping strategies as linked to a complex matrix of

Integrative Approaches to Abdominal Pain 363

potentially medical, as well as personal, family and community factors. Thus, when evaluating a patient with abdominal pain, a thorough biopsychosocial history of the patient and family is essential. Family pain histories are also quite important, as the frequency, severity, and level of catastrophizing of children with pain has been associated with degree of pain in the family (Schanberg et al., 2001).

PATIENT AND CLINICIAN EDUCATION

A number of resources are available to clinicians interested in better understanding NP/CAM as a means of improving patient communication and treatment options. These resources include print and online information on evidence-based use of NP/CAM, as well as continuing medical education courses available to clinicians. The H.E.R.B.A.L. Mnemonic is offered in Table 36.4 as a clinical tool for aiding clinicians when discussing and managing CAM use, especially dietary supplements.

Regulation* The regulation of NP/CAM varies widely based on the therapy described, the training of practitioners, and state laws. For example, acupuncture provided by a licensed acupuncturist (LAc) or physician acupuncturist may have vastly differing regulation as set forth by the state board, traditional Chinese medicine, medical board, or department of consumer affairs. In addition, the level of training, oversight, and continuing education for acupuncture varies widely by state, and the referring clinician should help guide patients in finding qualified and experienced CAM practitioners whenever possible. Verification of

Table 36.4. The H.E.R.B.A.L. Mnemonic© Hear the patient out with respect Educate the patient Record Be aware of potential interaction and side effects Agree to discuss and follow-up Learn

364

INTEGRATIVE GASTROENTEROLOGY

licensure can be obtained by contacting the state’s medical board, department of consumer affairs, or therapy-specific national certification organizations, as listed in Table 36.5. Dietary supplements are regulated according to the Dietary Supplement Health and Education Act (DSHEA) of 1994. Regulation differs from prescription medication, which must proceed through multiphase trials to gain approval from the FDA. Supplements (with established ingredients) are not strictly required to have safety, efficacy, or bioavailability data prior to marketing. The FDA must utilize adverse drug reports and product analysis to monitor products in the marketplace (FDA, 2002, 2003). Two more recent regulatory measures, The Dietary Supplement and Non-Prescription Drug Consumer Protection Act (S. 3546), which mandates the reporting of serious adverse events to the FDA, and Good Manufacturing Practices (GMPs) for dietary

Table 36.5. Regulatory and Practitioner Resources for Behavioral and Complementary and Alternative Medicine Organization / Agency

Website

Federation of State Medical Boards

http://www.fsmb.org/m_ pub.html

American Academy of Medical Acupuncture

http://www. medicalacupuncture.org

The National Certification Commission for Acupuncture and Oriental Medicine

http://www.nccaom.org/

American Psychological Association

http://www.apa.org/

American Society of Clinical Hypnosis

http://www.asch.net

The Center for Mind–Body Medicine

http://www.cmbm.org

The Biofeedback Certification Institute of America

www.bcia.org/

American Dietetic Association

www.eatright.org

American Chiropractic Association’s

http://www.acatoday.org

The National Certification Board for Therapeutic Massage and Bodywork

http://www.ncbtmb.com

Association for Applied Psychophysiology and Biofeedback.

www.aapb.org

American Association of Naturopathic Medicine

www.naturopathic.org

Association of Accredited Naturopathic Colleges

www.aanmc.org

Integrative Approaches to Abdominal Pain 365

supplements, which began incorporation in August 2007, should be helpful in ensuring better-regulated supplements (FDA, 2007). In addition to the above governmental measures, several agencies offer testing and monitoring services that allow manufacturers to demonstrate their adherence to regulatory standards. Those that pass inspection may carry an independent “Seal of Approval” on their label and advertising. Several of the government and independent agencies currently involved in oversight are listed in Table 36.6. Clinicians should become familiar with well-regulated and well-researched brands for the supplements that are most likely to be discussed with patients.

Interventions—Evidence-Guided Care Abdominal pain patients encounter, consider, and incorporate a large number of interventions for their condition and comorbidities. Understanding the motivation for, benefit from, and integrative potential for these treatments on

Table 36.6. Governmental and Independent Regulatory Agencies Agency

Website

GOVERNMENTAL Food and Drug Administration (FDA) Medwatch Program for collecting adverse reactions to prescription and OTC medications, as well as dietary supplements

www.fda.gov/medwatch

Federal Trade Commission (FTC) site for submitting complaints on false or misleading advertising

www.ftc.gov/ftc/complaint. htm

American Association of Poison Control Centers for reporting and management of adverse effects

www.poison.org or (800)222-1222

INDEPENDENT LABS PROVIDING SUPPLEMENT TESTING The Consumerlab Product Review

www.Consumerlab.com

Dietary Supplement Verification Program (DSVP) through www.uspverified.org the United States Pharmacopeia (USP) National Sanitation Foundation(NSF)

www.NSF.ORG/consumer/ dietary_supplements

366

INTEGRATIVE GASTROENTEROLOGY

an individual basis is essential in helping to frame an effective multidisciplinary treatment plan. Unfortunately, the research base in this area is quite heterogeneous and at times difficult to interpret. As an example, several meta-analyses of integrative options in the setting of abdominal pain, especially IBS, have been inconclusive. This includes meta-analyses of acupuncture and hypnosis, and all dietary interventions for treatment of IBS (Webb, Kukuruzovic, CattoSmith, & Sawyer, 2007; Lim et al., 2006; Huertas-Ceballos, Logan, Bennett, & Macarthur, 2009). Additionally, studies appear to be confounded by the high rate of placebo effect in CAM trials of IBS (Dorn et al., 2007). While awaiting more definitive evidence-based guidelines in this area, the clinician needs to provide evidence-guided care. In the setting of abdominal pain, because of the varied number of interventions and methodologies, the provider must often strive for evidence-guided care to find a successful compromise between available clinical evidence, patient preference, and clinical experience. In this paradigm, the clinician must review the available evidence to determine the safety and efficacy of various interventions. This is especially true of interventions that may be provided and initiated with varied methodologies, dosages, and directives. A prime example of this is hypnosis for IBS/ abdominal pain, which is covered in more detail below. If a clinician were to follow the conclusion of a recent meta-analysis in this area when encountering a pain patient interested in trying this intervention, his or her response might be to avoid this intervention. However, when more closely examined in the setting of hypnosis, or any NP/CAM, if there are no positive trials and/or the treatment demonstrated significant potential for harm, then the directive should be one of avoidance. However, if the treatment is of minimal harm and has the potential of benefit (such as hypnosis), or has positive evidence that demands a more focused detail of the intervention, the treatment may be recommended. This recommendation requires attention to specific protocols for modalities, and specific dosage and brand for supplements, along with appropriate monitoring and follow-up reassessment after a trial period. An example of this in the setting of hypnosis would be a specific gut-directed hypnotherapy in patients with IBS whose predominant symptom was abdominal pain. This specific, cost-effective modality was able to significantly decrease physical symptoms and in six of the eight health-related quality-of-life domains measured (emotional, mental health, sleep, physical function, energy, and social role). These gains were most significant in female patients with abdominal pain as their predominant symptom (Smith, 2006). In this example, through sifting of available trials, a positive protocol can be found that may be worth discussing and incorporating by a trained professional.

Integrative Approaches to Abdominal Pain 367

TREATMENT OVERVIEW

Acupuncture Acupuncture typically involves the therapeutic insertion of fine needles at selected body points based on a traditional or neuroanatomical basis. Acupuncture is often utilized in the setting of abdominal pain because it is believed to be helpful for pain management, based on specific and nonspecific local, neurochemical, and cortical modulation. (Pariente et al., 2005; Sprott, Franke, Kluge, & Hein, 1998).

From a mechanistic standpoint, acupuncture appears to increase solid gastric emptying and improve dyspeptic symptoms in patients with functional dyspepsia (Xu et al., 2006). There also appears to be improvement in heart rate response, consistent with an increased parasympathetic tone, with acupuncture that is not seen with placebo acupuncture. The increase in parasympathetic tone also correlates with positively with improvement in abdominal pain (Schneider, Weiland, & Enck, 2007). The potential for benefit in the setting of abdominal pain is difficult to answer from a research perspective largely based on the poor methodology and varied application of acupuncture in trials (Berman, Swyers, & Ezzo, 2000). The most recent Cochrane review of trials meeting inclusion criteria found that the evidence was inconclusive (Lim et al., 2006). A more recent trial found that quality of life related to IBS improved significantly whether real or sham acupuncture was utilized. This led the authors to conclude that the benefit in quality of life with acupuncture may be related to unspecific effects (Schneider, Streitberger, & Joos, 2007). This demonstrates the difficulty in studying acupuncture in the setting of IBS, as far as the placebo response. In one estimate, based on differences between real and placebo acupuncture, a study would need 566 patients to potentially prove benefit beyond placebo. This number is far beyond what is typically seen in trials of IBS (Schneider, Enck, Streitberger et al., 2006). The dichotomy between mechanistic/observation trials and clinic trials may be related to inappropriate study design. A more appropriate design may be similar to that seen in headache trials. This condition has also been demonstrated to have a nonspecific needle effect that is similar to sham acupuncture and superior to usual care (Vickers et al., 2004). Several trials have

368

INTEGRATIVE GASTROENTEROLOGY

demonstrated this phenomenon, and proceeded to not focus on the difference between real/sham but instead on any acupuncture and usual care in pragmatic design. These trials have shown benefit in severity of headache and related measures, which has correlated to a positive economic impact (Wonderling, Vickers, Grieve, & McCarney, 2004). Considering the economic impact of IBS ($30 billion/year), which exceeds that of common conditions such as migraine, future trials of acupuncture should focus on a pragmatic design approach. This design looks not only at differences between needle interventions, but whether acupuncture can have a meaningful impact compared to usual care on IBS symptoms, quality of life, and related costs (absenteeism, office visits, and medication). One such trial has explored this potential design (Reynolds, Bland, & MacPherson, 2008) and found that a pragmatic, randomized, intention-to-treat controlled trial compared 10 sessions of acupuncture plus usual primary care, with usual primary care alone. At three months, the patients receiving acupuncture in this trial had a significant 138-point improvement on the IBS Symptom Severity Score (scored 0–500). The authors estimate that a sample size of 108 patients per arm would be required for a fully powered study. The authors conclude, “A pragmatic trial design will not be able to distinguish between acupuncture specific effects and placebo effects; however, it is the design of choice to determine cost effectiveness.” In summary, as a recent systematic review noted, “. . . it must be discussed on what terms patients benefit when this harmless and obviously powerful therapy with regard to [quality of life] is demystified by further placebocontrolled trials” (Schneider, Streitberger, & Joos 2007). For clinicians advising patients regarding acupuncture while awaiting more definite evidence from pragmatic or placebo-controlled trials, it is wise to assess the global impact of the conditions and benefit from usual care. For those patients with refractory symptomology and reduced quality of life, it appears prudent to utilize a short trial of 8 to 10 treatments by a qualified practitioner to assess benefit. It is also advised that a standardized questionnaire, such as the IBS Symptom Severity Score, be utilized in conjunction with monitoring of medication use, productivity, and other lifestyle measures to pragmatically view the potential benefit of acupuncture in this setting.

PHYSICAL THERAPIES

Modalities and physical therapies include a wide range of therapies that are practitioner based and/or patient guided. The most common of these therapies utilized in abdominal pain/IBS are various electrostimulation or transcutaneous

Integrative Approaches to Abdominal Pain 369

electrical nerve stimulation (TENS) techniques. These therapies are based on several potential areas of benefit, which may correct areas of abnormality seen in abdominal pain/IBS, including muscular tension, autonomic hypersensitivity, altered skin temperature, and dysfunctional motility (McAllister, McGrath, & Fielding, 1990).

Electrical Stimulation Various types of transcutaneous electrical nerve stimulation (TENS) devices have been utilized in the setting of abdominal pain. One trial found that TENS at acupuncture points appears to improve dyspeptic symptoms and increases high-frequency heart rate variability in patients with functional dyspepsia (Liu et al., 2008). A pilot study also evaluated acupoint TENS in patients with diarrhea-predominant irritable bowel syndrome (IBS-D), constipation-predominant irritable bowel syndrome (IBS-C), functional constipation (FC) and healthy controls. IBS-D patients had significantly lower rectal sensory thresholds of the first sensation of stool, urgency of defecation, and pain than IBS-C or FC patients or healthy controls (P < 0.05). After 2 months of acupoint TENS treatment in IBS-D patients, there was significant improvement in rectal sensory thresholds, stool times, and the intensity of abdominal pain (Xiao & Liu, 2004). Electrostimulation may be considered based on preliminary data in the setting of refractory symptoms, especially diarrhea-predominant irritable bowel syndrome (IBS-D).

Mind–Body Therapies (MBT) Mind–body Therapies (MBTs) are diverse techniques that utilize cognitive, behavioral, and movement therapies to modify and increase awareness between mental and physiological functioning. These therapies can be as simple as onetime directed educational efforts, and as elaborate as long-term behavioral and psychological interventions. Several MBTs utilized in the setting of abdominal pain/IBS are reviewed below. Overall, the recent Cochrane review concluded that “psychological interventions may be slightly superior to usual care or waiting list control conditions at the end of treatment,” although few longterm follow-up results were available for review (Zijdenbos et al., 2009). Specifically, for improvement in abdominal pain, the standardized mean difference (SMD) at 2 and 3 months were 0.54 and 0.26 compared to usual care, and the SMD versus placebo at 3 months was 0.31.

370

INTEGRATIVE GASTROENTEROLOGY

reassurance Several articles have noted poor patient understanding of their condition, as well as catastrophizing, as factors related to increased symptom severity in IBS (Lackner, Quigley, & Blanchard, 2004). One trial attempted to determine the benefit of a single session of reassurance in self-perception of impairment in patients with IBS. In 55 patients seen for initial consultation, a questionnaire was provided to assess factors related to healthcare seeking. These included pain/discomfort, 78; cancer fear, 11; daily function impairment, 33; symptom related to stressfulness, 60; and none, 2. Afterwards, patients were provided with an explanation of the disease and reassurance, with readministration of the questionnaire. The authors found that one-time reassurance acutely decreased self-perception of daily function impairment (P=.003) and was independent of the subjects’ educational level (Schmulson, Ortiz-Garrido, Hinojosa, & Arcila, 2006).

cognitive-behavioral therapies (cbt) Cognitive-behavioral therapies enable patients to better understand how various beliefs, thoughts, and perceptions can affect their condition. Techniques such as restructuring, prioritization, and goal-setting are utilized to repattern behavior. Mechanistically, PET scanning in conjunction with CBT training has demonstrated reduction in limbic activity (Lackner et al., 2006). In the setting of CBT clinical trials, meta-analysis of 17 trials found an odds ratio of 12.0 in creating a >50 reduction in GI symptoms. Overall, the NNT to provide benefit versus controls was 2 (Lackner et al., 2004). This intervention should be freely recommended, especially in patients who exhibit psychological sequelae as a means of better approaching their condition or other therapies.

hypnosis Hypnosis has been defined in various ways, but typically involves, “the use of aroused, attentive, focused concentration and relative suspension of peripheral awareness to create opportunities for suggestion” (Astin, Shapiro, Eisenberg, & Forys, 2003). The overall evidence for hypnosis in the setting of IBS is inconclusive, as noted by a recent Cochrane meta-analysis (Webb, Kukuruzovic, Catto-Smith, & Sawyer, 2007). However, for short-term benefit in the setting of abdominal pain and IBS symptoms, the authors noted that hypnotherapy was superior to waiting list control or usual medical management in patients who fail standard medical therapy. As mentioned above, the most-studied regimen is known as gut-directed hypnotherapy, which has demonstrated significant benefit in the majority of clinical trials (Wald & Rakel, 2008). Unfortunately, incorporation has not been universal because trials have suffered from methodological weaknesses and treatment requires a 6 to 12 week commitment. Alternatives to the treatment have been investigated, including a self-hypnosis audio recording, which provided similar (52)

Integrative Approaches to Abdominal Pain 371

improvement to gut-directed hypnotherapy (Forbes, MacAuley, & ChiotakakouFaliakou, 2000). At this point, hypnosis may be considered as a likely effective mind–body therapy in the motivated or refractory pain/IBS patient.

biofeedback Biofeedback utilizes various techniques or sensors to increase mind-body awareness and identify areas of potential modification such as muscle tension (sEMG) or autonomic tone (peripheral temperature, heart rate variability [HRV], galvanic skin response). Because of the autonomic dysfunction described in IBS, biofeedback training affords a potential treatment for active nervous system retraining. Trials in this area have used various biofeedback techniques in a number of GI conditions including IBS, fecal incontinence, and pelvic floor dyssynergia (PFD)/functional constipation, which is often associated with anorectal pain. The most robust evidence for pain management appears to be in the area of PFD, in which a review of 38 trials found that the overall average probability of successful treatment outcome for patients treated with biofeedback was 62.4 (Palsson, Heymen, & Whitehead, 2004).

guided imagery Guided imagery encompasses various techniques, which combine “the use of inner images and symbols (self-guided or interactive) with therapies to induce a specific psychobiologic state (e.g., immune enhancement, relaxation, conflict resolution)” (Astin, Shapiro, Eisenberg, & Forys, 2003). In a preliminary trial of 22 children (aged 5 to 18 years), guided imagery with progressive muscle relaxation (GI +PMR) was compared to breathing exercises, as provided in 4 weekly sessions with a therapist. At baseline, the children who received guided imagery had more days of pain during the preceding month (23 versus 14 days). Children who learned guided imagery with progressive muscle relaxation had significantly greater decrease in the number of days with pain and days with missed activities, at one and two months. At 2-month follow-up, more children who had learned guided imagery had 4 or fewer days of pain each month, with no missed activities. Although a small trial, the ability to reduce days of pain from greater than 20 to fewer than 5, with a relatively short-term, benign intervention, deserves consideration while awaiting additional trials (Weydert et al., 2006).

Biologically Based Therapies A number of trials have attempted to investigate the use of dietary intervention for IBS-related symptoms including pain. These are subdivided in the following sections.

372

INTEGRATIVE GASTROENTEROLOGY

fiber Fiber supplementation studies for IBS symptoms vary based on types (soluble vs. insoluble), formulation (food based, dietary supplement) and amount recommended. Overall, fiber has been compared with placebo or a low-fiber diet in 6 studies with a total of 591 subjects (Quigley et al., 2008). Fiber improved symptoms in 48 of subjects versus 43 in the placebo or low fiber groups. The NNT with fiber for clinical success is 11, although the range was large a large range (5 to 100) based on varied methodology. Bran fiber has specifically been compared with placebo or a low-fiber diet in 5 studies with a total of 221 subjects. A summary of all trials demonstrates no statistically significant improvement in IBS symptoms with use of bran fiber. Psyllium (ispaghula husk) has specifically been compared with placebo in 6 studies with a total of 321 patients. Psyllium improved symptoms in 48 of subjects versus 36 in the placebo group. Overall, the number needed to treat with ispaghula to prevent one patient having persistent symptoms was 6, although the range was large (3–50) based on varied methodology. Lastly, guar gum (5 g/day) has been compared to wheat bran (30g/day) in one IBS. Although both treatments improved symptoms related to abdominal pain and bowel habits, guar gum was better tolerated and preferred by patients (Parisi et al., 2002).

probiotics Probiotics are broadly defined as beneficial microbes taken to improve health. Because IBS has been linked to microflora alteration, the use of probiotics has been discussed as a helpful treatment. The mechanism of benefit, in addition to reducing the population of symptom-causing microflora, may also include the anti-inflammatory and opioid-releasing ability of some strains. In a study of bifidobacteria, 8 different strains were analyzed for their effects on in vitro models of non-inflamed and inflamed intestinal epithelium. The results demonstrated that although none of the bifidobacteria induced nuclear factor κB (NF-κB) activation, six of the eight bifidobacteria tested inhibited lipopolysaccharide- (LPS-) induced NF-κB activation in a dose- and strain-dependent manner. This response was accompanied in specific strains by a dose-dependent reduction of interleukin 8 (IL-8) secretion and by decreased mRNA levels for inflammatory markers including IL-8, TNF-α, cyclooxygenase 2 (Cox-2) and intercellular adhesion molecule 1 (ICAM-1). The authors stated that certain bifidobacteria may be of benefit in the setting of chronic intestinal inflammation (Riedel et al., 2006). A number of clinical trials have attempted to test various probiotic strains in the setting of IBS pain and symptom management. In a meta-analysis of 20 such trials, McFarland and Dublin (2008) compared 23 probiotic treatment arms in 1,404 subjects. In this analysis, probiotic use was associated with improvement in global IBS symptoms compared to placebo (relative risk

Integrative Approaches to Abdominal Pain 373

RR=0.77, 95 confidence interval [95 CI; 0.62–0.94]). Specifically, probiotics were associated with decreased abdominal pain compared to placebo (RR = 0.78 [0.69–0.88]). The number needed to treat (NNT) for reducing abdominal pain was 8.9. Considering that this is a relatively benign intervention, a trial should be considered in the appropriate setting. Several limitations are present, however, in the use of probiotics for abdominal pain associated with IBS. Namely, numerous strains at various doses have been studied, as noted in Table 36.7. In the setting, the clinician should be aware of various formulations, as noted below, and may need to attempt various brands before finding one potentially helpful.

peppermint The use of peppermint extract for IBS-related symptoms has been studied in four placebo-controlled trials. These trials, which enrolled 392 patients, were reviewed by Ford et al (2008). While 65 of patients receiving placebo had persistent symptoms, this dropped to 26 of patients randomized to peppermint oil. The NNT with peppermint oil to prevent one patient having persistent symptoms was 2.5 (2.0 to 3.0). A review of these trials is noted in Table 36.8.

other dietary interventions A number of herbal medicines have demonstrated benefit versus placebo in IBS trials, including Chinese herbal formulas, STW 5, STW 5-II and Tongxie Yaofang, Tibetan herbal formula Padma Lax, and certain Ayurvedic formulas (Liu, Yang, Liu, Wei, & Grimsgaard, 2006). Other dietary interventions, including incorporating food antibody testing and dietary supplements such as l-glutamine, zinc, and cromolyn sodium, have been mentioned in the setting of IBS (Wald & Rakel, 2008). Although individualized cases may benefit from the incorporation of various interventions, the evidence for generalized benefit is either lacking or conflicting. Clinicians should openly discuss these options to ascertain the potential benefit of a particular intervention.

Conclusion and Coordination of Care Abdominal pain is a complex disorder that involves both central and peripheral sensitization, causing pain amplification and multisystem dysfunction, creating significant autonomic, functional, and psychological sequelae. It is quite important to take a biopsychosocial approach to this condition, as single modality approaches are rarely curative or of long-term benefit. A model of a biopsychosocial approach is noted in Figure 36.1. Because of the sometimes disparate presentation of patients with abdominal pain/IBS it is imperative to

Table 36.7. Relief of Abdominal Pain in 11 Probiotic/Placebo Treatment Arms Reference

Probiotic

Improvement in abdominal pain Probiotic n/n (%)

Placebo n/n (%)

Definition of secondary outcome1

Gade(46)

Strept faccalis

25/32 (78)

10/22(45)

Absence or presence of symptom

Nobaek(48)

L. plantarum

9/25 (36)

5/27 (18)

Decrease ≥ 1.5 on VAS symptom scale

O’Sullivan(49)

L. rhamnosus GG

9/19 (47)

12/19 (63)

Symptom improved

Niedzielin(50)

Lacto plantarum

20/20 (100)

11/20 (55)

Absence or symptoms

Bausserman(52)

Liicto rhamnosus GG

11/25 (44)

10/25 (40)

Decrease of ≥ 1 point symptom score

Kajander(54)

L. rhamnosus GG + L. rham. LC705 + Bifid. brene Bb99 +Prop. freudenreichii

27/41 (66)

17/40 (43)

Symptoms alleviated

Whorwell(35)

Bifido. infantis (106 dose)

32/74 (43)

39/76 (52)

Adequate relief of symptoms

Whorwell(35)

Bifido. infantis (108 dose)

42/72 (59)

39/76 (52)

Adequate relief of symptoms

Whorwell(35)

Bifido. infantis (1010 dose)

28/71(39)

39/76 (52)

Adequate relief of symptoms

Enck

E. coli + Strept faccalis

108/149 (72)

66/148 (45)

≥ 50% decrease in symptom score

Gawronska(60)

Lacto rhamnosus GG

6/18 (33)

1/19 (5)

Absence of pain

(59)

1 All secondary outcomes are defined based on patient report. Reprinted with permission from Lynne V. McFarland.

Table 36.8. Peppermint for IBS: Characteristics of randomized controlled trials of peppermint oil versus placebo in irritable bowel syndrome Study

Country

Setting

Diagnostic

Criteria to define symptom

Sample

Dose of peppermint

Duration of

Jadad

criteria for

improvement after therapy

size

oil

therapy

score

irritable bowel syndrome

Lech 1988w29

Denmark

Secondary care

Patient reported improvement in Clinical diagnosis and global symptoms investigations

47

200 mg three times 4 weeks daily

3

Liu 1997w30

Taiwan

Secondary care

Patient reported improvement in Clinical diagnosis and abdominal pain investigations

110

187 mg three or four times daily

1 month

4

Capanni 2005w32

Italy

Secondary care

Rome II

178

2 capsules three times daily

3 months

5

Cappello 2007w31

Italy

Secondary care

Rome II and ≥50% improvement from investigations baseline in overall irritable bowel syndrome symptom score using questionnaire data

57

225 mg twice daily 4 weeks

Improvement in global symptoms assessed by validated questionnaire

Reprinted with permission from Ford AC et al. BMJ. 2008 Nov 13;337:a2313. doi: 10.1136/bmj.a2313.

5

376 INTEGRATIVE GASTROENTEROLOGY

individualize care. In addition, because of several factors, including high levels of treatment failure, potential sensitivity to pharmacological interventions, and preference for specific treatment options, it is imperative for clinicians to be aware of NP/CAM options and to actively engage patients in discussion and coordination of these therapies when appropriate. Several resource tables and figures are provided to enable initial and ongoing discussion and management of NP/CAM options in abdominal pain. Several of the therapies reviewed in this chapter can provide safe, effective avenues of treatment for abdominal pain and its comorbidities. In many cases, the clinician is essential in helping abdominal pain patients to practically incorporate the various NP/CAM options available, to come up with a successful integrative management plan. If properly coordinated, there is evidence that an integrative/multidisciplinary approach, which typically involves both biological and MBT, may be more effective than monotherapy in creating a more satisfied abdominal pain patient with self-management skills. In the future, we look forward to additional research that helps to understand the synergy of NP/CAM therapies with conventional pharmacological care.

*Portions of this chapter are excerpted with permission from Non-pharmacological, Complementary & Alternative (CAM) Treatments for Fibromyalgia, McCarberg W and Clauw D, eds., Fibromyalgia, Informa Healthcare USA, Inc., New York, 2009.

37 Over-the-Counter Remedies for Digestive Health: Potion or Poison? JERRY HICKEY AND GERARD E. MULLIN

key concepts ■

■

■

■

■

■

More than 50 million American adults experience frequent heartburn. Proton-pump inhibitors (PPIs) are the third-bestselling class of medications in the United States. Omeprazole is the only PPI that inhibits CYP2C19 while increasing the expression of CYP1A2. Proven complications of PPI therapy include: ■ Bacterial colonization ■ C. difficle infection ■ Interstitial nephritis ■ Small bowel bacterial overgrowth ■ Community-acquired pneumonia ■ Hip fracture ■ Nutrient malabsorption (calcium [O’Connell et al., 2005], magnesium, iron, vitamin B12) H2 receptor antagonists (H2RAs) are weaker than PPIs but can suppress 24-hour gastric acid secretion by about 70. Cimetidine: ■ interacts with various Phase 1 detoxification enzymes including CYP1A2, CYP2C9, and CYP2D6 ■ can cause a broad array of CNS symptoms ■ can include galactorrhea in women, and gynecomastia, reduced sperm count, and impotence in men (Hoogerwerf WA, Pasricha PJ, 2006 1) For all H2 Receptor Antagonists (H2RAs), thrombocytopenia and other blood dyscrasias have also been reported.Nutrient depletions are similar to the PPIs. 377

■

■

Stimulant Laxatives: ■ induce low-grade inflammation and enhance gastrointestinal motility ■ long-term use of irritant laxatives may lead to colonic pathology, “cathartic colon” ■ mineral oil side effects include leakage of oil, greasy stools; rarely, if aspirated, it can cause lipid pneumonitis. Mineral Oil: ■ side effects include leakage of oil, greasy stools ■ rarely, if aspirated, it can cause lipid pneumonitis ■ can interfere with the absorption of minerals and all fatty soluble nutrients. ■

Outline ●

• • • • • • ●

• • • • • ●

• • • • •

Proton Pump Inhibitors Issues concerning OTC drugs for gastrointestinal indications: Side effects Toxicity Complications of PPIs Drug interactions Nutrient depletions H2 Receptor Antagonists (H2RAs) Issues concerning OTC drugs for gastrointestinal indications: Side effects Toxicity Drug interactions Nutrient depletions Antacids Issues concerning OTC drugs for gastrointestinal indications: Side effects Toxicity Drug interactions Nutrient depletions

Over-the-Counter Remedies for Digestive Health: Potion or Poison? 379 ●

• • • • •

Laxatives Issues concerning OTC drugs for gastrointestinal indications: Side effects Toxicity Drug interactions Nutrient depletions

Proton Pump Inhibitors for GERD TREATING FREQUENT HEARTBURN

Frequent heartburn is defined as symptoms occurring two or more days per week. More than 50 million American adults experience frequent heartburn. In the United States, 25 million adults experience heartburn daily. Heartburn affects quality of life, disrupting sleep and interfering with work and social activities (National Heartburn Alliance, 2003; Oliveria et al., 1999; Revicki et al., 1998). Heartburn is slightly more common in women; the mean age of reporting symptoms is 45 to 50 years of age. In rare cases it can lead to esophageal adenocarcinoma (Cappell, 2005). Access to OTC medications has been reported to improve patient adherence to a treatment regimen.

PROTON PUMP INHIBITORS FOR FREQUENT HEARTBURN

Increasingly, the more powerful proton pump inhibitors are replacing Histamine-2 (H2) antagonists in clinical practice. Omeprazole is the first proton pump inhibitor available without a prescription. Omeprazole is available as Prilosec OTC Delayed-Release Tablets 20 mg. • Prilosec OTC is the first proton pump inhibitor (PPI) to be available over-the-counter for frequent heartburn treatment. • Prilosec OTC is for people with frequent heartburn (two or more days per week). • One pill a day of Prilosec OTC works to relieve heartburn for up to 24 hours as part of a 14-day course of therapy.* • Directly shuts down many active proton pumps over time that make acid, but purported to leave enough acid for digestion, with one pill a day.

380

INTEGRATIVE GASTROENTEROLOGY

Side Effects The most common side effects are: • • • • •

Nausea Abdominal pain Constipation Flatulence Diarrhea

However, mild myopathy, arthralgias, headaches and skin rashes have also been reported. Chronic use of omeprazole may lead to hypergastrinemia in 5 to 10 of chronic users. Discontinuation of omeprazole after chronic use in patients with hypergastrinemia may cause a rebound hypersecretion of gastric acid (Freston, 1994).

Complications of PPIs

the top ten list 1) PPIs can lead to twofold increased rates of Clostridium difficile colitis Gastric acid provides a natural protective barrier to orally ingested pathogens. The significance of this association is accentuated by the emergence of a hypervirulent strain of C. difficile that is highly transmissible, causes severe colitis that sometimes requires colectomy, and has a fatality rate as high as 20. This disease is more commonly a complication of outpatient antibiotic usage, which is being overprescribed at record levels (Dial et al., 2005b). Development of drug resistance and alteration of the intestinal flora are felt to predispose to digestive disease. PPIs are a major contributor to nosocomial Clostridium difficile infection (Howell MD et al., 2010). 2) Bacterial colonization with resistant microbes in the intensive care unit (ICU) setting. Many investigations have reported the overuse and misuse of PPIs by physicians hospital-wide and in the intensive care unit (ICU) setting (Eid SM et al, 2010). Our own surveys demonstrate misperceptions, misuse, and overuse of PPIs by resident and attending physicians. Our findings led to restricted usage,

Over-the-Counter Remedies for Digestive Health: Potion or Poison? 381

to reduce inappropriate use and to diminish the risk from nosocomial infection in the intensive care setting (White, Storch & Mullin, 2003; Mian et al., 2003). 3) PPIs are associated with an increased risk of community-acquired pneumonia. PPIs increase the risk of bacterial infections by reducing the bactericidal activity of immune cells (Zedtwitz-Liebenstein et al., 2002). A study using a database of 500,000 records reported in JAMA found that current use of PPIs was associated with an increased risk of community-acquired pneumonia (CAP). 4) Drug-induced acute interstitial nephritis. PPIs are one of the most frequent causes of drug-induced acute interstitial nephritis (in some cases leading to renal failure), which is a trade secret, since most gastroenterologists are unaware of this potential toxic effect (Geevasinga et al., 2006). 5) Possible cardiovascular events. In 2007, Astra Zeneca provided the FDA data from two small ongoing studies showing that individuals taking the “purple pill” were at an increased risk for cardiovascular events, such as myocardial infarction and congestive heart failure. The agency did not issue a safety warning at that time. On August 7, 2007, the FDA made an unprecedented “early communication” to dismiss the adverse events as age-related and preexisting conditions. iiIn early 2009, some proton pump inhibitors were reported by Canadian researchers to reduce or eliminate the antiplatelet benefits of clopidogrel (Plavix) and increase the risk of a second heart attack (Juurlink et al., 2009). In a six-year population-based study of heart attack patients published in the Canadian Medical Association Journal, current use of three proton pump inhibitors was associated with a 27 increase in the risk of another heart attack.

Explain to interested patients that clopidogrel (Plavix) is prescribed after a heart attack for secondary prevention. Note that this study found that taking the drug along with some proton pump inhibitors increases the risk of recurrence.

382

INTEGRATIVE GASTROENTEROLOGY

The finding came as the FDA began a review of the so-called “clopidogrel resistance phenomenon,” in which between 5 and 15 of patients do not respond to the drug at all. Sanchez-Munoz-Torrerro et al (2010) subsequently reported that in patients with established arterial disease, concomitant use of PPIs and clopidogrel was associated with a nearly doubling of the incidence of subsequent myocardial infarction or ischemic stroke. The story of the interaction between clopidogrel and PPIs and their potential increase risk to patients with underlying coronary artery disease is unfolding. 6) Bacterial overgrowth of the stomach and proximal small intestine. A concern for physicians and their patients about PPI usage is that chronic acid inhibition may lead to bacterial overgrowth of the stomach and proximal small intestine. In GERD patients who are being treated with PPIs, there is an increased load of intragastric bacteria compared with those in whom PPI therapy has been discontinued (Gregor, 2004). Furthermore, a study that used a well-defined database consisting of about 500,000 patient medical records showed that acid-suppressive drugs such as PPIs are associated with an increased risk of community acquired pneumonia (CAP) (Laheij et al., 2004). Bacterial overgrowth may not only become a source of pneumonia from colonization, but it appears to become a susceptibility factor for a subtype of IBS that requires antibiotics to improve symptoms (Pimentel & Lezcano, 2007, Lombardo et al., 2010). 7) Pneumonia in the elderly: increased risk and worse prognosis. PPIs may be particularly risky for the elderly. Pneumonia is a major source of mortality in the elderly, immunocompromised patients, individuals with asthma or chronic obstructive lung disease, and children. Due to the agerelated reduction of gastric acid after 60 years, and partially due to a decreased immune response, elderly patients are likely to experience severe infection (Dial et al., 2005a). This study demonstrated a dose-response effect, as the relative risk of pneumonia was greatest for those taking more than one daily dose of a PPI. To avoid excessive pneumonia in the elderly, the study’s authors recommended that the elderly, “immunocompromised patients, those with asthma or chronic obstructive lung disease, and children should be treated with acid-suppressive drugs only when needed and with the lowest possible dose.” 8) Hip fracture. Most recently, and of particular concern, long-term PPI use appears to predispose to the development of hip fracture (adjusted odds ratio 2.6; see Yang et al., 2006). Millions of individuals have been using these medications

Over-the-Counter Remedies for Digestive Health: Potion or Poison? 383

on a continuous or long-term basis. Given that the elderly have reduced omeprazole clearance, caution should be exercised toward this complication, and bone density scanning may become necessary for early detection of osteoporosis from PPIs. 9) PPIs cause malabsorption of calcium, iron, and vitamin B12 from lowering gastric acidity Significant deficiency in gastric acid, called “hypochlorhydria,” is already prevalent among the elderly population without adding PPIs to the mix (Malfertheiner et al., 2007). The elderly appear to have decreased PPI clearance from their bloodstream, and may be more likely to have more profound hypochlorhydria at baseline (without any PPI usage), due to a higher prevalence of Helicobacter pylori infection, which itself causes hypochlorhydria (Lai & Sung, 2007). PPIs result in calcium malabsorption, since gastric acid is required for solubilization prior to absorption (Recker, 1985). In fact, limited animal and human studies have shown that PPI therapy may decrease insoluble calcium absorption or bone density (O’Connell et al., 2005; Camilleri et al., 2007). 10) Bacterial gastroenteritis. Gastric acid is a defense mechanism against gastrointestinal infections caused by ingested bacteria. Studies have suggested that the use of acidsuppressing drugs may increase the risk of gastroenteritis (GE). Current use of PPIs was found by scientists in Madrid, Spain, to be associated with an increased risk of bacterial GE compared with nonuse, regardless of the treatment duration (Garcia Rodriguez, Ruigomez, & Panes, 2007). In contrast, no association with gastroenteritis was observed with histamine receptor-2 antagonists (H2RA), which are weak stomach acid blockers. Doubling the PPI dose further increased the risk of developing bacterial GE. The effect of PPI use did not vary significantly with regard to treatment indication. The increased risk associated with PPI use was similar for both omeprazole and lansoprazole, whereas neither of the H2RAs, cimetidine nor ranitidine, showed any increased risk. Campylobacter (n = 4124) and Salmonella (n = 1885) were the two species most frequently responsible for GE episodes in the case group (n = 6414). The case-control group consisted of 50,000 non-PPI users. When analyzed separately, both species reproduced the increased risk associated with PPI use and not H2RA therapy. Conclusions: This study strongly suggests that gastric acid suppression induced by PPIs, but not H2RA, is associated with an increased risk of Campylobacter and Salmonella GE.

384

INTEGRATIVE GASTROENTEROLOGY

Fact Omeprazole therapy significantly decreased calcium absorption in elderly women. (O’Connell et al., 2005).

Proton-pump inhibitors (PPIs) are among the most commonly prescribed drugs, and a large number of patients use these on a daily basis as maintenance therapy for gastroesophageal reflux disease.

Fact about PPIs Despite the widespread use of PPIs in GERD, the prevalence of pre-neoplastic complications of GERD (Barrett’s esophagus) and esophageal adenocarcinoma are on the rise in the United States.

Although they are considered safe by the FDA and approved for long-term use, a number of concerns continue to be raised. Because of their strong acid-suppressive effect, PPIs lead to increased secretion and plasma levels of the hormone gastrin, which may support the development of neoplasia at high sustained levels. Two studies (Yang et al., 2007; Robertson et al., 2007) published in the journal Gastroenterology (United Kingdom, Denmark) found that long-term PPI therapy (> 5 years) at regular doses was not associated with a significantly increased risk of colorectal cancer (CRC). However, the study by Yang et al., found a strong association between recent (<1 year) PPI therapy and the risk of CRC (OR, 2.6; 95 CI, 2.3–2.9; P < .001). The increased risk in Yang’s study was observed exclusively with recent short-term use (within the preceding 12 months). Jan Tack and John M. Carethers wrote a commentary about these articles in the September 2007 issue of Gastroenterology. Their closing comment on the articles stated: “Both studies found that long-term PPI therapy was not associated with a significantly increased risk of CRC. These reassuring findings are important from a public health point of view for patients taking PPIs as well as for

Over-the-Counter Remedies for Digestive Health: Potion or Poison? 385

gastroenterologists prescribing PPIs. However, as PPI use increases over time, continued monitoring of the effect of PPI therapy on the risk of CRC over longer follow-up times seems warranted.”

Drug Interactions Omeprazole has a number of drug interactions because it is metabolized by various cytochrome-p 450 enzymes. Omeprazole is the only PPI that inhibits CYP2C19, therefore decreasing the rate of excretion of disulfiram, phenytoin, and other drugs. Omeprazole increases the expression of CYP1A2, thereby increasing the rate of excretion of imipramine, some antipsychotic drugs, tacrine, and theophylline. Additionally, omeprazole interacts with warfarin, diazepam, and cyclosporine (Relling MV & Giacomini KM, 2006). Nutrient Depletion Calcium. Researchers at the University of Pennsylvania School of Medicine report that chronic use of proton pump inhibitors, especially at higher doses, increases the risk of hip fracture. Hypochlorhydria interfered with the absorption of calcium (Yang, Lewis, Epstein, & Metz, 2006). Magnesium. There have been reports of severe magnesium depletion in users of omeprazole. Researchers from the University of Auckland found that omeprazole inhibited the absorption of magnesium, and this effect could be partially corrected by supplementing with high-dose oral magnesium (Cundy & Dissanayake, 2008). Other nutrients: omeprazole inhibits the absorption of zinc (Ozutemiz et al., 2002), vitamin B12, vitamin B1, folic acid, and iron, sodium, and beta-carotene (Vagnini & Fox, 2005). Although PPIs are considered by many to be devoid of adverse effects, nutrient depletions can be severe. Recently, there was a case of omeprazole-induced hyponatremic delirium accompanied with rhabdomyolysis in an emergency department patient. After cessation of omeprazole and emergency treatment, the patient recovered completely (Bebarta & King, 2008).

nutrients depleted by ppis: • • • • • • •

Calcium Magnesium Zinc Vitamin B12 Vitamin B1 Folic acid Iron

386

INTEGRATIVE GASTROENTEROLOGY

• Sodium • Beta-carotene

H2 RECEPTOR ANTAGONISTS (H2RAS)

H2-receptor antagonists competitively inhibit the binding of histamine at receptor sites on parietal cells, decreasing the production of acid. Although weaker than PPIs, H2RAs can suppress 24-hour gastric acid secretion by about 70 (PPIs; 80-95) (Hoogerwerf WA, Pasricha PJ, 2006-1). These drugs are approved for treating uncomplicated GERD, but are increasingly being replaced by PPIs in clinical practice. H2-receptor antagonists available without a prescription include: • • • •

Cimetidine (Tagamet HB) Famotidine (Pepcid AC) Nizatidine (Axid AR) Ranitidine (Zantac 75)

Side Effects The side effects of H2-receptor antagonists are considered to be minor, but include: • • • • • •

Diarrhea Headaches Drowsiness Fatigue Muscular pain Constipation

There are less common but more serious side effects that affect the CNS, including delirium, confusion, hallucinations, and slurred speech, which can occur in elderly subjects. Cimetidine, in particular, affects sex steroid hormones if used long term and, typically, at higher dosages. The drug influences estrogen metabolism in women and testosterone binding in men. The result can include galactorrhea in women, and gynecomastia, reduced sperm count, and impotence in men (Hoogerwerf WA, Pasricha PJ, 2006-2). Thrombocytopenia and other blood dyscrasias have also been reported (Freston, 1982). Increased incidence of community-acquired pneumonia has been linked to the use of famotidine (Hauben, Horn. Reich, & Younus, 2007).

Over-the-Counter Remedies for Digestive Health: Potion or Poison? 387

Drug Interactions Cimetidine interacts with various phase 1 detoxification enzymes, including CYP1A2, CYP2C9 and CYP2D6. Ranitidine also interacts with hepatic CYPs but with only 10 of the affinity seen with cimetidine. Famotidine and nizatidine have very little influence on these enzymes (Pharmacotherapy, 2006). Therefore, any drug metabolized by these CYPs will have an interaction with cimetidine and a possible interaction with ranitidine.

Nutrient Depletions Calcium is reportedly depleted at least to some extent by H2-receptor antagonists (Vagnini & Fox, 2005). Iron: Gastric acid secretion is required to facilitate iron absorption. Malabsorption of dietary iron may result from inhibition of acid secretion by the H2-receptor antagonists. H2-receptor antagonists are considered to be efficient chelators of Fe2+. This probably lacks clinical importance during the short term; however, long-term use of these drugs could contribute to the occurrence of iron-deficiency anemia. Such impairment of nonheme iron absorption could be amplified for individuals concurrently using antacids on a regular basis in conjunction with H2-receptor antagonists (Aymard et al., 1988). Zinc: Reduced gastric acid secretion can exert both direct and indirect effects on the absorption of zinc that parallel its impairment of iron absorption. In a study involving healthy adults, 300 mg/day of ranitidine for 3 days significantly reduced gastric acid and zinc absorption (Sturniolo et al., 1991). Vitamin B12: H2-receptor antagonists decrease acid secretion by the gastric parietal cells. Gastric acid and pepsin produced by these cells are required for the cleavage of vitamin B12 from dietary sources. H2-receptor antagonists prevent dietary B12 from being freed from its protein binder during digestion. Studies have demonstrated a significant reduction in food-bound vitamin B12 absorption secondary to decreased acid secretion in patients taking H2-receptor antagonists. This probably lacks clinical importance during the short term; however, long-term use could contribute to the occurrence of vitamin B12deficiency anemia. Such impairment of vitamin B12 absorption could be amplified for individuals taking antacids on a regular basis along with ranitidine (;Aymard et al., 1988; Force & Nahata, 1992). Other nutrients: H2-receptor antagonists have also been reported to interfere with the absorption of copper, folic acid, and vitamins B1 and D (Vagnini & Fox, 2005; Gaby et al., 1999).

388

INTEGRATIVE GASTROENTEROLOGY

Pharmacist’s Corner I have been recommending deglycyrrhizinated licorice (DGL) to clients with GERD for more than a decade with little or no untoward effects, although I have had a few complaints regarding taste. Licorice contains a chemical known as glycyrrhizic acid, which is responsible for many of its reported side effects, including those associated with electrolyte disturbances. The DGL form of licorice has the glycyrrhizic acid component removed, and therefore is considered safer to use (Medline Plus; Petry & Hadley, 2001). DGL is used for heartburn (PDR Health) and has a number of beneficial effects in patients with GERD. It enhances mucus secretion and accelerates healing of digestive tissue (van Marle, Aarsen, Lind, & van Weeren-Kramer, 1981; Das, Das, Gulati, & Singh, 1989).

ANTACIDS

Antacids have largely been replaced by more effective and convenient drugs. Nevertheless, they continue to be used by patients for a variety of indications (Hoogerwerf WA, Pasricha PJ, 2006-3). Antacids are used to relieve heartburn, acid indigestion, and stomach upset. They may be used to treat these symptoms in patients with peptic ulcer, gastritis, esophagitis, hiatal hernia, or too much acid in the stomach (gastric hyperacidity). They combine with stomach acid and neutralize it. Aluminum hydroxide, magnesium hydroxide, and calcium carbonate are common ingredients in antacids.Simethicone is added to a number of antacids. Simethicone is a surfactant that breaks up gas bubbles. It also may reduce foaming, and may hence aid esophageal reflux (Hoogerwerf WA, Pasricha PJ, 2006-3). Side effects from aluminum hydroxide and magnesium hydroxide are not common, but may include: • • • • •

Diarrhea Constipation Loss of appetite Unusual tiredness Muscle weakness

Side effects of calcium carbonate are rare and mild: • Belching • Abdominal distention

Over-the-Counter Remedies for Digestive Health: Potion or Poison? 389

• Flatulence • Rebound acid secretion

Drug Interactions Because they alter gastric acidity and urine pH, antacids can inhibit the absorption of some drugs including thyroid hormones, allopurinol, and imidazole antifungal agents. Aluminum and magnesium, antacids are notorious for their ability to chelate other drugs present in the GI tract, forming insoluble complexes that are not absorbed (Hoogerwerf WA, Pasricha PJ, 2006-3).

Nutrient Depletions Because they alter gastric acidity and have an affinity to chelate, antacids can inhibit the absorption of many nutrients. There is evidence that antacids decrease the levels of vitamins A and D and folic acid, as well as binding with calcium, chromium, iron, magnesium, phosphorus, and zinc (Vagnini & Fox, 2005; Gaby et al., 1999).

LAXATIVES

Johns Hopkins Medicine Health Alerts defines constipation as a common but typically benign condition characterized by infrequent bowel movements and difficulty passing stool. The eleventh edition of Goodman & Gilman cites a few interesting studies: by questionnaire, 25 of the U.S. population, more commonly women and the elderly, complain of constipation. A survey of bowel habits in the United States showed that 18 of respondents used laxatives at least once a month but nearly one-third of these users did not have constipation (Pashricha PJ, 2006). In the bowel, water accounts for at least 70 of stool weight, and fluid largely determines its volume and consistency. The digestive tract has to extract fluid, minerals, and nutrients from food to supply the body for its needs, and leave behind sufficient fluid for regular expulsion of waste matter via defecation. Normally, 8 or 9 liters of water enter the small intestine daily from exogenous and endogenous sources. Pressure differentials due to the flow of ions cause absorption of water from the small intestines, leaving only about 1 to 1.5 liters of water to cross into the large intestine. The colon extracts most of the remaining fluid, leaving about 100 ml daily for the feces (Pashricha PJ 2006).

390

INTEGRATIVE GASTROENTEROLOGY

So, fluid intake is important for avoiding constipation. Fiber intake is also important. Unfortunately, many Americans do not respond well to their physicians’ advice for consuming more fruits and vegetables, but many do respond to using fiber supplements A variety of fiber products are available on the market, including psyllium, wheat, and methylcellulose. Fiber also protects against colon diverticulosis, carcinoma of the large bowel and stomach, Type 2 diabetes, metabolic syndrome, and cardiovascular disease (Trepel, 2004).

Medication for Constipation NONSPECIFIC STIMULANT OR IRRITANT LAXATIVES

Stimulant laxatives have direct effects on enterocytes, neurons, and GI smooth muscle. These agents trigger low-grade inflammation in the bowels, inducing the accumulation of fluid and electrolytes and increasing intestinal motility. Stimulant laxatives include bisacodyl, and the herbs senna and castor oil. Bisacodyl is a common ingredient in OTC laxative products. The gastrointestinal tract is in a constant state of contraction, absorption and secretion. Bisacodyl works to inhibit net fluid absorption and secretion by augmenting intestinal permeability (Farack & Nell, 1984). It also increases motility. Food can decrease the absorption of bisacodyl. Laxatives with bisacodyl include Carter’s Little Pills, Correctol, Dulcolax, Feen-a-Mint and PMS-Bisacodyl. Castor oil is an age-old remedy. It is derived from the bean of the castor plant. Castor oil is a brisk cathartic, and as little as 4 ml if taken on an empty stomach can produce a laxative effect within just 1 to 3 hours. The cathartic dosage for an adult ranges from 15 to 60 ml. The products Neoloid and Purge contain castor oil (Pashricha PJ, 2006). Senna is obtained from the dried leaflets of pods of Cassia acutifolia or Cassia angustifolia. Senna is found in Senokot and Ex-Lax. Side effects of stimulant laxatives include: • • • • • • • • •

Upset stomach Stomach cramps Diarrhea Possible dehydration Stomach and intestinal irritation Faintness Irritation or burning in the rectum (from suppositories) Senna commonly causes yellow-brown urine; this is harmless Long-term use of irritant laxatives may lead to colonic pathology

Over-the-Counter Remedies for Digestive Health: Potion or Poison? 391

Drug Interactions Irritant laxatives can deplete potassium possibly increasing the toxicity of digoxin. Bisacodyl can decrease the effectiveness of warfarin.

Nutrient Depletions Irritant laxatives deplete calcium, potassium and sodium (Gaby et al., 1999; Vagnini & Fox, 2005).

STOOL-WETTING AGENTS

Stool-wetting agents include docusate and mineral oil. Docusate is a surfactant. It lowers the surface tension of the stool, allowing fatty soluble and water soluble components to mix and making the stool softer, permitting easier defecation. Dioctyl sodium sulfosuccinate is found in Colace, DSS, and Doxinate, and dioctyl calcium sulfosuccinate is in Surfak. Docusate is only marginally helpful in many cases of constipation. Mineral oil is a mixture of hydrocarbons obtained from petrolatum, which in turn is obtained from petroleum. These fatty hydrocarbons penetrate and soften the stool, easing passage. Mineral oil side effects include leakage of oil and greasy stools. Rarely, if aspirated, it can cause lipid pneumonitis. Depletions: Mineral oil can interfere with the absorption of minerals and all fatty soluble nutrients. These include beta-carotene, vitamins A, D, E, and K, calcium, phosphorus, and potassium (Vagnini & Fox, 2005; Gaby et al., 1999). Osmotic laxatives include magnesium citrate, magnesium sulfate, magnesium hydroxide, and sodium phosphate. They create an osmotic effect, bringing water to the stool stimulating peristalsis and evacuation. These drugs are fairly well tolerated.

38 Systemic Interactions Between Dental and Gastroenterological Diseases PHILIP E. MEMOLI

key concepts ■

■

■

■

GI conditions producing soft tissue oral lesions: ■ Crohn’s Disease ■ Behcet’s Disease ■ Celiac Disease The dental-systemic management of generalized immunodysfunction: ■ Infections and Antigens from Marginal Periodontitis ■ Infections and Antigens from Apical Periodontitis ■ Antigenic Potential of Dental Biomaterials ■ Clinical Nutritional Considerations GI disturbances producing hard tissue oral lesions: ■ Gastroesophageal Reflux ■ I Conditions Producing Halitosis ■ Bulimia Nervosa The dental-systemic management of GI-induced hard tissue lesions: ■ Prevention, Treatment and Monitor Model ■ Management of the Aggressive, Pathological Complex Lesion ■

392

GI Diseases Producing Soft Tissue Oral Lesions CROHN’S DISEASE

I

nflammatory bowel disease (IBD) consists primarily of Crohn’s disease and ulcerative colitis. Crohn’s disease is characterized as a panenteric inflammatory condition, while ulcerative colitis is, by definition, generally limited to the colon. The etiology is unknown although the mechanism of acute episodes is believed to be of an unknown antigenic origin that stimulates the immune cells of the intestinal mucosa to produce the pro-inflammatory cytokines TNF-α, IL-1b and IL-6, resulting in enteric inflammation (Griffiths, 1999). The oral lesions may precede GI lesions in up to 30 of cases where both oral and gastroenterological pathology are evident (Lisciandrano et al., 1996). A wide range of nonspecific oral lesions has been reported, ranging from a “cobblestone” appearance of the mucosa, to aphthous-like ulcerative lesions, to deep granulomatous ulcers. Perioral symptoms may occur, and include angular cheilosis and lip fissures. Other symptoms may include gingival bleeding, gingival hyperplasia and metallic dysgeusia. Pyostomatitis vegetans, an oral finding, appears to be a marker for IBD and precedes GI symptoms (Ficarra et al., 1993). The lesions appear as yellow-white pustules with a characteristic “snail-track” appearance, speckled over an erythematous palatal and vestibular mucosa. Oral management is rarely required except in the event pustules rupture and ulcerate (Neville et al., 2002). The lesions of pyostomatitis vegetans will, as stated, precede GI symptoms, and generally follow the pattern of appearing with GI exacerbations and regressing with GI remissions. One study found that healing of pyostomatitis vegetan lesions occurred when oral zinc was supplemented, a mineral frequently lost when chronic diarrhea is present. The conclusion was that oral lesions may, in specified cases, be a result of malnutrition caused by nutrient excretion (Ficarra et al., 1993).

BEHCET’S DISEASE

The syndrome, first described by Hulusi Behcet in 1937, compromised a combination chronic ocular inflammation with oral, genital, and anal ulcerations. The mechanism appears also to be immunodysregulatory and either primary or secondary to specific triggers, which may include streptococci, viruses, heavy metals, and pesticides.

394

INTEGRATIVE GASTROENTEROLOGY

The oral lesions appear similar to aphthous ulcers; that is, a diffuse erythematous mucosa with an irregular bordered ulceration, but differ in number and location. Whereas aphthae may number from one to five, Behcet’s patients will frequently have six or more lesions. Further, lesions differ in location; Behcet’s syndrome lesions usually appear on the soft palate and oropharynx, whereas aphthae are most commonly found on the ventral surface of the tongue, followed by the mucobuccal fold and floor of the mouth. The soft palate and keratinized gingiva are rarely involved, but may form as extensions from adjacent areas. Oral involvement is present at least once in 99 of patients, and is the first manifestation in 25 to 75 of those cases (Krause et al., 1999).

CELIAC DISEASE

Primary immunodysfunction, it is hypothesized, may be associated with specific histocompatibility antigen (HLA) types in the subgroups of patients with aphthous and aphthous-type ulcerative lesions in the oral cavity. Crohn’s disease and Behcet’s disease have been associated with HLA subgroups, which demonstrate aphthous-like lesions. Celiac disease has been associated with similar HLA subgroups and hence, has the potential to also demonstrate aphthous-like lesions.

Systemic Dental Management of Immunodysfunction The oral cavity, structurally, functionally, and immunologically, represents the “gateway” to the gastrointestinal system. As such, there are factors of immunological importance such as nutrition, flora, pathogens, and antigens of either bacterial or dental biomaterial origin, which must be considered in the interdisciplinary management of immunodysfunction. Dentate status can also affect nutritional status, and may indirectly compromise immune function. Further, the oral tissues possess the unique tendency to serve as a marker for nutrient deficiency which, in turn, is conducive when monitoring nutrient status, immunologic status, and malabsorption. Dentate status refers to the number of natural teeth and the ability of patients to properly chew or masticate their food. Poor dentate status, by contrast, refers to a condition in which there are insufficient teeth for mastication, resulting in the delivery of unchewed food into the stomach with the potential for maldigestion and malabsorption. Studies have found the chewing efficiency of people with full dentures to be 20 of those with a full dentition (Kapur & Soman, 1964). Various studies have consistently demonstrated that

Systemic Interactions Between Dental and Gastroenterological Diseases 395

poor dentate status results in food choices higher in carbohydrates, cholesterol, and saturated fats, with fewer vegetables and nutrient-dense foods (Joshipura. Willet, & Douglass, 1996). In cases of weight loss associated with protein-calorie malnutrition among the elderly, poor dentate status is often a causative factor (Sullivan et al., 1993). Poor oral health, and edentulousness in particular, has been found to be associated with various gastrointestinal disorders (Brodeur et al., 1993). Certain GI diseases, such as Crohn’s, Behcet’s, and celiac disease, appear, as previously indicated, to exhibit an etiopathological basis in immunodysfunction and, if one is susceptible, to produce aphthous-like lesions in the oral cavity. The immunodysfunction may be primary, which may involve one of several specific histocompatibility antigens (HLA) types, such as HLA-B12, B51 and CW7. Secondary immunodysfunction, at least for the oral aphthae, has a highly variable etiology, which contains numerous population subsets including nutritional deficiencies, infectious agents, allergies, stress, trauma, genetic predisposition, and hematologic and hormonal influences. Infectious agents may range from streptococci to viruses such as herpes simplex, cytomegalovirus, adenovirus, and varicella zoster virus (Neville et al., 2002). Antigens and infections, with the potential to elicit an immune dysfunction response in susceptible individuals, are present in the oral cavity. These include pathogens and their antigens from marginal and apical periodontal infections, as well as antigens from implanted dental biomaterials. In those gastroenterological cases mediated by immunodysfunction and exhibiting moderate– severe and severe–fulminant exacerbation, the treating physician must consider ruling out dental contribution as a predisposing secondary factor.

Infections and Antigens from Marginal Periodontitis Systemic implantation from periodontal disease is perhaps one of the most researched subjects in current dental studies. Mattila and colleagues discovered an epidemiological relationship between gum infections, myocardial infarction, ischemia and atherosclerosis (Mattila et al., 1989). The DeStefano study, the result of a 14-year follow-up of 9,760 individuals, further demonstrated the relationship of oral focal infections, strokes, and coronary artery disease (DeStefano et al., 1993). Relationships have thus far been demonstrated in the following areas, with other areas still under study: • Myocardial infarction (Genco, 1998; Mattila et al., 1989) • Coronary artery disease (Xu et al., 1991, 1993; Mattila et al., 1993, 1995; Syrjänen, 1990)

396

INTEGRATIVE GASTROENTEROLOGY

• Diabetes (Genco et al., 1998; Grossi et al., 1997, 1998; Loe, 1993) • Respiratory infections and complications (Scannapicco et al., 1996, 1998; Donowitz & Manell, 1990; Fiddian-Green & Baker, 1991) • Obstetric complications such as preterm birth and low birth weights (Dasanayake, 1998; Loe & Silness, 1963; Offenbacher et al., 1996, 1998, 1998) The periodontal flora comprise as many as 300 to 500 species, serotypes, and ribotypes of bacteria, all of which are considered nonpathogenic (Loesche, 1994, 1997; Kilian, 1982; Paige, 1998). When a patient has decreased immune function, virulence factors present in the oral flora may now initiate chronic inflammatory periodontal disease (CIPD). CIPD represents an opportunistic or endogenous infection, and efforts to control the systemic focal activity of such infections must be based in proper immune system nutrition, function, and regulation. Once the pathogens predominate, a complex biofilm can evade the immune system and function to gain access to systemic circulation (Socransy & Haffajee, 2002). There are three metastatic mechanisms by which microorganisms, bacterial antigens, and local cytokines from the oral tissue gain access to circulation to produce systemic and secondary site effects, such as in the gastrointestinal system (Van Velzen et al., 1984). Metastatic infection is the result of bacteremia, which, although transient, may find susceptible tissue. Those bacteria that have evolved or acquired mechanisms for cellular adherence and colonization have been demonstrated to cause such conditions as infective endocarditis, acute bacterial myocarditis, brain abscess, prosthetic joint infections, and others (Rams & Slots, 1992). Metastatic injury, another mechanism, may occur from microbial toxins such as exotoxins and endotoxins (Van Velzen et al., 1984). Gram-negative bacteria are constantly shedding endotoxins or lipopolysaccharides (LPS) which, in circulation, produce systemic effects. Even when Gram-negative bacteria are killed by antimicrobials, large amounts of LPS are released that continue to exert immunological reactions, such as pyrexia and malaise. Finally, metastatic inflammation is another mechanism whereby soluble antigen may react with a specific antibody, giving rise to immune complex formation (Van Velzen et al., 1984; Van Dyke et al., 1986; Rams & Slots, 1992). The risk of metastasis from the oral cavity must be considered in those conditions possibly involving an immunodysfunction mechanism. Regarding metastatic inflammation, it is believed this mechanism can cause immunological injury and promote secondary inflammation in inflammatory bowel disease (IBD; see Walker, 1975). Although circulating immune complexes have been found in IBD, their etiology is still unknown (Jewell & Machennan, 1973).

Systemic Interactions Between Dental and Gastroenterological Diseases 397

Among the various systemic manifestations of IBD are its oral symptoms, particularly ulcerations, and moderate to advanced involvement of periodontal disease. The oral flora of those with IBD was studied and was found to be remarkably different from those without IBS; see Van Dyke, 1986). Whereas typical oral florae consist of aerobic, Gram-positive cocci and rods, the IBD patients demonstrated motile, anaerobic, Gram-negative rods found to be consistent with the Wolinella species. Further, the altered florae were similar in all IBD patients with and without periodontal disease, although those subjects with CIPD simply showed higher gingival sulcus bacterial levels. Regarding host resistance, the patients afflicted with IBD and CIPD were found to possess a serum-mediated neutrophil chemotaxis defect (Van Dyke, 1986). A similar defect is found in localized juvenile periodontitis, although this form of CIPD is not particular to IBD patients. The goal of an interdisciplinary and integrated periodontal treatment plan for those with immunodysfunction follows the traditional prevention–monitor– treatment paradigm. CIPD patients with immune dysfunction do not respond well to conventional therapy such as root planing and periodontal surgery. Nonetheless, proper oral hygiene and a proper maintenance period to monitor signs of exacerbations are necessary to minimize disease activity. Further, inflammatory gingivitis and periodontitis must be closely controlled to minimize the risk of metastasis and the potential for secondary complications. Also, nutritional therapy should be instituted to determine whether the patient presents with nutrient deficiencies, has conditional nutrient requirements, or has any offending food sensitivities or allergies.

Infections and Antigens from Apical Periodontitis Another potential source of bacterial infection and antigens may reside in apical periodontitis (AP) or endodontal (root canal) lesions; that is, infections of tooth origin at the tip or “apex” of the root. AP is a condition characterized as an acute or chronic condition, existing in the untreated or pre-root-canal-treated tooth. Some researchers are questioning the persistence of AP in apparently healed and asymptomatic root-canal-treated teeth, and the potential for bacterial pathogens and antigens to gain access to systemic circulation. AP was studied in epidemiological studies in which those with chronic dental infections demonstrated associations between acute myocardial infarction (Mattila et al., 1989) and coronary atherosclerosis (Mattila et al., 1993). AP infections may possess 200 species of predominately anaerobic, Gram-negative rods, of which proximity to circulation can facilitate metastasis and systemic dissemination (Tronstad, 1992). A study isolated Gram-positive anaerobic bacteria from

398

INTEGRATIVE GASTROENTEROLOGY

patients undergoing treatment of AP and concluded, based on biochemical and antibiotic sensitivity testing, that recovered microorganisms from the bloodstream originated from the teeth undergoing endodontic therapy (Debilian, 1995). The primary cause of AP is untreated dental caries, which infect the pulpal cavity of the tooth resulting in apical extension into the surrounding bone to produce a lesion. Treatment options include tooth extraction or endodontic therapy, the former being the current treatment of choice. The goal of endodontic or root canal therapy is to sterilize the tooth and, by the use of bacterial sampling, to verify sterility before completion of the root canal. However, due to the inability to reach secondary canals and the dentinal microtubules, the assumption these teeth are sterile and not capable of focal infections is currently being questioned (Wu et al., 2006). Post-treatment AP, a condition characterized as an asymptomatic tooth with radiographic healing after root canal therapy, may, in fact, still present as a chronic infection capable of activating immune cells. (Wu et al., 2006) Further, post-treatment AP may be associated with 50 to 90 of root-canal-treated teeth (De Moor et al., 2000; Kirevang et al., 2001; Dugas et al., 2003) and may serve as a physiological attempt to prevent metastasis of bacteria and toxic metabolic byproducts into systemic circulation. (Wu et al., 2006) The standard of care in the determination of healing of the AP lesion is the absence of a radiographic translucency, as an indication that no osseous lesion is present. However, several researchers have repeatedly documented the presence of post-treatment AP despite radiographic evidence to the contrary. (Bender & Selzer, 1961; Bender, 1982; van der Stelt, 1985; Huumonen & Orstavik, 2002) Some have found that a lesion up to 8 mm may be present without any trace of radiographic evidence (Ricucci & Bergenholtz, 2003). The treatment of AP has recently been redefined as the elimination of post-treatment AP at both the radiographic and the histologic level. (Orstavik & Pitt Ford, 1998; Friedman, 2002; Trope, 2003) The causes of post-treatment AP are well documented and are, for the most part, not treatable with current endodontics. Apical microsurgery, recently perfected by microscopy (Rubenstein & Kim, 1999; Nari et al., 2005), removes the causative infected apical portion of the root and surrounding bone, resulting in clinical removal of the post-treatment AP lesion. The early reported successes of apical microsurgery are promising; 97 of lesions greater than 10 mm were completely healed within one year after surgery. (Rubenstein & Kim, 1999) It is a concern, particularly in patients presenting with immunodysfunction, to rule out apical periodontitis and chronic inflammatory periodontal disease as sources of longstanding, low-grade infections capable of activating immune cells, which may then cause secondary immunologic injury to other normal cells and infiltrate the gut. (Ridker et al., 1997, 2001)

Systemic Interactions Between Dental and Gastroenterological Diseases 399

Antigenic Potential of Dental Biomaterials Another area of metastatic concern may involve dental restorative and implant materials, or biomaterials proper. All materials are reactive, and all biological interfaces are receptive; hence, there is no such phenomenon as a nonreactive or universal biocompatible material. When biomaterials are placed in the oral cavity, they undergo corrosion, degradation, separation and absorption (Clifford, 1990; Wataha, 2003). Once absorbed, each individual’s immune system will independently react or not react to determine if the test material is compatible for the person. Sensitized biomaterial antigens, unlike environmental antigens, when placed into the mouth present the possibility of chronic (24 hours a day, 365 days a year) exposure. There are very few government or industry standards for biocompatibility testing and, until recently, such testing was not performed routinely (Wataha, 2003). Recently, toxicological research in Europe has generated intense interest in dental biomaterial compatibility (Ahlqwist et al., 1998; Richardson, 1999; Berlin et al., 1999; Lindh et al., 2001; Siblerud, 1990; Lindqvist et al., 1996; Lichtenberg, 1993; 1997; Halbach, 1998) and protocols are currently being developed to ensure a new level of safety can be achieved (Wahaha, 2003). Adverse reactions from sensitized dental materials include toxicity, inflammation, allergenicity, and mutagenicity (Wataha, 2003). Allergenicity in the oral cavity may occur by nickel, palladium or acrylic, which may result in contact dermatitis (Wataha, 2003). Thirty-eight percent of women demonstrate nickel allergies, whereas up to 3 of men may be affected (Hindsen et al., 1999). Nickel is utilized in adult crowns, pediatric stainless steel crowns, partial denture frameworks, and orthodontic brackets and wires (Wataha, 2003). Metal ions such as mercury (Hg2+) and palladium (Pd2+), components of restorative materials and crowns, both deplete glutathione levels in monocytes at subtoxic concentrations. Hydroxyethylmethacrylate (HEMA), a component of dental bonding systems, has also been demonstrated to reduce TNF-α secretion by monocytes at subtoxic levels (Wataha, 2003). Bonded composites and sealants contain bisphenol-A (BPA), an estrogenic substance, although the physiological impact is unknown (Wataha, 2003). Titanium, a component of implants, can negatively impact the immune system by causing hypersensitivity (Stejskal et al., 1999; Ahlgren et al., 2002; Ahnlinde et al., 2000). Further, titanium has been found to corrode in the body, particularly when exposed to fluoride. (Strietzel et al., 1998; Reclaro et al., 1998) IL-1 and complement were also found to be upregulated by titanium implants. (Perala et al., 1991) Nickel, copper, beryllium, some components of root canal sealers, and dental resins have demonstrated mutagenic potential (Wataha, 2003). The carcinogenicity

400

INTEGRATIVE GASTROENTEROLOGY

of arsenic, hexavalent chromium (Cr6+) and nickel (Ni2+) has been established, whereas antimony and cobalt may be human carcinogens (Hayes, 2005). Clinical biomaterials can corrode to produce systemic and remote site concentrations sufficient to predict that an adverse reaction could occur, particularly with immune responses, metal overload, and accumulation conditions (Black, 1984). Epidemiological studies on a large scale are necessary to assess the systemic effects of biomaterials, whether oral, knee, or hip (Black, 1984). Further, the release of metals in the mouth is of sufficient quantity to elicit an immunological reaction in sensitive individuals (Lindh et al., 2002). The management of a biomaterial-sensitized individual must focus on prevention and monitoring. The mechanism of toxicity, both individual and quantal, must be considered in relation to what these biomaterials can exert on the whole individual in terms of exposure, toxicokinetics, toxicodynamics, and toxic interactions. Treatment, if necessary, must consider the immunological record of the patient. All known allergens and mutagens, regardless of amount, concentration, or bioavailability, should not be implanted or placed in the oral cavity. If a sensitive or allergic material must be placed for lack of a biocompatible equivalent, steps should be taken, if possible, to desensitize the individual. A dental and orthopedic material reactivity screening test is now available to screen individuals for potential sensitization (Clifford Consulting and Research). There are at least 89 known reactive groups in more than 6,000 dental materials, and these can be analyzed to determine IgG or IgM sensitivity (Clifford, 1990). A positive or adverse immunological reaction would preclude the use of any material containing a proven reactant to that patient. Such precautions would prevent the corrosion of dental reactive products and the consequent release of chemical compoundsand haptens, and diminishsystemic and gastroenterological adverse events.

Clinical Nutritional Considerations The oral tissues, by virtue of a high mucosal cellular turnover rate, high salivary production, and high alveolar bone growth rate, are an excellent indicator of nutritional health due to a high nutrient demand, and may be the first visible body tissue to reflect nutritional status (DePaola et al., 1999). The relationship between nutrition and disease is illustrated in Figure 38.1, which exemplifies the multifactorial causative interactions that, if homeostatic mechanisms break down, will give rise to tissue disturbances (Memoli., 2007). It is interesting to note the role of the gastrointestinal system in this algorithm as being the centerpiece of the interactions between nutrients, metabolism, immune system, and exposure.

Systemic Interactions Between Dental and Gastroenterological Diseases 401

Diseases of malabsorption, ranging from maldigestion, to mucosal dysfunction, to luminal dysfunction may, as a result of nutrient deficiency, produce a sign or symptom in the oral cavity. Malabsorption most commonly presents with GI symptoms such as a watery diarrhea to a steatorrhea. Nongastrointestinal symptoms, however, are not uncommon and may produce other malabsorption-related conditions such as (Kelly, 1999): • • • • •

Fatigue, malaise Muscle weakness, tetany, cramps Bone pain, pathologic fractures Poor wound healing Paresthesia, numbness

Further, it is not uncommon for non-gastrointestinal diseases to have an underlying malabsorption syndrome resulting in systemic manifestation (Kelly, 1999): • Rheumatological (Raynaud’s) and arthralgias may suggest inflammatory bowel disease, scleroderma, or Whipple’s disease. • Vascular disease of an extensive nature may indicate mesenteric ischemia. • Endocrinopathies such as hyperthyroidism, hyperparathyroidism, and diabetes mellitus can result in malabsorption. The treating gastroenterologist who suspects malabsorption in a particular patient can survey the oral cavity, where systemic nutrient deficiency may first appear. Likewise, the treating dentist can apprise his or her colleague of any changes in the oral tissues that indicate malabsorption or a change in gastroenterological status. The following list highlights such oral manifestations (adapted from DePaola et al., 1999).

Oral Signs and Symptoms of Nutrient Deficiency MINERALS

Iron: burning tongue, angular cheilosis, dysphagia; non-oral: pale blue sclera, pagophagia (ice eating) Calcium: tooth mobility, osteomalacia, osteoporosis, excessive bone resorption and bone fragility Magnesium: alveolar bone fragility, gingival hypertrophy

402

INTEGRATIVE GASTROENTEROLOGY

Zinc: increased susceptibility to caries during tooth formation, increased susceptibility to infections and candidiasis, loss of taste and smell acuity Copper: decreased alveolar bone trabeculation, decreased tissue vascularity

Vitamins Vitamin A: impaired healing, mucosal desquamation, xerostomia (dry mouth), leukoplakia, gingival inflammation B-Complex: angular cheilosis, leukoplakia, burning tongue Folic Acid: angular cheilosis, stomatitis, mucositis, aphthous-like ulcers, sore or burning mouth Cobalamin: angular cheilosis, sore burning mouth, xerostomia, epithelial dysplasia, paresthesia, delayed wound healing, halitosis, tooth mobility; non-oral: yellow sclera (note: compare to iron deficiency) Vitamin C: susceptibility to infection, blood vessel fragility, increased risk of gingivitis and periodontitis, delayed healing Vitamin D: incomplete tooth and alveolar bone calcification, osteomalacia, osteoporosis Vitamin K: risk of hemorrhage, candidiasis

GI Disturbances Producing Hard Tissue Lesions GASTROESOPHAGEAL REFLUX (GERD)

GERD can be considered a major health concern for two overriding reasons. First, it is a common condition that affects up to an estimated 20 to 25 of the American population. Second, it may predispose one to esophageal cancer, which, over the last 25 years, has outdistanced all other malignancies by a 350 increase in incidence (Glenn, 2001). Regarding the symptomatic population reporting the condition, one-half of those report weekly dysfunction whereas one-quarter suffer daily symptomology. Recent studies (Vial M et al., 2010) have revealed male gender, obesity and GERD (in the form of heartburn) as high risk factors for the development of esophageal adenocarcinoma. Reflux of stomach acids in the oral cavity generally results in erosion of tooth structure. Loss of enamel after tooth formation can occur from dental caries, trauma, attrition, abrasion, amelogenesis imperfecta and dentinogenesis imperfecta, and erosion (Neville et al., 2002). Erosive-type lesions are characterized by a chemical or electrochemical breakdown of tooth structure.

Systemic Interactions Between Dental and Gastroenterological Diseases 403

The treating dentist, with proper history and examination, can rule out all other etiology and further determine whether the lesions are of an exogenous or endogenous nature (Dawson, 2007). Exogenous factors include prolonged oral exposure to many foods or drinks below the critical pH 5.5 necessary to induce tooth demineralization (Grippo et al., 2004). Acidic substances causing erosive-type lesions include chronic use of chewable vitamin C tablets, cola “swishers,” fruit “mullers” and exposure to industrial acids (Abrahamsen, 1992). Further, alcoholics undergoing disulfiram (Antabuse) therapy may suffer erosion as a result. Endogenous factors occur primarily from GERD or bulimia nervosa, and are primarily diagnosed by the treating gastroenterologist. The clinical lesion associated with GERD occurs at the lingual (inside) surface of the posterior molars (Dawson, 2007). Severity is dependent upon the degree of the condition and the oral health care measures taken by the patient. Dentists detecting such lesions should refer the patient to a gastroenterologist, and follow preventive dental management protocols.

GI Conditions Producing Halitosis Halitosis, that is, oral malodor, may affect up to 30 of the population and is most commonly associated with poor oral hygiene in combination with food debris accumulation (Porter & Scully, 2006). Oral microorganisms produce odiferous toxins such as volatile sulfides, diamines, and short-chain fatty acids, which have been determined to cause the disorder. Ten percent of halitosis cases have been determined to be systemic in origin, of which certain gastroenterological disorders may be etiologic (Hughes & McNab, 2008). The differential diagnosis between oral and systemic halitosis is based upon exhalation; a systemic condition is suspected when nasal exhalation produces the same malodor as oral exhalation. Another common etiology is respiratory, in the form of a sinus infection or nasal obstruction; however, this form is usually transient and occurs in the morning upon wakening as morning halitosis. GI disorders that may produce systemic halitosis include (Porter & Scully, 2006): • • • • •

Gastroesophageal reflux Pharyngoesophageal diverticulum Pyloric stenosis Duodenal obstruction Hepatic failure (fetor hepaticus)

Helicobacter pylori infection has also been implicated in subjective changes in oral odor. (Hoshi et al., 2002) A finding of chronic, nontransient halitosis

404

INTEGRATIVE GASTROENTEROLOGY

with no apparent oral etiology would therefore warrant a gastroenterological assessment. GERD-associated halitosis, as with GERD proper, possesses oral lesions and likewise requires interdisciplinary management.

Bulimia Nervosa Eating disorders, such as anorexia nervosa and bulimia nervosa, represent deviations in behavior that can result in esophageal irritation and dental erosion lesions. Bulimia is common in young adult women concerned with body shape and weight. The condition features binge eating followed by self-induced vomiting, the frequency of which determines the severity of the disorder. No symptoms may be present until frequency produces dental erosive lesions and calluses of the knuckles (Huse & Lucas, 1999). The bulimia-associated dental lesion is caused by the acidic purge, which consists of stomach acids in the pH 1 range, well below the critical pH 5.5 levels to induce enamel demineralization. The lesion proper is characterized as erosive on site-specific tooth surfaces; the palatal (inside) surface of the maxillary (upper) anterior teeth and the occlusal (biting) surfaces of the posterior teeth. The symptoms attending the lesions range from an asymptomatic dentition to tooth hypersensitivity, which may involve thermal or contact sensitivity and, in some cases, involve sensitivity to normal mastication. Hypersensitivity may further be indicative of chronicity and serve as a marker for cessation of purging and, hence, for recovery of the disorder. Further, parotid gland enlargement and sensitivity to palpation is another indication, as the parotids become symptomatic between two and six days after vomiting (DePaola et al., 1999). In the case of severe bulimia, an oral lesion characterized as a “complex” lesion may be seen primarily as an erosive lesion from the bulimia, and secondarily as a result of toothbrush attrition. Once erosion penetrates the enamel and exposes the underlying dentin, demineralization now proceeds sevenfold. Many of these patients, being concerned with their appearance, are equally obsessed with their dental cosmetic image and oral hygiene. In an effort to cleanse their mouth of vomitus and its taste, copious amounts of abrasivecontaining toothpastes are employed in aggressive brushing patterns, which together produce an attrition lesion on a previously compromised erosive lesion. The result is severe pathological loss of tooth structure and gum tissue which, in some cases, cannot be corrected with restorative dentistry. I have seen cases where complex lesions have so debilitated the dentition as to require prosthetic rehabilitation with full dentures in young women.

Systemic Interactions Between Dental and Gastroenterological Diseases 405

Dental Systemic Management of GI-Induced Hard Tissue Lesion When hard tissue lesions are present, the role of the dentist becomes one of interdisciplinary intervention with the treating gastroenterologist. The process of dental management for GERD and bulimia follows a prescribed prevention, monitoring, and treatment paradigm. Preventive measures are employed to minimize tooth loss during exposure. Monitoring occurs in the form of dental prophylaxis and communication of the dentist with the treating gastroenterologist. Treatment results when irreversible tooth loss occurs, which must be restored before the general dentition becomes compromised. In regard to GERD, preventive procedures must be tailored to the type of secretions that enter the oral cavity. While acid reflux from gastric acids is the dominant form of heartburn, an alkaline reflux from pancreatic secretions in the duodenum may also occur. Further, patients on antacids, proton-pump inhibitors (e.g., Prilosec) and histamine 2 receptor antagonists (Tagamet) may, in theory, produce a neutral reflux. Therefore, it is important for the treating dentist to measure pH to determine whether the reflux is acidic, alkaline, or neutral, and thereupon determine treatment. If the reflux is acidic in nature and enters the oral cavity, I will recommend an alkaline rinse for one minute. The patient will be instructed to mix one teaspoon of baking soda with four ounces of water and rinse for a full minute. If the reflux continues, the rinse should be repeated every hour. In severe cases, with nocturnal reflux associated with lower esophageal sphincter incompetence, a mouth guard can be employed with a slight alkaline solution to maintain a buffered environment around the teeth, particularly in those cases in which xerostomia (dry mouth) is a secondary factor. For those patients exhibiting an alkaline reflux, I instruct them to squeeze 10 to 20 drops from a fresh organic lemon in a four-ounce glass of water and to rinse for a full minute. Again, if the reflux continues, rinse continuously. Further, if there is a nocturnal component, employ a mouth guard. The monitoring component should first determine whether oral lesions are of a GERD-associated endogenous component or exogenous in nature. For those diagnosed with a history of GERD, monitoring protocols are meant to ensure that preventive measures are stabilizing the oral component. For undiagnosed cases, a history and inquiry into the patient’s dietary habits, and the result of the oral examination of the lesions, should determine the nature of the lesions. For cases of an exogenous nature, preventive behavioral changes

406 INTEGRATIVE GASTROENTEROLOGY

can easily retard the progress of such lesions. Progressive endogenous lesions likewise indicate further treatment measures. The treatment of GERD-associated oral lesions would primarily involve composite bonding to restore lost tooth structure. Monitoring of these restorations on a regular basis is essential to guard against microleakage of the bonding interface and decalcification around the margins. Either of those defects would result in the destruction of more tooth structure and the need to perform more extensive dental restorations. The dental preventive management of bulimia nervosa must also be tailored to the frequency of the reflux and the compliancy of the patient. General oral hygiene measures should include brushing only once per day, particularly in the morning. After a reflux episode, the patient should be instructed to avoid brushing altogether, especially with abrasive toothpastes. A mouth guard should be constructed, preferably for the patient to insert before vomiting. If the patient is not compliant with this procedure, the alkaline rinse previously described should be performed to cleanse the teeth, periodontium, and mucosa of acid residues. After rinsing, an alkaline paste of simply water and baking soda should be placed inside the mouth guard and worn for a minimum of thirty minutes.

PREVENTIVE MEASURES WITH BULIMIA

• Brush only once per day with nonabrasive toothpaste (do not use baking soda or whitening formulations). Note: one may rinse but not brush with baking soda. • Insert mouth guard before vomiting (if possible). • After vomiting, do not brush; instead, rinse or apply alkaline paste (baking soda and water) inside the mouth guard and wear for a minimum of 30 minutes. It is of particular importance to guard against the creation of the aggressive, pathological complex lesion; therefore, a monitoring system at a frequency suitable to prevent tooth destruction must be instituted. During the periodic dental examination, an acid exposure and lesion assessment must accompany the dental prophylaxis. Acid exposure must still be analyzed in terms of exogenous and endogenous exposure. Exogenous acids must be ruled out, and if the patient presents with such lesions she must be counseled to reduce such habits. Severe endogenous exposure must be communicated to the treating gastroenterologist in order for an interdisciplinary approach to treat recurrences. Lesion analysis should include charting,

Systemic Interactions Between Dental and Gastroenterological Diseases 407

measurement, and symptomology, in order to further determine frequency and recurrences. The treatment of the complex lesion must consider potential dental implications, such as the loss of lower facial skeletal height and pathological tooth destruction. A bonded hybrid composite restoration is primarily utilized to treat the early erosive lesions. Again, these restorations must be monitored for caries, microleakage, and decalcification. If the patient is noncompliant with preventative and monitoring measures, there is an increased risk of developing severe complex lesions. In general, as the teeth erode, there is a compensatory eruption of tooth and bone in order to maintain facial height. However, if the erosive lesions occur more rapidly than biological compensation, lower face height may be lost, resulting in cosmetic disfigurement. Prosthetic efforts such as restoring posterior teeth and maintaining proper anterior guidance can prevent edge-to-edge attrition, which can further result in accelerated tooth destruction. If such efforts cannot be performed, prosthetic rehabilitation in the form of implant-retained dentures may be necessary to reestablish function, comfort, and esthetics. (Neville et al., 2002). With the knowledge of the possibility of a bulimic or anorexic patient developing a pathological complex erosive lesion that could potentially destroy a patient’s dentition, it behooves both gastroenterologist and dentist to coordinate a preventive interdisciplinary treatment plan.

39 Upper Gastrointestinal Disorders: Dyspepsia, Heartburn, Peptic Ulcer Disease, and Helicobacter pylori ANIL MINOCHA

key concepts ■

■

■

■

■

Most complementary therapies are based on clinical-symptom complexes. There is a paucity of studies employing precise, modern day diagnostic criteria. Therapies based on Chinese medicine (e.g., multi-herbal formulation Iberogast also known as STW 5 and acupuncture) are effective in functional dyspepsia. The addition of probiotics to standard antibiotic treatment increases Helicobacter pylori eradication while reducing the therapy-associated side effects. On the other hand, vitamin C and E supplements may reduce the efficacy of H. pylori eradication therapy. Use of psychological interventions can improve outcome in functional GI disorders. Lifestyle modifications like cessation of smoking and drinking may help ameliorate dyspeptic symptoms. The role of diet in management of upper gastrointestinal disorders is patientspecific. ■

408

Introduction

U

pper gastrointestinal illness, whether induced by ulcers, gastritis, dysmotility, or H. pylori, is a common problem that affects hundreds of millions of people worldwide. However, patients are more interested in relief and less interested in what may be causing the problem. Whether the diagnosis is ulcer or gastritis based on modern medicine, or a disharmony of the body systems of Vata, Pita, or Kapha as in Ayurveda, the patient’s goal remains the same. Many patients just use over-the-counter medications, but complementary and alternative treatments are gaining in popularity. A smaller number of people actually see a doctor.

Historical Perspective Until the late eighteenth and early nineteenth centuries, most symptoms of possible gastroesophageal reflux disease (GERD) and peptic ulcer disease (PUD) were lumped into the category of dyspepsia or indigestion. Treatments varied depending upon the culture or civilization. Some of these treatments have stood the test of time and are still preferred over modern medicine by millions of people. The ancient descriptions of the use of powdered coral, chalk, and seashells for relief of dyspepsia provide clues to the occurrence of this problem long before the modern descriptions of GERD and PUD. Hunter in 1784 advocated the use of milk as a natural antacid. Illogical approaches, such as the use of antimony, arsenic, and mercury, as well as application of leeches to the abdomen, were in vogue in the eighteenth century. In 1876, Leube advocated the use of bowel rest on top of implausible interventions like alcohol and glucose rectal enemas. Other treatments used in the past include synthetic resins, cabbage, pectin, pituitary extract, insulin, and histamine. Surgeons like Billroth made the first advance in modern treatment by performing surgery for PUD in the 1880s. H. pylori was rediscovered by Warren and Marshall in the 1980s, which earned them the Nobel prize.

CAM Treatments Most diagnoses made by practitioners of complementary and alternative medicine (CAM) are based on symptoms and follow the holistic treatment pattern.

410

INTEGRATIVE GASTROENTEROLOGY

The diagnosis is mostly clinical, and centers on dyspepsia or some equivalent. Similar patients may receive different treatment plans, however, based on variety of other factors (e.g., based on body constitution in Ayurveda). In this chapter, we will review the human data wherever available; in addition, we will discuss the laboratory investigations supporting or refuting the biological plausibility of treatment effect. Since there is overlap in herbal therapies, we will review them as one category regardless of the system of medicine from which they are derived. The depth and breadth of discussion of any particular therapy in this chapter are related more to the extent of peer-reviewed literature on the subject than to the popularity of the treatment.

Herbal Therapies An herbal medicinal product is defined as any medicinal product containing as active ingredients only plants, parts of plants or plant materials, or combinations thereof, whether in the crude or processed state. Herbal therapies may be administered individually or as combinations of herbs.

PEPPERMINT OIL (MENTHA PIPERITA L)

Peppermint oil has been used for dyspepsia and spasms/colic in various cultures for centuries. It may be used singly or in combination with other herbs. The clinical efficacy of the combinations (except for caraway) will be discussed in the subsection about herbal combinations.

The Science Behind It In addition to relaxing pylorus, peppermint oil enhances the early phase of gastric emptying (Inamori et al., 2007), thus affecting gastroduodenal motility. Others have shown that the effect of peppermint oil and caraway on gastric emptying is similar to that of the drug, cisapride; however, there were no differences as compared to placebo (Goerg & Spilker, 2003). Caraway (Carum carvi) is frequently added to peppermint, and is also known to cause inhibition of smooth muscle relaxation. Peppermint oil and caraway act locally in the stomach and duodenum to produce smooth-muscle relaxation (Micklefield, Jung, Greving, & May, 2003). The principal effect of intraluminal peppermint oil on the gastrointestinal tract (Bell, 2004) is a dose-related antispasmodic action on the smooth musculature

Upper Gastrointestinal Disorders 411

due to the interference of menthol with the movement of calcium across the cell membrane (Grigoleit, 2005). A randomized, double-blind, double-dummy, controlled trial showed that peppermint oil reduces gastric spasm during upper endoscopy (Hiki Kurosaka, & Tatsutomi, 2003). An instillation of 20 ml of 1.6% peppermint oil solution in the duodenum during ERCP results in duodenal relaxation (Yamamoto et al., 2006). Peppermint has choleretic and antifoaming effects and attenuates postinflammatory visceral hyperalgesia in rats (Adam et al., 2006). Peppermint inhibits the in vitro proliferation of various bacteria, including H. pylori, in a dose-dependent manner (Imai et al., 2001). Interestingly, these antibacterial activities were almost the same against antibiotic-resistant and antibiotic-sensitive strains of H. pylori. Peppermint aromatherapy has major effects on decreasing pain and depression levels, suggesting another possible mechanism for peppermint in dyspepsia i.e., analgesia (Kim, Nam & Paik 2005) Peppermint oil inhibits daytime sleepiness, and this invigorating effect may favorably affect psychological disturbances associated with various upper gastrointestinal disorders (Norrish & Dwyer, 2005).

Clinical Data Peppermint oil improves abdominal symptoms in patients with abdominal pain and irritable bowel syndrome. May and colleagues conducted studies of the efficacy and tolerability of a combination of peppermint oil and caraway oil versus placebo in patients with functional dyspepsia. They found the active treatment was superior with respect to pain intensity, sensation of pressure and heaviness plus fullness, as well as the investigators’ rating of global improvement (May, Köhler, & Schneider, 2000; May, Kuntz, Kieser, & Köhler, 1996). A multicenter, reference-controlled, double-blind equivalence study using a peppermint/caraway oil preparation or cisapride found them to be equivalent for treatment of functional dyspepsia (Madisch et al., 1999). The efficacy of peppermint oil and caraway oil in patients with functional dyspepsia is unaffected by H. pylori (May, Funk, & Schneider, 2003). The beneficial effects of a peppermint/caraway oil combination in functional dyspepsia are similar whether the drug is taken in an enteric-coated capsule or as an enteric soluble formula (Freise & Kohler, 1999). Patients with GERD have long been warned to avoid peppermint oil. However, this recommendation appears to be based predominantly on theoretical grounds and lacks good scientific data to support it. This recommendation also flies in the face of centuries-old use of peppermint after meals, with

412 INTEGRATIVE GASTROENTEROLOGY

perceived beneficial effects against indigestion. The administration of peppermint oil eliminates chest pain, as well as simultaneous esophageal contractions, in patients with diffuse esophageal spasm (Pimentel et al., 2001). Aromatherapy effectively reduces the perceived severity of postoperative nausea. However, aromatherapy with peppermint is no better than saline placebo in relieving postoperative nausea, suggesting that beneficial effects may be related more to controlled breathing patterns than to the actual aroma inhaled (Anderson & Gross, 2004). Side effects of peppermint oil include allergic contact dermatitis.

LICORICE

Licorice is widely used in the medicinal and the confectionery sectors. However, the ingestion of licorice, and/or its active metabolites, can lead to an acquired form of apparent mineralocorticoid excess syndrome manifested by sodium retention, potassium loss and suppression of the renin-angiotensinaldosterone system, leading to increased blood pressure and edema. Compared to licorice, deglycyrrhizinated licorice (DGL) does not significantly affect blood pressure and salt retention, and some practitioners have advocated its use.

The Science Behind It Numerous studies have documented the gastroprotective effects of licorice. Cimetidine and DGL combined provide greater protection than either drug alone against aspirin-induced gastric mucosal damage in rats (Bennet et al., 1980). Most studies that show beneficial effects have used licorice as part of an herbal combination product.

Clinical Trials Clinical trials using DGL in peptic ulcer disease have yielded conflicting results. Turpie et al. (1969) conducted a randomized, placebo-controlled clinical trial of DGL in gastric ulcers. They found a reduction in ulcer size in patients on DGL versus the placebo (78% vs. 34%). In addition, the ulcer completely resolved in 44% of patients in the treatment group, compared to 6% in the placebo group. Other researchers have reported similar results (Doll & Hill, 1962; Doll, Hill, & Hutton, 1965; Engqvist, von Feilitzen, Pyk, & Reichard, 1973). Some studies,

Upper Gastrointestinal Disorders 413

however, have failed to confirm these gastroprotective findings (Bardhan, Cumberland, Dixon, & Holdsworth, 1978; Feldman & Gilat, 1971). DGL does not appear to have prophylactic effects against recurrence of healed gastric ulcer (Hollanders et al., 1978).

TURMERIC (CURCUMA)

The Science Behind It Turmeric increases bile formation and secretion and promotes gallbladder contraction in addition to having antispasmodic activity. It protects against gastric ulcers by blocking H2 type histamine receptors (Kim, 2005).It also increases the gastric wall mucus and restores the nonprotein sulfhydryl content in glandular stomachs (Rafatullah, Tariq, & Al-Yahya, 1990). Phenolic fractions of Curcuma amada are potent inhibitors of proton potassium ATPase activity, as well as H. pylori growth (Siddaraju & Dharmesh, 2007).

Clinical Trials One study found that turmeric (Curcuma longa Linn 600 mg x 5/d x 4 weeks) resulted in healing of 48% of cases of peptic ulcer. Seventy-six percent of patients did not have ulcers at the end of 12 weeks (Prucksunand et al., 2001). A controlled clinical trial found liquid antacid and Curcuma longa Linn to be equivalent in the treatment of gastric ulcers (Kositchaiwat, Kositchaiwat, & Havanondha, 1993). Another randomized, placebo-controlled study comparing curcuma with an herbal formulation is described in the section on herbal combinations (Thamlikitkul et al., 1989).

CHILI POWDER

The Science Behind It A chili-rich diet decreases capsaicin-stimulated gastrin secretion from human antral glands (Ericson, Nur, Petersson, & Kechagias, 2008). Intragastric perfusion of aqueous spice extracts of red pepper increases acid secretion in anesthetized albino rats (Vasudevan, Vembar, Veeraraghavan, & Haranath, 2000). Both black and red pepper may induce epigastric pain by removing the

414 INTEGRATIVE GASTROENTEROLOGY

stomach’s hydrophobic lining and activating intramucosal pain receptors (Lichtenberger et al., 1998).

Human Studies Capsaicin administered as 20g of chili orally protects against aspirin-induced gastroduodenal injury in healthy human subjects (Yeoh et al., 1995). Endoscopy showed that the median gastric injury score after chili was 1.5 compared to 4 in the control group (P < 0.05). On the other hand, capsaicin enhances noxious postprandial heartburn, presumably by direct effects on sensory neurons (Rodriguez-Stanley et al., 2000).

While chili pepper may cause symptoms in susceptible subjects in the short term, over the long term it relieves functional dyspepsia by capsaicininduced desensitization of the selective nociceptive C fibers.

Epidemiologic surveys in Singapore have shown that gastric ulcers are three times more common in people of Chinese descent than in those of Malaysian and Indian descent, who tend to consume more chili peppers (Satyanarayana, 2006). Among Chinese patients, the median amount of chili use per month was much lower in those with ulcers than in the controls (Kang et al., 1995). Bortolotti et al. (2000) examined the effect of red pepper (2.5g/d) on the treatment of functional dyspepsia (n=30) in a double-blind, placebo-controlled trial. The overall symptom score, as well as the epigastric pain, fullness, and nausea scores, improved significantly in the red pepper group compared to the placebo.

AMALAKI

Amalaki is an Ayurvedic herbal remedy derived from pericarp of the dried fruit of Emblica officinalis. Chawla et al. (1982) compared the treatment of dyspepsia using Amalaki or gel antacids for 4 weeks. Patients (n=38) included those with peptic ulcer (n=10) and non-ulcer dyspepsia (n=28). Compared to the baseline, symptoms improved in both treatment groups. Side effects during Amalaki treatment included diarrhea and vomiting in some patients.

Upper Gastrointestinal Disorders 415

BANANA POWDER (PLANTAIN BANANA)

The Science Behind It The natural flavonoid present in unripe plantain banana pulp protects the gastric mucosa from aspirin-induced erosions (Lewis, Fields, & Shaw, 1999). Plantain banana powder strengthens mucosal resistance and promotes the healing of ulcers via its action on gastric mucosal shedding (Mukhopadhyaya et al., 1987).

Clinical Studies Treatment with banana powder (8 capsules per day for 8 weeks) results in marked improvement (partial or complete relief) of patients with non-ulcer dyspepsia compared to controls (Arora & Sharma, 1990).

MASTIC

Mastic is a concrete resinous exudate obtained from the stem of the tree Pistacia lentiscus.

The Science Behind It It reduces the intensity of experimentally induced gastric mucosal damage associated with decrease of free acidity (Al-Said, Ageel, Parmar, & Tariq, 1986). Mastic gum kills H. pylori (Huwez, Thirlwell, & Cockayne, 1998), although the effect is modest (Al-Said et al., 1986). Monotherapy with mastic does not eradicate H. pylori infection in mice (Loughlin, Ala’Aldeen, & Jenks, 2003).

Clinical Studies A double-blind, placebo-controlled trial of mastic (1g/d for two weeks) for the treatment of duodenal ulcer demonstrated endoscopically proven healing in 70% patients on mastic compared to 22% patients on placebo (Al-Habbal, Al-Habbal, & Huwez, 1984).

416

INTEGRATIVE GASTROENTEROLOGY

BRAHMI

Fresh juice from the whole plant of Bocapa monniera Wettst, commonly known as Brahmi, is used in Ayurveda for dyspepsia. Brahmi promotes mucosal defenses via enhanced mucin secretion and mucosal glycoprotein, and decreased cell shedding in experimental models of ulcer (Rao, Sairam, & Goel, 2000).

ASPARAGUS RACEMOSUS (SHATAVARI)

Asparagus racemosus (Shatavari) is used in Ayurveda for dyspepsia and as a galactogogue. It reduces gastric emptying time in normal healthy volunteers. Asparagus racemosus has an inhibitory effect on the release of gastric hydrochloric acid, and its protection against indomethacin-induced gastric mucosal damage in animals is comparable to that of ranitidine (Bhatnagar, Sisodia, & Bhatnagar, 2005).

ASHWAGANDHA (WITHANIA SOMNIFERA DUNAL)

W. somnifera shows potent inhibitory activity towards the complement system, mitogen induced lymphocyte proliferation, and delayed-type hypersensitivity reaction. This Ayurvedic remedy, also known as ashwagandha, is effective in the treatment of stress-induced ulceration in animals and its efficacy is comparable to that of ranitidine (Bhatnagar et al., 2005).

GREATER CELANDINE (CHELIDONIUM MAJUS)

Greater celandine or tetterwort is derived from the celandine plant, which is a member of the poppy family. Its roots, herb, and juice are used for medicinal purposes. It is reputed to have calming effects and is widely used for intestinal spasms.

The Science Behind It Celandine contains about 20 biologically active alkaloids, which have antispasmolytic action on smooth muscles and also stimulate bile flow.

Upper Gastrointestinal Disorders 417

Clinical Studies Ritter and colleagues studied the effect of a standardized celandine extract in a placebo-controlled, double-blind trial of 60 patients with functional dyspepsia over a 6-week period (Ritter et al., 1993). Patients in the treatment group reported fewer gastrointestinal symptoms compared to those on placebo (27% vs. 60%).

ARTICHOKE LEAF EXTRACT

Holtmann et al. (2003) studied the efficacy of artichoke leaf extract (2 x 320 mg plant extract 3 times a day for 6 weeks) in the treatment of patients with functional dyspepsia in a double-blind, randomized placebo-controlled trial. The artichoke leaf extract demonstrated superior efficacy in alleviating symptoms and improved the disease-specific quality of life in patients with functional dyspepsia.

GINGER ROOT

Ginger root has been studied for postoperative nausea and morning sickness, as well as chemotherapy-induced nausea. The results are promising (Ernst & Pittler, 2000).

The Science Behind It Ginger accelerates gastric emptying and stimulates antral contractions in healthy volunteers (Wu et al., 2008). These effects could potentially be beneficial in symptomatic patient groups.

TERMINALIA

Terminalia arjuna is a deciduous tree, the bark of which is used in herbal medicine. Terminalia is widely used in Ayurveda to regulate blood pressure and promote cardiovascular health. It suppresses the release of nitric oxide and superoxide from macrophages, and also inhibits aggregation of platelets. Terminalia has antioxidant actions and may reduce oxidative stress and inhibit anaerobic metabolism. It ameliorates severe cellular damage and pathological

418

INTEGRATIVE GASTROENTEROLOGY

changes caused by H. pylori lipopolysaccharide (Devi, Kist, Vani, & Devi, 2008). Terminalia arjuna has protective effects on diclofenac sodium-induced gastric ulcer in experimental rats. Terminalia chebula is commonly advocated in Ayurveda to improve gastrointestinal motility. It has been shown to reduce gastric emptying time in rats (Tamhane, Thorat, Rege, & Dahanukar, 1997).

TANGWEIKANG

Tangweikang is a Chinese herbal preparation used in diabetes. It improves glucose and lipid metabolism and regulates microcirculation. It hastens gastric emptying in diabetic gastroparesis (Jiang, Zhang, & Bai, 2007).

Herbal Combinations Both functional and organic disorders have multiple underlying pathogenic mechanisms. The use of herbal combinations has the potential to affect a disease process at multiple levels in its pathogenesis.

STW 5

STW 5 is a fixed combination of nine herbs: bitter candytuft plant (aka clown’s mustard), German chamomile flower, peppermint leaves, caraway fruit, licorice, lemon balm leaves, celandine, angelica root and rhizome, and milk thistle.

The Science Behind It STW 5 modulates the amplitude and frequency of slow waves in circular smooth muscle of the mouse small intestine (Storr et al., 2004). It also lowers gastric acidity and inhibits secondary hyperacidity (Khayyal et al., 2006). In addition, STW 5 lowers serum gastrin levels in rats, an effect that runs parallel to its ability to lower gastric acid production (Khayyal et al., 2006). STW 5-induced stimulation of gastric relaxation and antral motility may contribute to its effects on functional dyspepsia (Pilichiewicz et al., 2007).

Upper Gastrointestinal Disorders 419

Clinical Studies of STW 5 Multiple studies have documented the efficacy of STW 5 and STW 5-II in the treatment of functional dyspepsia (Madisch et al., 2004). A multicenter, double-blind, placebo-controlled study on the effects of STW 5 in 315 patients with functional dyspepsia for 8 weeks reported a significant improvement in the Gastrointestinal Symptom Score of patients taking STW 5 compared to placebo, irrespective of H. pylori status (von Arnim, Peitz, Vinson, Gundermann, & Malfertheiner, 2007). A double-blind, double-dummy study demonstrated that the effects of STW 5 and STW 5-II administered for 4 weeks are equivalent to those of cisapride for the treatment of patients with functional dyspepsia of dysmotility type (Rösch et al., 2002). A retrolective multicenter epidemiological cohort study with parallel groups found STW 5 to be superior to metoclopramide in patients with functional dyspepsia (Raedsch et al., 2007). Significantly more patients were symptomfree after STW 5 treatment (71.6% vs. 62.8% p = 0.012). The median duration of inability to work (1 vs. 3 days) was significantly different in favor of STW 5, and more physicians assessed STW 5 as effective (71.6% vs. 63.1% p<0.01) and very well tolerated (90% vs. 70.6% p<0.001). Meta-analysis of double-blind, randomized, clinical trials on the efficacy of STW 5 in patients with functional dyspepsia has demonstrated a clear, highly significant overall therapeutic effect (Gundermann, Godehardt, & Ulbrich, 2003; Melzer et al., 2004). Tolerability of the drug was excellent (Gundermann et al., 2003). A recent review came to similar conclusions (Rösch et al., 2006). Adverse events are rare and, with respect to frequency and spectrum, essentially similar to those found with placebo.

Based on efficacy and safety, STW 5 is a valid therapeutic option for patients seeking phytotherapy for symptoms of functional dyspepsia.

LIU-JUN-TANG

Liu-Jun-Zi-Tang, also known as Rikkunshi-to and TJ-43, is a Chinese herbal medicine that contains spray-dried aqueous extracts of Atractylodis laneae

420

INTEGRATIVE GASTROENTEROLOGY

rhizoma, Ginseng radix, Pinelliae tuber, Hoelen, Zizyphi fructus, Aurantii nobilis pericarpium, Glycyrrhizae radix and Zingiberis rhizoma. It increases gastric emptying and plasma somatostatin and gastrin levels, and promotes gastric adaptive relaxation. It prevents intracellular signaling disorders in gastric smooth muscle of diabetic rats (Sakai et al., 2004). Compared to placebo, TJ-43 (2.5g three times a day) improves gastric emptying as well as gastrointestinal symptoms of epigastric fullness, heartburn, belching, and nausea (Tatsuta & Iishi, 1993). Liu-Jun-Zi-Tang can rarely cause interstitial pneumonia (Maruyama et al., 1994).

SHENXIAHEWINING

Shenxiahewining is a Chinese herbal medicine that contains Ginseng radix, Pinelliae tuber, Coptidis rhizoma, Zingiberis rhizoma exsiccatum and Glycyrrhizae radix. Chen (1994) studied 100 subjects with non-ulcer dyspepsia. Patients received either Shenxiahewining (15 capsules/d; 0.42g/capsule) or a control drug in similar capsules for 20 days. Improvement was seen in 92% of the treatment group compared to only 20% in the control group.

GOREI-SAN (TJ-17)

Gorei-san (TJ-17) is a Japanese herbal medicine composed of five herbs (Alismatis rhizoma, Atractylodis lanceae rhizoma, Polyporus, Hoelen, and Cinnamomi cortex). It is used for treatment of nausea, dry mouth, headache, and dizziness. Yamada et al. (2003) examined the efficacy of TJ-17 for treatment of SSRI-induced nausea or dyspepsia. TJ-17 was added to the previous regimen in 20 such patients. Symptoms disappeared completely in 9 patients and were decreased in 4 patients. No adverse events related to TJ-17 were reported.

HANGE-KOBOKU-TO (BANXIA-HOUPO-TANG, HKT)

Hange-koboku-to accelerates gastric emptying in patients with dyspepsia, as well as in healthy controls (Table 39.1). This improvement in gastric emptying is accompanied by improvement in dyspeptic symptoms in patients with functional dyspepsia (Oikawa et al., 2005).

Upper Gastrointestinal Disorders 421

Table 39.1 Treatments to Enhance Gastric Emptying Asparagus racemosus (Shatavari) Ginger Tangweikang Liu-Jun-Tang (TJ-43) Hange-koboku-to Terminalia chebula Peppermint oil Probiotics Acupuncture Hypnosis Music therapy

PEPPERMINT PLUS GINGER

A randomized, double-blind, placebo-controlled trial of peppermint oil plus ginger extract (180 mg/day and 25 mg/day x 4 weeks) in patients with functional dyspepsia found that the drug improved symptoms in 74% of the patients compared to only 30% in the placebo group (Stadelmann et al., 1999).

The therapeutic efficacy of herbal combinations challenges the current trend of highly targeted drug molecules that usually focus on one single target or mechanism for disorders with redundancies in the pathogenic pathways, wherein no single receptor group may play a critical role for the control of symptoms.

Miscellaneous Herbal Combinations Borgia et al. (1985) conducted a double-blind, double-controlled multicenter trial on the therapeutic activity of a combination of medicinal herbs, including boldo (Peumus boldus), cascara (Rhamnus purshianus), gentian (Gentiana lutea), and rhubarb (Rheum sp.). This combination produced significant improvements in appetite, dyspepsia, and constipation. Mechanisms include

422

INTEGRATIVE GASTROENTEROLOGY

boldine-induced smooth muscle relaxation and gallbladder contraction, increasing bile secretion, as well as gentian-induced stimulation of salivary and gastric secretions. Pepticare® is an Ayurvedic herbomineral formulation that includes Glycyrrhiza glabra, Emblica officinalis and Tinospora cordifolia. In an experimental rat model, it results in reduction in gastric ulcer index along with the reduction in total gastric acid and an increase in the pH of gastric fluid (Bafna & Balaraman, 2005). Rats treated with a mixture of an Ayurvedic medicine mixture of Glycyrrhiza glabra, Terminalia chebula, Piper longum and Shanka Bhasma recover faster with concomitant increase in beta-glucuronidase activity in the Brunner’s glands (Nadar & Pillai, 1989).This suggests that this Ayurvedic formulation does not act as an antacid, but rather by improving the secretory status of Brunner’s glands involved in protection against duodenal ulcer. Thamlikitkul et al. (1989) conducted randomized, double-blind, placebocontrolled study of Curcuma domestica Val for dyspepsia in a multicenter study (n=116). Patients received turmeric (2 g/day), placebo or a combination treatment known as Flatulence®, which includes cascara dry extract, nux vomica extract, asofoetida tincture, capsicum powder, ginger powder, and diastase. Eighty-three percent of people in the Flatulence® formula group and 87% of patients receiving Curcuma responded to the treatment, compared to only 53% in the placebo group (p<0.05). Niederau and Gopfert (1999) studied the effect of chelidonium and turmeric root extract on upper abdominal pain due to functional disorders of the biliary system in a placebo-controlled double-blind trial. The reduction of dumpy and colicky pain was faster in the treatment group, suggesting that the beneficial effect on pain may be due to its actions on biliary dyskinesia.

Acupuncture and Other Electromagnetic Treatments Electroacupuncture (EA) has been used to treat gastrointestinal diseases (Diehl, 1999). Evidence suggests that in addition to dyspepsia, acupuncture may help prevent postoperative nausea, and treat postoperative nausea and vomiting of pregnancy (Linde et al., 2001).

THE SCIENCE BEHIND IT

EA has variable effects on gastrointestinal physiology depending upon the site of application. EA at ST-36 increases gastric contractions in rats, and the effect

Upper Gastrointestinal Disorders 423

is mediated via the vagal pathway (Tatewaki et al., 2003). It also stimulates the parasympathetic pathway and accelerates colonic transit in rats (Iwa et al., 2006). EA at acupoints of the Foot-Yangming meridian causes enhanced gastric motility, improves gastric mucosal blood flow, and regulates the motilin and somatostatin levels in sinus ventriculi and bulbus in an experimental rat model, suggesting that the effects of acupuncture may be related to the content of brain–gut peptides (Lin, 2007). EA in dogs at both ST-36 and PC-6 accelerates gastric emptying of liquids (Ouyang, Yin, Wang, Pasricha & Chen, 2002). EA at ST-36 improves gastric emptying in gastroparesis, and restores vagotomy-induced impaired gastric accommodation in dogs (Ouyang, Xing & Chen, 2004; Ouyang et al., 2002). It also increases the percentage of normal gastric slow waves in healthy volunteers (Lin et al., 1997). EA at PC-6 reduces the dominant power of the gastric slow waves in humans, while EA at ST-36 increases it, suggesting that EA at different acupoints may have opposing effects on motility (Shiotani et al., 2004). Although acupuncture reduces both the mean basal acid output, as well as maximal acid output in duodenal ulcer patients (Sodipo & Falaiye, 1979), its beneficial effects in dyspepsia appear to be mediated via modification of gastroduodenal motility patterns. The analgesic effect of acupuncture appears to be mediated via the opioid pathway (Diehl, 1999).

CLINICAL STUDIES

EA not only improves gastric emptying in subjects with gastroparesis but also improves symptoms of functional dyspepsia in patients with normal, as well as delayed, gastric emptying (Xu et al., 2006). A randomized, controlled study of acupuncture and cisapride on gastric motility in 90 patients with functional dyspepsia demonstrated a significant symptomatic improvement in both groups, accompanied by an improvement in gastric emptying as well as plasma motilin levels (Chen, Pan, & Xu, 2005). A multicenter randomized, controlled trial of acupuncture at Zhongwan (CV 12) in 276 patients with peptic ulcer found that acupuncture group experienced alleviated stomachache and improved appetite faster than the control group, although the total effective rate was similar in the two groups (Niu et al., 2007).

Acupuncture administered by an expert may be a reasonable option for patients with functional dyspepsia refractory to standard management.

424

INTEGRATIVE GASTROENTEROLOGY

Various kinds of electromagnetic therapies have also been studied. However, the data is sparse at best. Acupuncture with a low-frequency alternating magnetic field has a positive effect on “emotional and personality spheres, as well as vegetative regulation” accompanied by faster relief of the basic symptoms and healing of the ulcer (Kravtsovo, Tiu, Golovanova, & Rybolov, 2000). A comparison of therapeutic effects of low-frequency pulse plus auricular point magnetic therapy and Propulsid in 50 patients with functional dyspepsia documented 93% efficacy in the treatment group compared to 75% in the controls (Wang et al., 2007). A controlled study found that the addition of transcutaneous and reflex magnetolaser impact to anti-H. pylori treatment shortens time to ulcer healing and promotes eradication of H. pylori in patients with duodenal ulcer exacerbation (Minakov, Romanova, & Khimina, 1999). EHF-puncture results in significantly better healing of gastric and duodenal ulcers compared to standard medical treatment (Razumov & Voznesenskaia, 1999).

COMPLICATIONS OF ACUPUNCTURE

Complications of acupuncture are rare but can be serious. Significant complications include bleeding, viral hepatitis, HIV, bacterial infections including endoscarditis, pneumothorax, cardiac tamponande, and spinal cord injuries (Ernst & White BMJ. 2000 Feb 19;320(7233):513-4., 2000). Acute pancreatitis may occur (Uhm, 2005). Acupuncture may also affect the functioning of demand pacemakers.

Probiotics Limited evidence exists regarding the role of probiotics in upper digestive disorders, including their effect on H. pylori.

THE SCIENCE BEHIND IT

Infections exert their effect through critically altering T-helper (Th1/Th2) regulation, which is supported by the examination of the cytokine profiles. Treatment with probiotics helps produce a balanced T-helper cell response and prevent imbalances (Th1>Th2 or Th2>Th1) that in part contribute to clinical disease (Th2 imbalance contributes to atopic disease, while Th1 predominance is found in conditions such as H. pylori gastritis and Crohn’s disease).

Upper Gastrointestinal Disorders 425

IL-8 is involved in Hp-induced gastric inflammation, and live Lactobacillus gasseri (LG21) suppresses H. pylori and reduces H. pylori-induced inflammation (Sakamoto et al., 2001), as well as H. pylori-induced IL-8 production within gastric mucosa (Tamura et al., 2006). LG21 inhibits HCl-induced gastric lesions in a dose-dependent manner and is associated with prostaglandin E2 generation (Uchida & Kurakazu, 2004). Fungal colonization of gastric ulcers delays ulcer healing of mucosa in rats, and this effect can be attenuated by probiotic therapy (Zwolińska-Wcisło et al., 2006). LG21 can enter into the gastric mucus layer, which may in part explain its mechanism of action (Fujimura et al., 2006).

CLINICAL STUDIES

The gastric emptying rate is significantly faster in the newborns receiving L. reuteri compared with formula with placebo, and the L. reuteri supplemented babies have a motility pattern resembling that of newborns fed with breast milk (Indrio et al., 2008). Studies on the use of probiotics for dyspepsia have largely yielded mixed results. An open label trial found that Lactobacillus acidophilus improves symptoms of bloating, abdominal pain and pressure and flatulence in patients with dysbioisis/maldigestion (Kocián, 1994). LGG may be beneficial for bloating by altering the intestinal gut flora and thus the production of intestinal gas (Di Stefano, Miceli, Armellini, Missanelli, & Corazza, 2004). In contrast, Kim and colleagues failed to demonstrate any beneficial effect of commonly used probiotics on GI symptoms in patients with functional gastrointestinal disorders (Kim et al., 2006). A double-blind, randomized controlled trial of Lactobacillus rhamnosus GG for functional abdominal pain in children found that it improves symptoms in subjects with irritable bowel syndrome, but not in those with functional dyspepsia (Gawrońska, Dziechciarz, Horvath, & Szajewska, 2007). AB-yogurt (made by the President Enterprise Corporation, Tainan, Taiwan) is fermented milk that contains sugar, high-fructose corn syrup, pectin, galactooligosaccharide, and an approximately equal mixture of L. acidophilus La5, B. lactis Bb12, L. bulgaricus, and S. thermophilus at a concentration of at least 107 bacteria/ml. Regular intake of AB-yogurt significantly decreases the urease activity of H. pylori after 6 weeks of therapy in asymptomatic H. pylori-positive subjects (Wang et al., 2004). A recent epidemiologic study documented a protective effect of yogurt consumption on prevalence of H. pylori (Ornelas, Galvan-Potrillo, & López-Carrillo, 2007).

426

INTEGRATIVE GASTROENTEROLOGY

Adding Lactobacillus- and Bifidobacterium-containing yogurt to triple therapy for H. pylori eradication results in greater eradication (91% vs. 78%) than the triple-only group (Sheu, 2002). Similarly, pretreatment with Lactobacillus- and Bifidobacterium-containing yogurt to quadruple therapy for eradicating H. pylori infection after failed triple-therapy regimen results in a higher eradication rate than the quadruple-therapy-only group (85% versus 71%; see Sheu et al., 2006). Regular intake of cranberry juice or probiotic Lactobacillus johnsonii La1 may be useful in the management of asymptomatic children colonized by H. pylori, although there are no synergistic inhibitory effects of consumption of both on H. pylori colonization (Gotteland et al., 2008). Other studies using different probiotic strains have yielded negative results (Cindoruk Erkan, Karakan, Dursun, & Unal, 2007; Goldman et al., 2006). Multiple studies have documented that probiotic therapy reduces the side effects induced by anti-H. pylori therapy (Cremonini et al., 2002; Nista, Candelli, Cremonini, & Cazzato, 2004; Armuzzi et al., 2001). A recent review of literature regarding H. pylori and probiotics (LesbrosPantoflickova, Corthésy-Theulaz, & Blum, 2007) concluded that probiotics are inhibitory and are effective in reducing H. pylori-associated gastric inflammation. The addition of probiotics to standard antibiotic treatment increases H. pylori eradication while reducing the therapy-associated side effects. Long-term intake of probiotics may have a favorable effect on H. pylori infection in humans, thus reducing the risk of gastritis and, potentially, functional dyspepsia, peptic ulcer disease, and gastric malignancy.

Psychological Therapies THE RATIONALE BEHIND IT

War and stress are risk factors for peptic ulcer disease (Levenstein, 1999). PUD is common during wars and among war survivors (Jhun, Ju, Kim, & Kim, 2005). Psychological factors are involved in both noncardiac chest pain and functional dyspepsia. These data suggest a potential target for psychological interventions in treatment of functional as well as organic gastrointestinal disorders.

ESOPHAGEAL DISORDERS

Relaxation exercises ameliorate gastroesophageal reflux symptoms by reducing esophageal acid exposure (McDonald-Haile et al., 1994). Anecdotal reports

Upper Gastrointestinal Disorders 427

support the use of psychological therapies for esophageal dysmotility. Successful treatment of refractory diffuse esophageal spasm by biofeedback and selfregulation, resulting in weight gain and reduction in chest pain, has been described (Latimer, 1981). Use of psychological therapies for noncardiac chest pain appears promising. A randomized, controlled trial of cognitive-behavioral therapy for treatment of persistent noncardiac chest pain demonstrated significant reductions in chest pain, limitations on daily life, autonomic symptoms, and psychological morbidity compared to the control group (Klimes, Mayou, Pearce, Coles, & Fagg, 1990). Other studies have yielded similar positive results (Mayou et al., 1997; van Peski-Oosterbaan et al., 1999). One study compared a psychological treatment package (education, relaxation, breathing training, graded exposure to activity and exercise, and challenging automatic thoughts about heart disease) to waiting-list controls for treatment of noncardiac chest pain (Potts, Lewin, Fox, & Johnstone, 1999). Treatment significantly reduced chest pain episodes from median 6.5 to 2.5 per week, accompanied by improvements in anxiety and depression scores, disability rating, and exercise tolerance.

GASTRODUODENAL DISORDERS

Gut-oriented hypnosis accelerates gastric emptying in dyspeptic as well as healthy subjects (Chiarioni, Vantini, De Iorio, & Benini 2006). Listening to enjoyable music increases the amplitude of gastric myoelectrical activity in healthy humans. Music therapy may improve gastric motility and may be used to stimulate gastric emptying (Lin, 2007). There are scant data on the use of psychological therapies for peptic ulcer disease. Colgan, Faragher, and Whorwell (1988)conducted a controlled trial of hypnotherapy in relapse prevention of duodenal ulcers healed with ranitidine. After discontinuation of ranitidine, randomly selected patients received either hypnotherapy or no hypnotherapy for 10 weeks. After a follow-up of 12 months, 100% of the control subjects had relapsed, in contrast to only 53% of the hypnotherapy group. A case of hypnotic control of upper gastrointestinal hemorrhage has also been described (Bishay, Stevens, & Lee, 1984). Multiple studies have documented the positive effects of psychological therapies for functional dyspepsia. A randomized, placebo-controlled trial of hypnotherapy found that both the short-term as well long-term symptom scores improved, accompanied by better quality of life and fewer physician visits in the hypnotherapy group compared to the supportive and medical treatment groups (Calvert et al., 2002). Similarly, a randomized, placebo-controlled

428

INTEGRATIVE GASTROENTEROLOGY

comparison of cognitive-behavioral therapy found it to be better than education alone for treatment of functional bowel disorders (Drossman et al., 2003). Biofeedback has the potential to allow patients to manipulate the pathogenic gastroduodenal alterations implicated in dyspepsia. Gastric myoelectric activity can be modified using biofeedback and relaxation techniques through imagery, while watching EGG activity on the screen (Stern et al., 2004). A simpler alternative may be the use of a nasogastric tube to provide feedback about gastric pressure waves (Whitehead & Drescher, 1980). Breathing exercises with vagal biofeedback can increase drinking capacity and improve quality of life in patients with functional dyspepsia without altering the vagal tone (Hjelland, Svebak, Berstad, Flatabø, & Hausken, 2007).

Psychological therapies may be a cost-effective option in patients with noncardiac chest pain, as well as in those with functional dyspepsia.

A systematic review of psychological interventions for non-ulcer dyspepsia concluded that while psychological interventions appear to benefit dyspepsia symptoms, there is insufficient evidence to confirm their efficacy in functional dyspepsia (Soo et al., 2005). More recently, a prospective randomized, controlled trial comparing the long-term outcome of intensive medical therapy (with or without cognitive-behavioral or muscle relaxation therapy) with standard medical therapy in patients with refractory functional dyspepsia reported that intensified medical management with psychological intervention improves long-term outcomes and helps control concomitant anxiety and depression (Haag et al., 2007).

Homeopathy Homeopathy is based on the principle of dilutions. It defies biological plausibility and continues to baffle scientists, and the debate on its effectiveness is ongoing. There is paucity of data examining effect of homeopathy in upper digestive disorders. Many, but not all, of the independent reviews and placebocontrolled trials of homeopathy have concluded that its benefits seem to be more than just placebo effect (Jonas, Kaptchuk, & Linde, 2003; Shang et al., 2005). Spence Thompson, and Barron (2005) recently published the results of

Upper Gastrointestinal Disorders 429

their 6-year, university hospital outpatient observational study of homeopathic treatment for chronic diseases (n=6544) including gastrointestinal diseases. They found that 71% of the patients reported positive health changes, with 51% recording their improvement as better or much better. Homeopathy is generally believed to be devoid of side effects. However, a case of esophageal ulcer due to a homeopathic pill has been described, suggesting that pill esophagitis can be triggered by substances generally thought to be devoid of toxicity (Corleto et al., 2007).

Minerals Most of the data in this category pertain to the use of zinc. Exogenously administered zinc compounds have been shown to possess anti-ulcer activity against a wide variety of ulcerogenic agents in animals as well as humans. Because of their widespread use in mainstream medicine, antacids/alginate will not be discussed here.

THE SCIENCE BEHIND IT

The onset, development, and spontaneous healing of experimental gastroduodenal lesions in rats are associated with an alteration in serum, as well as in duodenal tissue, zinc concentrations (Troskot et al., 1996). Zinc pretreatment protects against the development of experimental duodenal lesions in a dosedependent manner (Troskot et al., 1997). Zinc levels in serum and gastric mucosa of patients with peptic ulcer disease are altered, possibly due to the migration of the zinc from serum to the gastric mucosa (Bandyopadhyay et al., 1995). Zinc sulfate reduces basal gastric acid secretion in duodenal ulcer patients by 60% (Puscas, Sturzu, & Búzás, 1985). The antisecretory effect of zinc may be mediated via inhibition of the carbonic anhydrase.

CLINICAL STUDIES

A multicenter, double-blind comparison of 600 mg/d of zinc acexamate and 40 mg/d of famotidine for 4 weeks showed that zinc acexamate is as effective as famotidine for the symptom resolution as well as healing of duodenal ulcer (García-Plaza et al., 1996). Another multicenter, double-blind, placebocontrolled trial (n=276) found that 300 mg/d of zinc reduces the incidence of

430

INTEGRATIVE GASTROENTEROLOGY

NSAID-induced gastric and duodenal ulcers by 92% (Rodríguez de la Serna & Díaz-Rubio, 1994). A meta-analysis found zinc acexamate to be superior to placebo, and as effective as H2 receptor antagonists for the treatment of peptic ulcer disease (Jiménez, Bosch, Galmés, & Baños, 1992).

Vitamins Limited data support the use of vitamins in upper gastrointestinal disorders. Adding vitamin C to one-week triple therapy for H. pylori can allow reduction of clarithromycin dose, while preserving the eradication of clarithromycinsusceptible H. pylori (Chuang et al., 2007). In contrast, vitamin C and E supplementation to lansoprazole-amoxicillin-metronidazole triple therapy may reduce the eradication rate of metronidazole-susceptible H. pylori infection (Chuang et al., 2002).

Preventive Strategies Aside from pharmacotherapeutics for gastroduodenal illness, patients may be advised to follow some lifestyle modifications and to take care using medications, including over-the-counter medicines. 1. Patients should avoid NSAIDs as much as possible, including both prescription and over-the-counter varieties. If NSAIDs are needed, use the lowest possible dose and avoid multiple NSAIDs. Talk to your doctor before making any changes. 2. Smoking increases gastric acidity and affects gastroprotective mechanisms, which predisposes patients to peptic ulcers as well as GERD. In addition to cancer prevention, smoking cessation may reduce dyspeptic symptoms and potentially prevent ulcers in some patients. 3. Alcohol has direct toxic effects on the gastric mucosa and may lead to gastritis and even gastrointestinal bleeding in some cases. Excessive drinking also increases gastroesophageal reflux. Avoiding excess alcohol may help reduce dyspeptic symptoms and ulcers in otherwise predisposed individuals. 4. Other routine lifestyle measures for GERD include raising the head of the patient’s bed, avoiding large fatty meals, especially at dinner, not eating within 3 hours of bedtime, and losing weight if overweight.

Upper Gastrointestinal Disorders 431

5. The role of diet is patient-specific and may affect symptoms in some individuals with dyspepsia. Dietary modifications must be individualized based on the patient’s symptom triggers. Patients who suffer from recurrent peptic ulcer disease may benefit from eating complex carbohydrates, fresh fruit and vegetables, and avoiding red and fried meats.

40 Celiac Disease S. DEVI RAMPERTAB AND PETER H.R. GREEN

key concepts ■

■

■

■

■

■

■

■

■

Celiac disease occurs in nearly 1% of the population in most countries. Ingested wheat gluten and related proteins of rye and barley trigger an immune response in genetically predisposed individuals. Aside from gastrointestinal symptoms, celiac disease has multiple extraintestinal manifestations including anemia, osteoporosis, and neurological deficits. All patients with celiac disease have either HLA-DQ2 or DQ8 haplotypes. Upper endoscopy with small bowel biopsy remains the gold standard for diagnosis of celiac disease. Histologically, the affected small bowel mucosa displays villous atrophy, crypt hyperplasia, and increased intraepithelial lymphocytes. With the advent of sensitive and specific serological testing, more celiac patients with atypical symptoms or no symptoms are being diagnosed. Untreated celiac disease can lead to significant complications, such as increased risk of malignancy. Treatment of celiac disease is a diet devoid of gluten. ■

432

Introduction

C

eliac disease is a very common autoimmune disorder that involves close interaction of genetic, environmental, and immunologic components. Ingested wheat gluten and related proteins of rye and barley trigger an immune response in genetically predisposed individuals that results in inflammation, villous atrophy, and crypt hyperplasia in the intestine. Approximately 95% of patients with celiac disease will express human leukocyte antigen-DQ2, while the vast majority of the remaining patients will have HLA-DQ8 (Green & Jabri, 2003). Once thought to be a rare intestinal disorder of childhood, celiac disease is now becoming increasingly recognized as a common condition that has a wide spectrum of clinical manifestations. While a large percentage of patients are asymptomatic, classic gastrointestinal symptoms of abdominal pain, diarrhea, and weight loss can be present. In addition, some of the extraintestinal features associated with celiac disease include anemia, osteoporosis, neurological deficits, malignancy, and other autoimmune disorders. Elimination of gluten and related proteins from the diet of patients with this condition results in clinical and histological improvement.

Epidemiology Serologic screening tests have revealed that the incidence of celiac disease approaches 1% of the population, based on several studies from Europe and the United States (West et al., 2003; Mäki et al., 2003; Fasano et al., 2003; Bingley et al., 2004; Tommasini et al., 2004). The disease has also been noted worldwide: Asia (Sood et al., 2003), the Middle East (Shahbazkhani et al., 2003; Tatar et al., 2004), North Africa (Catassi et al., 1999), South America (Gomez et al., 2001) and Australia (Hovell et al., 2001). In a recent large national survey from the United States, it was determined that there was a female predominance of celiac disease (2.9 to 1). In addition, the majority of respondents were diagnosed in their fourth to sixth decades of life. It is interesting to note that symptoms preceded the diagnosis of celiac disease a mean of 11 years in this study (Green et al., 2001). The investigators concluded that this delay was due to decreased awareness of celiac disease, and its various atypical presentations, among physicians in the United States.

434

INTEGRATIVE GASTROENTEROLOGY

Physicians often regard adult celiac disease as rare, and fail to consider it in clinical situations other than the classical chronic diarrhea and malabsorption.

Another possible concept is the “Celiac iceberg” theory proposed by Logan, which states that for every case of celiac disease diagnosed on clinical suspicion (tip of the iceberg), there are many more that remain undiagnosed (area below the waterline; see Logan, 1996, and Figure 40.1). These cases may remain undetected, either because patients have latent or asymptomatic disease or have been misdiagnosed by their physicians.

Pathogenesis I. GENETIC FACTORS

Genetic factors are thought to participate in the pathogenesis of celiac disease. Celiac disease is an HLA-associated illness limited to genetically predisposed individuals who express HLA-DQ2 or HLA-DQ8 haplotypes (Sollid & Lie, 2005). HLA-DQ2 is present in about 95% of those afflicted with celiac disease, and most of the remainder have HLA-DQ8 (Green & Jabri, 2003).

These HLA genes confer up to 40% of the genetic risk; therefore, the rest is attributable to non-HLA genes (Louka & Sollid, 2003). Interestingly, about 30%–40% of Caucasians carry DQ2 or DQ8, yet <3% of them will develop celiac disease. This suggests that the presence of these alleles is necessary but not sufficient for the eventual development of the disease. The concordance rate for celiac disease is much higher in monozygotic twins (approximately 70%) as compared to HLA-matched siblings (30%; see Greco et al., 2002). This indicates that there may be non-HLA susceptibility genes involved that are shared by monozygotic twins that may not necessarily be shared by siblings. About 10% of first-degree relatives of affected individuals have celiac disease overall (Green & Jabri, 2006).

II. THE ROLE OF GLUTEN

The causative agent in celiac disease is gluten, a protein derived from wheat, barley, and rye. It is enriched in glutamine and proline, and poorly absorbed in the human upper digestive tract (Vader et al., 2003).

Celiac Disease 435

Gliadin is the alcohol-soluble fraction of gluten, and houses the bulk of the toxicity associated with it. Undigested molecules of gliadin are resistant to degradation by gastric, pancreatic, and intestinal brush-border membrane proteases in the human intestine, and therefore will remain in the intestinal lumen long after gluten ingestion. After changes in intercellular tight junctions and increased intestinal permeability (i.e., after gastrointestinal infection), gliadin enters the lamina propria to interact with antigen-presenting cells.

III. MUCOSAL IMMUNE RESPONSES

Figure 40.2 provides an illustrative review of the immunological mechanisms responsible for potentiating the mucosal damage seen in celiac disease. The enzyme tissue transglutaminase (TTG) has an important role in the pathogenesis of celiac disease, in that it is responsible for converting glutamine residues on the gliadin protein into glutamic acid, thereby producing a negative charge which favors binding and presentation by the HLA-DQ2 and DQ8 molecules in the lamina propria. This process is critical and is termed deamidation.

Deamidated gliadin, when presented by HLA-DQ2 and/or HLA-DQ8 molecules to CD4 T cells, stimulates the production of cytokines. These cytokines are then responsible for the host of immune responses that occur, ultimately resulting in damage within the intestinal mucosa (as evidenced by villous atrophy and crypt hyperplasia) and activation of plasma cells to produce antibodies to gliadin, tissue transglutaminase (TTG), and endomysium (Green & Cellier, 2007).

Two types of immunity are responsible for the propagation of intestinal damage in celiac disease. Innate immunity refers to the antigen-nonspecific defense mechanisms that a host uses immediately, or within several hours, after exposure to almost any microbe. This is the immunity one is born with, and is the initial response by the body to eliminate microbes and prevent infection. Adaptive (acquired) immunity, refers to antigen-specific defense mechanisms that take several days to become protective and are designed to react with and remove a specific antigen. This is the immunity one develops throughout life. Whereas the actions of gliadin in the lamina propria are mediated by the adaptive immune system, the innate immune system is the vector by which gliadin induces damage to the intestinal epithelial lining. In the epithelium,

436

INTEGRATIVE GASTROENTEROLOGY

gliadin is directly toxic to epithelial cells, resulting in increased expression of interleukin-15. This, in turn, activates intraepithelial lymphocytes. These lymphocytes subsequently become cytotoxic and kill intestinal cells that express MIC-A (a stress protein) on their surface (Green & Cellier, 2007).

IV. ENVIRONMENTAL FACTORS

Epidemiologic studies have suggested that there is a protective effect of breastfeeding in the development of celiac disease (Persson, Ivarsson, & Hernell, 2002). Also, the initial administration of gluten before 4 months of age is associated with an increased risk of disease development, and the introduction of gluten after 7 months also denotes a marginal increase in risk (Norris et al., 2005).

The best time to introduce gluten to the infant, which would pose the least risk of celiac disease development, would be between 4 to 6 months of age.

Clinical Manifestations The clinical presentation of celiac disease involves a wide spectrum of features including, but not limited to, the intestinal tract. Patients can range from asymptomatic to severe malnutrition. It is key to note that the majority of patients with celiac disease have a silent or atypical presentation and are not diagnosed, therefore substantiating the “iceberg model” theory. Also, since gastrointestinal symptoms may be vague and nonspecific, patients are often diagnosed with irritable bowel syndrome (Green et al., 2001). Celiac disease should be excluded in all patients who are diagnosed with irritable bowel syndrome.

Celiac disease is sometimes divided into clinical subtypes based on presence/absence of symptoms. The terms “symptomatic” or “classic” denote those cases that satisfy the classic features of celiac disease. These include chronic diarrhea, abdominal distension and pain, weakness, and sometimes malabsorption. Malabsorption-related symptoms include steatorrhea, weight loss, failure to thrive, bloating, flatulence, and a variety of nutrient and mineral deficiency states.

Celiac Disease 437

In contrast, the disease is now evolving and patients are increasingly displaying the more common “atypical” form of the disease, whereby gastrointestinal symptoms may be absent or less pronounced.

Approximately half of the adult-onset celiac disease cases lack any gastrointestinal symptoms (Farrell & Kelly, 2002).

Rather, extraintestinal manifestations such as anemia, osteoporosis, short stature, infertility, and neurological deficits are present (Rampertab et al., 2006). Table 40.1 outlines some of the key disorders associated with celiac disease. Lastly, those with “latent” or “silent” celiac disease are asymptomatic. In these patients, there are no classic or atypical symptoms. These individuals are incidentally discovered to have celiac disease, evidenced by villous atrophy, during endoscopy or intestinal biopsy for other reasons (Green et al., 2000), or as a result of serological screening.

Extraintestinal Manifestations I. HEMATOLOGIC

Anemia is one of the most frequent presenting features of celiac disease, and it is most commonly due to iron deficiency. The pathogenesis of iron deficiency in celiac disease is multifactorial; however, malabsorption of dietary iron from damaged gastrointestinal tract mucosa is the primary etiology. Iron is exclusively absorbed by the proximal duodenum, and this area is almost universally affected in celiac disease. In addition, there have been reports of occult bleeding in 40% to 50% of patients with celiac disease (Fine, 1996). B12 deficiency has also been documented in celiac disease (Dahele & Ghosh, 2001). Glutenfree diet is usually sufficient to correct these nutritional deficiencies and supplementation is usually not required.

II. DERMATOLOGIC

Dermatitis herpetiformis is an extremely pruritic bullous skin lesion with characteristic distribution over the extensor surfaces of the major joints such as the elbows and knees, as well as the buttocks (Karpati, 2004). The diagnosis of dermatitis herpetiformis is based on pathognomonic granular immunoglobulin A

438

INTEGRATIVE GASTROENTEROLOGY

Table 40.1. Disorders Associated with Celiac Disease Endocrine Type I Diabetes Autoimmune Thyroid Disorders Addison’s Disease Reproductive Disorders Alopecia Areata Neurologic Cerebellar Ataxia Neuropathy Epilepsy Migraine Cardiac Idiopathic Dilated Cardiomyopathy Autoimmune Myocarditis Hepatic Primary Biliary Cirrhosis Autoimmune Hepatitis Autoimmune Cholangitis Other Anemia (Iron deficiency) Osteoporosis Selective IgA Deficiency Intestinal Lymphoma Autoimmune Atrophic Gastritis Sjogren’s Syndrome Turner Syndrome Down’s Syndrome Dental Enamel Defects Psoriasis Recurrent Aphthous stomatitis

Celiac Disease 439

deposits in the dermal papillae (Reunala, 2001). Long-term remissions are maintained only with strict compliance to a gluten-free diet, although dapsone may be used in conjunction with the diet to quickly and effectively resolve the itching and the rash.

III. NEUROLOGIC

Neurologic complications have been estimated to occur in 6% to 10% of patients with celiac disease (Chin et al., 2003). Peripheral neuropathy and cerebellar ataxia are the more common neurologic symptoms; however, epilepsy, myelopathy, myopathy, dementia, and psychiatric illness have also been described (Hadjivassiliou et al., 1996). The etiology of neurological dysfunction may be related to vitamin deficiencies (i.e., B6, B12) or autoimmune activity against neural antigens.

IV. HEPATIC

Hepatic manifestations of celiac disease range from asymptomatic elevation of serum aminotransferases to severe liver failure. Mild to moderate elevations in serum aminotransferases may be seen in 15% to 55% of patients with celiac disease. Conversely, celiac disease is found in approximately 10% of patients with unexplained transaminasemia (Abdo, Meddings, & Swain, 2004). Both the serum transaminases, as well as the celiac disease serology, normalized after initiation of a gluten-free diet. Interestingly, celiac disease has been found in 3% to 7% of patients with primary biliary cirrhosis, 4% to 5% of patients with Type I autoimmune hepatitis, and 7% to 10% of those with Type II autoimmune hepatitis (Kaukinen et al., 2002; Sedlack et al., 2002; Volta et al., 2002). Moreover, in a recent Finnish study, severe liver disease was reported in 4 patients with untreated celiac disease. Marked improvement of their liver disease after initiation of a gluten-free diet raised the possibility of causality for celiac disease (Kaukinen et al., 2002). In addition, this study has suggested that perhaps all patients with advanced liver disease of unknown etiology, and liver transplant candidates for cryptogenic cirrhosis, ought to be screened for celiac disease.

V. BONE DISEASE

The most frequent clinical features of celiac disease-associated bone disease include bone pain, altered gait, retardation of growth, osteopenia/osteoporosis,

440

INTEGRATIVE GASTROENTEROLOGY

bone deformities, and fractures (Moreno, 2004). Most studies that have evaluated bone mineral density in celiac patients have noted a low bone mass in both adults and children with celiac disease ((Meyer et al., 2001). Specifically, osteoporosis (T score < – 2.5) was present in 34% of the patients at the lumbar spine, 27% at the femoral neck, and 36% at the radius. Low bone mass (T score between – 1.0 and – 2.5) was present in 38% at the lumbar spine, 44% at the femoral neck, and 32% at the radius. In adult patients responsive to the glutenfree diet, the bone density becomes comparable to that of healthy individuals (Valdimarsson et al., 1996).

VI. ENDOCRINE DISORDERS

Celiac disease is associated with some immune-mediated endocrine disorders, most commonly Type I diabetes and thyroid disease. Each of these conditions affects 5% to 10% of patients with celiac disease (Collin et al., 2002). The effect of adherence to a gluten-free diet on the management of diabetes and thyroid disease is unknown currently.

VII. INFERTILITY

Reduced fertility has been reported in both males and females with celiac disease. In pregnant women, there is an increased risk for miscarriage, stillbirth, perinatal deaths, and intrauterine growth retardation (Ciacci et al., 1996; Gasbarrini et al., 2000; Tata et al., 2005). Ciacci et al. have reported that the relative risk of spontaneous abortion in women affected by celiac disease is 8.8 times higher than in healthy subjects, and a gluten-free diet reduced the relative risk of abortion.

Diagnosis The diagnosis of celiac disease requires both a duodenal biopsy that shows the characteristic findings of intraepithelial lymphocytosis, crypt hyperplasia, and villous atrophy while on a gluten-containing diet and clinical improvement in response to a gluten-free diet. The diagnostic criteria developed by the European Society for Pediatric Gastroenterology and Nutrition require only clinical improvement with the diet, although histologic improvement on a gluten-free diet is frequently sought and is recommended in adults. However, roughly 10% of cases are difficult to diagnose because of a lack of concordance

Celiac Disease 441

among serologic, clinical, and histologic findings. A diagnostic schema is presented in Figure 40.3.

I. SEROLOGICAL TESTING

Typical indications for serologic testing include unexplained bloating or abdominal distress, chronic diarrhea with or without malabsorption, abnormalities on laboratory tests that might be caused by malabsorption (i.e., folate deficiency and iron deficiency anemia), first-degree relatives with celiac disease, and autoimmune diseases and other conditions known to be associated with celiac disease. The most sensitive antibody tests for the diagnosis of celiac disease are of the IgA class. The available tests include those for antigliadin antibodies, connective-tissue antibodies (antireticulin and anti-endomysial antibodies), and antibodies directed against tissue transglutaminase. The antigliadin antibodies are no longer considered sensitive or specific enough to be used for the detection of celiac disease. Antireticulin antibodies are also rarely measured, having been surpassed in use by endomysial and anti-tissue transglutaminase antibodies. The diagnostic standard in celiac serologies remains the endomysial IgA antibodies; they are highly specific markers for celiac disease, approaching 100% accuracy. The recognition that the enzyme tissue transglutaminase is the autoantigen for the development of endomysial antibodies (Dieterich et al., 1997) allowed development of automated enzyme-linked immunoassays that are less expensive and less operator dependent than the endomysial antibody test. Overall, the sensitivity of the tests for both endomysial antibodies and anti-tissue transglutaminase antibodies is greater than 90%, and a test for either marker is considered the best means of screening for celiac disease (Rostom et al., 2005). (See Table 40-2). The titers of endomysial antibodies and anti-tissue transglutaminase antibodies correlate with the degree of mucosal damage (Sategna-Guidetti et al., 1993; Tursi et al., 2003). Therefore, serological tests may not detect partial villous atrophy. Selective IgA deficiency is more common in patients with celiac disease than in the general population, with 1 case in 40 as compared to 1 in 400. Consequently, patients with celiac disease and selective IgA deficiency lack IgA endomysial antibodies and IgA anti-tissue antibodies against tissue transglutaminase. It is recommended that the test for anti-tissue transglutaminase antibodies be used as a single screening test for celiac disease (Rostom et al., 2005; Rostom et al., 2006). If the levels of this marker are within the normal range (or if it is absent) and there is a high suspicion of celiac disease, selective

442

INTEGRATIVE GASTROENTEROLOGY

Table 40.2 Serologic Tests for Celiac Disease Antibody test

Sensitivity (%)

Specificity (%)

Time course

IgA EMA

85 to 100

96 to 100

Antibody disappears within several months after institution of gluten-free diet

IgA anti-TTG

95

90

Limited data; correlated with IgA anti-endomysial antibody in studies

IgA antigliadin

53 to 100

65 to 100

More persistent than IgA antiendomysial antibody; may persist for 6 months or longer

IgG antigliadin

57 to 100

42 to 98

Most persistent; may be detectable up to 12 months after institution of gluten-free diet False positive tests reported in patients with Crohn’s disease, wheat protein allergy, and post-diarrhea states

IgA deficiency needs to be ruled out by measuring total IgA levels. In such cases, a test for IgG antibodies against tissue transglutaminase should be performed (Lenhardt et al., 2004). The clinician should be aware that timing of the serological testing is critical, as sensitivities may be affected by either a reduced gluten or gluten-free diet.

II. UPPER ENDOSCOPY AND HISTOLOGICAL ASSESSMENT

Biopsy of the small intestine remains the gold standard for diagnosing celiac disease, and it should always be performed when clinical suspicion is high, irrespective of the results of serologic testing. Biopsy confirmation is crucial, given the lifelong nature of the disease and the resulting need for an expensive and socially inconvenient diet. At least four to six endoscopic-biopsy specimens should be obtained from the duodenum, given the patchy nature of the disease (Bonamico et al., 2004; Ravelli et al., 2005). In addition to patients whose serologic tests are positive, any patient who has chronic diarrhea, iron deficiency, or weight loss should undergo duodenal biopsy, irrespective of whether serologic testing for celiac disease has been performed. The recognition of endoscopic signs of villous atrophy, such as scalloping of mucosal folds, absent or reduced duodenal folds, mucosal

Celiac Disease 443

fissures, or a mosaic pattern of the mucosa, should prompt biopsy (Lee & Green, 2005). See Fig 40-4. However, because these abnormalities are not sensitive markers of the presence of celiac disease (Oxentenko et al., 2002), biopsy should be performed even if they are absent. It is also important to note that not all scalloping visualized endoscopically is secondary to celiac disease (Shah et al., 2000). Some of the characteristic features leading to the diagnosis of celiac disease include villous atrophy (partial or total), crypt hyperplasia, increased intraepithelial lymphocytes, and infiltration of the lamina propria with inflammatory cells (Figure 40.5). Pitfalls in the pathological diagnosis include over-interpretation of villous atrophy in poorly oriented biopsy specimens, and inadequate biopsy sampling in patients with patchy villous atrophy. The histologic findings in celiac disease are characteristic but not specific. Indeed, celiac disease is not the only cause of villous atrophy (Table 40.3). The diagnosis is confirmed when there is a favorable response to the diet.

Table 40.3 Differential Diagnosis of Villous Atrophy Celiac Disease Giardiasis Collagenous sprue Common-variable immunodeficiency Autoimmune enteropathy Radiation enteritis Whipple’s disease Tuberculosis Tropical sprue Eosinophilic gastroenteritis Human immunodeficiency virus enteropathy Intestinal lymphoma Zollinger-Ellison syndrome Crohn’s disease Intolerance of foods other than gluten (e.g., milk, soy, chicken, tuna)

444 INTEGRATIVE GASTROENTEROLOGY

III. HLA-DQ2/HLA-DQ8

Approximately 40% of the general population in the United States has either HLA-DQ2 or HLA-DQ8. However, virtually all those afflicted with celiac disease have either DQ2 (about 95% of patients with celiac disease) or DQ8 (about 5% of patients with celiac disease; see Green & Jabri, 2003). Because virtually all patients with celiac disease have these celiac disease-associated alleles, the absence of these alleles provides a negative predictive value for the disease that approaches 100%. If the individual lacks one of these alleles (DQ2, DQ8), the disease is virtually excluded. Thus HLA testing may be a useful addition to exclude celiac disease when other diagnostic testing is not clear.

Treatment The only accepted treatment for celiac disease currently involves the lifelong elimination of wheat, rye, and barley from the diet, and is termed “the glutenfree diet.” Clinical studies suggest that oats are tolerated by most patients with celiac disease; however, oats are not uniformly recommended, because most commercially available oats are contaminated with gluten-containing grains during the growing, transportation, and milling processes (Thompson, 2003; Peraaho et al., 2004). Table 40.4 Fundamentals of the Gluten-Free Diet Grains that should be avoided Wheat (includes spelt, kamut, semolina, triticale), rye, barley (including malt) Safe grains (gluten-free) Rice, amaranth, buckwheat, corn, millet, quinoa, sorghum, teff (an Ethiopian cereal grain), oats Sources of gluten-free starches that can be used as flour alternatives Cereal grains: amaranth, buckwheat, corn (polenta), millet, quinoa, sorghum, teff, rice (white, brown, wild, basmati, jasmine), montina (Indian rice grass) Tubers: arrowroot, jicama, taro, potato, tapioca (cassava, manioc, yucca) Legumes: chickpeas, lentils, kidney beans, navy beans, pea beans, peanuts, soybeans Nuts: almonds, walnuts, chestnuts, hazelnuts, cashews Seeds: sunflower, flax, pumpkin

Celiac Disease 445

Other grains can serve as substitutes (Table 40.4). Because the substitute flours are not fortified with B vitamins, however, vitamin deficiencies may occur. Therefore, vitamin supplementation is advised. The cost of the glutenfree products varies by country, but the diet is usually expensive, making dietary treatment problematic for patients with limited financial resources. Meats, dairy products, fruits and vegetables are naturally gluten-free foods. Patient-support organizations are a valuable source of information about the disease and the diet. After the diagnosis of celiac disease has been established, the patient should be assessed for deficiencies of vitamins and minerals, including folic acid, B12, fatsoluble vitamins, iron, and calcium, and any such deficiencies should be treated. All patients with celiac disease should undergo screening for osteoporosis, which has a high prevalence in this population (Meyer et al., 2001). The healthcare team should include a skilled dietician who monitors the patient’s nutritional status and dietary adherence on a regular basis.

The elimination of gluten usually induces clinical improvement within days or weeks, though histologic recovery takes months or even years, especially in adults, in whom mucosal recovery may be incomplete (Lee et al., 2003). A gluten-free diet fails to induce clinical or histologic improvement in 7% to 30% of patients, and such lack of response should prompt a complete evaluation (Figure 40.6). The first step is to reassess the initial diagnosis, since villous atrophy with associated crypt hyperplasia is not exclusive to celiac disease (Table 40.3). In patients with a questionable diagnosis, HLA-DQ2 or HLA-DQ8 typing may be useful, since the negative predictive value of this test is almost 100%. The second step is to address the likelihood of dietary nonadherence, the most common cause of unresponsive celiac disease. The persistence of endomysial antibodies or anti-tissue transglutaminase antibodies in patients on a gluten-free diet for a year or more is suggestive of poor dietary adherence (Vahedi et al., 2003). Other causes of persistent symptoms in patients on a strict glutenfree diet are listed in Table 40.5.

Complications I. MALIGNANCY

There are a few noteworthy complications of celiac disease, which include intestinal adenocarcinoma, enteropathy-associated T-cell lymphoma, and refractory sprue (Cellier et al., 2000; Rampertab et al., 2003).

446 INTEGRATIVE GASTROENTEROLOGY

Table 40.5 Causes of Poor Response to the Gluten-Free Diet Incorrect diagnosis Gluten ingestion (intentional or unintentional) Microscopic colitis Lactose intolerance Pancreatic insufficiency Bacterial overgrowth Intolerance of foods other than gluten (e.g., fructose, milk, soy) Inflammatory bowel disease Irritable bowel syndrome Anal incontinence Collagenous sprue Autoimmune enteropathy Refractory celiac disease (with or without clonal T-cells) Enteropathy-associated T-cell lymphoma

The rate of malignancy is increased as a whole with celiac disease, although more recent population studies demonstrate that the risk is less than what had previously been quoted (Askling et al., 2002). Malignancies that are seen in patients with celiac disease with increased frequency are non-Hodgkin’s lymphomas (both B- and T-cell) that may be intestinal or extraintestinal, oroesophageal and esophageal adenocarcinoma, as well as cancers of the small intestine, colon, hepatobiliary system, and pancreas (Askling et al., 2002; Smedby et al., 2005). Compared with expected rates, the risks of small bowel adenocarcinoma, esophageal cancer, non-Hodgkin’s lymphoma, and melanoma were increased significantly in a recent study looking at cancer rates in a population of celiac disease patients at a large tertiary care referral center. Specifically, the ageadjusted incidence rates for these cancers among the celiac disease group were: non-Hodgkin’s lymphoma, 135 per 100,000 person-years (normal, 14.8 per 100,000 person-years) and small bowel cancer, 40 per 100,000 person-years (normal, 1.2 per 100,000 person-years; see Green, 2003). These carcinomas are often located in the jejunum, as opposed to sporadic small intestinal adenocarcinomas, which tend to localize to the duodenum.

Celiac Disease 447

In addition, small bowel adenocarcinoma in the setting of celiac disease is more likely to follow the adenoma-carcinoma sequence of development, as opposed to dysplasia in flat mucosa, which is more often seen in Crohn’s disease (Green & Rampertab, 2004). Although there is currently no data to support the use of video capsule endoscopy to screen for cancers of the small intestine in patients with celiac disease, there is a definite role for this modality in investigating symptoms such as occult bleeding, abdominal pain, or recurrence of symptoms in a patient who had initially responded to a gluten-free diet (Culliford, 2005). Enteropathy-associated T-cell lymphoma is another diagnosis that must be entertained when a patient develops clinical relapse of symptoms of celiac disease after a period of doing well on a gluten-free diet. Unfortunately, due to the fact that it is usually discovered at an advanced stage, prognosis is extremely poor and less than 20% of people survive beyond 30 months (Howdle et al., 2003).

II. REFRACTORY CELIAC DISEASE

Refractory sprue is a condition whereby the patient develops persistent symptoms in the setting of villous atrophy, despite strict adherence to a gluten-free diet (Trier, 1991). The most common symptoms include diarrhea, weight loss, recurrence of malabsorption, abdominal pain, bleeding, and anemia. Ulcerative jejunitis often arises as well. Refractory celiac disease may be classified as Type 1, in which there is a normal intraepithelial lymphocyte phenotype, or Type 2, in which there is a clonal expansion of an aberrant intraepithelial lymphocyte population. Type 2 is associated with a high risk of ulcerative jejunitis and frank enteropathyassociated T-cell lymphoma. In active celiac disease, most intraepithelial lymphocytes express CD3 and CD8 (CD3+, CD8+) receptors, whereas in Type 2 (clonal) refractory celiac disease, most of these lymphocytes express CD3 but not CD8 (CD3+,CD8−; Cellier et al., 1998; Daum et al., 2001). It is interesting to note that patients with Type 1 refractory sprue, as well as celiac patients who are not compliant with the diet, display a normal phenotype (CD3+, CD8+) (Patey-Mariaud De Serre et al., 2000). Thus, the development of new symptoms (e.g., weight loss, abdominal pain, or fever) or the recurrence of diarrhea in patients who are on a strict gluten-free diet, often requires extensive investigation. Treatment of refractory sprue includes nutritional support with repletion of losses, and a strict gluten-free diet coupled with corticosteroids to help induce clinical remission.

448 INTEGRATIVE GASTROENTEROLOGY

Future Directions The development of nondietary therapies that might either supplement or supplant the rigorous gluten-free diet are currently being investigated. At present, one possible alternative involves the use of recombinant enzymes that digest the toxic gliadin fractions in the stomach or the upper small intestine (Siegel et al., 2006; Stepniak et al., 2006). Therapies that interfere with steps in the immune response (i.e., blocking the action of tissue transglutaminase or blocking the binding of deaminated gliadin to HLA-DQ2 or HLA-DQ8 antigenpresenting cells) can also be considered; however, these may come coupled with unwanted adverse effects.

41 Food Reactions and Their Implications in the Irritable Bowel Syndrome TRENT W. NICHOLS , GERARD E. MULLIN, AND LAURA K. TURNBULL

key concepts ■

■

■

■

Over 3 million children have IgE-mediated food allergies in the United States—representing an 18% increase over the past 5 years. Up to 25% of adults report symptoms related to foods; only 3% are proven to be IgE -mediated food allergies, with the remainder possibly being delayed IgG food sensitivities and intolerances. More than 50 million Americans suffer from allergies on a yearly basis, with allergy ranking as the sixth leading cause of chronic disease, costing the U.S. healthcare system $18 billion per year in 2001. Recent food allergy tests are more reproducible, reliable and valid. ■

Introduction: History of Food Allergy

T

he first recorded instance of food sensitivity was by Hippocrates, who observed that milk could cause gastric upset and urticaria. In 200 A.D. Galen described a case of allergy to goat’s milk, and Willis in 1679 observed that the ingestion of wine could precipitate asthma. Shloss described several cases of atopic dermatitis and food allergy soon after the turn of twentieth century. In the early 1920s, W.W. Duke published several papers linking 449

450

INTEGRATIVE GASTROENTEROLOGY

food ingestion to bladder pain, Meniere’s syndrome, colitis, gastrointestinal upset, and diarrhea. Walzer and his associates performed experiments that demonstrated how ingested food antigens penetrate the GI barrier and are transported through the bloodstream to mast cells in the skin. In the 1930s, Rinkel first described food sensitivities that differed from classic immediate anaphylactic reactions. The symptoms occurred hours to days subsequent to ingestion, and could be masked or unmasked by the offending food. Rinkel’s discovery has been borne out by recent research confirming that delayed-type food allergies (IgG mediated) play a primary role in the immune system’s response to ingestants (Rinkel, 1936).

EPIDEMIOLOGY

IgE–mediated food allergies affect between 6%–8% of children in the United States and United Kingdom.

Up to 25% of adults report symptoms that may be related to foods, although the prevalence of only 3% is proven to be IgE -mediated food allergies with the remainder possibly being delayed IgG food sensitivities and intolerances. More than 50 million Americans suffer from allergies on a yearly basis, with allergy ranking as the sixth leading cause of chronic disease and costing the U.S. healthcare system $18 billion per year in 2001 (American Academy of Allergy, 1996–2001). A recent article was published reporting that food allergies in American children seem to be on the rise, now affecting 3 million of them according to the Center for Disease Control and Prevention (Smith, 2007). While no one is certain as to what is driving this increase, there are numerous studies validating the trend. For example, earlier studies have demonstrated a doubling in peanut allergies among children. Additionally, children seem to be taking longer to outgrow milk and egg allergies than they did in decades past.

CLINICAL PRESENTATION

Food allergies typically appear between 6 months and 2 years of age. The organ systems most commonly involved include the skin (flushing, urticaria, angioedema, and worsening eczema), the gastrointestinal tract (vomiting, abdominal pain, diarrhea, and cramping) and the respiratory tract (rhinitis, stridor

Food Reactions and Their Implications in the Irritable Bowel Syndrome

451

Table 41.1. Most Common IgE-Mediated Food Allergens Chicken Corn Dairy Egg Nuts Soy Wheat

and asthma). Eczema generally develops in the first 6 months to 12 months of life, is usually the first clinical manifestation of atrophy, and is present in more than 80% of children with egg allergy. Respiratory allergies like asthma and rhinitis are also common, and are typically diagnosed after the appearance of food allergies, usually after age 3. Egg allergy or sensitization is the strongest predictor of respiratory allergies in children and adults with asthma. Although eczema and food allergies (IgE mediated) usually resolve in children, they may persist in a substantial number of them, causing illnesses and impaired quality of life through multiple food allergies, eczema, allergic rhinosinusitis, asthma, or combinations of these conditions (Lack, 2008). Different foods affect different age groups, according to Dr. Gideon Lack. Cow’s milk, hen’s eggs, peanuts, tree nuts, and sesame seeds account for most of the immediate food allergies in young children, and kiwi allergy has been increasing in this group. Wheat and soy allergies are rarely confirmed, although frequently suspected (Lack, 2008). Shellfish, fish, peanuts, and tree nuts are the most common causes of food allergies in adults (Khakoo, Roberts & Lack, 2000). Food sensitivities to tyramine, phenylalanine, phenolic flavonoids, alcohol, and caffeine have been noted. Food additives such as sodium nitrate, monosodium glutamine, and aspartame are thought to induce migraine headaches by modifying vascular tone (Meletis, 2003).

In general, higher IgE is not greater among people with migraine than the general population.

452 INTEGRATIVE GASTROENTEROLOGY

Table 41.2. Foods that have been Linked as Causative Agents to Migraine Headaches Chocolate Citrus fruits Coffee Cola drinks Milk Nuts Pork Tea Vegetables (adapted from Leira & Rodríguez, 1996)

Classification of Food Reactions Reactions to foods may be classified as immediate (IgE-mediated) or delayed (non IgE-or IgG-mediated). The IgE-mediated food allergies can range from hives to tingling and swelling of the mucous membranes of the mouth, lips, tongue, throat, and airway, with the most serious reaction being anaphylaxis. The foods involved in the latter are usually peanuts, shellfish, and tree nuts. However, eggs, fish, cows milk, citrus fruits, bananas, sesame, chocolate, mango, grains, Chinese foods, seeds, and vegetables have been known to cause anaphylaxis (Frankland, 1987).

TYPE I HYPERSENSITIVITY AND IGE TESTING

In Type I reactions, mast cells sensitized with IgE antibody degranulate, releasing mediators when the antibodies are cross-linked by the relevant antigen (Figure 41.1, Table 41.3). When Type I reactions occur after food ingestion, the reaction may include, rhinorrhea, asthma, diarrhea, and vomiting, in addition to the more common presentations of anaphylaxis and urticaria. These reactions are often associated with a positive skin prick test, and with positive radioallergosorbent test (RAST) to the relative food (Brostoff, 1987).

Food Reactions and Their Implications in the Irritable Bowel Syndrome

453

Table 41.3. Pharmacologic Mediators of Immediate Hypersensitivity Mediator

Preformed mediators in granules histamine

bronchoconstriction, mucus secretion, vasodilatation, vascular permeability

tryptase

proteolysis

kininogenase

kinins and vasodilatation, vascular permeability, edema

ECF-A (tetrapeptides)

attract eosinophil and neutrophils

Newly formed mediators leukotriene B4

basophil attractant

leukotriene C4, D4

same as histamine but 1000x more potent

prostaglandins D2

edema and pain

PAF

platelet aggregation and heparin release: microthrombi

TYPE II HYPERSENSITIVITY

Type II or cytotoxic hypersensitivity also involves antibody-mediated reactions. However, the immunoglobulin class (isotype) is generally IgG. In addition, this process involves K-cells rather than mast cells. K-cells are, of course, involved in antibody-dependent cell-mediated cytotoxicity (ADCC). Type II hypersensitivity may also involve complement that binds to cell-bound antibody. The difference here is that the antibodies are specific for (or able to cross-reactivity with) “self ” antigens. When these circulating antibodies react with a host cell surface, tissue damage may result. There are many examples of Type II hypersensitivity. These include: • Pemphigus: IgG antibodies that react with the intracellular substance found between epidermal cells. • Autoimmune hemolytic anemia (AHA): This disease is generally inspired by a drug such as penicillin that becomes attached to the surface of red blood cells (RBC) and acts as hapten for the production of antibody, which then binds the RBC surface, leading to lysis of RBCs.

454 INTEGRATIVE GASTROENTEROLOGY

• Goodpasture’s syndrome: Generally manifested as a glomerulonephritis, IgG antibodies that react against glomerular basement membrane surfaces can lead to kidney destruction.

TYPE III HYPERSENSITIVITY

Type III hypersensitivity is also known as immune complex hypersensitivity (Brostoff, 1987). The reaction may be general (e.g., serum sickness) or may involve individual organs including skin (e.g., systemic lupus erythematosus, Arthus reaction), kidneys (e.g., lupus nephritis), lungs (e.g., aspergillosis), blood vessels (e.g., polyarteritis), joints (e.g., rheumatoid arthritis), or other organs. This reaction may be the pathogenic mechanism of diseases caused by many microorganisms. The reaction may take 3–10 hours after exposure to the antigen (as in Arthus reaction). It is mediated by soluble immune complexes. They are mostly of the IgG class, although IgM may also be involved. The antigen may be exogenous (chronic bacterial, viral, or parasitic infections), or endogenous (non-organspecific autoimmunity; e.g., systemic lupus erythematosus, SLE). The antigen is soluble and not attached to the organ involved. Primary components are soluble immune complexes and complement (C3a, 4a and 5a). The damage is caused by platelets and neutrophils. The lesion contains primarily neutrophils and deposits of immune complexes and complement. Macrophages infiltrating in later stages may be involved in the healing process (Brostoff et al., 1979). The affinity of antibody and size of immune complexes are important in production of disease and determining the tissue involved (André et al., 1975). Diagnosis involves examination of tissue biopsies for deposits of immunoglobulin and complement by immunofluorescence. The immunofluorescent staining in type III hypersensitivity is granular (as opposed to linear in type II such as seen in Goodpasture’s syndrome). The presence of immune complexes in serum and depletion in the level of complement are also diagnostic. Polyethylene glycol-mediated turbidity (nephelometry), binding of C1q and Raji cell test are utilized to detect immune complexes. Treatment includes anti-inflammatory agents.

TYPE IV HYPERSENSITIVITIES

Type IV hypersensitivity is involved in the pathogenesis of many autoimmune and infectious diseases (tuberculosis, leprosy, blastomycosis, histoplasmosis,

Food Reactions and Their Implications in the Irritable Bowel Syndrome

455

toxoplasmosis, leishmaniasis, etc.), and granulomas due to infections and foreign antigens. Another form of delayed hypersensitivity is contact dermatitis (poison ivy, chemicals, heavy metals, etc.) in which the lesions are more papular. Type IV hypersensitivity can be classified into three categories depending on the time of onset and clinical and histological presentation (Table 41.4). A summary of the types of hypersensitivity responses is presented in Table 41.5. 1. Mechanisms of damage in delayed hypersensitivity include T lymphocytes and monocytes and/or macrophages. Cytotoxic T-cells (Tc) cause direct damage, whereas helper T-cells (TH1) secrete cytokines that activate cytotoxic T-cells and recruit and activate monocytes and macrophages, which cause the bulk of the damage (Figure 41.2). The delayed hypersensitivity lesions mainly contain monocytes and a few T-cells. 2. Major lymphokines involved in delayed hypersensitivity reaction include monocyte chemotactic factor, interleukin-2, interferon-gamma, TNF alpha/beta, etc. 3. Diagnostic tests in vivo include delayed cutaneous reaction (e.g., Montoux test) and patch test (for contact dermatitis). In vitro tests for delayed hypersensitivity include mitogenic response, lymphocytotoxicity, and IL-2 production. 4. Corticosteroids and other immunosuppressive agents are used in treatment. Table 41.4. Delayed Hypersensitivity Reactions Type

Reaction Time

Clinical

Histology

Antigen and Site

Appearance

contact

48–72 hr

eczema

lymphocytes, followed by macrophages; edema of epidermis

epidermal (organic chemicals, poison ivy, heavy metals, etc.)

tuberculin

48–72 hr

local induration

lymphocytes, monocytes, macrophages

intradermal (tuberculin, lepromin, etc.)

granuloma

21–28 days

hardening

macrophages, epitheloid and giant cells, fibrosis

persistent antigen or foreign body presence (tuberculosis, leprosy, etc.)

456 INTEGRATIVE GASTROENTEROLOGY

Table 41.5. Comparison of Different Types of Hypersensitivity Characteristics

Type I

Type II

Type III

Type IV

(anaphylactic)

(cytotoxic)

(immune

(delayed type)

complex)

Antibody

IgE

IgG, IgM

IgG, IgM

None

Antigen

exogenous

cell surface

soluble

tissues & organs

Response Time

15–30 minutes

minutes-hours

3–8 hours

48–72 hours

Appearance

weal & flare

lysis and necrosis erythema and edema, necrosis

erythema and induration

Histology

basophils and eosinophil

antibody and complement

complement and neutrophils

monocytes and lymphocytes

Transferred with

antibody

antibody

antibody

T-cells

Examples

allergic asthma, hay fever

erythroblastosis fetalis, Goodpasture’s nephritis

SLE, farmer’s lung disease

tuberculin test, poison ivy, granuloma

SKIN PRICK TESTING

The principle behind the skin prick testing method is that sensitized tissue mast cells display IgE antibodies on their cell membranes. When specific antigens or nonspecific antigens such as lectins cross-link with the Fc receptor for IgE, the mast cell release ohistamine and other inflammatory mediators. This reaction results in a wheal and flare of the skin, marked by redness and swelling. The results of skin prick testing do not exhibit a strong correlation to food allergy symptoms.

Due to the lack of consistency of correlation of skin prick testing to symptoms, conventional allergists are beginning to abandon this test. Skin prick testing also suffers the risk of inducing anaphylaxis and false positives in patients with dermatographia and eczema to IgE ELISA (Enzyme-Linked Immunosorbent Assay) testing.

Food Reactions and Their Implications in the Irritable Bowel Syndrome

457

ELISA is reported to be more sensitive than skin prick testing in the identification of IgE-mediated food allergies. (Sampson & Albergo, 1984)

Recently, ImmunoCAP, a specific IgE blood test (Phadia, Uppsala Sweden) has been touted as a vast improvement over earlier blood allergy testing (RAST). Three hundred twenty-four patients (61% male: median age 6.1 years) were evaluated. The patients were highly atopic (57% with atopic dermatitis and 58% with asthma). Sera from the patients were analyzed for specific IgE antibodies to peanuts, tree nuts, and seeds, using ImmunoCAP Specific IgE. The majority of patients with peanut allergy were sensitized to tree nuts (86%), and documented clinical allergy was found in 34% of patients. High correlations were found between pistachio, peanut, and cashew (Maloney & Rudengren, 2008). Quantification of food-specific IgE is a valuable tool that will aid in the diagnosis of symptomatic food allergy, and might decrease the need for double-blind, placebo-controlled food challenges, the gold standard for food allergies.

FOOD CHALLENGE TESTING

The double-blind, placebo-controlled food challenge is performed with an incremental dose of food allergen, or placebo, given at 20-minute intervals while the patient is observed for objective signs of food allergy. Patients who tolerate the final dose of this challenge then undergo an open (unblinded) challenge in which a regular-size portion of the food is eaten, in order to establish tolerance. The double-blind challenge test is used routinely in research, and the incremental challenges without placebo are used in the clinical setting. (Lack, 2008) Until recently, double-blind, placebo-controlled food challenge testing has been the gold standard for IgE-mediated food allergies. However, there have been many pitfalls in this testing. 1. Time-consuming, both for patient and clinician 2. Reproducibility – this can be affected by multiple variables in the process of presentation, ingestion, and absorption of food 3. Specificity – coincidental factors are highly likely to affect outcomes 4. Sensitivity – false negative

458 INTEGRATIVE GASTROENTEROLOGY

5. Discrimination – false positives commonly occur 6. Lastly, so wide is the range of possible clinical responses, and the possible range of implicated substances, that a standardized form of testing is difficult to conceive, according to one authority (Radcliffe, 1987) 7. Mechanism of Oral Tolerance Mucosal or oral tolerance represents the most important immune response to food antigens that affords systemic hyporesponsiveness, or protection from inflammatory events and bodily disorder. The concept of oral desensitization draws its mechanism from oral tolerance. It has been known since the work of Besredka in 1909, and H. G. Wells in 1911, that animals fed soluble proteins lose their ability to respond to that specific antigen on subsequent systemic challenge (Challacombe & Tomsai, 1987).

Oral tolerance mechanics is the cornerstone of setting up a reaction, or nonreaction, against self and nonself (dietary challenge). It has been asserted that oral tolerance to dietary antigens is the result of B cells switching from IgE/IgG antibody production to IgA under the influence of cytokines. (Suen, 2004).

HYPERPERMEABILITY

The abrogation of tolerance to otherwise innocuous food proteins may well be involved in the pathogenesis of a variety of disease states (as covered in Chapter 7. Loss of mucosal barrier integrity resulting in hyperpermeability or “leaky gut” is often the first step in this loss of oral tolerance, by reducing tight junctions and basement membranes that form the cohesive bonding among the mucosal epithelial cells. Excessive stimulation of antigen-presenting cells favors overstimulation of T-helper type 1 cells, Th1 cells, and a cytokine profile that is incompatible with the induction of tolerance.

Other defense factors for the gut include low luminal pH, digestive enzymes, mucus, enteric microflora, regenerative mucosal cell rate, and glycocalyx.

A breach of any of these defense factors and loss of the integrity of the mucosa leads to aberrant antigen handling and subsequent production of

Food Reactions and Their Implications in the Irritable Bowel Syndrome

459

cytokines, allowing the induction of immunological hypersensitivity (Figure 41.3; also see Suen, 2004). Crohn’s disease, ulcerative colitis and celiac disease with loss of mucosal integrity or villous atrophy, respectively, allow loss of oral tolerance. A breach of oral tolerance may also be triggered through the use of NSAIDs (nonsteroidal anti-inflammatory drugs) which can cause microscopic and macroscopic breaks in the mucosal gut barrier to food antigens, and drives a proinflammatory immune response (Postlethwaite, 2001).

70% of the entire immune system resides in the gut, and approximately 80% of plasma cells (mainly immunoglobulin A [IgA]-bearing cells) reside in GALT.

GUT-ASSOCIATED LYMPHOID TISSUE (GALT)

The gut-associated lymphoid tissue (GALT) is the prominent part of mucosalassociated lymphoid tissue (MALT) and is the second line of defense against food antigens. As part of its protective role, GALT interacts with gastrointestinal functions in a dynamic manner. For instance, GALT can decrease intestinal permeability, orient the immune response toward luminal content, or allow either tolerance or elimination/degradation of luminal antigens. On the flip side, GALT can provoke damage to the intestinal mucosa, such as in celiac disease, inflammatory bowel disease, or food allergy (Vighi et al., 2008).

FOOD ALLERGY AND THE IGG IMMUNOGLOBULIN CLASS

The IgG immunoglobulin class has an exceptionally long half-life in circulation (serum half-lives of IgG ranging from 22 to 96 days) and constitutes about 75% of the total serum immunoglobulin pool. While IgM is involved in the primary antibody response, IgG antibodies drive the secondary antibody response. IgG antibodies are elaborated approximately one month following antigen recognition; thus, the presence of specific IgG generally corresponds to a “maturation” of the antibody response. IgG also plays an important role in antibody dependent cell-mediated cytotoxicity (ADCC) and is also associated with Type II and Type III hypersensitivity. Despite the substantial evidence to support a role for IgE in food allergy, there is considerable research supporting the role of IgG as a marker of delayed

460 INTEGRATIVE GASTROENTEROLOGY

allergy to food antigens. Repeated exposure to an antigen can eventually produce allergy-like responses or hypersensitivities. These reactions are usually delayed, with symptoms not being evident for hours or even days after the initial exposure. Since reactions to food antigens mediated by IgE are immediate, IgG antibodies drive these “delayed” reactions. The IgG antibodies may do more than just “trigger” a cascade of mediators that produce the allergy response to food. IgG antibodies have been shown experimentally to increase the permeability of the intestinal wall. Intestinal hyperpermeability has been implicated in the pathogenesis of allergic diseases, such as chronic urticaria.

Delayed Food Allergy Symptoms The symptomatic process begins with the action of food materials in the digestive tract, continues into the bloodstream, and then affects the function of any target organ that receives the food problem. For example: • Symptoms may be limited to the digestive tract—indigestion, abdominal pain, bloating, nausea, vomiting, and diarrhea. • Symptoms may be general or systemic—fever, fatigue, sweating, and chills. • The lungs are the target organ in food-induced bronchitis and asthma. • The joints are target organs in food-allergic arthritis. • Muscles and connective tissue react with pain, stiffness, and swelling. • Weakness and reduced exertional tolerance are associated with pain. • The skin reacts with itching, rashes, hives, thickening, redness, swelling, and scaling, as in eczema and psoriasis. • The brain is the target organ when disorganized, disturbed thinking, feeling, remembering, and behaving occur.

ELISA IG G DELAYED FOOD ALLERGIES (SENSITIVITY) TESTING

ELISA IgG IgE is a quantitative/semiquantitatve in vitro analysis designed to detect and quantify IgG antibodies and IgE reactive to various food proteins. In the ELISA testing method, lyophilized food proteins are immobilized by adsorption to plastic wells, and reacted with the serum portion of the individual’s blood sample. Washing is then performed, and the plate is reacted with an HRP-labeled antihuman IgG or IgE antibody conjugate. The enzyme tag horseradish peroxidase facilitates a color change upon addition of its substrate, a chromagen, to allow for easy detection of antigen–antibody interaction within the wells. The intensity of the color change is quantified via spectrophotometric

Food Reactions and Their Implications in the Irritable Bowel Syndrome

461

analysis, and is proportional to the concentration of food antigen-specific IgG or IgE antibodies present in the serum sample (Suen, 2004). The ELISA method is reported to be reproducible, reliable, and valid. (Westgard Quality Corporation, 2004).

SCIENTIFIC VALIDITY OF ELISA

Laboratory implementation of ELISA methodology for the detection of IgG and IgE food-specific antibodies must clearly identify its suitability for this purpose, in yielding reproducible and consistent results for each patient tested, on every occasion. Reproducibility is the ability of the test to reproduce the same test results for identical samples under identical test conditions. Duplicate testing provides an internal measure of control and assures reproducibility. If the testing method is precise, there should be minimal variation between the duplicate runs. Daily in-house blinded split-sample reproducibility checks constitute good laboratory practice for quality assurance. Most laboratories also participate in periodic blinded testing through an approved accredited organization to further insure reproducibility of test results.

Testing for IgG4 against Food Remains Controversial The European Academy of Allergy and Clinical Immunology (EAACI) has announced that testing for IgG4 against foods is not recommended as a diagnostic tool.

The European Academy of Allergy and Clinical Immunology (EAACI) contends that enzyme-linked immunosorbent assay-type and radioallergosorbenttype for food antigens from serum samples show positive IgG4 results without corresponding clinical symptoms. They further state that its presence should not be considered as a factor that induces hypersensitivity, but rather an indicator for immunological tolerance, linked to the activity of regulatory T-cells (Stapel, 2008).

462

INTEGRATIVE GASTROENTEROLOGY

A number of tests may be useful in identifying foods to which a patient is reactive, but no one test is likely to identify all reactive foods. (Herman & Drost, 2004)

IGG FOOD SENSITIVITY TESTING IN THE IRRITABLE BOWEL SYNDROME

Patients with irritable bowel syndrome (IBS) often report some form of dietary intolerance and self-experiment with elimination diets. The utilization of food allergy testing to predict food sensitivity in IBS has been, overall, disappointing for many years, when using IgE antibodies. Studies that support the use of IgG antibody testing and elimination diets for IBS are reviewed below.

Atkinson et al. (2004) Atkinson et al. were the first to study IgG antibodies in conjunction with elimination diets for IBS (Atkinson et al., 2004). A total of 150 outpatients with IBS at the University Hospital of South Manchester, United Kingdom, were randomized to receive, for three months, either a diet excluding all foods to which they had elevated IgG antibodies by ELISA (true diet) or a sham diet excluding the same number of foods but not those to which they had antibodies. Primary outcomes measured were changes in IBS symptom severity and global rating scores. Quality of life, anxiety/depression and non-colonic symptomatology were secondary outcomes. Results: After 12 weeks, the true diet resulted in a 10% greater reduction in symptom score than the sham diet, with a mean difference 39 (95% confidence intervals; p=0.024) with this value increasing to 26% in fully compliant patients (difference 98 (95% CI: p<0.001; see Figure 41.4.). Global rating also significantly improved in the true diet group as a whole (p=0.048) and even more in compliant patients (p=0.006). All other outcomes demonstrated trends favoring the true diet. Relaxing the diet led to a 24% greater deterioration in symptoms in those on the true diet (95% CI: 18–88); p=0.003).

Based upon their findings, Atkinson and colleagues concluded that food elimination based on IgG antibodies may be effective in reducing IBS symptoms, and is worthy of further biomedical research. (Atkinson et al., 2004)

Food Reactions and Their Implications in the Irritable Bowel Syndrome

463

Zar et al. (2005) These investigators used the same hypothesis as the previous study by Atkinson’s team, with data from dietary elimination and food challenge studies. Investigators from the St. Georges Hospital Medical School, London, compared IgG4 and IgE titers to common food antigens in IBS and controls (Zar, Benson & Kumar, 2005). Results: One hundred and eight IBS (52 diarrhea-predominant; 32 constipation-predominant; 24 alternating) and 43 controls were included in this study. IgG4 and IgE titers and skin prick testing to 16 common foods including milk, eggs, cheese, wheat, rice, potatoes, chicken, beef, pork, lamb, fish, shrimps, soya bean, yeast, tomatoes, and peanuts were measured. There was no significant difference in IgE titers to any of these foods between IBS and controls. Serum IgG4 antibodies to common foods like wheat, beef, pork, and lamb were elevated in IBS patients. In keeping with the observation in other atopic conditions, these findings suggest the possibility of similar pathophysiological role for IgG4 antibodies in IBS (Zar et al., 2005). Testing for IgE food antibodies usually is not helpful for IBS, except in a small subgroup of patients with diarrhea-predominant disease and atopy. (Whorwell & Lea, 2004).

Drisko et al. (2006) In an open label pilot study of 15 patients with irritable bowel syndrome by Rome II criteria, subjects who had failed standard medical therapy in a tertiary medical clinic at the University of Kansas Medical Center, were tested with baseline serum IgE and IgG food and mold panels, comprehensive stool analyses (CSA) and quality of life (QOL) questionnaires (Drisko et al., 2006). Patients underwent food elimination diets based on the results of food and mold panels, followed by controlled food challenge. Probiotics were also introduced, and repeat testing was performed at 6 months. McCallum and his associates followed up with cohort at 1 year after trial completion to assess the reported intervention and for placebo effect. Results: Baseline abnormalities were identified on serum IgG food and mold panels in 100% of the study subjects after food elimination and rotation diet (p<0.005). Significant improvements were documented in stool frequency (p<0.005), pain (p<0.05), and IBS-QOL scores (p<0.0001). Dysbiosis

464 INTEGRATIVE GASTROENTEROLOGY

(imbalance in gastrointestinal flora) was identified in 100% of subjects by CSA. The one-year follow-up demonstrated significant continued adherence to the food rotational diet (4.00+/-1.45), minimal symptomatic problems with IBS (4.00+/-1.17), and perception of control over IBS (4.15+/-1.23). The continued use of probiotics was considered less helpful (3.40+/- 1.60).

Yang and Li (2007)

Based on their findings, Drisko and colleagues (2006) concluded that identifying and addressing food sensitivity in IBS patients who had not responded to medical therapy can result in a sustained clinical response, which impacts on well-being and quality of life.

The therapeutic effects of eliminating allergic foods according to foodspecific IgG antibodies in irritable bowel syndrome study was conducted at Shandong Provincial Hospital in 55 cases with diarrhea-dominant IBS, 32 with constipation-dominant IBS, and 18 normal controls. Results: The positive rate of serum food-specific IgG antibodies was 63.5% in patients with diarrhea-dominant IBS and 43.8% in constipation-dominant IBS. After eliminating allergic foods, the overall health score in patients with IBS increased significantly compared to those before treatment. At the end of eight weeks, the symptoms relieved completely in 31.4% of cases and remarkably in 34.3% (Yang & Li, 2007).

Zuo et al. (2007) Thirty-seven IBS patients, 28 functional dyspepsia (FD) patients, and 20 healthy controls participated in a study of serum food antigen-specific IgG and IgE antibodies. Serum IgG and IgE antibody titers to 14 common foods including beef, chicken, codfish, corn, crab, eggs, mushroom, milk, pork, rice, shrimp, soybean, tomatoes, and wheat were analyzed by ELISA. Serum total IgE titers were also measured. Lastly, symptoms were assessed in the study. Results: IBS patients had significantly higher titers of IgG antibody to crab (P=0.000), egg (P=0.000), shrimp (P=0.000), soybean (P=0.017), and wheat (P=0.004) than controls. Serum IgG antibody titers to some common foods are increased in IBS and FD patients compared to controls (Zuo et al., 2007).

Food Reactions and Their Implications in the Irritable Bowel Syndrome

465

Ou-Yang et al. (2008) The causes of chronic diarrhea in children are complex. Food allergy is generally viewed as an important cause of this disorder, and IgG-mediated delayed allergy plays a major role in this process. Eighty-two children with chronic diarrhea and 30 healthy controls were enrolled in the study. Serum levels of specific IgG antibody to 14 kinds of food were detected using ELISA. Results: In the 82 children with chronic diarrhea, 79 (96.2%) had increased specific IgG levels for one or more of the 14 foods tested, compared to 8 (26.7%) of the controls (p <0.01). The majority of patients demonstrated increased specific IgG levels for milk (68.3%) and egg (62.2%). Only 2.4% were allergic to chicken, and no patient was allergic to pork. The symptoms were improved in 65 patients (79.3%) after 1 week to 3 months of diet treatment (Ou-Yang et al., 2008).

SHORT-TERM MANAGEMENT OF IGE FOOD ALLERGIES

Anaphylactic reactions require prompt treatment of symptoms with rapidacting antihistamines and intramuscular epinephrine, inhaled beta-agonist, and IV corticosteroids. Patients should be rapidly transported to a hospital where oxygen and IV fluids support should be given (Muraro et al., 2007).28 Intramuscular epinephrine should be administered within minutes after an allergic reaction, with the lateral thigh as the optimal route of administration. Subcutaneous or inhaled epinephrine provides suboptimal therapeutic levels of the drug (Simons, 2004).

LONG-TERM MANAGEMENT OF IGE FOOD ALLERGIES

The management of food allergies is the avoidance of the relevant food allergens. The management of multiple food allergies is often complex, and needs the help of a trained dietician in developing a plan to avoid relevant food allergens and to prevent secondary dietary deficiencies such as iron deficiency anemia, rickets, osteoporosis, and impaired growth in children (Christie et al., 2002). While subcutaneous immunotherapy is highly effective in patients with allergies to grass pollens and insect stings, this therapy has not been shown to be safe in patients with food allergies.

466

INTEGRATIVE GASTROENTEROLOGY

Table 41.6. Protective Roles for IgG in Host Defense Against Pathogens Binds to pathogens inducing immune killing Agglutination and immobilization Complement activation (classical pathway) Opsonization for phagocytosis Neutralization of bacterial toxins

Oral desensitization with egg white and other foods has some efficacy. This appears to increase the threshold dose of reactivity to the food, although the exact mechanism is uncertain (Buchanan et al., 2004). The bottom line is that food allergies, intolerances, and/or sensitivities are widespread in patients complaining of a multitude of symptoms, which they may attribute to food that they ate. Enlightened physicians or other healthcare providers, with the proper questioning, inspection of patient’s diet diary, or testing, can then provide them with an elimination diet and other dietary strategies, nutrients, vitamins, or medication to help ameliorate their symptoms. A visit to a health food store to buy organic may also be another recommendation for both patients and practitioners.

42 An Evidence-Based Review of Complementary and Integrative Approaches for Irritable Bowel Syndrome OCTAVIA PICKETT-BLAKELY, ASHWINI S. DAVISON , AND GERARD E. MULLIN

key concepts ■ ■ ■ ■ ■ ■

IBS is the most commonly diagnosed GI disorder. Patients are dissatisfied with conventional treatment of IBS. Half of IBS patients have tried CAM. Probiotics may be a key component in treating IBS. CBT is beneficial in select patients with IBS. Larger studies with well-defined outcomes are needed. ■

Introduction

I

rritable bowel syndrome (IBS) is a complex disorder of the gastrointestinal and nervous systems characterized by abdominal pain or discomfort and altered bowel habits, and is diagnosed according to Rome III criteria (Table 42.1; Camilleri et al., 2007). It is the most frequently diagnosed gastrointestinal condition, with an estimated U.S. prevalence of 10 to 15% (Thompson, 1986). In 2003, the estimated U.S. annual direct costs for IBS rose to $1.35 billion, resulting in an impact of $30 billion annually (excluding prescription and over-the-counter medications; also see Leong et al., 2003; Inadomi, Fennerty, & Bjorkman, 2003; Hulisz, 2004). IBS adversely affects quality of life (QOL) and work productivity, and is the second most common excuse for missing 467

468

INTEGRATIVE GASTROENTEROLOGY

work (Quigley et al., 2006). A survey of more than 5,000 people from U.S. households found that IBS patients missed an average of 13.4 days per year from work or school due to illness. The average subject without a GI disorder missed only 4.9 days (Drossman et al., 1993). Recent research advances have provided some insight into the pathophysiology of IBS, leading to the development of targeted medical therapy. However, over the past decade, the FDA withdrew three IBS medications (Cisapride, Alosetron and Tegaserod) from the market. As a result, many patients have been dissatisfied with the lack of conventional medical therapies for the condition. Complementary and alternative medicine (CAM) encompasses a wide range of therapeutic modalities intended for use with, or as an alternative to, traditional medical therapy. CAM may be broadly categorized into botanicals, probiotics, psychological/mind-body therapies, and manipulation (Breuner, 2006). Herbal remedies are an example of botanical therapy. Within the realm of psychological and mind–body therapies are cognitive-behavioral therapy, hypnosis, and relaxation. Acupuncture, acupressure, and reflexology are considered energy manipulation techniques. A key concern for clinicians is that CAM interventions may offer nothing more than a placebo effect. An analysis of 31 trials of CAM in IBS patients estimated the placebo response rate to be greater than 40% (Dorn et al., 2007). This rate is similar to that seen in IBS patients enrolled in other medical trials (Akehurst. & Kaltenthaler, 2001; Drossman et al., 2002). Another drawback of research of CAM in IBS is that outcome measures are often determined with symptom diaries and questionnaires, which may only partially reflect symptom relief (Meissner, Blanchard, & Malamood, 1997).

Table 42.1. Rome III Diagnostic Criteria for IBS Recurrent abdominal pain or discomfort at least 3 days per month in the last 3 months, associated with 2 or more of the following Criteria fulfilled for the last 3 months with symptoms onset at least 6 months prior to diagnosis Discomfort means an uncomfortable sensation not described as pain (adapted from Drossman, 2006)

• improvement with defecation • onset associated with a change in frequency of stool • onset associated with a change in form of stool

An Evidence-Based Review of Complementary and Integrative Approaches 469

Regardless of the efficacy of CAM for IBS, patients and practitioners are certainly interested in nonpharmacologic treatments (Cox, Lusignan, & Chan, 2004). In 1980s about 16% of IBS patients had sought out CAM practitioners (Smart, Mayberry & Atkinson, 1986). More recently, 51% of patients with IBS reported using CAM, with out-of-pocket expenditures totaling more than $34 million annually (Haas, McClain, & Varilek, 2000; Kong et al., 2005; Herman, Craig, & Caspi, 2005). In view of the public interest in CAM, and patient dissatisfaction with conventional IBS therapies, clinicians should be aware of how CAM can be integrated into a patient’s medical regimen.

METHODS

MEDLINE (OVID: 1966 through September 2007), EMBASE (OVID: 1988 through September 2007) and the Cochrane Library (OVID: Issue 1, 2007), were systematically searched for evidence relevant to this chapter. References listed within related papers and recent review articles were cross-referenced for additional citations. Searches of electronic databases combined the terms functional gastrointestinal disease, irritable bowel syndrome, IBS, complementary and alternative medicine, CAM, integrative medicine, mind-body medicine, cognitive behavioral therapy, acupuncture, hypnotherapy, botanicals, herbal therapies, herbs, energy medicine, probiotics, reflexology and yoga.

STUDY SELECTION CRITERIA

Articles selected for inclusion were randomized, controlled trials, uncontrolled trials, and anecdotal data evaluating CAM therapies in patients with IBS. We specifically included studies that reported data on at least one of the following outcomes: bowel symptoms, disease activity, adverse events, or quality of life (QOL). Practice guidelines, meta-analyses, or systematic reviews explicitly based on randomized trials related to the guideline question were also eligible for inclusion. Articles written in a language other than English were excluded.

Botanicals For centuries, botanicals have been used for medicinal purposes and are now a commonly used form of CAM (Tindle et al., 2005). The appeal of botanicals likely stems from their accessibility and perceived safety as “natural” products.

470

INTEGRATIVE GASTROENTEROLOGY

Table 42.2. Peppermint Oil for IBS Author

Design

Pts (enrolled/

Treatment

Global improvement

dropout)

period (weeks)

vs. control

Carling et.al. 3-armed, doubleblind, cross over

40/2

2

17/30 vs. 5/13

Dew et.al.

double-blind, cross over

29/nr

2

24/29 vs. 5/29

Lech et.al.

double-blind, 2 parallel groups

47/5

4

13/19 vs. 6/23

Nash et.al.

double-blind, cross over

41/8

2

13/33 vs. 17/33

Rees et.al.

double-blind, cross over

18/2

3

13/16 vs. 2/16

Lawson et.al. double-blind, cross over

25/0

4

ND

Shaw et.al

Open, 2-parallel groups

35/0

26

3/17 peppermint oil, 13/18 CBT

Schneider et.al.

double-blind, cross over

60/13

6

Pain relief p=0.03, vs. placebo

Pittler, M.H. & Ernst, E. Peppermint oil for irritable bowel syndrome: a critical review and metaanalysis. American Journal of Gastroenterology 93 (7), 1131-1135. Reprinted with permission from Pittler & Ernst (1998)

Various botanical preparations have been studied in IBS, with varied results. Peppermint is one of the most well-known botanicals shown to relieve symptoms in IBS patients (Table 42.2; also see Pittler & Ernst, 1998). Of the 75 randomized trials for combination herbal therapy identified in one systematic review, only three double-blind, placebo-controlled trials were considered to be high quality (Madisch et al., 2004; Bensoussan et al., 1998; Leung et al., 2006). A comparison of herbal formulations used in these three studies is shown in Table 42.3. In a study of 116 patients, both standard and individualized combination Chinese herbal medicine significantly improved bowel symptoms. The benefit of individualized herbal treatment was maintained at 14 weeks following completion of treatment (Bensoussan et al., 1998). Another study in 208 patients demonstrated efficacy with the herbal preparations STW 5 and STW 5-II. The most recent of the three trials randomized 119 patients to a standard preparation of traditional Chinese medicine (TCM)

An Evidence-Based Review of Complementary and Integrative Approaches 471

Table 42.3. Herbal Therapies Studied in IBS Madisch (1998)

Madisch

Bensoussan [(1998)

Leung [(2006)

STW5

STW5-II

TCM-individ, standard

TCM – standard prep

Candytuft

Candytuft

Codonopsis pilosulae

Astragalus membranaceus

Chamomile

Chamomile

Agastaches pogostemi

Atractylodes macrocephala

Peppermint

Peppermint

Coicis lachryma-jobi

Paeonia lactiflora

Caraway

Caraway

Ledebouriellae seseloids

Buplerum chinense

Licorice root

Licorice root

Glycyrrhizae uralensis

Citrus reticulata

Lemon balm

Lemon balm

Bupleurum chinense

Saposhnikovia divaricata

Celandine

Artemisiae capillaris

Murraya paniculata

Milk thistle

Atractylodis

Punica granatum

Angelica

Angelica

Portulaca oleracea

Magnoliae officinalis

Coptis chinensis

Citri reticulatae Ginger Fraxini cortex Poriae cocos Plantaginis Phellodendri Saussureae vladimirae Paeoniae lactiflora Coplidiis Schisandrae

extracts containing eleven herbs or placebo (Madisch et al., 2004). However, the use of this herbal formulation for diarrhea-predominant IBS did not improve symptoms. Unfortunately, these studies reflect the lack of consistency in formulations, mechanisms of action, and results, often seen in CAM trials. Further studies substantiating the efficacy of standard versus individualized herbal preparations for IBS would help practitioners appropriately advise patients on the efficacy of botanicals.

472 INTEGRATIVE GASTROENTEROLOGY

Probiotics Probiotics are dietary supplements containing live microorganisms that, when ingested, exert a beneficial effect on the host. Among the most commonly utilized and studied species are lactobacillus, bifidobacteria, and Saccharomyces boulardii (Quigley et al., 2006; Quigley, 2007; Quigley & Flourie, 2007). The association between IBS and small intestinal bacterial overgrowth (SIBO) is well established. Pimentel and colleagues demonstrated that successful treatment of SIBO with antibiotics improved IBS symptoms (Pimentel, Chow, & Lin, 2000). The results of randomized, controlled clinical trials using probiotics to treat IBS symptoms are shown in Table 42.4. In a study by O’Mahony et al. (2005), Bifidobacterium infantis 35624 (B. infantis) showed improvement in all IBS symptoms except stool frequency and consistency. This coincided with normalization of the proinflammatory cytokine profile (elevated IL-10/IL-12 ratio) in those patients. A confirmatory trial by the same group evaluated optimal therapeutic dosages, finding the daily, 108 cfu dose of B. infantis, given for 4 weeks, superior to alternative doses of B. infantis and placebo in improving abdominal pain and global symptom assessment scores (Whorwell et al., 2006). In the placebo group, there was decrease in composite IBS scores (6-point scale) by 1.27, versus a 2.12 point decrease in the 108 dose group (p<0.02). This study was well designed, with a practical primary end point of abdominal pain or discomfort. Similarly, a recent study in pediatric IBS patients showed that those treated with Lactobacillus GG were more likely to have treatment success and reduced frequency of pain compared to placebo (Gawronska et al., 2007). Although all of these results are provocative, the placebo response remains quite high in each of the studies. One limitation of the previously cited studies is the use of one probiotic strain. The microbial milieu of the gastrointestinal tract includes multiple species. Therefore, one could surmise that an ideal probiotic regimen aimed at treating IBS symptoms would include a mixture of organisms. Kajander et al. (2005) studied a probiotic mixture containing Lactobacillus rhamnosus GG, L. rhamnosus LC705, Bifidobacterium breve Bb99, Propionibacterium freudenreichii ssp, and Shermanii JS in IBS patients over six months. There was improvement in total symptom scores composed of abdominal pain, distension, flatulence, and borborygmi in the treatment group compared to placebo (7.7 points lower 95% CI: 13.9 to –1.6). This study differs from those previously discussed, in that the treatment period was much longer and a probiotic mixture was used. Another placebo-controlled trial comparing VSL#3 to placebo in IBS patients with significant bloating found that patients had reduced

Table 42.4. Randomized, Controlled Clinical Trials of Probiotics in the Treatment of IBS Reference

No. of patients

Probiotic(s) mixture

Treatment Period

Results

L. rhamnosus GG, L.rhamnous LC705, B. breve Bb99 and P. freudenreichii ssp. Shermanii JS

6 months

42% vs. 6% mean reduction symptom score

[30]

103

[31]

48

VSl#3

4 weeks or 8 weeks

Improved flatulence in treatment group vs. placebo

[27]

77

L. salivarius UCC4331, B. infantis 35624

8 weeks

Improved score for abdominal pain and bloating

[28]

362

B. infantis 35624 (doses 106, 108, 1010)

4 weeks

Improved global symptom score >20% vs. placebo (108 dose)

[32]

274

Bifidobacterium animalis, S. Thermophilus, L. Bulgaricus (yogurt)

6 weeks

Improved health-related QOL scores and bloating

[33]

86

L. rhamnosus GG, L. Rhamnosus Lc705, P. Freudenreichii, B. Animalis

5 months

Improved IBS score

474

INTEGRATIVE GASTROENTEROLOGY

flatulence during the treatment period (Kim et al., 2005). In this study, colonic transit was retarded in the VSL#3 group relative to placebo. More recently, fermented milk containing Bifidobacterium animalis, S. thermophilus and L. bulgaricus was compared to placebo in constipation-predominant IBS patients (Guyonnet et al., 2007). The health-related QOL discomfort score and bloating were improved in the both groups, though to a greater extent in the treatment group. A multispecies probiotic formulation used in a smaller study again showed improvement in composite IBS scores, specifically abdominal distension and pain, compared to placebo (Kajander et al., 2007). In summary, probiotics may prove to be a key component in the comprehensive approach to treating IBS. Future randomized studies should aim to enroll more participants, and should compare different probiotic mixtures to each other, as well as controls, to see if there truly are improvements in standardized endpoints.

Energy Manipulation In evaluating acupuncture as a therapeutic modality for IBS, a recent Cochrane review stated that the evidence is inconclusive given the poor quality of studies (Lim et al., 2006). After this review, Schneider and colleagues (2007) published a small randomized trial evaluating acupuncture in patients with IBS symptoms. This study used validated QOL questionnaires, including the SF-36 and FDDQL, to assess treatment response. Both groups’ (acupuncture and sham acupuncture) global QOL scores improved, with no significant difference between them. Unfortunately, this study was underpowered to detect a difference between groups. Similar findings were reported by Forbes et al. (2005). Reflexology is an ancient form of natural healing that uses pressure on the soles of the feet to evoke a change in energy flow through the body (Blunt, 2006). Reflexology points are also found in the hands, and reflect certain organs in the body. Though there have been reports in the lay press suggesting the efficacy of this modality, there are very limited data on the use of reflexology for IBS symptom management. The first trial was conducted in 34 patients in a single-blind fashion. Patients were randomized to receive six 30-minute sessions of reflexology foot massage or a non-reflexology foot massage (Tovey, 2002). There was no improvement in abdominal pain, bloating, or altered bowel habits in either group. Given the paucity of data, further randomized trials should be performed before this modality is recommended for IBS patients.

An Evidence-Based Review of Complementary and Integrative Approaches 475

Mind–Body Interventions The pathophysiology of IBS involves dysregulation of the complex interplay between the nervous system and the viscera. Visceral hypersensitivity has been demonstrated in both animal models and humans (Dizdar, Gilja, & Hausken, 2007; Mayer et al., 2007). The physiological effects of psychological and physical stressors on gut function and brain–gut interactions are mediated by outputs of the emotional motor system (Figures 42.1 and 42.2; also see Mayer et al., 2007; Mayer, Naliboff, & Chang, 2001). Studies on corticotropin-releasing hormone (CRH) have demonstrated the relationship between stress and IBS. Symptoms in IBS patients increase with CRH, and improve with CRH receptor antagonists (Heitkemper et al., 1996; Posserud et al., 2004; Sagami et al., 2004; Dinan et al., 2006). Mind–body approaches such as meditation, relaxation, hypnotherapy, and cognitive-behavioral therapy (CBT) have also been investigated for use in IBS patients. Given the aforementioned role of stress in the provocation and perception of IBS symptoms, meditation would seem to be a logical therapeutic option. Relaxation produces physiological effects characterized as the hypometabolic physiologic state (Wallace, Benson, & Wilson, 1971). The relaxation response is a physical state of deep rest that alters physical and emotional responses to stress. One form of relaxation, mindfulness-based stress reduction (MBSR), has been shown to down regulate proinflammatory cytokines elevated in IBS. Carlson et al. (2003, 2004, 2007) showed improvement in neuroendocrine function, inflammatory markers, QOL, and stress when using MBSR for cancer patients. Although there are few studies exploring meditation in IBS, one found that relaxation response meditation (RRM) was superior to placebo in improving flatulence and belching (Keefer & Blanchard, 2001). Additionally, at 3-month follow-up, improved flatulence, belching, bloating, and diarrhea persisted according to symptom diaries. One-year follow-up of this cohort showed continued reductions in abdominal pain, diarrhea, and flatulence (Keefer & Blanchard, 2002). These findings are encouraging and justify further study of meditation as a therapeutic option in IBS. There is limited data on the effect of yoga on IBS symptoms. One randomized, controlled study compared yoga to conventional treatment in patients with diarrhea-predominant IBS (Taneja et al., 2004). Twenty-two patients fulfilling Rome II criteria of IBS were randomized to two months of yoga twice daily, or to conventional treatment with loperamide daily for two months.

476

INTEGRATIVE GASTROENTEROLOGY

Although patients in both groups experienced symptom improvement, those in the yoga group had greater improvements in scores for bowel symptoms and autonomic symptoms. This study was limited by small sample size and short therapeutic duration. The external validity of the study is also of concern, given the largely male study population. A separate group studied yoga in adolescents with IBS (Kuttner et al., 2006). Twenty-five patients were randomized to either have the yoga intervention first, or to a waiting list for a later yoga intervention. After four weeks of daily yoga, patients had lower levels of functional disability and anxiety. Patients with IBS have alterations in visceral sensation and hyperalgesia that have been targeted by many different therapies (Posserud et al., 2007). Body awareness therapy (BAT) has been evaluated to help these patients deal with body image and tension. BAT focuses on reducing body tension by focusing on movements, breathing, coordination, and posture. It has been studied in female victims of sexual abuse, patients with pain disorders, and outpatient psychiatric patients (Green et al., 2001). In one trial, 12 weeks of BAT led to improvement in gastrointestinal and psychological symptoms, especially in patients with constipation-predominant IBS (Eriksson et al., 2007). A 24-week study was conducted by the same group to evaluate the effect of BAT on body tension in IBS patients (Eriksson et al., 2007). Patients received two hours of BAT over 24 weeks, with a focus on body tension during movements that are a part of daily life. In comparison to healthy controls, IBS patients had higher levels of body tension, stress markers, gastrointestinal symptoms, and psychological complaints at baseline. After 24 weeks, patients with IBS reported improvements in pain, coping ability, GI symptoms, psychological symptoms, and somatic complaints. They also had decreased saliva cortisol levels, possibly indicating a reduction in overall stress levels. Hypnotherapy is another form of CAM, in which the induction of hypnotic states is achieved by deep relaxation, mental imagery, or other techniques (Gonsalkorale, 2006; Gonsalkorale, Houghton, & Whorwell, 2002; Gonsalkorale et al., 2003; Gonsalkorale, Toner, & Whorwell, 2004; Gonsalkorale & Whorwell, 2005). Gut-directed hypnotherapy (GDH) is a more specific intervention that has been studied in IBS patients (Gonsalkorale, 2006; Gonsalkorale, Houghton, & Whorwell, 2002; Whorwell, Prior, & Faragher, 1984; Prior, Colgan, & Whorwell, 1990; Lea et al., 2003; Simren et al., 2004). Improved tolerance of rectal balloon distension has been demonstrated in patients with diarrhea-predominant IBS after GDH (Prior, Colgan, & Whorwell, 1990). The earliest RCT investigating hypnotherapy in IBS showed a more dramatic improvement in IBS symptoms of abdominal pain, distension, general well-being, and bowel habit in comparison to psychotherapy (Whorwell, Prior, & Faragher, 1984). In addition, there were no relapses noted

An Evidence-Based Review of Complementary and Integrative Approaches 477

over the course of the 3-month follow-up period. Gonsalkorale et al. published their experience in a cohort study of IBS patients undergoing hypnotherapy in a specialized center devoted to providing this service (Gonsalkorale, 2006; Gonsalkorale, Houghton, & Whorwell, 2002). Patients underwent 12 hypnotherapy sessions over the course of 3 months and were required to practice techniques between sessions. They reported marked improvement in symptom measures of pain, bowel habit dissatisfaction, bloating, and life interference. Although many of the symptom parameters were subjective, the symptom ratings of bowel habit dissatisfaction correlated with actual changes in bowel habits. A follow-up study by the same group evaluated the symptom scores more than one year after hypnotherapy and showed that 81% reported sustained clinical improvement (based on symptom scores) initially experienced with hypnotherapy (Gonsalkorale et al., 2003). There were similar improvements in quality of life, depression, and anxiety. The authors later reported that symptom improvement in IBS patients receiving GDH is associated with cognitive changes (Gonsalkorale, Toner, & Whorwell, 2004). Further studies are needed to validate hypnotherapy as a treatment for IBS patients. Cognitive-behavioral therapy (CBT) is a form of psychotherapy aiming to correct erroneous thoughts and maladaptive behavior (Toner et al., 1998). The application of CBT to IBS treatment is described in the literature (Hutton, 2005). Boyce et al. (2000, 2003) compared conventional treatment to CBT and relaxation therapy. There was no significant difference in bowel symptom frequency scores among the three treatment arms (conventional treatment alone, conventional treatment with CBT, and conventional treatment with relaxation therapy). The authors concluded that the combination of CBT and relaxation therapy offered no additional benefit over conventional medical therapy alone for IBS. Greene and Blanchard (1994) compared CBT with symptom monitoring control and noted improved composite symptom reduction and depression. A recent study by the same group compared CBT to psychoeducational support group therapy and intensive symptom monitoring (Blanchard et al., 2007). The authors reported improved gastrointestinal composite symptom scores, and individual symptoms such as bowel regularity, abdominal pain, and flatulence. Three-month follow-up data also indicated maintenance or continued improvement of all IBS symptoms. As with many IBS studies, selection bias and placebo effect must be kept in mind when interpreting these data. Indeed, highly motivated patients are more likely to seek participation in clinical trials. Additionally, underlying psychiatric illness portends a worse prognosis for response to CBT (Blanchard et al., 1992). Preexisting psychiatric disease was one exclusion criterion for the trial. Although there are indicators

478

INTEGRATIVE GASTROENTEROLOGY

that CBT is potentially beneficial in the treatment of IBS, physicians must be highly selective in deciding which patients should pursue this therapy.

Discussion IBS is a common gastrointestinal disorder that truly affects a patient’s quality of life. Current management focuses on symptom-specific therapy, but has left many patients and providers disappointed. For patients with IBS, some forms of CAM may be useful adjuncts to conventional treatments. Although there is inconsistent evidence regarding some CAM methods, patients and practitioners continue to be interested in these therapies. Primary care providers and gastroenterology specialists need to be aware of these options in order to properly advise their patients. In the future, perhaps a better approach to IBS treatment will involve a combination of CBT with conventional symptombased therapy, or a behavioral multimodality approach (Schwarz, Blanchard, & Neff, 1986). Stress, abuse, and emotional feelings influence bowel symptoms via activation of the brain’s central circuitry called the emotional motor system (EMS), to produce autonomic and neuroendocrine responses. Bowel symptoms then cause more distress, triggering the release of mediators (cytokines, cortisol and adrenaline) that act on the EMS, producing a feed-forward cycle of bowel symptoms and emotional distress.

43 Nutrition Strategies for the Treatment of IBS and the Prevention of Digestive Complaints ASHLEY KOFF

key concepts ■

■

■

■

Specific dietary choices can correct the disruption of motility that characterizes irritable bowel syndrome (IBS). An integrative approach allows today’s practitioner to move beyond recommendations of symptom management to recommendations for treatment. An anti-inflammatory diet provides the framework of the ideal dietary choices for IBS patients. Behavior modifications of IBS patients, as well as practitioners, are necessary to achieve sustainable long-term results. ■

Introduction

I

rritation of the gastrointestinal tract manifests disruptions in normal digestive function, laying the foundation for health problems as well as detracting from quality of life. Research and anecdotal evidence demonstrates a link between diet and digestive system function (Lipski, 1999). Thus, dietary modifications are an integral part of IBS treatment. Historically, protocols for irritable bowel syndrome (IBS), including diet recommendations, focused on symptom relief only and tended to be “one size fits all.” Today, the opportunity exists to employ an integrative approach to IBS that focuses on 479

480 INTEGRATIVE GASTROENTEROLOGY

treatment, with sustained digestive wellness as the achievable end goal. To eliminate digestive irritation, the practitioner must understand contributing factors and develop effective implementation strategies, taking a personalized approach.

Dietary Recommendations While the causes of IBS may not be clear, the definition, which includes “a disruption of the digestive tract’s motility resulting in chronic symptoms such as constipation, diarrhea, cramping pain, distention and flatulence,” provides key insights into how dietary choices may aid or exacerbate these symptoms. Whereas “disruption of the digestive tract’s motility. . .” hones in on a need for IBS dietary guidance to optimize motility, the latter portion of the definition (“resulting in chronic symptoms”) reveals the need to address factors that contribute to ongoing GI disturbance.

Beyond the definition, IBS recommendations must include behavior modifications—both for the practitioner and the patient—to achieve longterm, lasting results.

Thus, IBS dietary recommendations stem from a two-pronged approach: One prong examines the key words of the IBS definition, and the other prong addresses behavior modifications.

The IBS Types CONSTIPATION

Constipation can occur for different reasons: dehydration, medication, quitting smoking or caffeine, increased fiber without sufficient fluid, lack of fiber, magnesium deficiency (can be conditional or clinical), excessive calcium supplementation, lack of activity (especially that which moves the lower abdomen), menstrual cycle, or historic use of laxatives. It is important to ask the patient questions about each of these, so that recommendations can be tailored for optimal results.

Nutrition Strategies for the Treatment of IBS 481

Recommending an increase in fiber for all constipation patients is not an effective strategy. In many people, it can have the reverse, and undesirable, effect of worsening bloating and flatulence, and even constipation (Bijerk, 2004; Koff, 2005).

For these patients, it may actually be necessary to reduce fiber and suggest magnesium-rich foods, modify their supplementation, and suggest motilityenhancing stretches to yield optimal results. For IBS constipation patients, the first step is to identify the potential cause of the constipation, and then begin with individualized strategies to alleviate it.

DIARRHEA

For those patients who suffer from increased motility resulting in loose stools, frequency and bowel control issues, dietary approaches may also help achieve regularity. Diarrhea-dominant IBS patients typically reduce their dietary choices to minimal variety, and often low-nutrient density, by avoiding fiber and non-animal sources of protein and fat, and by choosing refined grains and other higher glycemic carbohydrates. While perhaps effective at managing diarrhea, such dietary choices not only fail to control symptoms in the long term, they also contribute to increased risk of other chronic diseases (e.g., obesity, diverticulosis, elevated cholesterol, heart disease, and diabetes) (McCoubrey, 2008).

The best plan for diarrhea-dominant IBS patients incorporates nutrientdense choices that help heal their digestive tract, modification of their supplementation plan to provide optimal nutrient intake, and evaluation of their diet for known gastric irritants that contribute to loose stools.

ALTERNATING

For these patients, who experience both constipation and diarrhea in alternating cycles, following any one set of dietary guidelines often results in a full pendulum swing back to their other set of symptoms. Potential areas to explore for these patients are hormonal triggers, especially menstrual cycles for

482

INTEGRATIVE GASTROENTEROLOGY

women, stress, and food allergies. Furthermore, teaching these patients to only partially modify their food and supplement intake, as symptoms shift from one to the other, may dramatically reduce the severity of their symptoms, allowing for a greater period of normalcy and ultimately enabling healing and digestive wellness.

Part 1: Core Goals: Motility Several factors, such as food processing, diet trends, nutrient quality of soils, and medication use in the last century, are collectively responsible for an exponentially negative impact on the digestive tract motility of Americans. For example, the refining of grains to flour significantly reduces its content of magnesium, a powerful motility agent. Similarly, dietary trends such as no- or lowcarbohydrate plans also affect the intake of nutrients found in carbohydrates (e.g., fiber, magnesium), which play major roles in motility. The increase in the use of preservatives—such as sugar, salt, and chemical preservatives—to achieve extended shelf stability and create ready-to-eat food options, often replaces motility-regulating nutrients found naturally foods prior to processing. The explosion of the non-water-based beverage industry contributes to dehydration, which also negatively affects digestive tract motility. Many of these beverages contain caffeine, a powerful motility agent, which further exacerbates their impact on the digestive tract’s motility control. The use of antibiotics and other medications that affect gut flora also plays a role in digestion and motility.

When the effects of any known irritant or challenge to optimal motility accumulate, the result is exponentially negative. Disruption of digestive tract motility becomes evident as constipation, diarrhea or an alternation of the two.

The following reviews nutrition recommendations to address digestive tract motility issues for IBS patients.

MINERALS

A balance of minerals is necessary for optimal cellular function, especially in the digestive tract. This applies to both food and supplement sources.

Nutrition Strategies for the Treatment of IBS 483

1. Calcium/Magnesium: While calcium has a tightening (contracting) effect on the body’s muscles, magnesium acts as Mother Nature’s muscle relaxant. Together, these two minerals create normative muscle contractions—contracting and relaxing the muscle—including those of the digestive tract responsible for normalizing bowel function. In a person suffering from chronic constipation, practitioners should first conduct an assessment of calcium and magnesium balance. As mentioned previously, food processing (especially of grains) plays a major role in magnesium reduction, as do low-carbohydrate diets, which exclude many of the richest sources of magnesium. Today’s food and health trends favor calcium dominance. Beyond reduction or elimination of magnesium-rich carbohydrates, low-carbohydrate plans include calcium-rich foods (e.g., cheese, full-fat dairy products). News reports further promote the benefits of calcium for weight loss and bone density, emphasizing food choices for patients to improve calcium intake, often without mention of magnesium. Finally, the popularity of coffee, tea drinks, and smoothies made with calciumrich and calcium-fortified beverages further increases calcium intake in the absence of magnesium. Beyond dietary choices, calcium–magnesium balance must factor into the minerals patients obtain through nutrient supplementation. Often told to take a “calcium supplement,” not a “mineral supplement,” patients unknowingly omit other minerals, including magnesium; if these products include magnesium, they often do it at a ratio of at least 2:1 in favor of calcium. When combined with dietary changes that also typically favor calcium intake, such supplementation exacerbates an imbalance that affects digestive tract motility.

For the IBS constipation patient, a needs assessment should certainly include the level of calcium necessary for maintaining bone health while balancing the need for sufficient magnesium to enable optimal motility.

Additional attention should be paid to establishing a desirable balance between dietary calcium intake (compared to magnesium), supplemental calcium, and both sources of magnesium. a. Foods rich in calcium: 1. Naturally: a. Dairy: yogurt, cheese, cream

484 INTEGRATIVE GASTROENTEROLOGY

b. Nondairy: green leafy vegetables, almonds, pistachios, blackstrap molasses, broccoli, figs, tofu, sea vegetables 2. Fortified: orange juice, milk alternatives (rice, soy, etc.), English muffins, breads, cereals b. Foods & Supplement sources of magnesium: 1. Leafy greens (arugula, spinach, Swiss chard), seeds (pumpkin, sesame, flaxseed, sunflower), tahini, summer squash, okra, barley, salmon, quinoa, beans (black, pinto), dried unsweetened coconut, chocolate (cacao) 2. Supplements: glycinate and citrate; Natural Calm 2. Sodium/Potassium: The balance of these minerals affects cellular hydration, with potassium responsible for maintaining intracellular hydration and sodium responsible for extracellular water balance. Hydration plays a critical role in the optimal functioning of the digestive tract. If a patient’s diet is potassium deficient or sodium rich (creating a conditional potassium deficiency), dehydration will inhibit optimal function of the colon. Many patients turn to laxatives to address this issue, but optimizing potassium/sodium balance and, of course, improving overall water intake, can produce positive results by enabling the body’s normal cellular function. a. Foods rich in potassium: coconut water, spinach, tomatoes, cantaloupe, papaya, carrots, beets, winter squash, white potato, banana, yogurt b. Foods high in sodium: salt, processed foods, soups, sauces, soda, pickled and cured foods (pickles, olives, hot dogs, jerky), soft drinks, sparkling water 3. Iron: This mineral is critical for cell growth and function. During certain life stages (childhood, adolescence, pregnancy), the body’s increased needs may require additional intake of iron-rich foods and/ or supplementation. Additionally, many vegan and vegetarian patients supplement their food intake with iron; this issue has increased relevance with growing awareness of the health benefits of vegetarian choices.

While increased consumption of iron-rich foods doesn’t commonly generate constipation, the opposite is true of iron supplementation; constipation is a known side effect.

Nutrition Strategies for the Treatment of IBS 485

The benefit of combining vitamin C-rich foods with iron-rich foods goes beyond increasing absorption of the iron; it can also help minimize the iron’s constipating effect. Supplement manufacturers have taken advantage of this knowledge by creating an iron supplement that is known to be effective without creating constipation in most people (Floradix). a. Foods rich in iron: shrimp, venison, beef, calf ’s liver, greens (spinach, chard), cooked beans, sesame seeds b. Foods rich in vitamin C: bell peppers, parsley, broccoli, strawberries, lemon juice, cauliflower, papaya, kiwi, orange, cantaloupe, raspberries, pineapple, green beans, kale Fiber, stimulants, water, lubricants, and chemical compounds all affect motility as well.

FIBER

The kind and quantity of fiber, as well as the frequency of intake, play important roles in motility. This can be both positive and negative for IBS patients. While daily fiber intake is critical to regularity and digestive health, the type of fiber one introduces to an irritated bowel—and how one introduces it—can mean the difference between success and distress. The following provides the keys to success for fiber introduction for IBS patients: 1. Fiber intake basics (even for the non-IBS patient) a. Introduce in small increments, whether in food form or supplement (Miskovitz, 2005). For example, begin with a baked apple without the skin, then baked apple with the skin, then a fresh apple with the skin; or, half a teaspoon of a supplement daily for a week, then half or one teaspoon twice daily, and so on. b. Adding fiber to a dehydrated system will prove unsuccessful. The fiber requires moisture to move throughout the digestive tract. (In some instances, this technique has been used to help the loosestool patient decrease bowel movement frequency. This strategy should not be used long term.) 2. IBS-specific a. Limit wheat bran (Lipski, 1999). Wheat tops the list of known shared irritants among IBS patients, so supplementing with it is counterintuitive (Francis, 1994).

486

INTEGRATIVE GASTROENTEROLOGY

b. Use different fibers (emphasize soluble fiber) for constipation (oat bran, flaxseed, psyllium, etc.) versus diarrhea (rice bran) (Bijerk, 2004). c. Many IBS sufferers feel their worst in the morning. Adding fiber to an acutely irritated system may be less successful than incorporating it throughout the day, or taking a supplement at night. The following is a list of recommended fiber-rich foods and supplements: 1. Fiber-rich foods: berries, greens, beans (smaller beans are usually better for IBS patients), apples, pears, oats, flaxseeds 2. Fiber supplements: Citrucel, Genesis Today 4 Fiber, Konsyl, Fiber Choice, oat bran, rice bran, psyllium

WATER

The digestive tract requires water to facilitate nutrient absorption and cellular activity, including muscle contractions and waste removal (Miskovitz, 2005). Yet many people consume insufficient quantities of water. Two common issues arise: First, many complain that they don’t like the taste of water. Second, they are confused about how much water to consume. With regard to the first issue, partial blame rests with the popularity of non-water-based beverages, to which the “taste” of water may pale by comparison. To resolve confusion about the right amount of water and to obtain actionable results, patients should be given their desirable water intake. Identifying what’s desirable for each individual also takes into account hydration needs, overall health benefits of exchanges (non-water-based beverages to water-based ones, reduction of stimulants, etc.), and what feels doable to them without generating stress. (Having to go to the bathroom more frequently, even if to urinate, may not be well received by, nor beneficial for, IBS patients if it produces additional stress). The majority of “good-tasting” beverages play a role in health issues, such as obesity and chronic disease. These products (even artificially sweetened, noncaloric ones) raise the bar for satisfaction by acclimating taste buds to higher intensities of sweetness or flavor than exist naturally. These beverages can overwhelm the digestive tract, contribute to gas and bloating, and feed bad bacteria. They are not a significant source of fiber, which further contributes to digestive tract “laziness” and may yield energy storage (fat), encourage suboptimal blood sugar levels, and hamper optimal digestion.

Nutrition Strategies for the Treatment of IBS 487

The following water-based beverages and foods can help patients increase their daily water intake: 1. Water-based beverages: herbal tea, water with lemon/lime juice (1 oz. juice to 8 oz. water) 2. Water-based foods: cucumber, celery, tomatoes, iceberg lettuce, bamboo shoots, apple, watermelon, homemade broth (made with water and spices, not salt)

LUBRICANTS

Lubricant foods and herbs help the stool move through the digestive tract. Known as demulcents, these herbs, seeds, and oils lubricate the digestive tract, thereby relieving irritation. Practitioners should teach patients to incorporate demulcents into their meals, as well as to explore the use of herbal supplements. 1. Demulcents: okra, flaxseed, oat, kelp, cactus, natto, toasted sesame oil, olive oil, acacia, chia seeds.

CHEMICAL COMPOUNDS

Chemical compounds are a significant factor in motility disruption. Numerous medications, either intentionally or as a side effect, override the body’s motility-regulating capabilities. Consider other sources of chemicals, as well as natural stimulants, that a patient may consume regularly or that the patient used to consume regularly.

Caffeine, nicotine, and herbal laxatives are all stimulants and thereby affect the motility of the digestive tract. The digestive tract appears to adapt to the routine use of these substances, thus developing a reliance on the substance for motility messages.

The problem intensifies when patients discontinue their intake of these substances. Without adequate support, food choices, and possible nutrient supplementation prior to or during discontinuation, digestive tract motility may simply stall, producing or worsening constipation. It can take a great deal

488

INTEGRATIVE GASTROENTEROLOGY

of effort to retrain the body’s signaling and response. The chronic consumption of medications that affect the GI, and the use of stimulants, can have a singular or cumulative effect on a patient’s GI motility.

Part 2: Factors that Result in Chronic Symptoms The “chronic” nature of gastrointestinal disturbances in the absence of structural dysfunction satisfies the criteria for an IBS diagnosis. To identify and address the root causes of ongoing digestive irritation, practitioners must evaluate the patient for frequent consumption of known gastric irritants, potential food allergies, gut dysbiosis, and subclinical inflammation. A multifactorial approach allows the provider to address the patient’s symptoms and to make significant inroads on the healing path to digestive wellness. 1. Known Gastric Irritants and Food Allergies Research shows that IBS sufferers appear to share certain factors that contribute to chronic irritation of the digestive tract. While IBS patients may have individual intolerances, several intolerances appear to occur in the majority of patients (Lipski, 1999).

The most common irritants, or “triggers,” include wheat, corn, alcohol, dairy, coffee, caffeine (including chocolate), citrus fruits, sugar, and sugar alcohols (Koff, 2005).

For guidance on teaching patients about modification options, see the “Usual Suspects” section of Recipes for IBS (Koff, 2005). Many practitioners and patients should also consider food allergy testing. Anecdotally, I find the majority of IBS patients initially intolerant to a wide range of foods (often confirmed by testing), with their list typically including foods frequently consumed. Because these are IBS patients and their digestive systems are irritated, it follows that the body may not tolerate a majority of the food introduced into it. Thus, before testing for food allergies (which can be costly and overwhelming), I recommend trial eliminations or reductions of known irritants, while simultaneously addressing the motility issues as previously discussed. Additional trial eliminations can be used on a case basis, with care taken to maintain a nutrient-rich nutrition plan.

Nutrition Strategies for the Treatment of IBS 489

2. Gut Dysbiosis Dietary choices, antibiotic use, and low-grade antibiotic exposure collectively contribute to the potential for a gut flora imbalance. Discussed elsewhere in this book by Dr. Gerald Friedman (Chapter 29), probiotic supplementation should be part of the treatment for IBS. Clinical research demonstrates the value of strain specificity in the selection of the right probiotic (Huffnagle,2007). The Bifantis strain appears to be the sole probiotic strain to address the entire spectrum of IBS symptoms. Food sources alone will likely not yield the same results as probiotic supplementation for IBS patients, for two reasons. First, many probiotic-containing foods and food products fall under the “known irritants” food list. Second, the quantity of probiotic shown to be effective for IBS patients proves challenging to consume in foods. Appropriate food sources of probiotics still should be used to improve overall gut flora balance (Wald, 2008). Food sources of probiotics and prebiotics include: a. probiotic (natural): cultured (fermented) vegetables, kimchi, raw sauerkraut, yogurt, dairy kefir, coconut water kefir, fermented soy (tempeh, miso, natto) b. prebiotic: Jerusalem artichoke, chicory root, asparagus, oats, raw honey, barley, flaxseeds (ground), onions 3. Inflammation It is increasingly apparent that an anti-inflammatory diet is best for patients suffering from IBS (Huffnagle, 2007). As Dr. Andrew Weil (2005) discusses in his book, Healthy Aging, there is increasing acceptance by the scientific community that subclinical inflammation plays a role in “so-called functional diseases (where there is) real suffering without objective changes in body structure that physicians can document.” Historically, patients with digestive disturbances avoid whole categories of nutrient-rich foods in an effort to minimize their symptoms (McCoubrey, 2008). Such efforts likely shift the balance away from an anti-inflammatory approach to one where nutrient-poor choices and a lack of variety promote increased risk for chronic disease. In essence, the danger of an IBS patient’s dietary plan that only focuses on how to reduce symptoms is that such a dietary plan likely increases the patient’s risk for chronic disease. Because chronic inflammation plays a role in IBS, patients would benefit an anti-inflammatory diet which focuses on the quality of macronutrients to achieve nutrition for optimal health.

490 INTEGRATIVE GASTROENTEROLOGY

At the core of an anti-inflammatory diet is the notion of choice: The foods one chooses not to eat are equally important as what one does eat. What does emphasizing choice mean? It means that the patient isn’t told he or she can’t eat certain foods. Rather, with education about how certain foods affect their system, patients choose to include healing foods most often and choose not to eat (or to eat less often) those foods likely to produce or exacerbate irritation.

Part 3: Behavior Modifications for Long-Term Results An irritated digestive system needs time off to heal. It is critical to explore how to accomplish the dietary recommendations for IBS, which focus on getting the necessary nutrients, while simultaneously learning to keep the gut underwhelmed. Achieving and maintaining an underwhelmed digestive tract is the key dietary objective for IBS sufferers, regardless of their IBS “type.” This section provides implementation strategies for necessary behavior modifications. • Aim to achieve a consistent nutrient supply. When a patient consumes nutrients at regular intervals, the body does not have to function at an energy deficit, which helps minimize irritation. In an energy deficit, the body sends urgent messages for energy, thus creating potential traps such as refined carbohydrate cravings, caffeine and soda consumption, and excessive nutrient intake. To achieve regular intervals of intake, use the analogy that the body is designed like a race car—it routinely needs nutrient-balanced pit stops at regular intervals throughout the day.

In my practice, I don’t use the terms “meal” or “snack.” Instead, I use “eating occasion,” which correctly focuses the patient on the desired goal—taking in nutrients—rather than focusing on portion size and time of day. Example: “We want an eating occasion within 45 minutes of waking up” versus “Eat breakfast.” An eating occasion can be soup, a beverage, fish and vegetables, but breakfast often connotes a “breakfast” food such as high-fiber cereal, muffin, juice, etc. • Aim for macronutrient balance at each “eating occasion.” Understanding and implementing macronutrient balance at each “eating occasion” helps generate physiologic as well as mental satisfaction. Practitioners should first teach patients what fats, carbohydrates, and

Nutrition Strategies for the Treatment of IBS 491

proteins are, where they are found, and portion sizes to help patients view foods as providers of nutrient complexes that offer energy and taste, and support the body’s numerous functions. Example: Choose half a sandwich and salad; then, three hours later, have a piece of fruit with peanut butter—instead of eating a whole sandwich and an apple at once. • Improve eating mechanics. Adjusting one’s eating mechanics is seemingly the simplest change, and one that yields significant results. However, it is also the one modification (or series of modifications) with which patients struggle the most. It requires undoing years of habits and environmental influences. With busy lives, it can be difficult to learn to slow down. That certainly applies to eating mechanics. Chewing, taking smaller bites, and pausing between bites will improve digestion and absorption almost immediately (Lipski, 1999). Similarly, behaviors such as drinking with straws or guzzling directly from a bottle can translate to added bloating or flatulence. When advising patients to modify their eating mechanics, providing explanations instead of listing foods and behaviors on a “No” list should dramatically improve compliance. Examples: a. Instead of saying, “no Perrier,” advise patients that they should “Limit carbonated beverages, as taking in gas is likely to produce more gas.” Suggest that patients drink iced herbal tea, or add lemon or lime to flat water, as their regular beverage choices; not only will eliminating the carbonation reduce irritation, but the herbal tea, lemon, and limes help improve digestion. b. Instead of saying, “Chew more slowly,” say “Chew more, because your teeth help break down the food so that it comes through your digestive tract in a form that is easier for your system to use. If you are in a rush, choose items that require less chewing, such as soups, scrambled eggs, mashed or cooked vegetables (versus raw) or oatmeal.” • Create awareness. While IBS affects millions of Americans, each person’s digestive tract is his or her own, and his or hers to explore. Using a food–symptom journal can help each patient refine general IBS nutrition guidelines into a personalized nutrition plan. Personalization is the key to long-term digestive wellness for optimal health.

492

INTEGRATIVE GASTROENTEROLOGY

• Practitioners also need behavior modifications. Our patients aren’t the only ones whose habits have built up over the years. The key is to shift to a teaching role versus a prescribing role. In doing so, patients receive education, which empowers them and enables them to make choices. To accomplish this, practitioners need resources and references such as those presented in this book.

Conclusion An exploration of the multifactorial dietary influences on the digestive tract demonstrates the potential impact for IBS recommendations to move beyond symptom management to effective treatment for sustained digestive wellness. The dietary recommendations described should allow the practitioner to identify areas of opportunity for each patient that, in concert with other recommendations, lay the foundation for a healing plan for digestive wellness and optimal health.

44 Alternative Approaches to the Patient with Inflammatory Bowel Disease LEO GALLAND, KATARZYNA KINES , AND GERARD E. MULLIN

key concepts ■

■

■

■

■

■

Inflammatory bowel disease (IBD) is characterized by idiopathic chronic intestinal inflammation, oxidative injury to tissues, and frequent nutritional deficiencies. Impairments in tissue antioxidant defenses poses vulnerability threats to uninvolved intestine–supplementation with antioxidants may help spare further damage. Functional foods and nutraceuticals attenuate inflammatory mediators such as tumor necrosis factor alpha (TNF-α) and nuclear factor kappa beta (NFkB). Supplementation should be considered for patients with IBD. Probiotics can direct the immune system toward a favorable response in IBD and the data supports its efficacy and safety. Prebiotics derived from food can support and sustain the growth of beneficial/friendly bacteria. Research studies show that prebiotics can induce remission and maintain response in colonic disease. Therapeutic modalities that integrate anti-inflammatory nutrients into the diet of patients with IBD should be considered by clinicians who manage these complex and challenging diseases. ■

493

Introduction

C

rohn’s disease (CD) and ulcerative colitis (UC) are chronic intestinal diseases that have in common uncontrolled intestinal inflammation and mucosal injury causing systemic illness, poor quality of life, immunosuppressant medication use, surgical intervention, and an increased risk for gastrointestinal and systemic cancer(s). The gross and histological lesions associated with IBD are thought to result from an inappropriate activation of the mucosal immune system, causing the release of noxious biochemicals with consequent tissue injury and intestinal symptoms. There are a multitude of theories as to the etiology and pathogenesis of IBD. The common thread is a genetically improperly programmed overactive immune response, after an initial insult to the gut (Figure 44.1).

In CD, genetic variants confer susceptibility vis-a-vis the immune system’s interaction and reaction to constituent enteric flora along with regulatory defects in the mucosal immune response. Ultimately a breakdown of the protective mucosal barrier that separates immune response cells from the contents of the intestinal lumen occurs which drives the process in a feed-forward manner. The normal floras of the gut lumen act as triggers for the inflammatory response and appear to play a central role in pathogenesis (Podolsky, 2002). In both Crohn’s disease and ulcerative colitis, an increased number of surfaceadherent and intracellular bacteria have been observed in mucosal biopsies (Darfeuille-Michaud et al., 1998; Swidinski et al., 2002). The immune responses provoked by these bacteria, however, are different in the two disorders (MacDonald, DiSabatino, & Gordon, 2005). In Crohn’s Disease, the immune response in CD is driven by lymphocytes with a type 1 helper-T-cell (TH1) phenotype and their cytokines: interleukin-2 (IL-2) and gamma-interferon (γ−IFN). These TH-1 products promote a selfsustaining cycle macrophage activation that includes interleukin 12 (IL-12), which further increases TH-1 activity, interleukins 1 and 6 (IL-1, IL-6) and tumor necrosis factor alpha (TNF-α), which create a broader inflammatory response. Ulcerative colitis is associated with lymphocytes that organize the inflammatory response in UC demonstrate an atypical type 2 helper-T-cell (TH2) phenotype, with interleukin-5 (IL-5) as a distinctive cytokine mediator (Fuss et al., 1996).

Alternative Approaches to the Patient with Inflammatory Bowel Disease 495

Malnutrition is a major reversible complication of inflammatory bowel disease (IBD). The mechanisms of malnutrition include: • anorexia resulting from the systemic effects of IL-1 • a catabolic state induced by TNF-alpha • malabsorption due to disease or surgical resection • nutrient losses through the inflamed and ulcerated gut • small bowel bacterial overgrowth resulting from strictures or fistulas • increased nutrient utilization and requirement due to higher intestinal cell turnover, inflammation, fever, and infection • Blood loss or wound healing requirements • the side effects of drug therapy (Gassull, 2003)

• Inflammation increases oxidative stress in the bowel mucosa and decreases levels of antioxidants (Figure 44.3; see Simmonds & Rampton, 1993). • Zinc and copper, or the zinc-dependent and copper-dependent enzyme, superoxide dismutase (Cu-Zn SOD), are reduced in mucosal biopsies from patients with both types of IBD (Lih-Brody et al., 1996). • Oxidative stress caused by inflammation decreases the mucosal concentration of vitamin C (Buffinton & Doe, 1995). • Plasma levels of vitamins A and E are lower, and plasma levels of the oxidative stress marker, 8-hydroxy-deoxy-guanosine (8-OHdG) are higher, in IBD patients than in controls (D’Odorico et al., 2001). • Compared to controls, children and adults with IBD have lower blood levels of zinc and selenium, mineral cofactors of antioxidant enzymes (Ojuawo & Keith, 2002; Hendricks & Walker, 1988; Hinks, Inwards, Lloyd, & Clayton, 1988). • Adults with UC may show lower levels of beta-carotene, magnesium, selenium, and zinc (Geerling, Badart-Smook, Stockbrugger, & Brummer, 2000). • Micronutrient deficits may favor self-perpetuation of IBD by causing defects in the mechanisms of tissue repair (Gassull, 2004). Micronutrient deficiencies may also contribute to some complications of IBD, such as growth retardation, osteopenia, urolithiasis, and thromboembolic phenomena (Gassull, 2003).

In CD, abnormal mucosal barrier function may play a primary role in pathogenesis. • Small intestinal permeability is increased among healthy first-degree relatives of patients with CD (Hollander et al., 1986) and is increased in noninflamed enteric tissue obtained from patients (Peeters et al., 1994).

496

INTEGRATIVE GASTROENTEROLOGY

• Aspirin, a drug which increases intestinal permeability of healthy controls, causes an exaggerated increase in intestinal permeability of first-degree relatives of patients with CD (Hilsden, Meddings, & Sutherland, 1995). • The rate of relapse among patients who have entered remission is directly proportional to the degree of small intestinal hyperpermeability measured with chemical probes (Wyatt et al., 1993). • Hyperpermeability is associated with polymorphism of genes, associated with regulation of epithelial barrier function (MacDonald, DiSabatino, & Gordon, 2005); it increases exposure of the intestinal immune system to luminal antigens.

DIETARY ASSOCIATIONS AND IBD

No consensus has emerged, however, regarding the role of dietary patterns as antecedents of inflammatory bowel disease (Loftus, 2004). Increased refined sugar intake and high overall carbohydrate intake has been associated with the development of Crohn’s disease (Reif et al.,1997). Increased consumption of chemically modified fats (such as those found in margarine) may be involved in the etiology of ulcerative colitis (Epidemiology Group, 1994). High consumption of a fast food diet is an antecedent of both ulcerative colitis and Crohn’s disease (Persson, Ahlbom, & Hellers, 1992). There is an inverse association between dietary intake of vegetables, fruits, fish, fiber, and omega-3 fatty acids, and the subsequent development of Crohn’s disease in children (Amre et al., 2007). Interestingly, studies in Japan indicate that the rise in CD in Japan strongly correlates with increased total fat, animal fat, ratio of omega-6 to omega-3, with increased animal protein (but not fish protein) being the strongest independent factor. It inversely correlates with vegetable protein (Shoda et al., 1996).

FORMULA FEEDING AND IBD

Short duration of breastfeeding or the absence of breastfeeding) may be an antecedent of inflammatory bowel disease. Breastfeeding may protect against enteric infections during infancy, aid with early development of a competent gastrointestinal immune system, or delay exposure to foreign antigens such as cow’s milk. Several studies have found that people who develop inflammatory bowel disease are less likely to have been breastfed than controls (Cashman & Shanahan, 2003; O’Sullivan & O’Morain, 2006). Intolerance to cow’s milk has also been implicated as antecedent precursor of IBD although the data are somewhat conflicting

Alternative Approaches to the Patient with Inflammatory Bowel Disease 497

(Cashman & Shanahan, 2003). Patients with a history of milk allergy during infancy who subsequently developed ulcerative colitis did so at an earlier age than those without a history of milk allergy (Glassman, Newman, Berezin, & Gryboski, 1990). Allergy to milk proteins still remains a possible cause of dairy sensitivity or milk intolerance in a small percentage of inflammatory bowel disease patients. Several studies have demonstrated an association between allergic symptoms asthma, rhinitis, and the subsequent development of inflammatory bowel disease, particularly ulcerative colitis (Ceyhan, Karakurt, Cevik, & Sungur, 2003; D’Arienzo et al., 2002; Weng, Liu, Barcellos, Allison, & Herrinton, 2007).

INTESTINAL PERMEABILITY AND IBD

The intestinal mucosal barrier has evolved to maintain a delicate balance between absorbing essential nutrients while preventing the entry and responding to harmful contents. In IBD, disruptions of essential elements of the intestinal barrier lead to permeability defects, immune system activation resulting in tissue damage. The epithelial phenotype in active IBD is very similar in CD and UC. It is characterized by increased secretion of chloride and water, leading to diarrhea, increased permeability via both the transcellular and paracellular routes, and increased apoptosis of epithelial cells. Abnormal gut permeability is a feature of established Crohn’s Disease whether active or quiescent (Buhner et al., 2006; D’Inca et al., 2006). Relatives of patients with Crohn’s Disease demonstrated increased permeability suggesting that increased permeability is an antecedent of disease while hyperpermeability has been shown to precede the development of frank disease (Irvine & Marshall, 2000). Therapeutic restoration of the mucosal barrier could conceivably protect and prevent antigenic overload of the mucosal immune system due to intestinal “leakiness (Salim SY, Soderholm JD, 2010).

LOW VITAMIN D STATUS AND IBD

Vitamin D is now widely recognized as a regulator of the immune system. Vitamin D is an immunoregulatory biochemical which acts in part by inducing T regulatory cells to downregulate TH-1 responses. Deficiency of vitamin D may also be antecedent precursor of inflammatory bowel disease (Lim, Hanauer, & Li, 2005). Epidemiologic studies have observed that the incidence of inflammatory bowel disease is higher in populations with lower vitamin D levels (northern latitudes) and relapses occur more commonly in autumn and winter months, when levels of sunlight are low. Experimental evidence of a possible role of vitamin D in IBD stems from work in animal models of the

498

INTEGRATIVE GASTROENTEROLOGY

disease whereby the active form of this nutrientinhibits the development of inflammatory bowel disease (Froicu & Cantorna, 2007). Furthermore, the absence of the vitamin D receptor is associated with activation of the innate immune system and the development of colitis. Clinical trials utilizing vitamin D as a therapeutic intervention are presently underway. A recent trial of vitamin D for Crohn’s Disease showed that supplementation with 1200 international units of vitamin D3 significantly increased serum vitamin D levels and reduced the risk of relapse from 29% to 13%, (P = 0.06) (Jørgensen SP, Agnholt J, Glerup H et al., 2010). Larger studies are required.

OTHER FACTORS THOUGHT TO BE PRECURSORS OF INFLAMMATORY BOWEL DISEASE

• Oral contraceptives or hormone replacement therapy (Godet, May, & Sutherland, 1995) • Perinatal passive smoke exposure (Russell et al., 2005) • Childhood smoke exposure (passive or active; see Mahid, Minor, Stromberg, & Galandiuk, 2007) • Smoking (for Crohn’s disease; see Cosnes, 2004) • Prematurity (but not mode of delivery; see Sonntag et al., 2007) • Appendectomy (for Crohn’s disease; see Cosnes, Seksik, NionLarmurier, Beaugerie, & Gendre, 2006) • Treatment of acne with isotretinoin (Reddy, Siegel, Sands, & Kane, 2006)

Alternative Therapies The specific carbohydrate diet (www.scd.org) is a food-based approach to enteral nutrition for patients with inflammatory bowel disease that has been used by patients with CD and UC, with anecdotal reports of long-term remission without medication (Nieves & Jackson, 2004).

SPECIAL DIETS USED FOR IBD

The Specific Carbohydrate Diet for Crohn’s Disease The specific carbohydrate diet (SCD) is a strict grain-free, lactose-free and sucrose-free diet that was designed for people with Crohn’s disease, ulcerative

Alternative Approaches to the Patient with Inflammatory Bowel Disease 499

colitis, celiac disease, inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). The specific carbohydrate diet was developed by Sydney Valentine Haas, MD. Elaine Gottschall helped to popularize the diet after using it to help her daughter recover from ulcerative colitis leading her to write a book Breaking the Vicious Cycle: Intestinal Health Through Diet (Gottschall, 1994). The purported mechanism of action of enteral feeding as therapy for IBD is related to improvement of nutritional status, favorable alteration in ileocecal flora and fermentation by the proper choice of nutritious sources of carbohydrate (Gottschall, 1994). The SCD is far more effective for patients with CD than UC. In practice, the SCD consists of meat, poultry, fish, eggs, most vegetables and fruits, nut flours, aged cheese, homemade yogurt, and honey. Forbidden foods include all cereal grains and their derivatives (including sweeteners other than honey), legumes, potatoes, lactose-containing dairy products and sucrose. Related studies have found that high sucrose intake predisposed to CD (Matsui et al., 1990; Martini & Brandes, 1976; Thurnton, Emmett, & Heaton, 1979; Mayberry, Rhodfes, & Newcombe,) and that control of disease was enhanced by its avoidance (Heaton, Thornton, & Emmett, 1979).

FODMAPs and Crohn’s Disease A new hypothesis is proposed, by which excessive delivery of highly fermentable but poorly absorbed short-chain carbohydrates and polyols (designated FODMAPs–Fermentable Oligo-, Di- and Mono-saccharides And Polyols) to the distal small intestinal and colonic lumen is a dietary factor underlying susceptibility to Crohn’s disease. The subsequent rapid fermentation of FODMAPs in the distal small and proximal large intestine induces conditions in the bowel that lead to increased intestinal permeability, a predisposing factor to the development of Crohn’s disease. Evidence supporting this hypothesis includes the increasing intake of FODMAPs in western societies, the association of increased intake of sugars in the development of Crohn’s disease, and the previously documented effects of the ingestion of excessive FODMAPs on the bowel (Gibson PR, Shepard SJ, 2005).

Effective diet therapy for IBD must be individualized according to food preferences and diagnosis. Patients with CD are more likely to be food-sensitive than patients with UC.

500

INTEGRATIVE GASTROENTEROLOGY

Diets that induce remission of CD do not usually induce remission of UC, although they improve patients’ nutritional status and prevent complications related to surgery. Recent dietary approaches to treatment of UC have examined the therapeutic potential of short-chain fatty acids (SCFA), butyric acid in particular (Dionne et al., 1998). SCFA’s: Nourish the colonic epithelium, lower intraluminal pH, favor the growth of Lactobacilli and Bifidobacteria (considered to be beneficial organisms, or probiotics) and inhibit the growth of Clostridia, Bacteroides, and Escherichia coli, potential pathogens. In addition to serving as the preferred energy substrate for colonic epithelial cells, butyrate has a true anti-inflammatory effect, preventing activation of the proinflammatory nuclear transcription factor, NF-k-B (Inan et al., 2000). When added to 5-ASA enemas, butyrate (80 mM per liter), induces remission in ulcerative proctitis that is resistant to combined 5-ASA/hydrocortisone enemas (Vernia et al., 2003). Because butyrate is normally produced by bacterial fermentation of indigestible carbohydrate in the colon, studies have examined the effect of fiber supplementation on the course of UC. These studies are described below in the section on Prebiotics (Table 44.1).

Table 44.1. Prebiotics in Ulcerative Colitis Author

Fiber

Study

Outcome

Fernandez- 1999 Banares

Plantago Ovata seed fiber 10 gm

Fiber +/Mesalamine

= to Mesalamine

Kanauchi

2002 2003

30 gm barley

Mod to active UC

Hallert

2003

Oat bran 60 gm (20gm fiber)

In remission

Inulin 24 gm

IAPA

Welters

Year

2002

disease activity abd pain Increase fecal butyrate pouch inflammation

In these four RCTs, prebiotics were looked at for their effect on ulcerative colitis. The rationale for performing these studies is that short-chain fatty acids (acetate, propionate, butyrate), which are metabolized into acetyl CoA and are the primary energy source for the colon and necessary to maintain integrity, are deficient in ulcerative colitis. As you can see in this table, in all four studies patients benefited from using prebiotics. NB: Barley foodstuffs are also very high in glutamine, which may benefit the small bowel as a primary fuel source.

Alternative Approaches to the Patient with Inflammatory Bowel Disease 501

Low Sulfur Diet in UC • Patients with UC are not deficient in butyrate, but appear unable to utilize it, perhaps because organic sulfides produced by their enteric flora inhibit the epithelial effects of butyrate (Roediger, Duncan, Kapaniris, & Millard, 1997; Roediger, Moore, & Babidge, 1997). • Protein consumption is a major determinant of sulfide production in the human colon (Magee, Richardson, Hughes, & Cummings, 2000). • For patients with UC in remission, the risk of relapse is directly influenced by higher consumption of protein, especially meat protein, and by total dietary sulfur, and sulfates (Jowett et al., 2004). • A low sulfur diet has been advocated for maintenance of remission in UC. • The low sulfur diet, which is markedly different from the specific carbohydrate diet used for treatment of CD, eliminates beef, pork, eggs, cheese, whole milk, ice cream, mayonnaise, soy milk, mineral water, nuts, cruciferous vegetables, and sulfited alcoholic beverages. • Controlled studies have not been performed, but a small preliminary study demonstrated the feasibility and safety of a low sulfur diet for patients with UC over a 5-year period (Roediger, 1998).

The differences in dietary response patterns between patients with CD and patients with UC make clarity of diagnosis essential for proper nutritional therapy. EXCLUSION DIETS

Exclusion diets eliminate specific symptom-producing foods and have been used to maintain remission of a number of digestive diseases including the irritable bowel syndrome (IBS) and IBD.

Crohn’s Disease and Exclusion Diets Although self-reported food intolerance is common among patients with IBD (Ballegaard et al., 1997), most of the data from controlled studies has been gathered from patients with CD.

The East Anglia Multicenter Controlled Trial Investigators who conducted the East Anglia Multicenter Controlled Trial observed that 84% of patients with active CD entered clinical remission

502 INTEGRATIVE GASTROENTEROLOGY

after two weeks of a liquid elemental diet produced a significant decrease in erythrocyte sedimentation rate and C-reactive protein, and an increase in serum albumin. (Riordan et al., 1993). Patients were then randomized to receive treatment with prednisolone or treatment with a specific food exclusion diet. To determine which foods each patient needed to avoid, a structured series of dietary challenges was conducted. Patients would introduce foods of their choice, one at a time. Any food that appeared to provoke symptoms was excluded from further consumption; foods that did not provoke symptoms were included into a maintenance diet. At six months, 70 percent of patients treated with diet were still in remission, compared with 34 percent of patients being treated with prednisolone. After two years, 38 percent of patients treated with specific food exclusion were still in remission, compared to 21 percent of steroid-treated patients. In previous uncontrolled studies, some of the same authors had used a diet consisting of one or two meats (usually lamb or chicken), one starch (usually rice or potatoes), one fruit and one vegetable instead of the elemental diet, in order to induce remission. Structured food challenges were then used to construct a maintenance diet free of symptom-provoking foods. Compliance with the specific food elimination diet was associated with a rate of relapse of under 10 percent per year (Alun Jones, Workman, & Freeman, 1985). Individual foods found most likely to provoke symptoms in this study were wheat, cow’s milk and its derivatives, cruciferous vegetables, corn, yeast, tomatoes, citrus fruit, and eggs.

Crohn’s Disease and Dietary Yeast Elimination A large proportion of CD patients develop antibodies to baker’s and brewer’s yeast, Saccharomyces cerevisiae (ASCA; see Barnes et al., 1990). Lymphocytes of ASCA-positive patients proliferate after stimulation with mannan, an antigen common to most types of yeast. Lymphocyte proliferation of ASCApositive patients is associated with increased production of the key inflammatory mediator, TNF-α (Konrad et al., 2004). Rectal exposure to yeast and citrus antigens produced increased rectal blood flow and submucosal edema in CD patients, when compared to controls (Van Den Bogaerde et al., 2002). Patients with stable chronic CD experienced a significant reduction in the CD activity index during 30 days of dietary yeast elimination and a return to baseline disease activity when capsules of S. cerevisiae were added to their diets (Barclay, McKenzie, Pennington, Parratt, & Pennington, 1992). Most recently, a study analyzed IgG antibodies to common foods in Crohn’s disease and and healthy controls. In Crohn’s Disease 84 and 83% of the patients, respectively, IgG antibodies against processed cheese and yeast were detected.

Alternative Approaches to the Patient with Inflammatory Bowel Disease 503

The daily stool frequency significantly decreased by 11% during a specific diet compared with a sham diet. Abdominal pain reduced and general well-being improved (Bentz S, Hausmann M, Pilberger H, Kellermer S et al, 2010).

SUPPLEMENTS

Nutritional supplements may be used to correct or prevent the deficiencies that are common among patients with inflammatory bowel disease (Table 44.2.) or to achieve an anti-inflammatory effect.

Folic Acid 5-ASA derivatives, sulfasalazine in particular, impair folic acid transport (Mason, 1989). Reduced folic acid in patients with IBD is associated with hyperhomocysteinemia (Chowers et al., 2000), a risk factor for deep vein

Table 44.2. Malnutrition in IBD Deficiency

CD

UC

Treatment

Negative nitrogen balance

69%

Unknown

Adequate energy and protein

Vitamin B12

48%

5%

1000 mcg/d x 7 d then Q mo

Folate

67%

30%–40%

1 mg/d

Vitamin A

11%

Unknown

5,000–25,000 IU/d

Vitamin D

75%

35%

5,000–25,000 IU/d

Calcium

13%

Unknown

1,000–1,200 mg/D

Potassium

5%–20%

Unknown

Variable

Iron

39%

81%

Fe Gluconate 300 mg TID

Zinc

50%

Unknown

Zn Sulfate 220 mg daily or BID

This table illustrates the frequency of vitamin and mineral insufficiencies in patients with IBD. Of note, patients with Crohn’s disease are vulnerable to vitamin B12, folate, zinc, and vitamin D deficiency due to their small bowel disease and malabsorption of fat, and diminished surface area for absorption due to damage to the surface epithelium. Thus, all patients with IBD should be screened annually for vitamins and minerals as shown here, to avoid deficiencies of these micronutrients.

504

INTEGRATIVE GASTROENTEROLOGY

thrombosis (Den Heijer et al., 1996), an extraintestinal complication of inflammatory bowel disease. One study found that a high dose of folic acid (15 mg/day) reversed sulfasalazine-induced pancytopenia in two patients (Logan, Williamson, & Ryrie, 1986). Folic acid has been studied for its ability to circumvent dysplasia as a consequence of longstanding IBD with disappointing results (Table 44.3.).

Vitamin B12 Because vitamin B12 absorption may be impaired by ileal inflammation and by small bowel bacterial overgrowth, deficiency of vitamin B12 has long been described as a potential complication of CD (Beeken, 1975). Lower vitamin B12 levels are associated with increased serum homocysteine in patients with CD (Romagnuolo, Fedorak, & Dias, 2001). Ischemic strokes in a woman with CD were associated with vitamin B12-reversible hyperhomocysteinemia (Penix, 1998). Cobalamin injection can correct the megaloblastic anemia associated with CD (Abe, Wakabayashi, & Hirose, 1989). One needs to correct deficiencies of low B12 status prior to supplementing with folic acid or risk precipitating neurological deficits.

Table 44.3. Folate Does Not Prevent IBD-Related Cancer or Dysplasia Senior Author

Cases/

End point

RR/OR

Controls

Significant Protection?

Lashner 1997

29/69

Cancer or dysplasia

0.54 RR

NO

Pardi 2003

11/52

Cancer or dysplasia

0.68 RR

NO

Smith 2006

2/22

Dysplasia

NA

NO

Lashner 1989

35/64

Cancer or dysplasia

0.38 OR

NO

Lashner 1993

6/61

Cancer or dysplasia

0.82 OR

YES

Rutter 2004

68/136

Cancer or dysplasia

0.40 OR

NO

Folate is commonly deficient in ulcerative colitis and Crohn’s disease. Folate is felt vis-a-vis methyl donation to be “chemopreventive”; however, there is evidence to suggest that at higher doses folate may be cancer promoting (Sauer, Mason, & Choi, 2009). This table shows that folate, in 5 of 6 studies, does not prevent IBD-related dysplasia. Thus, for IBD it is best to test individuals for folate status using RBC folate, and only supplement to sufficiency using the dietary reference intake (DRI) of 400 micrograms daily as a guideline for therapy.

Alternative Approaches to the Patient with Inflammatory Bowel Disease 505

Vitamin B6 Median vitamin B6 levels are significantly lower in patients with IBD than controls; low levels are associated with active inflammation and hyperhomocysteinemia (Saibeni et al., 2003). Although some homocysteine is removed by folate-B12-dependent remethylation, the bulk of homocysteine is converted to cystathionine in a reaction catalyzed by vitamin B6. Ischemic stroke and high grade carotid obstruction in a young woman with CD were attributed to hyperhomocysteinemia, vitamin B6 deficiency, and a heterozygous methylenetetrahydrofolate reductase gene mutation. The authors believed that vitamin B6 deficiency was the principal cause of hyperhomocysteinemia in this patient (YounesMhenni et al., 2004). Low B6 status can cause neuropathy, oftentimes falsely attributed to low B12 status in Crohn’s Disease.

Vitamins E and C Blood levels of vitamins E and C are often reduced in patients with IBD (Fernandez-Banares et al., 1989). Low Vitamin E status can first present with neurological sequelae, and should be suspected in Crohn’s Disease with intestinal malabsorption of long chain fats. Administration of alpha-tocopherol 800 IU per day and vitamin C 1000 milligrams per day to patients with stable, active CD decreased markers of oxidative stress but had no effect on the CD activity index (Aghdassi et al., 2003). In combination with Selenium, vitamin E has been shown to protect animals against experimental colitis (Protective effects of selenium and vitamin E combination on experimental colitis in blood plasma and colon of rats. Bitiren M, Karakilcik AZ, Zerin M, Ozardali I et al, 2009).

Vitamin A Although levels of carotenoids (Rumi et al., 2000) and retinol (Bousvaros et al., 1998) are diminished in patients with active CD, low levels may not be entirely related to malabsorption, but to inflammation (Reimund et al., 2005; Sampietro et al., 2002) and a reduction in circulating retinol binding protein (Janczewska et al., 1991).In experimental colitis, all-trans retinoic acid ameliorates intestinal injury by shifting the immune response from a Th1 to a Th2 cytokine profile All-trans retinoic acid ameliorates trinitrobenzene sulfonic acid-induced colitis by shifting Th1 to Th2 profile (Bai A, Lu N, Zeng H, Li Z et al., 2010).

506 INTEGRATIVE GASTROENTEROLOGY

Vitamin D and Bone Status in Inflammatory Bowel Disease IBD is associated with a high prevalence of deficiencies of vitamin D, vitamin K and bone mineral density (Kuwabara A, Tanaka K, Tsugawa N, Nakase H et al. Osteoporos Int. 2009 Jun;20(6):935-42. Reduced blood levels of 25-OH cholecalciferol, the major vitamin D metabolite, are common in patients with CD, and are related to malnutrition and lack of sun exposure (Harries et al., 1985; Vogelsang et al., 1989). Administration of vitamin D, 1000 IU per day for one year, prevented bone loss in patients with active CD (Vogelsang, Ferenci, Resch, Kiss, & Gangl, 1995). The major causes of bone loss in IBD, however, are the effects of inflammatory cytokines and glucocorticoid therapy (Trebble et al., 2004), not vitamin D status. Calcitriol (1,25-dihydroxycholecalciferol), the most active metabolite of vitamin D, may actually be increased in patients with inflammatory bowel disease as intestinal macrophages increase its synthesis. Elevated calcitriol is associated with increased risk of osteoporosis, and may serve as a marker of disease activity (Abreu et al., 2004). Hypercalcemia is a rare complication of excess calcitriol, and serum calcium should be monitored in patients with IBD receiving vitamin D supplements (Tuohy & Steinman, 2005).

Vitamin K and Bone Status in Inflammatory Bowel Disease Biochemical evidence of vitamin K deficiency has been found in patients with ileitis and in patients with colitis treated with sulfasalazine or antibiotics (Krasinski et al., 1985). Serum vitamin K levels in CD are significantly decreased compared with normal controls and are associated with increased levels of undercarboxylated osteocalcin, indicating a low vitamin K status in bone. In patients with CD, undercarboxylated osteocalcin is inversely related to lumbar spine bone density (Schoon et al., 2001). A sensitive method for measuring the serum level of protein-induced by vitamin K absence or antagonist II (PIVKA-II) has become widely available (Kuwabara A, Tanaka K, Tsugawa N et al, 2009). In a recent study, Compared with ulcerative colitis (UC) patients, CD patients had significantly lower plasma vitamin K and 25OH-D concentrations; significantly higher serum levels of PIVKA-II, and undercarboxylated osteocalcin; and significantly lower bone mineral density scores at almost all measurement sites. The rate of bone resorption in CD is inversely correlated with vitamin K status, suggesting that vitamin K deficiency might be another etiological factor for osteopenia of inflammatory bowel disease (Duggan et al., 2004).

Alternative Approaches to the Patient with Inflammatory Bowel Disease 507

Optimal dose of vitamin K for correction of deficiency is not known. Patients with active small bowel disease may not absorb oral vitamin K, even at high dosage (Fugate & Ramsey, 2004).

Calcium and Bone Status in Inflammatory Bowel Disease In experimental animals, low dietary calcium increases severity of IBD (Cantorna, Zhu, Froicu, & Wittke, 2004). Calcium supplementation is recommended for maintaining bone density in patients with IBD though there is conflicting data regarding its efficacy. Calcium supplementation (1000 milligrams per day) with 250 IU of vitamin D per day, conferred no significant benefit to bone density at one year in patients with corticosteroid-dependent inflammatory bowel disease and osteoporosis (Bernstein et al., 1996). However, a more recent study showed that daily supplementation with calcium (500 mg) and vitamin D (400 I.U.) increased bone mineral density Siffledeen JS, Fedorak RN, Siminoski K et al., 2005).

Zinc Zinc is an important cofactor for antioxidant defenses. Copper-zinc superoxide dismutase is impaired in patients with clinically active IBD whose intestinal mucosal biopsies demonstrate increased oxidative stress. Low plasma zinc is common in patients with CD and may be associated with clinical manifestations such as acrodermatitis, altered taste and smell, decreased activity of zinc-dependent enzymes like thymulin and metallothionein and reduction in muscle zinc concentration and poor taste acuity. Zinc absorption is impaired and fecal zinc losses are inappropriately high (Griffin, Kim, Hicks, Liang, & Abrams, 2004). Zinc status is very important to monitor in children and adolescents as zinc deficient adolescents with CD grow and mature more normally when zinc deficiency is treated. Correction of zinc deficiency as a specific intervention for IBD has been associated with global clinical improvement (Hendricks & Walker, 1988). Zinc supplementation may improve immune function, epithelial renewal and maintain mucosal integrity. zinc has been shown to improve barrier function in CD, although the inherent mechanisms are unknown (Hering & Schulzke, 2009). High dose supplementation with zinc sulfate, 110 milligrams three times a day for eight weeks, significantly decreased small intestinal permeability in CD for a period of twelve months (Sturniolo, Di Leo, Ferronato, D’Odorico, & D’Inca, 2001). In CD patients with active disease, zinc sulfate, 200 milligrams per day (but not 60 milligrams per day) significantly increased plasma zinc and thymulin activity (Brignola et al., 1993).

508 INTEGRATIVE GASTROENTEROLOGY

Zinc competes with copper, iron, calcium, and magnesium for absorption. When administering high doses of zinc, consider administering a multimineral at a separate time of day. Zinc will be absorbed best if not taken at the same time as calcium, magnesium, or iron.

Selenium Like zinc, selenium is an important cofactor for antioxidant enzyme systems such as Se-dependent glutathione peroxidase, which is impaired in IBD. Low selenium levels in patients with Crohn’s disease are associated with increased levels of TNF-α and decreased levels of the antioxidant enzyme, glutathione peroxidase (GSHP; see Reimund, Hirth, Koehl, Baumann, & Duclos, 2000). Patients with small bowel resection are at risk for severe selenium deficiency and monitoring of selenium status and selenium supplementation has been recommended for this group in particular (Rannem, Ladefoged, Hylander, Hegnhoj, & Jarnum, 1992). Patients on enteral feeding with liquid formula diets experience decreased selenium concentrations proportional to duration of feeding, suggesting that additional selenium supplementation is also needed by them (Kuroki, Matsumoto, & HIida, 2003).

Magnesium Magnesium deficiency is a potential complication of IBD, a result of decreased oral intake, malabsorption and increased intestinal losses due to diarrhea. Urinary magnesium and RBC magnesium are better predictors of magnesium status than serum magnesium in this setting (Galland, 1988). Reduced urinary magnesium excretion is a significant risk factor for urolithiasis, one of the extraintestinal manifestations of IBD (Böhles et al., 1988). For patients with IBD, the urinary ratio of magnesium and citrate to calcium is a better predictor of lithogenic potential than urinary oxalate excretion (McConnell et al., 2002). Supplementation with magnesium and citrate may decrease urinary stone formation, but diarrhea is a dose-related, limiting side effect.

Chromium Chromium is an important cofactor for glucose tolerance. Levels of chromium are often overlooked in patients with inflammatory bowel disease who are on

Alternative Approaches to the Patient with Inflammatory Bowel Disease 509

glucocorticosteroid therapy. Glucocorticoid therapy increases urinary chromium excretion and chromium picolinate, 600 micrograms per day, can reverse steroid-induced diabetes in humans, with a decrease in mean blood glucose from 250 milligrams per dl to 150 milligrams per dl. Chromium supplementation may be of benefit for patients receiving glucocorticoids who manifest impaired glucose tolerance (Ravina et al., 1999).

Iron Anemia occurs in about 30 percent of patients with IBD (Gasche, Lomer, Cavill, & Weiss, 2004). Its causes include: iron deficiency due to blood loss, cytokine-induced suppression of erythropoiesis from chronic inflammation and side effects of medication. Iron deficiency actually increases the IFN-γ response in TH-1 driven inflammation and may contribute to aggravation of Crohn’s disease Lih-Brody L, Powell SR, Collier KP, Katz R et al., 1996). Oral iron supplements may increase oxidative stress in the gut via Fenton chemistry. Very high dose iron supplementation consistently aggravates experimental colitis in rodents (Oldenburg et al., 2001). The relative risks and benefits of oral iron supplementation for patients with IBD are uncertain.

ESSENTIAL FATTY ACIDS PHYSIOLOGY AND BACKGROUND

Essential fatty acids (EFA) refer to dietary constituents that cannot be synthesized endogenously and must be obtained via the diet for optimal health. Biochemical studies indicate that 25 percent of patients with IBD show evidence of essential fatty acid deficiency (Siguel & Lerman, 1996). In experimental animals, fish oil feeding ameliorates the intestinal mucosal injury produced by methotrexate (Vanderhoof et al., 1991). In tissue culture, omega-3 fatty acids stimulate wound healing of intestinal epithelial cells (Ruthig & MecklingGill, 1999). It is interesting to note that omega-6 EFAs are markedly more common in the current Western diet and may have a proinflammatory effect. Omega-3 EFA are found in a wide variety of foods including, flax seeds, eggs of hens on a diet rich in flax seed (otherwise one yolk has only 0.2 g omega 3), walnuts (other nuts do not have sufficient amounts for a therapeutic effect, FYI e.g. 1 tbsp of almond butter = 0.06g; walnuts: 1 cup = 10.6g), cultivated plants (FYI e.g. kale–1 cup chopped kale = 0.12 g omega 3), berries (e.g. 1 cup raw

510

INTEGRATIVE GASTROENTEROLOGY

strawberries = 0.09g, while blueberries 0.08g, which is traces; berries are not a reliable source of omega 3, hemp seeds and fish (deep water fatty fish such as mackerel, herring, sardines, wild caught salmon) FYI, 3 oz. wild Atlantic salmon cooked in dry heat = 1.88g. Long-term of fish oil use raises theoretical concerns for possible; increased bleeding lipid peroxidation and toxicity of mercury and halogenated biphenyls. Fish oil can be administered as either raw fish oil or as an enteric-coated capsule. A dose of up to 3 grams per day of EPA plus DHA has been determined to be safe for general consumption. Omega-3 EFA appears to work through a plethora of mechanisms (Figure 44.4.). Eicosanoids appear to affect both the cyclooxygenase (COX) pathway (primarily COX-2) and the 5-lipoxygenase pathway (Figure 44.4.). Prostaglandin E2 is a proinflammatory, nociceptive factor that is produced through the COX-2 pathway while arachidonic acid (AA) is the usual substrate for this pathway. EPA is a chemical homologue that differs from AA by only the presence of the n3 double bond. Therefore, EPA represents both an inhibitor of AA and an alternate substrate for COX. EPA also results in inhibition of the 5-lipoxygenase pathway and decreased production of proinflammatory leukotriene B4. EPA and DHA can themselves act as substrates for the formation of novel protective mediators (termed E-series and d-series resolvins) that may have direct anti-inflammatory effects (Figure 44.5.). Furthermore, omega-3 EFA regulates transcription factors such as peroxisome proliferatoractivated receptors (PPARs) with resultant downregulation of inflammatory processes as well as inhibition of NFkB expression and downregulation of the proinflammatory cytokines IL-1β and TNF-α.

CLINICAL TRIALS

Ulcerative Colitis Numerous studies have evaluated the effects of fish oil on ulcerative colitis. Several early studies supported the notion that enteral fish oil supplements led to improvement in IBD in animal models. The findings of animal studies were corroborated in small clinical trials (Table 44.4). The methodology and endpoints have been varied in these clinical studies and it is difficult to directly compare the results obtained. When clinical scores were used as an outcome (Disease Activity Index, Ulcerative Colitis Activity Index or undefined “clinical score”), three of five studies showed significant clinical improvement in the fish oil arm of the study at some point during the course of therapy (although only two). When endoscopic endpoints were used

Alternative Approaches to the Patient with Inflammatory Bowel Disease 511

Table 44.4. Fish Oils and Remission in UC Study

EPA

DHA

Clinical

Endo

Almallah 1998

3.2 g/d

2.4 g/d

p<0.05

p=0.013

Aslan 1992

2.7 g/d

1.8 g/d

∗p<0.05

NR

Stenson 1992

3.24 g/d

2.16 g/d

p=0.001

p=0.054

In ulcerative colitis, 3 RCTs looked at whether fish oils could induce remission of disease—in all 3 studies, using a range of therapeutic doses of n3 fatty acids (combined EPA-DHA over 3 grams) showed statistical clinical benefit.

to evaluate the role of fish oil in the treatment of ulcerative colitis, all studies showed statistically significant improvement in the study group that received fish oil supplementation. Future studies should assess the effects of pharmaceutical grade enteric-coated n–3 fatty acids on clinical outcomes in IBD, including requirements for corticosteroids. Recently, a randomized controlled trial evaluated a “nutritionally balanced oral supplement” (UCNS) enriched with fish oil, fructooligosaccharides, gum Arabic, vitamin E, vitamin C and selenium was found to improve disease activity and medication use in patients with mild to moderate ulcerative colitis. The group treated with the supplement containing fish oil showed a significantly greater rate of decrease in the dose of prednisone required to control clinical symptoms when compared to the group that received placebo. This type of integrated approach with synergistic nutraceuticals may achieve superior outcomes in future IBD studies.

FISH OIL AND CROHN’S DISEASE

The Cochrane Collaboration recently published a systematic review evaluating this topic. Evaluated 214 publications and identified 15 randomized controlled trials. Only four studies were of sufficient quality to be included in the analysis (Table 44.5). Enteric-coated omega-3 EFA supplementation reduced the one-year relapse rate by half with an absolute risk reduction of 31% and a number needed to treat (NNT) of only 3. A much larger RCT asked whether n3 fatty acids could sustain remission once it is achieved (Figure 44.6.). Subsequently, two randomized, double-blind, placebo-controlled studies (Epanova Program in Crohn’s Study 1 [EPIC-1] and EPIC-2) were conducted between January 2003 and February 2007 at 98 centers in Canada, Europe, Israel, and the United States. Data from 363 and 375 patients with quiescent Crohn’s disease were evaluated in EPIC-1 and EPIC-2, respectively. Patients with a

512

INTEGRATIVE GASTROENTEROLOGY

Table 44.5. Fish Oils and CD Author

Patients

Time

Intervention

Outcomes

Belluzzi 1996

39/39

1 year

1.8 g EPA 0.9 g DHA

CDAI<150

Lorenz-Meyer 1996

70/65

1 year

3.3 g EPA 1.8 g DHA

CDAI<150

Belluzzi 1997

26/24

1 year

1.8 g EPA 0.9 g DHA

CDAI<150

Romano 2005

18/20

1 year

1.2 g EPA 0.6 g DHA

PCDAI <20

In Crohn’s disease, 4 RCTs all showed clinical efficacy for achieving remission.

Crohn’s Disease Activity Index (CDAI) score of less than 150 were randomly assigned to receive either 4 g/d of omega-3 free fatty acids or placebo for up to 58 weeks. No other treatments for Crohn’s disease were permitted. Clinical relapse, as defined by a CDAI score of 150 points or greater and an increase of more than 70 points from the baseline value, or initiation of treatment for active Crohn’s disease. In both EPIC-1 and EPIC-2, there were no significant differences in the CD relapse rate for placebo versus fish oils. A second metaanalysis by the Cochrane group combined the data from their original report along with the results from EPIC-1, EPIC-2 showed a marginal benefit for enteric-coated fish oil for the maintenance of Crohn’s Disease (Turner D, Zlotkin SH, Shah PS et al., 2009). A recent metaanalysis echoed the marginal benefit for enteric coated fish oils for the maintenance of Crohn’s disease. (Turner D, Shah PS, Steinhart AH, Zlotkin S et al, 2010) (figure 44-x).

Glutamine Glutamine appears to have a special role in restoring normal small bowel permeability and immune function. Patients with intestinal mucosal injury secondary to chemotherapy or radiation benefit from glutamine supplementation with less villous atrophy, increased mucosal healing and decreased passage of endotoxin through the gut wall (van der Hulst et al., 1993). Although integrative practitioners often advocate glutamine therapy for treatment of inflammatory bowel disease, controlled studies have shown no benefit from glutamine supplementation at doses as high as twenty grams per day in patients with CD (Akobeng et al., 2000; Den Hond et al., 1999). Glutamine excess aggravates experimental colitis in rodents (Shinozaki, Saito, & Muto, 1997). Glutamine is commonly used in commercially available nutraceutical medical foods for improving gut barrier health.

Alternative Approaches to the Patient with Inflammatory Bowel Disease 513

N-Acetylglucosamine (NAG) NAG is a substrate for synthesis of glycosaminoglycans, glycoproteins that protect the bowel mucosa from toxic damage. Synthesis of NAG by N-acetylation of glucosamine is impaired in patients with IBDD (Burton & Anderson, 1983). In a pilot study, NAG (3 to 6 grams per day for for more than two years) given orally to children with refractory IBD produced symptomatic improvement in the majority of patients and an improvement in histopathology (Salvatore et al., 2000). In children with distal colitis or proctitis, the same dose of NAG was administered by enema with similar effects.

Probiotics Table 44.6. Probiotics in Ulcerative Colitis Study

Probiotic

Result

Kruis et al. (1997)

Escherichia coli Nissle 1917

Equal to mesalamine

Venturi et al. (1999)

E. coli Nissle 1917

Equal to mesalamine

Rembacken et al. (1999)

E. coli Nissle 1917

Equal to mesalamine

Gustlandi et al. (2003)

S. boulardii

Equal to mesalamine

Ishikawa et al. (2003)

Bifidobacterium Milk

Superior to placebo

Borody et al. (2003)∗

Stool enema

Improved

Kruis et al. (2004)

E. coli Nissle 1917

Superior to conventional medications

Kato et al. (2004)

Bifidobacteria Milk

Superior to placebo

Furrie et al. (2005)

Bifidobacteria + fiber

Improved

This table summarizes the data for randomized clinical trials of probiotics in ulcerative colitis. In 4 of the studies, probiotics were found to be equal to mesalamine; in 1 study superior to medications; in 2 studies superior to placebo; and in 2 studies improved. Borody, using fecal transfer or “bacteriotherapy” to change flora, permanently improved patients with resistant disease to conventional medications. In a small group of 6 patients with refractory UC gave broad-spectrum antibiotics and PEG to clear bowel. Then given freshly prepared fecal enema from a healthy donor. Reported reversal of all symptoms by 4 months and sustained reversal of 1–3 years. J. Clinical Gastroenterology 2003 37:42-47. In these studies, the mechanisms for UC benefit were noted in biopsy specimens. Probiotics were noted to decrease proinflammatory TNF, NFkB, while increasing in IL-10 It is important to note that changes in flora observed only temporarily (transiently) change the total flora without permanently changing the flora-thus as, he probiotics are working on the gut barrier and immune system to establish an effect not by merely repopulating the gut. The strains given in these studies vary widely and individual hosts may selectively respond to various preparations.

514 INTEGRATIVE GASTROENTEROLOGY

Probiotics are beneficial microorganisms. Their therapeutic use in IBD is attracting considerable attention, because of the recognition that alteration of intestinal microflora may modulate intestinal immune responses (O’Sullivan et al., 2005).

Immunoregulatory Roles for Probiotics in IBD • Upregulate Th2 cytokines (IL-10) • Downregulate Th1 cytokines (IL-12) • Inhibit IFNg by T-cells • Inhibit NFkB • Stabilize IkB levels • Induce T-regs

Because of the large number of probiotic preparations available, this section will only discuss those preparations that are commercially available in the United States and that have been studied in clinical trials of patients with IBD. More data exist for their benefits in UC than in CD. For a more comprehensive discussion of probiotics, please see Chapter 28.

VSL-3

Is a proprietary mixture of Lactobacillus acidophilus, L. bulgaricus, L. casei, L plantarum, Bifidobacteriium brevis, B. infantis, B. longum and Streptococcus salivarius ssp thermophilus, supplied in sachets containing 900 billion organisms each. When added to therapy with the 5-ASA derivative balsalazide, VSL-3 (one sachet twice a day) induced faster remission of active UC than balsalazide or mesalazine alone (Tursi et al., 2004). In an uncontrolled trial, two sachets of VSL-3 twice a day for six weeks as monotherapy yielded clinical and endoscopic remission of mild to moderate UC in 54 percent of patients treated (Bibiloni et al., 2005). VSL-3 also prevents relapse of pouchitis (postcolectomy inflammation of the ileal pouch; see Gionchetti et al., 2000), with two sachets once a day producing remission rates far better than placebo over a one-year period (Mimura et al., 2004). A survey done at the Cleveland Clinic, however, found poor compliance with this therapy in patients not participating in clinical trials (Shen et al., 2005). In children, VSL-3 has been shown to induce remission with moderate activate disease and maintain remission (Huynh HQ, deBruyn J, Guan L, Diaz H et al 2009; Miele E, Pascarella F, Giannetti E, Quaglietta L, 2009). Overall, a metaanalysis shows benefit for

Alternative Approaches to the Patient with Inflammatory Bowel Disease 515

using probiotics for the maintenance of remission in ulcerative colitis (Figure 44-x; Sang LX, Chang B, Zhang WL, Wu XM et al, 2010).

LACTOBACILLUS GG

Lactobacillus rhamnosus var GG at a dose of 10 to 20 billion organisms per day, was found to prevent onset of pouchitis in patients with ileal pouch-anal anastomosis during the first three years after surgery in a placebo-controlled trial (Gosselink et al., 2004). Lactobacillus GG has been ineffective in inducing or maintaining remission of patients with CD (Schultz et al., 2004) or in preventing relapse of CD after surgical resection (Prantera et al., 2002).

SACHHAROMYCES BOULARDII

This plant-derived yeast has shown benefit in the treatment or prevention of: • traveler’s diarrhea (McFarland & Bernasconi, 1993) • C. difficile diarrhea (Surawicz CM, McFarland LV, Elmer G, 1989a) • antibiotic-induced diarrhea (Surawicz CM Elmer GW, Speelman P, 1989b). Experimental data suggest that the yeast owes its antibacterial effects to stimulation of secretory IgA secretion (Buts et al., 1990) and macrophage activation (Machado Caetano et al., 1986). Despite its stimulation of mucosal immune responses and its antigenic similarity to baker’s yeast, S. boulardii has shown benefit in both UC and CD. The addition of S. boulardii (250 milligrams three times a day) to maintenance mesalazine therapy of patients with chronic, active UC was associated with induction of remission within four weeks in 17 out of 25 patients (Guslandi, Giollo, & Testoni, 2003). In a placebo-controlled trial, the same dose was given to patients with stable, active CD and mild to moderate diarrhea. S. boulardii reduced the frequency of diarrhea and the clinical activity index when given over a ten-week period, with benefits apparent within two weeks (Plein & Hotz, 1993). When added to mesalazine therapy of patients with CD in remission, S. boulardii (1000 milligrams per day) reduced the frequency of relapse from 37.5% to 6.25% during six months, when compared to mesalazine alone (Guslandi et al., 2000). Two studies have demonstrated that patients with CD having altered intestinal permeability normalized their markers of mucosal

516 INTEGRATIVE GASTROENTEROLOGY

integrity following S. boulardii therapy. Although S. boulardii is considered non-pathogenic, case reports of S. boulardii fungemia have been described in critically ill or immunocompromised patients exposed to S. boulardii. At least eighteen reports of this complications have been published, including one in which airborne spread of S. boulardii occurred in an intensive care unit (Cassone et al., 2003). S. boulardii has been shown to improve intestinal permeability in Crohn’s disease that is in remission (Garcia Vilela E, De Lourdes De Abreu Ferrari M, Oswaldo Da Gama Torres H, Guerra Pinto A et al, 2008).

Prebiotics DEFINITIONS AND PHYSIOLOGICAL EFFECTS

Prebiotics are nondigestible food ingredients that stimulate the growth or modify the metabolic activity of intestinal bacterial species that have the potential to improve the health of their human host. Criteria associated with the notion that a food ingredient should be classified as a prebiotic are that it remains undigested and unabsorbed as it passes through the upper part of the gastrointestinal tract and is a selective substrate for the growth of specific strains of beneficial bacteria (usually Lactobacilli or Bifidobacteria), rather than for all colonic bacteria. Prebiotic food ingredients include bran, psyllium husk, resistant (high amylose) starch, inulin (a polymer of fructofuranose), lactulose, and various natural or synthetic oligosaccharides, which consist of short chain-complexes of sucrose, galactose, fructose, glucose, maltose or xylose (Table 44.1) The best known effect of prebiotics is to increase fecal water content, relieving constipation. Bacterial fermentation of prebiotics yields short-chain fatty acids like butyrate. Fructooligosaccharides (FOS) have been shown to alter fecal biomarkers (pH and the concentration of bacterial enzymes like nitroreductase and beta-glucuronidase) in a direction that may convey protection against the development of colon cancer (Galland, 2005). Several studies have suggested benefits of various prebiotics for the treatment of patients with ulcerative colitis (Table 44.1): Efficacy of Prebiotics in IBDOat bran, 60 grams per day (supplying 20 grams of dietary fiber), increased fecal butyrate by 36 per cent in patients with UC and diminished abdominal pain (Hallert et al., 2003). A dietary supplement containing fish oil and two types of indigestible carbohydrate, FOS and xanthum gum, allowed reduction of glucocorticoid dosage when compared to a placebo, in patients with steroid-dependent UC (Seidner et al., 2005). A Japanese germinated barley foodstuff (GBF) containing hemicellulose-rich

Alternative Approaches to the Patient with Inflammatory Bowel Disease 517

fiber, at a dose of 20 to 30 grams per day increased stool butyrate concentration (Bamba, Kanauchi, Andoh, & Fujiyama, 2002), decreased the clinical activity index of patients with active UC (Kanauchi et al., 2003) and prolonged remission in patients with inactive UC (Hanai et al., 2004). Wheat grass juice, 100 milliliters twice daily for one month was tested in a small placebo-controlled trial of patients with distal UC (Ben-Ayre et al., 2002). Interestingly, use of wheat grass juice was observed to be associated with a significant reduction in rectal bleeding, abdominal pain and disease activity as measured by sigmoidoscopy. A mixture of B. longum and inulin-derived FOS administered for one month as monotherapy to patients with UC produced improvement in sigmoidoscopic appearance, histology, and several biochemical indices of tissue inflammation when compared to a placebo control (Furrie et al., 2005). Prebiotics appear to provide benefit to patients with ulcerative colitis.

Bovine Colostrum Colostrum is the first milk produced after birth and is particularly rich in immunoglobulins, antimicrobial peptides (e.g., lactoferrin and lactoperoxidase), and other bioactive molecules, including growth factors. Recent studies suggest that the peptide growth factors in colostrum might provide novel treatment options for a variety of gastrointestinal conditions (Playford, Macdonald, & Johnson, 2000). Colostrum enemas, 100 milliliters of a 10 percent solution, administered twice a day by patients with distal UC, proved superior to a control enema in promoting healing; all patients were also taking a fixed dose of mesalazine (Khan et al., 2002). Studies of oral colostrum in IBD have not been reported, but 125 milliliters three times a day fed to healthy human volunteers was shown to prevent the increase in intestinal permeability produced by indomethacin (Playford et al., 2001), suggesting that peptide growth factors survive passage through the stomach and upper small bowel. Dehydroepiandrosterone (DHEA). DHEA is the steroid hormone produced in greatest quantity by the human adrenal cortex, circulating primarily in the sulfated form, DHEA-S. DHEA has interesting effects that may be relevant to IBD. DHEA inhibits activation of nuclear factor kappa B (NF-kB), which is known to be activated in inflammatory lesions. Patients with IBD have lower levels of DHEA-S in serum and intestinal tissue than controls (de la Torre et al., 1998), partially associated with prior treatment with glucocorticoids (Straub et al., 1998). In men with IBD, low DHEA-S is associated with increased risk of osteoporosis (Szathmari et al., 2002). DHEA has been tested in clinical trials for IBD. In a pilot study, six of seven patients with refractory CD and eight of thirteen patients with

518

INTEGRATIVE GASTROENTEROLOGY

refractory UC responded to DHEA (200 milligrams per day for 56 days) with decrease in the clinical activity index (Andus et al., 2003). A case report demonstrated benefit of the same dose of DHEA in a woman with severe refractory pouchitis, with relapse occurring 8 weeks after discontinuation of DHEA (Klebl et al., 2003). Thus, DHEA may show promise as a therapeutic adjunct in IBD. Future trials are warranted.

Melatonin The gastrointestinal tract is a major source of extrapineal melatonin, which is produced in mucosal serotonin-rich enterochromaffin cells. In the gut, melatonin may affect mucosal function, lymphocyte activation and motility. Melatonin may protect gut mucosa from ulceration by its antioxidant action, stimulation of the immune system and by fostering microcirculation and epithelial regeneration (Bubenik 2001). Melatonin is being studied as therapy for UC in humans (Malhotra et al., 2004). In rats with experimental colitis, melatonin reduces colonic inflammatory injury through inhibition of NF-kB signalling (Li et al., 2005). An appropriate human dose has not been determined. Melatonin doses for other conditions vary from one milligram for prevention of jet lag to 30 milligrams per day in the treatment of patients with cancer.

Botanicals In traditional Chinese medicine and Ayurveda, herbal extracts are the mainstay of treatment for IBD and appear to be effective when used by practitioners trained in those systems. Botanicals commonly taken by patients with IBD include: • • • • • •

Slippery elm Fenugreek Devil’s claw Gingko biloba Angelica sinensis (Dong quai) Licorice.

These herbs express antioxidant or anti-inflammatory activity in vitro (Figure 44.7; see also Kang et al., 2005; Langmead et al., 2002; Dong et al., 2004).

Alternative Approaches to the Patient with Inflammatory Bowel Disease 519

POLYPHENOLS

Polyphenols are phytochemicals that are found in food substances produced from plants. Polyphenols are separated from essential micronutrients in that a deficiency state has not been identified nevertheless, they are believed to play a biologically active role, and have been shown to be potentially immunemodulating (Shapiro, Singer, Halpern, & Bruck, 2007) Four polyphenols in particular have a preponderance of evidence in the role of immune modulation and will be addressed in this chapter: resveratrol, epigallocatechin, curcumin and boswellia (Table 44.7; see Mazzon et al., 2005).148

RESVERATROL

Resveratrol is most abundant in the skin of red grapes—contributing to a high concentration in red wine and grape juice (Athar et al., 2007). Resveratrol is a

Table 44.7. Polyphenols in IBD Polyphenol

# of

Route, dose

Results

Studies

Resveratrol

2

5–10 mg/kg 2/2 IG

2/2 improvement: clinical, path, mediators, cytokines

EGCG

3

5 gm/l, 50 mg/kg/D 1 IP, 2 PO

3/3 improvement: clinical, path, mediators, cytokines

Curcumin

6

2 %, 30–300 mg/kg/D 6 PO, 1 IP

6/6, improvement: clinical, path, mediators, cytokines, markers 4/7 ↑ survival

Boswellia

3

5.0–34.2 mg/kg/D, 2 PO, 1 IP

2/3 improvement: clinical, macroscopic, microscopic, mediators; 1/3 no improvement

This table illustrates rodent studies of chemical-induced colitis and protection by polyphenolic compounds (polyphenols). Resveratrol, EGCG (found in green tea), and curcumin were found to protect the colon from chemical-induced injury, while quercetin produced mixed results. Research has shown the quercetin may become metabolized and inactivated locally in the gut tissues. Reprinted from Scholz & Williamson (2007) with permission from Verlag Hans Huber.

520 INTEGRATIVE GASTROENTEROLOGY

potent inhibitor of cyclooxygenase activity in vivo (Khanduja, Bhardwaj, & Kaushik, 2004). In rodent models of inflammatory colitis, resveratrol has been shown to reverse weight loss, increase stool consistency, improve mucosal appearance, improve histopathology, decrease inflammatory infiltrate, and decrease mucosal levels of IL-1B, COX-2, and PGD2 (Martin, Villegas, La Casa, & de la Lastra, 2004). Table 44.7 summarizes the work of resveratrol administration in animal models of IBD. To date, resveratrol has not yet been studied in human subjects with IBD.

CATECHINS

These compounds are particularly abundant in green (non-fermented) tea, whereas black tea contains theaflavins and thearubigins (Cabrera, Artacho, & Gimenez, 2006). They work through a combination of both antioxidant effect and alteration of intracellular signaling (primarily through inhibition of the NF-kB pathway). Catechins are effective free radical scavengers in vitro (Heijnen et al., 2001). Catechins can modulate and inhibit NF-kB activity (Nomura, Ma, Chen, Bode, & Dong, 2000). Table 44.7 summarizes the work of catechin administration in animal models of IBD

CURCUMIN

Turmeric, the major spice in curry, is a natural spice made from the herb Curcuma longa, a member of the ginger family. Besides being a culinary staple, it has been used in Ayurvedic medicine since ancient times. The major chemical constituents of turmeric are curcuminoids, the most prominent of which is curcumin. Recently, investigational focus has shifted toward the role of curcumin as an intracellular signaling agent and studies have demonstrated that curcumin, much like green tea polyphenols, is an inhibitor of NF-kB and leads to downstream regulation and inhibition of proinflammatory genes and cytokines (Figure 44.8; see also Jobin et al., 1999). Administration of curcumin has also been reported to modulate a host of other cytokines and signaling pathways including iNOS, MMP-9, TNF-a, JNK, p38, AKT, JAK, ERK and PKC (Duvoix et al., 2005). Four studies involving curcumin administration to murine colitis models showed clinical and histopathological improvement and, where measured, decreased inflammatory cytokine production (Table 44.6; also see Sugimoto et al., 2002; Kim et al., 2005; Deguchi et al., 2007). These findings were echoed in three studies

Alternative Approaches to the Patient with Inflammatory Bowel Disease 521

involving rodent models of colitis (Jian et al., 2005; Zhang, Deng, Zheng, Xia, & Sheng, 2006; Sugimoto et al., 2002). Holt and colleagues reported in 2005 the preliminary results of a pilot study involving open-label administration of curcumin preparation to five patients with ulcerative colitis and five patients with Crohn’s disease. Of the ten patients, nine reported improvement at the conclusion of the two-month study. Four of the five patients with ulcerative colitis were able to decrease or eliminate their medications (Holt, Katz, & Kirshoff, 2005). In a larger, randomized, doubleblind multicenter trial involving 89 patients with quiescent ulcerative colitis, administration of 1 gram of curcumin twice daily resulted in both clinical improvement and a statistically significant decrease in the rate of relapse (Hanai et al., 2006). Given its excellent safety profile, plausible mechanism for affecting inflammation, and the results above, curcumin is poised to have a prominent role in the future management of IBD.

BOSWELLIA

The Ayurvedic herb, Boswellia serrata (Indian frankincense) contains boswellic acids, which inhibit leukotriene biosynthesis in neutrophilic granulocytes by noncompetitive inhibition of 5-lipoxygenase (Ammon, 2002). During a small six-week trial, 350 milligrams three times a day of Boswellia gum resin was as effective as sulfasalazine 1000 milligrams three times a day in reducing symptoms or laboratory abnormalities of patients with active UC (Gupta et al., 2001).The rate of remission was 82 percent with Boswellia and 75 percent with sulfasalazine (Gupta et al., 1997). A proprietary Boswellia extract, H15, was found as effective as mesalazine is improving symptoms of active CD, in a randomized, double-blind study from Germany (Gerhardt et al., 2001).

ALOE VERA

Aloe vera gel has a dose-dependent inhibitory effect on production of reactive oxygen metabolites, prostaglandin E2 and (at high doses) IL-8 by human colonic epithelial cells grown in tissue culture (Langmead, Makins, & Rampton, 2004). Oral aloe vera gel, 100 milliliters twice a day for four weeks, produced a clinical response significantly more often than placebo (response ratio 5.6) in patients with UC (Langmead et al., 2004. Remission occurred in 30 percent of patients taking aloe vera gel and 7 percent of patients receiving placebo. Aloe also reduced histological disease activity, whereas placebo did not. No significant

522

INTEGRATIVE GASTROENTEROLOGY

side effects were described, although it should be noted that aloe vera gel is often used as a laxative. Acemannan, an extract of Aloe vera, concentrated to a mucopolysaccharide (MPS) concentration of thirty percent of solid weight, has been demonstrated to reduce symptoms and indices of inflammation in controlled studies of patients with UC (Robinson, 1998).

Mind–Body Therapies Although it is widely believed that stress aggravates IBD, a German study found no relationship between stressful life events, feelings of pressure or conflict or fear of separation and symptoms of CD or UC (von Wietersheim, Kohler, & Feiereis, 1992). A prospective study did not validate the notion that stressful life events can trigger relapse (North, Alpers, Helzer, Spitznagel, & Clouse, 1991). Three prospective studies of different types of psychotherapy for patients with IBD failed to show any improvement in medical outcome compared with standard care (Maunder & Esplen, 2001; Jantschek et al., 1998; Schwarz & Blanchard, 1991). Adaptive adjustment to IBD has been conceptualized as a process involving the interaction of three challenges: illness uncertainty, loss and change, and suffering (Maunder & Esplen, 1999). Enhancement of adaptive adjustment and prevention of psychosocial distress should play an important role in the treatment of patients with IBD. Interventions of potential value include: enhancing problem-solving and coping skills, enhancing the positive appraisal of uncertainty, increasing personal control, and increasing social support (Dudley-Brown, 2002). An easily taught, “patient centered” self-management intervention addresses the adaptive challenges of living with IBD and improves clinical outcome, dramatically reducing doctor visits and hospitalization rates.

This educational tool effectively addresses the adaptive challenges of living with IBD. During a 15 to 30 minute consultation, physicians designed personalized self-management strategies for each patient. The goal was to ensure that patients could recognize relapse and that patients and physicians could agree on a mutually acceptable treatment protocol for the patient to initiate at onset of a relapse. Physicians specifically asked patients about the symptoms they had experienced during past relapses and reviewed past and current treatments that had been used to control symptoms, emphasizing the specific effectiveness of each and its acceptability to the patient. Compared to a control

Alternative Approaches to the Patient with Inflammatory Bowel Disease 523

group that received customary care, the intervention group required one-third as many doctor visits and one-third as many hospitalizations. The difference in outcome was not related to specific treatments employed but rather to the empowerment of patients to be actively involved in managing their own care (Robinson et al., 2001).

The efficacy of 5-ASA derivatives in inducing remission of IBD can be enhanced by fish oils supplying 4000 milligrams of EPA plus DHA per day, and by probiotics (VSL-3, 2 packets a day, or S. boulardii 250 milligrams 3 times a day).

Adverse Events with Corticosteroids • Early events – Cosmetic side effects (acne, moon facies, edema), sleep disturbance, mood disturbance, glucose intolerance, dyspepsia • Events with prolonged use (usually > 12 weeks) – Posterior sublenticular cataracts, osteoporosis, osteonecrosis of the femoral head, myopathy, susceptibility to infections • Events with withdrawal – Acute adrenal insufficiency, myalgias, malaise, arthralgias, increased intracranial pressure

Adverse Events with Biologic Agents (Clark et al., 2007) • Increased risk of opportunistic infections, including tuberculosis • Development of autoimmunity (antinuclear and anti-DNA antibodies) • Infusion and injection site reactions • Development of antibodies against therapies • Neurological disorders such as optic neuritis, seizure, and new onset or exacerbation of central demyelinating disorders, including multiple sclerosis • Congestive heart failure • Lymphomas and other malignancies

Acupuncture Acupuncture and moxibustion are commonly employed by practitioners of Chinese medicine for treatment of ulcerative colitis. Uncontrolled studies

524 INTEGRATIVE GASTROENTEROLOGY

from China claim excellent results (Yang & Yan, 1999; Zhang, 1998). One small study of moxibustion found evidence of enhanced cellular immunity and decreased antibody production associated with improvement of diarrhea in patients with ulcerative colitis (Wu et al., 1997), suggesting downregulation of the TH-2 response network. A review of studies from both the Chinese and Western literature supports the efficacy of acupuncture in the regulation of gastrointestinal motor activity and secretion through opioid and other neural pathways (Li, Tougas, Chiverton, & Hunt, 1992). Controlled clinical trials of patients with inflammatory bowel disease have not yet been conducted.

Preventive Prescription Despite abundant speculation about the reasons for the dramatic increase in incidence of IBD in industrialized nations over the past century, no convincing strategy for primary prevention has been devised. Secondary prevention may benefit from the following interventions: • Prolonged use of 5-ASA derivatives and folic acid (typically one milligram per day) to maintain remission and prevent colon cancer. Fish oils supplying about 5000 milligrams per day of omega-3 fatty acids and S. boulardii 1000 milligrams per day may enhance efficacy of 5-ASA derivatives in maintenance of remission. • Folic acid, vitamin B6, and vitamin B12 at doses that keep circulating homocysteine low, to prevent thrombotic complications. • Vitamin D (1000 international units per day) and vitamin K (optimal dosage unknown) to prevent bone loss. • A specific food exclusion diet, individually tailored (described above), cessation of tobacco use, and reduced consumption of sucrose, for maintenance of remission in patients with CD. • An anti-inflammatory diet for maintenance of remission in patients with ulcerative colitis. • Dietary restrictions are very common in patients suffering from IBD, both iatrogenic and self-imposed, also possibly as a result of confusion by conflicting information in media. • Patients may have decreased nutritional intake from pain, bleeding, or severe diarrhea, and as a result, many patients eat only when absolutely necessary. • Food sensitivities may be particularly difficult to assess through the standard elimination diet, as it leads to more calorie restriction.

Alternative Approaches to the Patient with Inflammatory Bowel Disease 525

• Finally, IBD is emotionally difficult, especially when various medications produce a limited effectiveness. As a result, individual nutritional counseling becomes essential for moral support, education, and guidance, and can be a source of needed reassurance and compliance.

45 Obesity LAWRENCE J. CHESKIN AND KATRINA SEIDMAN

key concepts ■

■

■

■

■

■

The prevalence of obesity has skyrocketed in the past 20 years, particularly among the extremely obese and children. While genetic and medical causes of obesity exist, the vast majority of treatment needs to be directed toward modifiable dietary and physical activity behaviors. An individualized approach to treatment of the obese patient is most useful, and takes into account his or her dietary and medical history and specific problem areas related to food choices, triggers for eating, and physical activity level. While a number of over-the-counter medications and botanicals purport to control appetite or body weight, most are ineffective or lack efficacy data. A few prescription anorexic-inducing medications—and one fat-blocking medication—provide a modest benefit over placebo, though their effectiveness tends to diminish over time. Bariatric surgery is the most effective available treatment, though it is not a first-line treatment because of the risks involved and because surgery patients also frequently regain lost weight. ■

526

Introduction

I

n the past generation, the prevalence of obesity has nearly doubled: Twothirds of American adults are now overweight or obese, and if current trends continue, we will essentially all be overweight by 2030. (Wang et al., 2008) Obesity has reached epidemic proportions in the United States. The recent increase in prevalence is even more dramatic among children and the extremely obese. Even developing nations are seeing an increase in obesity, in part related to adoption of Western diet and exercise patterns. What is causing this epidemic? In the United States, although the percent of energy intake derived from fat is decreasing (from a high of 40% to about 32% today), total daily caloric intake is increasing, and refined carbohydrate intake has increased. In addition, increasing numbers of adults and children are sedentary; one-quarter of adults engage in virtually no physical activity aside from activities of daily living. Despite recent discoveries in the molecular genetics of obesity, a major role for genetic influences is not a likely explanation for the rapid recent changes in the prevalence of obesity. Obesity is a close second to cigarette smoking as the most important modifiable medical risk factor for diseases of virtually every organ system, including certain cancers (Table 45.1). Obesity is the most important risk factor in the development of Type 2 diabetes. The risk of complicating medical conditions increases with the degree of obesity, although for some complications—notably coronary artery disease, Type 2 diabetes and stroke—the risk correlates best with the regional distribution of fat. Central (visceral) deposition of fat (the “apple-shape” pattern), seen more commonly in men, increases risk, while excess fat in the lower body (thighs, hips and buttocks), seen more commonly in women (the “pear-shape” pattern), is associated with a lower risk of such complicating conditions. Obesity also increases overall mortality, and has recently been shown in Framingham, MA and other populations to shorten life expectancy by at least several years. In addition to the medical risks, and often more motivating for many people seeking to lose weight, are the unfortunate psychosocial consequences of obesity. There is widespread prejudice against obese individuals, even detectable in the opinions of young children. The resulting social and job discrimination contributes to low self-esteem and the high rate of depression among obese people who seek treatment. Notable also is the greater social stigma borne by obese women compared with obese men in our society, and the higher prevalence of obesity among those of low socioeconomic status, African Americans, Latinos, and Native Americans. For example, about 80%

528

INTEGRATIVE GASTROENTEROLOGY

Table 45.1. Major Health Risks of Obesity Type 2 diabetes mellitus Hypertension Coronary artery disease Dyslipidemias Strokes Carcinoma (especially endometrial, colorectal, esophageal, breast) Sleep apnea Gallbladder disease Gastroesophageal reflux disease Nonalcoholic fatty liver disease Osteoarthritis Gout Infertility Thromboembolism

of middle-aged African-American women in the United States are overweight or obese. We all know obesity when we see it, but obesity is technically defined as an excess of body fat (> 25% of body weight for men and > 30% for women) rather than an excess of body weight per se. However, the measurement of percent body fat is more difficult to obtain, and not as intuitive as body weight. Thus, relative weight is a reasonable surrogate measure for adiposity (percent of body weight constituted by fat). Weight adjusted for height, or body mass index (BMI), defined as weight in kilograms divided by the square of the height in meters, is very useful for defining and grading the severity of obesity and its attendant risks. BMI is now the standard measure of relative weight, though it may be a poor reflector of the actual degree of adiposity in very muscular individuals (e.g., certain types of athletes and laborers), and may understate adiposity in very sedentary individuals with little muscle mass. The latter is called sarcopenic obesity—a normal or low BMI with increased percent body fat and reduced lean body mass. A BMI of 25 to 30 kg/m2 is defined as overweight, 30 to 40 kg/m2 as obese, and 40 kg/m2 as extremely/morbidly obese. It is probably best to encourage

Obesity 529

weight loss for medical reasons only, especially if the patient is young, already suffers from complicating medical conditions, or has a strong family history of diabetes, cardiovascular, or cerebrovascular disease. For those with cosmetic/ trivial obesity, the benefits (and motivators) for successful weight loss are perhaps more psychosocial than medical. These patients should be encouraged to focus on a healthier (low refined carbohydrate, low saturated fat, high fiber) diet and increased physical fitness, rather than just the number on the scale. In the case of abdominal fat deposition, however, even mild excess adiposity may pose a medical problem. It should be noted that visceral obesity can exist even in the absence of overall obesity (i.e., at BMIs below the cut-off point for obesity, or even below the cut-off point for overweight). A waist circumference of more than 40 inches for men, and more than 35 for women, suggests the diagnosis of abdominal obesity, and can be easily measured with a tape rule around the narrowest point above the navel. Fortunately, this metabolically active abdominal fat is usually first to diminish with weight loss. The pear shape is both safer and more durable than the apple, as many women who diet have learned. From an evolutionary perspective, lower-body obesity may have conferred a selective advantage by helping to ensure survival through times of food shortage; lower body fat deposits are easily and selectively mobilized only under the hormonal influences of pregnancy and breastfeeding. Despite the inescapable fact that strong genetic influences on adiposity exist (as evidenced by adopted child and twin studies, as well as the increasing number of genetic markers being discovered), genetics does not appear to account for the majority of variability in BMI seen in the population, nor is it an insurmountable barrier in most of those who were fortunate (or unfortunate) enough to draw the genes leading to metabolic efficiency in the lottery of conception. Both the environment and learned behaviors are extraordinarily important as modifiers of genetic predisposition, and are good places to focus treatment. Do not allow your patient to accept obesity as their genetic destiny. While genetic factors do influence who is most susceptible to becoming obese, obesity can only occur when caloric intake exceeds expenditure—and both sides of this energy balance equation are eminently alterable for almost everyone!

Treatment Perhaps no other field of medicine today is as subject to the fads and hype, as well as to unreasonable patient expectations, as is obesity treatment. Part of

530

INTEGRATIVE GASTROENTEROLOGY

the reason lies in the inherent difficulty of reconciling a society whose main fuels are high-density and tasty, with an ideal body form typified by the Barbie doll. Given that our profession is unlikely to have any say in what body form people are striving for, the next best approach is to encourage reasonable goal weights for our own patients, press those who really need to lose weight to do so, and steer them toward safe, comprehensive treatment options. The components of a comprehensive approach to weight loss are listed in Table 45.2. The omission of any of these components is likely to adversely affect long-term results. The long-term success rate, defined as losing weight and keeping most of it off for 5 years, is low; perhaps 5% to 15% from the limited data provided by published studies. Although this rate is clearly poor, it must be viewed in context and compared with our similarly poor success in treating other chronic conditions and addictions, for example, cigarette smoking and drug abuse. In fact, if one views the chronic pleasurable overconsumption of food energy as a kind of addiction, an instructive distinction between food and other reinforcing substances appears. The cigarette smoker need never smoke again; the obese person, however, must learn to coexist with the offending substances in order to live. As such, we cannot expect many complete cures, and we will need to be constantly on the alert for relapses in those who appear to be in remission.

Medical Assessment The first step in treating the obese patient is the medical evaluation. The patient may desire weight loss, or may be reluctant. By all means, encourage the reluctant patient who has medical complications of obesity to lose weight, but recognize that any attempt at weight loss will be almost certain to fail if the patient is not self-motivated to change. Another important ingredient for success is

Table 45.2. Components of Comprehensive Weight Control Programs Medical assessment and monitoring Behavioral assessment and modification Dietary assessment and modification Physical activity assessment and modification Long-term maintenance support

Obesity 531

called self-efficacy, and is the patient’s belief that this change is attainable. Negative expectations are often a self-fulfilling prophecy.

INTEGRATIVE ASSESSMENT

Begin with a complete history and physical. The weight history may be of value in identifying precipitants of weight gain, and may suggest both avenues of treatment to pursue and avenues to avoid. For example, a change in job leading to a reduction in physical activity may be detected. Also of interest is whether the onset of obesity was in childhood or later in life. Although only about a fifth of obese adults were obese children, about four-fifths of obese children go on to become obese adults. Obesity in childhood can result in an increase in average cell number, not just size, while this occurs less frequently in adults, usually only when rapid weight gain occurs. Treatment of the hyperplastic form of obesity is said to be more difficult because weight reduction does not greatly reduce the number of fat cells, only their average size. Other information that can be gleaned from the weight history include postpartum weight gain (the average woman weighs about 10 lbs. more 2 years postpartum compared to pre-pregnancy, but the amount is extremely variable); weight gain after smoking cessation (average gain of about 6 lbs., again highly variable, and the most common excuse women give for not wanting to quit smoking); and evidence of yo-yo dieting and eating disorders such as binge eating (consuming inordinately large amounts of food within a specified period, three times a week or more, in private, for more than 1 year with loss of control and negative emotional sequelae); or bulimia nervosa (bingeing plus purging, either by vomiting, use of diuretics, or excessive exercise). When an eating disorder is suspected, referral to a center experienced in the treatment of these problems is recommended. The history should also include questions to help rule out endocrine conditions that can lead to obesity, such as hypothyroidism, hyperadrenalism, and neuroendocrine tumors, although even the most common of these, hypothyroidism, is rarely a significant cause of obesity in adults. Also inquire about drugs that may be associated with weight gain, such as sulfonylureas, insulin, steroids, most psychotropics, and anti-seizure medications. (Cheskin et al., 1999) Also assess for symptoms suggestive of diseases that often complicate obesity, such as Type 2 diabetes, coronary artery disease, hypertension, and sleep apnea. Symptoms and signs of depression should also be sought, as depression commonly accompanies severe obesity and may require additional treatment. Childhood or adult sexual or physical abuse is also common. Because it is usually not volunteered, it needs to be specifically elicited after

532 INTEGRATIVE GASTROENTEROLOGY

rapport has been established with the patient. The family history is of particular interest for endocrine disorders, extreme obesity, and its complications.

PHYSICAL EXAMINATION

The physical examination may be somewhat limited when the patient is extremely obese, but it can yield evidence of endocrine causes and detect complicating conditions. It is necessary to obtain not only an accurate weight and height for calculation of the BMI, but also tape measurement of the waist circumference, which, as noted, is an important modifier of the risk in obesity.

LABORATORY EXAMINATION

Laboratory evaluations should serve to screen for the complications of obesity. Blood chemistries should include, in particular, counts of fasting serum glucose, cholesterol, and triglycerides and liver function tests. A thyroid-stimulating hormone (TSH) should be obtained, and other endocrine and metabolic tests if a problem is suspected.

Fewer than 5% of obese adults will have a newly identified medical cause of weight gain, such as hypothyroidism, and fewer still will see resolution of their weight problem with treatment of any newly identified conditions.

Behavioral Assessment It is critical to gain a sense of the behavioral triggers to obesity. This can be accomplished by referral to an appropriately skilled behavioral psychologist and/or through your own discussions with the patient. First, it is important to assess the impact of the obesity itself on the patient’s level of functioning and quality of life. Some very important aspects of the patient’s problem may only emerge with specific inquiry: For example, the patient may have withdrawn from all unnecessary social interactions, may no longer be able to enjoy certain activities or interests because of weight gain, or may have suffered job discrimination, to name a few possibilities. Also related to quality of life are the patient’s expectations about what changes will occur with successful weight control. Although it may be motivating for the patient to believe that life will improve with weight loss, disappointment may follow

Obesity 533

unless the changes likely to occur have been placed in proper perspective. Medical benefits can certainly be expected with weight loss in many of those suffering from medical complications of obesity. For example, patients with Type 2 diabetes can often discontinue insulin or oral agents, antihypertensive medications may become unnecessary, and sleep apnea usually disappears with as little as 10% to 15% loss of initial weight. On another level, however, although self-assurance often increases, the wallflower does not become the life of the party and the average, competent worker does not get a promotion upon losing weight. Encourage obese patients toward a balanced view by reminding them that societal prejudices about body weight and character are in no way based on fact, and that they are the same good people whether they weigh 300 or 150 lbs.

BEHAVIORAL FACTORS

In exploring specific behaviors, it is useful to assist the patient in identifying their specific triggers to eating. These eating cues are situations or feelings that lead to eating, often in an inappropriate way. In our society, physical hunger is rarely a significant part of life, even for the poorest among us. In fact, physical hunger is not an important eating cue for many people, in part because they rarely let themselves get to the point of true hunger. Instead, they may eat in response to a host of other cues, most of which are inappropriate. The most common eating cues cited are: habit (“It’s noon so I guess I’ll have lunch” or “I have a jelly doughnut and coffee in the car on the way to work”); stress (“I’ve got to finish this paper, and eating while I write helps me concentrate”); boredom (“There’s nothing else to do”); emotions (“I eat when I’m depressed or upset”); and food as a reward (“After a hard day, I deserve a rich dessert”). Underlying some of these cues is the association of food with love, caring, and comfort, which may have its antecedents in early childhood but persists into adult life and is pervasive in our culture. The patient should be helped to recognize that using food to deal with stress, boredom, and emotions is, at best, ineffective. The stressful situation does not resolve with eating. In fact, eating may worsen the problem by distracting a person from dealing directly with the situation. Unfortunately, simply telling a patient not to eat when under stress is generally ineffective, given the long-ingrained nature of using food inappropriately by many obese patients. Instead, use the following 3-step approach. First, recommend a period of observation and recording to enable the patient to recognize the cue. For instance, you can ask the patient to wear his or her watch upside-down as a reminder to ask, “Why am I reaching for the food at

534

INTEGRATIVE GASTROENTEROLOGY

this time?” If the patient is not physically hungry, one of the possibly inappropriate eating cues is most likely occurring, and its nature should be recorded. Second, suggest the substitution of other responses for inappropriate eating. For stress, this might be writing down what the stress is, formulating a plan for doing something about it, doing something (besides eating) to relieve the stress on the spot, or, at the very least, substituting the cookies with a walk around the block or a call to a friend. The third step is repetition, continuing to practice making appropriate responses to the problematic cue. The rewards of substituting a new behavior include the positive responses of others to the change in approach—not just to eating, but to life—that the patient makes. Although some degree of behavior change is necessary, not every maladaptive behavior must be completely eliminated, nor must every rich food be replaced by celery sticks. While losing a large amount of weight in a reasonable amount of time does require a fairly aggressive diet program, maintaining a new lower weight does not. If the patient can learn to even partially control a few of his or her more important inappropriate eating behaviors, and to shift to a diet somewhat lower in calories than baseline, that is often sufficient to maintain weight in the new, lower range.

DIETARY MODIFICATION

Another behavior of interest in obesity is dietary restraint. Restrained eaters believe that they must exercise a good deal of control over their eating—they are always conscious of what they can and cannot eat. Unrestrained eaters do not control their eating to any great extent. Restrained eating may lead to some paradoxical sequelae: Once restraint is relaxed, an exaggerated response may follow (all-or-nothing behavior). Such patients may be superb dieters, but are equally superb at overeating once the diet has been “broken.” Although a certain amount of control and monitoring is necessary to maintain weight control, a high level of dietary restraint may be more problematic than a low level in the long run. One solution is to couple the teaching of ways to control inappropriate eating cues with dietary changes that emphasize foods lower in fat and calories, and higher in fiber and water content (i.e., low energy-density foods), so that lower restraint is required to maintain a given intake. Skipping meals when the patient is physically hungry should be discouraged.

“What’s hunger got to do with it?” Most obese individuals experience no more physical hunger than do lean people, but may misinterpret learned

Obesity 535

habits and situations that lead to eating as “hunger.” A major breakthrough in the ability to control unnecessary eating can result when individuals learn to accurately distinguish physiological from learned forms of hunger.

Dietary Assessment Although most aspects of diet are more properly characterized as behaviors, the need remains to understand patients’ tastes and food choices. Although the physician can and should get some idea of the patient’s diet, a formal dietary assessment is best done by a dietitian, using either a prospective or retrospective food diary. The results of a food diary must be interpreted with caution, as both retrospective underreporting and prospective restrained eating are more common among obese individuals (and may in fact explain some of the propensity towards obesity, if the obese are less aware of the foods and quantities they choose). Despite these shortcomings, the information gathered can be very useful. For example, the macronutrient composition of a patient’s diet will often be weighted toward fats, simple carbohydrates, and protein. By cutting fat and increasing intake of complex carbohydrates, especially vegetables and fruit, such patients can considerably increase the volume of food they consume as they attempt to reach and maintain a lower weight. A helpful tool in altering the composition of the patient’s diet is the technique of gradual change. For example, a patient reluctant to switch from whole milk to skim milk could first try 2% milk, get used to this for a month or so, then move on to 1% fat milk for another month. At this point, the patient should notice that the once-favored whole milk will now taste too oily. At some later date, the final step to skim milk can be made with few feelings of deprivation, demonstrating that taste preferences are acquired and eminently changeable, even in later life. Recommend scouring the supermarket aisles (at a time when the patient is not hungry) for tasty, low-fat, low-calorie alternatives to favored foods. Encourage the patient to explore the wide variety of foods now available, and to focus on the good taste of the new choice rather than comparing it to the “real thing.” The presentation of nutritional information on food labels is becoming more and more useful, listing not just grams of fat, for example, but also the percentage of the daily dietary fat allotment those grams represent. The patient should be taught to read labels and to stay within the calorie “budget.”

536

INTEGRATIVE GASTROENTEROLOGY

This is also a good time to improve the dietary habits of the patient’s family, something that is particularly easy to do when the patient is the primary cook and food shopper. Including the family in this process not only improves their diet, but also makes it easier for the patient if the home can be a temptationfree zone. If other members of the family insist on consuming junk food, they can be instructed to partake outside the home, or to put only individually packaged items in the cupboard. Small-size purchases of rich desserts and the like are desirable in general—the smaller the dietary indiscretion, the less severe the consequences. Unfortunately, portion sizes have risen greatly in the United States in recent years, especially in meals consumed outside the home. Specific types of diets are discussed under “Types of Diets” below.

Food preferences are mostly learned, rather than inherent, and are thus quite alterable. With repeated exposure to lower calorie, more healthful foods, taste preferences change. You may have experienced this yourselves, perhaps in switching from whole milk to reduced-fat or skim milk.

Exercise Assessment Exercise alone is not a terribly effective method for shedding weight. It is difficult for the untrained person to do enough of it and most, if not all, of the expended energy is compensated by increased caloric intake. Exercise is, however, an excellent aid to maintaining a lower weight after weight loss, enabling a person to eat somewhat more than a non-exerciser and still maintain their weight. Regular aerobic exercise and strength training will also improve cardiovascular fitness, reduce adipose tissue depots (especially visceral fat), and promote growth of metabolically more active muscle tissue. An exercise assessment should include an exploration of the patient’s usual degree of physical activity, any limiting factors such as joint disease or previous injuries, types of physical activity the patient finds enjoyable, and a measurement, preferably by an exercise specialist, of the current fitness level. An exercise stress test is not required unless cardiovascular disease is suspected. A rule of thumb in devising an exercise regimen that will be most likely to be followed is to utilize a phased-in approach. Most obese individuals start out with a limited capacity to exercise. Rather than suggesting a type or level of activity that is high, and unlikely to lead to sustained adherence, make sure that the plan fits into the patient’s schedule and lifestyle.

Obesity 537

The first phase consists of increasing the amount of everyday physical activity, so-called “lifestyle” activity, rather than prescribing a formal exercise regimen. Lifestyle activities include taking the stairs in gradually increasing increments, parking the car farther away from the destination, walking the dog farther, and the like. This step alone may double the level of physical activity in a very sedentary individual. The next phase is a structured walking plan. People are most likely to adhere to a plan if the walk is scheduled during a break or lunchtime at work, or when the daily energy level is often the highest (for example, early morning, as opposed to evening after a long day’s work). Having a companion to walk with and a place to walk indoors are also helpful in increasing compliance. A patient should make a minimum of 20 to 30 minutes available for each session of exercise. Studies suggest that an hour is best for weight control, and 90 minutes for weight loss. The intensity of the exercise is not critical to the burning of calories: Walking at a leisurely pace for one hour is roughly equal to walking briskly for half an hour. Allow the patient to set the pace. Initially, it may be quite slow, but in the absence of severe cardiopulmonary or joint disease, most patients soon find the going easier and faster. Goal setting can strengthen this process. Have the patient keep a log of the time spent walking and the distance covered after each session. The patient can then see the progress being made and set the goal a bit higher regularly. Next, the types of activities performed should be broadened. Walking or jogging can and should remain a component of the plan, but with the addition of other forms of aerobic exercise. Recommend aerobics classes, stationary or outdoor bicycling, swimming, a cross-country skiing machine, or just about anything else that will burn calories and be enjoyable to the patient. Strength/ resistance training of large muscle groups is an important component to include, as this can build muscle mass and raise resting metabolic rate, an aide to future weight control. Team or racquet sports and golf can be suggested to provide social interaction and thus increase the likelihood of long-term adherence to the exercise plan. Again, the most important criterion for a good exercise plan is that it be one that the patient is likely to follow and be comfortable with as a lifelong habit.

Despite the multiple medical benefits of exercise, exercise in the absence of concurrent dietary change is a remarkably ineffective way to lose weight for most people. This is probably because exercise elicits hunger, thus largely counterbalancing the calories burned in the exercise. Without this feature, manual laborers would be doomed to steady starvation!

538

INTEGRATIVE GASTROENTEROLOGY

Types of Diets It is best to instill in your patients a degree of skepticism about commercially advertised weight-control diets. Many are based on very limited menus, the rationale being that monotony helps curb consumption. Some involve use of diuretic agents. In fact, any substantially reduced-calorie diet will initially cause diuresis, which will be regained as soon as the period of severe caloric restriction ends. After the diuretic phase, the amount of weight loss to be expected on any diet obeys a simple formula. Lipolysis of one pound of adipose tissue yields about 3,500 kilocalories; it is therefore necessary to restrict energy intake and/ or increase energy output by about 500 kilocalories per day to lose one pound of fat per week. Because some muscle may also be lost, and muscle is poorer in energy than fat, the rate of weight loss may be somewhat higher than predicted. However, two counterbalancing factors are at work. First, with sustained caloric restriction, a moderate reduction in metabolic rate occurs. This decrease makes weight loss somewhat more difficult to achieve, but caloric requirement, corrected for the new, lower weight, appears to return the prediet level within a few months of resuming a eucaloric diet. Second, because lower weight means reduced caloric need, the same caloric intake will represent less of a deficit as the patient continues to lose weight. A regular program of physical activity, especially one that includes resistance exercise, can partially counteract both these factors by helping blunt the decrease in metabolic rate and by building muscle mass, which is more metabolically active and therefore has a higher caloric requirement, even at rest, than an equal weight of adipose tissue. How much of a caloric deficit should be recommended, and in what form should the calories be taken? The answer depends on the degree of obesity, the presence or absence of comorbidities such as Type 2 diabetes, the results of the behavioral assessment and, to some extent, the patient’s preferences. In any case, it is important to remind the patient that the diet is only part of the overall plan, and will fail in the long term unless accompanied by sustained changes in behavior. For patients who are overweight or moderately obese (BMI of 25 to 32), I recommend a caloric deficit of 500 to 750 calories per day to achieve 1 to 1.5 pounds of weight loss per week. A dietitian can design a low-calorie, foodbased diet that is either balanced-deficit (reducing total number of calories while keeping proportions from carbohydrate, fat, and protein roughly the same as before), or fat-deficit, with most of the caloric reduction resulting from restriction of fat intake. The latter approach is preferable because the

Obesity 539

typical American diet is too high in fat, especially saturated and trans fats, and simple sugars. Also, a greater volume of food can be eaten on a diet that emphasizes fiber-rich complex and vegetable-source carbohydrates and reduces fat to less than 30% of calories consumed. Patients with a BMI of 33 to 40 will also benefit from a fat-and-caloriereduced diet. It is important, however, to recognize that at this level of caloric restriction it will take more than a year to attain a weight loss of 50 to 70 pounds. Few patients can sustain this degree of restriction for that long; therefore, for a limited period of time, a very-low-calorie diet (VLCD) of fewer than 800 calories per day may be needed. The VLCD is justified particularly if the patient already suffers from comorbidities that are likely to be alleviated with significant weight loss. VLCDs can consist of food, commercially available liquid supplements, or a combination of both. With full compliance, the amount of weight lost on a VLCD ranges from 2.5 to 4 pounds per week, depending on body mass and level of physical activity. The initial diuretic phase may be pronounced and accompanied by lightheadedness, headache, or fatigue, which are usually transient. Later symptoms may include constipation and intolerance of cold. Electrolyte abnormalities are rare, but serum should be monitored occasionally, and more frequently if the patient is prone to electrolyte problems because of renal insufficiency or diuretic use. Because of the greater stress on the body and greater need for monitoring of true VLCDs, I prefer to keep the caloric intake above 800 to 1,000 kilocalories per day. Gallstones may occur or become symptomatic, probably due to gallbladder stasis and a decrease in bile acids, which occurs during or immediately after any severely restricted (especially fat-restricted) diet. To prevent stasis, the patient can add to the diet a tablespoon of a fat (preferably an unsaturated fat such as canola or olive oil), taken in one daily dose, which will allow the gallbladder to contract. A VLCD should be administered only under a physician’s supervision and with full attention to the behavioral changes necessary to sustain the weight loss that this regimen will produce. In extreme (“morbid”) obesity corresponding to a BMI of 40 kg/m2 or more, the only practical initial diet for most patients is a highly restricted diet with careful medical monitoring and long-term follow-up. It should be noted, however, that even a modest weight loss can yield substantial health benefits for morbidly obese patients. Sleep apnea often disappears with as little as a 10% loss in weight, and with even 5% weight loss, hypertension, diabetes, and hyperlipidemias may also improve significantly. I do not view, nor let my patients view, modest weight loss as a failure or a waste of time. The same is true for patients with lesser degrees of obesity.

540

INTEGRATIVE GASTROENTEROLOGY

The glycemic index, a measure of speed of absorption of carbohydrates, is increasingly popular in constructing diets. Data are mixed at this point, but foods with high complexity and high-fiber content may well prove to be particularly helpful in controlling appetite and metabolic complications of overeating.

Drugs and Surgery Adjunctive anorectic medications may be useful for the obese patient, either from the start, to enhance compliance with the diet, or later, when compliance begins to waver or hunger becomes more prominent. There is little doubt that such medications significantly increase weight loss during the period in which they are used, and may help maintain some weight loss (although regain tends to occur even with continued use). Commonly used anorectic drugs are phentermine and sibutramine. One reasonably effective agent, ephedra, is no longer available because it has been associated with adverse cardiovascular events. The true amphetamines, diuretics, and thyroid medications should generally not be prescribed for weight loss. An agent that holds some appeal to me as a gastroenterologist is orlistat (sold by prescription as Xenical, and in a nonprescription strength as Alli). This is the only nonsystemically acting obesity medication currently available. It acts in the lumen of the small bowel by binding to lipases, and thus causes malabsorption of about 30% of ingested fat for the prescription strength, and 25% of ingested fat for the over-the-counter strength. Along with dietary fats, these agents also block the absorption of fatsoluble vitamins and cholesterol. This has two consequences: A multivitamin supplement must be taken at a time when the orlistat or Alli is not being taken to prevent deficiencies, and there seems to be a greater degree of reduction in cholesterol levels for a given amount of weight loss compared with weight loss resulting from diet alone. While orlistat and Alli have no appetite-curbing effects, they may have an Antabuse-like effect, in that consumption of more than a moderate amount of fat at a sitting will result in unpleasant GI consequences. I view these agents as more suitable for patients who are having difficulty avoiding junk food and fats than for patients with increased physical hunger. Whether obesity should be considered a chronic disease and treated on a long-term basis with anorectic or other drugs is in part a philosophical issue. I use these agents only after attempts at dieting have failed, or when progress is stalled in patients who are severely obese and/or who suffer from comorbid conditions, or if physical hunger is a problem during the diet. Herbal medications are also widely used for weight control. Agents that appear to have limited efficacy include fiber supplements and ephedra-like

Obesity 541

agents (e.g., citrus aurantium). Agents that do not appear to have a clinically significant effect include DHEA, Hoodia gordonii, and chitin/chitosan. The latter is a polymer of glucosamine that can bind fat in the GI tract, thus blocking fat absorption; in randomized controlled trials, however, there was no significant weight loss with chitin compared to placebo. While the mechanism of chitin is plausible, it appears to be ineffective at reasonable doses, and could block absorption of fat-soluble vitamins. Chromium picolinate is often an ingredient in OTC weight loss formulations, but the FTC recently concluded that there is insufficient evidence of any effect on weight, body composition, metabolic rate, and appetite. The evidence on conjugated linoleic acid is mixed, but may prove to have some modest effect in weight control. It is important to recognize that herbal agents are still drugs: Natural products can be as toxic as synthetic products. Not all natural, orally consumable ingredients are subjected to the degree of scientific scrutiny that pharmaceuticals undergo, but it is best to insist on some degree of safety and efficacy testing for such products. The surgical treatment of morbid obesity has improved considerably since the days of the jejunoileal bypass and jaw wiring. Generally, patients are referred for surgery only if they have a BMI of 40 or greater, or of 37 or greater if there are significant coexisting medical complications of obesity and they have failed to lose or maintain weight loss with a comprehensive nonsurgical approach. Probably the best procedure currently available is the gastric bypass, preferably performed laparoscopically. This procedure combines stapling of the stomach to make a small-capacity proximal gastric pouch, along with a short-segment bypass of the proximal small bowel created by a Roux-en-Y loop. Results are quite good in the short term. Long-term results, as with all methods of weight loss, depend largely on the patient’s ability to make behavioral changes. Therefore, aside from access to a hospital with adequate experience in this procedure, the best chance of long-term success is to refer the patient to a center that offers and insists upon extensive preoperative evaluation and long-term maintenance therapy consisting of regular sessions in dietary management and behavioral modification. Do not make the mistake of viewing surgery as a treatment that does not require the patient’s active involvement—an unmotivated or unguided patient can and will defeat the procedure.

While medications and surgery are often the mainstays of treatment of most health conditions, obesity is one area in which changes in lifestyle, when sustained, are safer and more effective, and thus must be considered the first line of treatment.

542 INTEGRATIVE GASTROENTEROLOGY

Maintenance The physician and the patient both know that the long-term results of attempts at weight loss are often poor. It is therefore important to expose the patient, at the beginning of treatment, to the attitudes and behaviors that are likely to foster long-term maintenance of weight loss. These may be summarized as follows: Readiness: Correct timing for change is vital. It is folly to begin a diet when you are not yet convinced of the need to do so, or are in the midst of a stressful life event such as divorce. Setting reasonable goals: Aiming for attainable rather than an “ideal” body weight is advisable. A reasonable long-term goal might be the lowest weight the patient has successfully maintained for one year or more during the previous ten years. Reliable support systems: Obtaining helpful assistance aids in both weight loss and maintenance. This usually involves seeking out a friend or relative who knows how to listen and not just give advice. Building in maintenance: Planning and executing behavioral changes from day one is essential. Becoming invested in one’s goals: Learning how to talk to oneself in a positive way in order to enhance commitment to self-set objectives is a useful technique. Making gradual changes: Modifying food choices and level of physical activity reduces the sense of deprivation, and may make the process of change easier and the changes themselves more likely to be permanent. Keeping records: Recording weight, foods eaten, exercise, and precipitants of inappropriate eating is an excellent way to identify problem areas and to spot a relapse before it gets out of hand, thereby improving the chances of long-term success. Making it enjoyable: This is self-explanatory. It is much easier to comply with the new behaviors if they can be enjoyed. If your patient cannot stand to exercise, do not tell him or her to do it anyway. Instead, suggest taking a child to the park or walking around the mall to people-watch. The achievement of a positive change in lifestyle is, by itself, very reinforcing and should not be discounted as a source of satisfaction and enjoyment. Being flexible: This applies to both the physician and the patient. If an approach that has been given a fair trial is not working, or if the patient’s circumstances change (a new job, for example), the weight loss plan may need to change, too.

Obesity 543

Studies have shown that people who are successful at losing weight and keeping it off long term share certain behaviors: in short, they regularly monitor their weight, what they eat, and their physical activity; they usually follow low-calorie, low-fat diets; and they exercise regularly. Emulating the habits of successful weight maintainers holds much promise for those struggling with weight control.

Summary (Expert Opinion) In closing, it should be clearly accepted that helping patients lose weight and keep it off requires a comprehensive and sustained effort that involves devising an individualized approach to diet, behavior and exercise, as described in detail above. Although it is true that only the patient can do this work, this is one area where the diligent and caring physician, with a commitment to the principles of integrative medicine, can make a major difference.

46 Nutrition and Colorectal Health MITRA RANGARAJAN AND GERARD E. MULLIN

key concepts ■

■

■

■

Colorectal cancer is a leading cause of cancer-related deaths in the United States. The goal of screening programs is early detection of pre-invasive lesions or early cancer. Chemoprevention has emerged as a promising and pragmatic medical approach to reduce the risk of cancer. Diet plays an important part in the prevention of colon cancer. ■

Introduction

C

olon cancer is ranked as the third leading cause of death from cancer. Colorectal cancer is a disease with high mortality rate secondary to diagnosing the condition at a late stage. Therefore, attention is now focused on preventive strategies, which include early detection of treatable precursor lesions of this disease. Endoscopic polypectomy has been shown to reduce the incidence of colorectal cancer. However, it is not practical to employ this strategy for the population as a whole. Screening the general population would require extensive manpower and monetary resources, and its success is fully dependent on the compliance of the population. The American Cancer Society estimates the incidence of all cancers to be approximately 1,479,350 cases. An estimated 9% of all cancer mortality is sue to colorectal cancer. Mortality rate for colon cancer has steadily declined, reflecting improvements in early detection and treatment. However, we are yet

544

Nutrition and Colorectal Health 545

Table 46.1. BP:

115/69

RR:

16

Pulse:

72

HT:

67 in

WT:

178 lbs

BMI:

28

Temp:

98.6

to prevent the incidence of colon cancer. This is largely due to the lack of implementation of preventative strategies. The precursor for colon cancer is the formation of adenomas. Adenomas are more common than colon cancer, especially in individuals over the age of 50. Therefore, the best strategy to prevent colon cancer is to prevent the formation of adenomas. Colorectal cancer is another condition whereby Western diets high in saturated fat and red meat, low in fiber, and compounded by sedentary lifestyles with high obesity rates, contributes towards a greater susceptibility. Colorectal cancer is the most common cancer of the digestive organs, accounting for more than 60% of all digestive organ cancers and 25% of all cancer mortality in the United States (Boyle & Ferlay, 2005). In 2004, more than 660,000 Europeans were living with a diagnosis of colon cancer. Colorectal cancer is the second most common cancer in Europe and the United States. Colon cancer is rare in Africa and Asia (except Japan), as with diverticular disease. In both conditions, a high-fiber diet appears to be protective. For colorectal cancer, a high-fat SAD is a risk factor for disease development Table 46.2. Complete Blood Count WBC

4670/mm3

Hemoglobin

3.76 M/mm3

Hematocrit

32.4%

MCV

86.2 fl

RDW

18.2%

Platelet

242 K/mm3

546 INTEGRATIVE GASTROENTEROLOGY

and recurrence (Rennert, 2007). The seven Western behavioral risk factors associated with an increased risk for colorectal cancer include: • • • • • • •

Smoking Low physical activity Low fruit and vegetable intake High caloric intake from fat Obesity High alcohol intake Low intake of multivitamins (Coups, Manne, Meropol, & Weinberg, 2007) THE SAD FACTS

The standard American diet (SAD) is low in nutrient quality and is a major risk factor for colorectal cancer.

QUESTIONS 1. What are your diagnostic considerations? 2. Which laboratories would you order at this point?

QUESTION What would you do or order next?

Author’s Approach to Her Digestive Health Issues 1. Short-term: i. Surgical opinion ii. Dietary counseling iii. Stress management: Mind–body rebalancing

Kristin’s Digestive Health Issues 1. Long-term: A Prevention of colorectal cancer recurrence

Nutrition and Colorectal Health 547

Integrative Approaches to the Prevention of Colorectal Cancer Recurrence CHEMOPREVENTION

QUESTION Which of the following is not associated with a higher prevalence of colorectal cancer in the United States? 1. Regular exercise 2. High intake of red meat 3. High intake of saturated fat 4. Strong family history of colorectal cancer

Chemoprevention is a way to prevent or delay the development of benign or malignant lesions by taking medicines, vitamins, or other agents. Cancer chemoprevention was first defined by Sporn in 1976 as the use of natural, synthetic or biologic chemical agents to reverse, suppress or prevent carcinogenic progression to invasive cancer (Sporn MB, Dunlop NM, Newton DL, Smith JM, 1976). Potential chemopreventive agents for colorectal cancer include nonsteroidal anti-inflammatory drugs (NSAIDs), vitamins, and hormones, as listed in Table 46.3. As well, dietary factors and exercise have been implicated in the primary prevention of colon cancer.

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS

NSAIDs, cyclooxygenase-2 (COX-2) inhibitors, and aspirin have all been studied in prevention of colon cancer. Strong support for a chemopreventive effect of NSAIDs is provided by in vitro experiments, animal models, epidemiological studies, and clinical trials (DuBois, Giardiello, & Smalley, 1996). The mechanism of action of NSAIDs is inhibition of cyclooxygenase, which is a key enzyme in conversion of arachidonic acid to prostaglandins, prostacyclin, and thromboxanes. Prostaglandins affect cell proliferation and tumor growth through activation of second messengers in signal transduction pathways, and prostaglandin levels are increased in many cancers, including colorectal adenomas and adenocarcinomas (Giardiello, Offerhaus, & DuBois, 1995). COX-1 is present in most tissues, whereas COX-2 is expressed in response to growth factors, cytokines, mitogens, and tumor promoters. Much of the initial

548 INTEGRATIVE GASTROENTEROLOGY

Table 46.3. Potential Chemopreventive Agents NSAIDs Sulindac Celecoxib Aspirin Ursodeoxycholic acid Hormones Estrogen Medroxyprogesterone acetate Vitamins/Antioxidants Calcium Folate Selenium Curcumin Vitamin D Supplements/Sunshine Curcumin Ginger Glucosinolates Sulforaphane and indole-3-carbinol (I3C)

data on NSAIDs and chemoprevention of colon cancer in humans came from literature on familial adenomatous polyposis (FAP), which is an autosomal dominant disorder characterized by innumerable colorectal adenomas and eventual carcinoma. Multiple studies have evaluated sulindac in FAP, and all report either complete or partial regression of adenomas after three to six months of treatment with sulindac at doses of 300 to 400 mg per day (Keller & Giardiello, 2003). NSAIDs such as sulindac have gastrointestinal toxicity that may limit its use for prevention in colorectal cancer. This led to studies on COX-2 inhibitors. Cyclooxygenase-2 is expressed in inflammatory states, premalignant lesions, and colorectal cancer. COX-2 inhibitors were speculated to have a role in chemoprevention of colon cancer. Celecoxib led to polyp regression in FAP, which led to investigation of NSAIDs in sporadic adenomas and

Nutrition and Colorectal Health 549

colorectal neoplasia (Table 46.3; see Steinbach, Lynch, Phillips et al., 2000). Epidemiologic studies have shown a reduction in colorectal cancer in individuals taking NSAIDs A series of case-control studies revealed a 40% to 50% reduction in the risk of colonic adenomas or colorectal cancer among patients taking aspirin (DuBois, Giardiello, & Smalley, 1996). Giovannucci and associates measured cancer incidence in a cohort of women and found that regular aspirin use, at doses similar to those recommended for cardiovascular disease prevention, reduced risk of colorectal cancer—but this effect may require greater than a decade of use to occur (Giovannucci, Rimm, Stampfer et al., 1994). In a prospective cohort study involving 47,900 males in the United States, Giovannucci and associates showed that regular use of aspirin decreased the incidence of adenomas. The major trials evaluating the use of aspirin in the chemoprevention of colorectal cancer are displayed in Table 46.4.

CALCIUM

Vitamins, including calcium, vitamin D, folate, and selenium have also been implicated in chemoprevention of colon cancer. Dietary calcium has been hypothesized to neutralize fatty acids and free bile acids, which have an irritative effect on the colonic epithelium (Newmark & Heaney, 2006). Numerous murine studies have shown that calcium decreases colonic mucosal hyperproliferation, decreases markers of colorectal mucosal proliferation, and inhibits colonic tumor development (Lipkin, 1999). Though two early meta-analyses showed little or no protection against colorectal cancer with calcium (BergsmaKadijk, van’t Veer, Kampman, & Burema, 1996; Martinez & Willett, 1998), numerous subsequent prospective cohort studies have reported modest decrease of colorectal cancer in high-intake calcium groups compared to low-intake groups (McCullough et al., 2003; Wu, Willett, Fuchs, Colditz, & Giovannucci, 2002; od et al., 2005; Baron et al., 1999a, 1999b). In a pooled analysis of 10 prospective studies looking at intake of dairy foods, calcium and colorectal cancer, Cho and colleagues concluded that increased consumption of milk and calcium were related to a lower risk of colorectal cancer. This data, along with other previous experimental studies that demonstrate a beneficial effect of calcium supplementation on colonic epithelial cell turnover and colorectal adenoma recurrence, support the concept that moderate milk and calcium intake decreases the risk of colorectal cancer (Cho, Smith-Warner, & Spiegelman, 2004). Finally, a meta-analysis of three randomized controlled trials (Shaukat, Scouras, & Schunemann, 2005) suggested that calcium prevents recurrent colorectal adenomas with an overall relative risk of 0.80 (95% CI, 0.68–0.93). Calcium has recently been associated with higher ischemic

550

INTEGRATIVE GASTROENTEROLOGY

Table 46.4. Major Trials of Chemoprevention in Colorectal Cancer with Aspirin First Author

Date

Study Design

Patients

Effect

Thun

1997

Prospective cohort

662,424 patients providing information on frequency and duration of aspirin use

Regular aspirin use associated with reduced risk of colorectal cancer

Giovannucci

1994

Prospective cohort

89,446 women reporting number of consecutive years of aspirin use

Regular, long-term aspirin use associated with reduced risk of colorectal cancer

Giovannucci

(YEAR)

Prospective Cohort

47,900 males in U.S. Questionnaire sent in 1986, 1988, and 1990 about use of aspirin and occurrence group using of cancer

Result: lower incidence of colorectal adenomas in aspirin

Sturmer

1998

Prospective cohort following randomized placebo controlled

No association of 22,071 male physicians randomly aspirin use with assigned aspirin use colorectal cancer protection

Baron

2003

Randomized, placebo controlled

1,121 patients with sporadic adenomas randomized to aspirin or placebo

Low-dose aspirin prevents recurrence of adenomas

Sandler

2003

Randomized, placebo controlled

635 patients with previous colorectal cancer with curative resection randomized to aspirin or placebo

Daily aspirin use associated with reduction of adenomas in patients with previous colorectal cancer

Benamouzig

2003

Randomized, placebo controlled

272 patients with sporadic adenomas randomized to soluble aspirin or placebo

Daily aspirin use associated with reduction in recurrent adenomas

Nutrition and Colorectal Health 551

cardiovascular events in post-menopausal women (Bolland et al., 2008). Many more studies are required to confirm and validate this observation. Also, recent data showing that vitamin D deficiency appears to be a risk factor for developing cardiovascular disease would contradict these findings, as many women co-supplement calcium and vitamin D together.

VITAMIN D

The possible effects of vitamin D in colon cancer prevention were first brought to light when Cedric Garland and Frank Garland reported in 1980 that people who lived in sunny locations had a lower incidence of colon cancer compared to those who lived in colder regions (Garland CF, Garland FC, 1980). In 1989, the Garland brothers went on to furnish further evidence that deficiency of vitamin D may pose a significant risk for the development of colon cancer. They analyzed air pollution data from 20 Canadian cities and found that cities where polluted air obscured vitamin d-producing sunlight had higher death rates from both colon and breast cancer. Furthermore, they pointed out that colon cancer rates were 4 to 6 times higher in North America and Northern Europe when compared to the incidence of colon cancer in countries close to the equator (Armstrong, 2006). Vitamin D has also been found to be inversely associated with risk of colorectal cancer (Wu, Willett, Fuchs, Colditz, & Giovannucci, 2002). In a prospective cross-sectional study of 3121 asymptomatic patients aged 50 to 75 years, a multivariate analysis found vitamin D to dominate calcium as a beneficial risk factor. Dr. Freedman and colleagues studied a total of 16,818 participants in the Third National Health and Nutrition Examination Survey (Freedman, Looker, Chang, & Graubard, 2007). Levels of serum 25(OH)D were measured at baseline by radioimmunoassay. Cox proportional hazards regression models were used to examine the relationship between serum 25(OH)D levels and mortality from specific cancers. Colorectal cancer mortality was inversely related to serum 25(OH)D level, with levels 80 nmol/l or higher associated with a 72% risk reduction (95% confidence interval = 32% to 89%) compared with lower than 50 nmol/l, P(trend) = .02, supporting an inverse relationship between 25(OH)D levels and colorectal cancer mortality. Overall, a meta-analysis showed that a significant protective effect against developing colorectal cancer was conferred by vitamin D sufficiency (Gorham et al., 2007).39 The most “natural” way to enhance vitamin D status is to soak in the rays of sunshine. The body can convert pre-vitamin D3 in the skin to vitamin D in the presence of ultraviolet light (UVB) from the sun, depending upon the latitude,

552 INTEGRATIVE GASTROENTEROLOGY

time of day, presence of sun block, skin color, and skin concentration of 7-dehydro-cholesterol (Mullin & Dobs, 2007).

FOLATE

Several cohort and case-control studies have suggested a reduced risk of colorectal cancer with a higher consumption of vegetables and fruits (Lance, 2008). Folate is a B vitamin found in leafy green vegetables, citrus fruits, and dried beans and peas. Folic acid is involved in DNA synthesis and repair, DNA methylation, and modulation of cell proliferation, shown in both in vitro and animal studies (Mason & Levesque, 1996). Murine models of colorectal cancer report that folate administration is associated with decreased risk of colonic neoplasm, and epidemiologic studies show an inverse relationship between dietary folate and colorectal cancer incidence (Kim, 2007). Two large prospective cohort studies show an association between folate intake and reduced colorectal cancer incidence (Su & Arab, 2001; Giovannucci, 2002). In the Nurses’ Health Study, 88,756 women provided diet assessments including multivitamin use. This investigation found that long-term use of folate at doses greater than 400 micrograms daily was associated with a substantial decreased risk for colon cancer (Giovannucci et al., 1998). In the National Health and Nutrition Epidemiologic Follow-up Study (Su & Arab, 2001) subjects were followed for 20 years, and an inverse relationship of folate intake and colon cancer was found for men (RR 0.40; 95% CI, 0.18–0.88). Vitamin B6 appears to be inversely associated with risk of colorectal neoplasia (Wei et al., 2005). Despite the beneficial effects of folic acid for the prevention of colorectal cancer, future studies are needed to determine the exact amount to be consumed for optimal benefit.

SELENIUM

Selenium is an essential trace element in the human diet and is incorporated into proteins. Selenoproteins are involved in the neutralization of reactive oxygen species, and are important for the antioxidant defense of cells (Al-Taie et al., 2003). Selenium is found in plant foods, and the concentration of selenium in food correlates with the content of the soil where plants are grown. In ecologic studies selenium intake has an inverse relationship to colon cancer risk (Shamberger, 1985). In colon cancer cell lines, selenomethionine inhibits growth and

Nutrition and Colorectal Health 553

decreased levels of cyclooxygenase proteins in the cells (Baines et al., 2002), and animal studies have consistently shown selenium has activity against colorectal cancer (Duffield-Lillico, Shureiqi, & Lippman, 2004). Though in vitro and animal studies show activity of selenium against colorectal cancer, epidemiologic studies have been inconsistent (Nomura et al., 1982; Early, Hill, Burk, & Palmer, 2002). However, several investigations reveal a protective relationship for selenium and colorectal adenomas and cancer (Willett et al., 1983; Clark et al., 1993). A pooled analysis of three randomized trials of 1763 individuals found an inverse association between higher blood selenium concentration and adenoma risk (Jacobs et al., 2004). Other vitamins have been studied as well. In a prospective, randomized trial, beta carotene and vitamins C and E failed to prevent colorectal adenomas (Greenberg et al., 1994).

CURCUMIN

Numerous components of edible plants, collectively termed phytochemicals, have been reported to possess substantial chemopreventive properties. Curcumin, a diferuloylmethane derived from the plant Curcuma longa, is a potent antioxidant with anti-inflammatory and antitumor activities (Lev-Ari et al., 2005). Curcumin is commonly consumed as turmeric spice. Both in vitro studies and animal models have demonstrated a chemopreventive effect of curcumin (Li, Ahmed, Mehta, & Kurzrock, 2007; Kwon, Malik, & Magnuson, 2004). Curcumin inhibits COX-2 expression, inhibits growth in human colon cancer cell models, and suppresses nuclear factor κB, a transcription factor that controls expression of cytokines (Johnson & Mukhtar, 2007). Curcumin is one of the most extensively investigated and well-defined chemopreventive phytochemicals. Curcumin has been shown to protect against skin, oral, intestinal, and colon carcinogenesis, and also to suppress angiogenesis and metastasis in a variety animal tumor models (Surh & Chun, 2007). Curcumin inhibits the proliferation of cancer cells by arresting them in the various phases of the cell cycle and by inducing apoptosis. Curcumin has a capability to inhibit carcinogen bioactivation via suppression of specific cytochrome P450 isozymes, as well as to induce the activity or expression of Phase II carcinogen detoxifying enzymes. In patients with advanced colorectal cancer refractory to standard chemotherapy, 5 of 15 individuals given daily oral curcumin had stable disease after 2 to 4 months of treatment (Sharma et al., 2001). Furthermore, a recent study of 5 FAP patients with prior colectomy treated with oral curcumin and quercetin (flavonoid found in green tea, onions and red wine) had a reduction

554 INTEGRATIVE GASTROENTEROLOGY

in number and size of ileal and rectal adenomas after 6 months of treatment (Cruz-Correa et al., 2006). Well-designed intervention studies are necessary to assess the chemopreventive efficacy of curcumin in normal individuals as well as high-risk groups. Sufficient data from pharmacodynamics, as well as mechanistic studies, are necessary to advocate clinical evaluation of curcumin for its chemopreventive potential.

GLUCOSINOLATES (SULFORAPHANE AND INDOLE-3-CARBINOL [I3C])

In 1992, Johns Hopkins researcher Paul Talalay, MD, and colleagues found that an antioxidant called sulforaphane, produced in the body from a compound in broccoli, triggered the production of enzymes that helped detoxify cancercausing chemicals. The discovery, published in the Proceedings of the National Academy of Sciences, attracted worldwide attention and was hailed as a major breakthrough in our understanding of the link between increased fresh vegetable consumption and reduced cancer risk (Prochaska, Santamaria, & Talalay, 1992). Subsequent studies found that sulforaphane prevented the development of breast and colon cancer, as well as other tumors, in mice, exhibiting a powerful role in cancer prevention and protection. Talalay’s team found that the key protective compound in broccoli (a chemical called glucoraphanin, which the body turns into sulforaphane) was 20 times more concentrated in young, 3-day-old broccoli sprouts than it is in more mature broccoli plants. More recently, the team launched a line of teas enhanced with the antioxidant SGS (sulforaphane glucosinolate). Cruciferous vegetables are a rich source of glucosinolates and their hydrolysis products, including indoles and isothiocyanates, and high intake of cruciferous vegetables has been associated with lower risk of lung and colorectal cancer in some epidemiological studies (Higdon, Delage, Williams, & Dashwood, 2007). Glucosinolate hydrolysis products alter the metabolism or activity of sex hormones in ways that could inhibit the development of hormone-sensitive cancers, but evidence of an inverse association between cruciferous vegetable intake and breast or prostate cancer in humans is limited and inconsistent. Organizations such as the National Cancer Institute recommend the consumption of five to nine servings of fruits and vegetables daily, but separate recommendations for cruciferous vegetables have not been established. Isothiocyanates and indoles derived from the hydrolysis of glucosinolates, such as sulforaphane and indole-3-carbinol (I3C), have been implicated in a variety of anticarcinogenic mechanisms, but deleterious effects also have been reported in some experimental protocols, including tumor promotion over prolonged periods of exposure. Epidemiological studies indicate that

Nutrition and Colorectal Health 555

human exposure to isothiocyanates and indoles through cruciferous vegetable consumption may decrease cancer risk, but the protective effects may be influenced by individual genetic variation (polymorphisms) in the metabolism and elimination of isothiocyanates from the body. Cooking procedures also affect the bioavailability and intake of glucosinolates and their derivatives (Higdon, Delage, Williams, & Dashwood, 2007). Supplementation with I3C or the related dimer 3,3’-diindolylmethane (DIM) alters urinary estrogen metabolite profiles in women, but the effects of I3C and DIM on breast cancer risk are not known. Small preliminary trials in humans suggest that I3C supplementation may be beneficial in treating conditions related to human papilloma virus infection, such as cervical intraepithelial neoplasia and recurrent respiratory papillomatosis, but larger randomized controlled trials are needed (Marshall, 2003).

DIET AND EXERCISE

Diet has been implicated in colon cancer, including meats, vegetables, fruit, and fiber. Numerous prospective cohort studies have demonstrated an increase in risk of colorectal cancer in patients who consume red meat frequently (Giovannucci, Stampfer, Colditz, Rimm, Willett, 1992; Willett, Stampfer, Colditz, Rosner, &, Speizer, 1990).Red meat is associated with increased risk of colorectal cancer and increases the endogenous formation of N-nitroso compounds (NOC), DNA, and protein oxidation products, along with inhibition of apoptosis of cancer cells (Lewin et al., 2006; de Vogel et al., 2008; Lih-Brody et al., 1996; Cross, Pollock, & Bingham, 2002). There does appear to be convincing evidence for a correlation between high vegetable and fruit intake and low rates of colorectal neoplasia. The majority of case-control and cohort studies published show a relative risk of less than 0.8 for colorectal neoplasia in subjects with the highest intake of fruits and vegetables (Gatof & Ahnen, 2002). The role of fiber in the risk of colorectal cancer is less clear. About 60% of epidemiologic studies have linked high-fiber diets with a decreased risk of colorectal adenomas and cancer, and a large European prospective study showed similar results (Bingham, 2006; Bingham et al., 2003). Increase the amount of wheat bran in the diet. As an insoluble fiber, wheat bran increases the fecal bulk and weight, as well as increasing the frequency of eliminating the fecal matter, thereby reducing the colon’s exposure to toxins, e.g., carcinogens. Two large prospective, randomized controlled studies showed that adopting a diet low in fat and high in fiber, fruits, and vegetables

556

INTEGRATIVE GASTROENTEROLOGY

did not influence the risk of recurrence of colorectal adenomas (Alberts et al., 2000; Schatzkin et al., 2000; Lanza et al., 2007; Schatzkin et al., 2007). Along with diet, body habitus and physical activity have been studied in relation to colon cancer. A meta-analysis of the association of physical activity and colon cancer shows an inverse association between physical activity and colon cancer. The author of this study concluded that if individuals participate in physical activity, they will have a 24% reduction in the risk of developing colon cancer. Two large studies investigated dose-related response of exercise on colon cancer reduction. The Harvard Alumni Study followed 17,148 men for a maximum of 26 years. During the study period, 225 men developed colon cancer. Those men who participated in physical activity equivalent to at least 30 minutes per day, 5 days per week, had a 50% reduction in colon cancer rates compared with men who were sedentary. Physical activity was defined in this study as both the time set aside for daily exercise, as well as other daily physical activities such as climbing stairs. The actual mechanism of how exercise helps prevents colon cancer is not fully understood. However, it is well known that exercise decreases intestinal transit time, therefore decreasing the exposure of dietary procarcinogens, which are activated by intestinal bacteria and transformed into carcinogens within the intestinal lining. This theory is not well supported by data, but nevertheless a mechanism that we must entertain in understanding the role of exercise in prevention of colon cancer. A revolutionary theory of colorectal cancer chemoprevention is that exercise strengthens the immune system by promoting the function of many types of immune cells that prevent and fight cancer, including natural killer cells. Another possible mechanism is that exercise imparts protection from colorectal cancer by improving insulin responses to meals. Insulin and insulin-like growth factors appear to promote the growth of colorectal cancer in laboratory and animal studies. Thus, the hyperinsulinism that is associated with obesity, Type 2 diabetes, and the metabolic syndrome (syndrome X) may be the means by which these conditions predispose toward the development of colorectal cancer. Finally, exercise is able to ward off unwanted cellular proliferation as well as decrease some factors such as prostaglandin E2, which is thought to promote colon cell proliferation. In order to make concrete recommendations with regard to the type, duration, and intensity of exercise, additional research is deemed necessary. Overall, case-control and cohort studies have demonstrated a positive association between obesity, hyperinsulinism, and cancer risk, whereas the majority of studies have shown an inverse relationship between physical activity and colorectal cancer risk (Gatof & Ahnen, 2002). ∗The Mediterranean diet includes omega-3 fatty acids and olive oil, which appear to be chemopreventive. A pooled analysis of the small but ever-growing

Nutrition and Colorectal Health 557

body of science of omega-3 and colorectal cancer indicates that fish oil does protect against the cancer (Brivio et al., 2007; Calviello, Serini, & Piccioni, 2007; Geelen et al., 2007). For each extra 100 g of fish consumed per week, the risk of colorectal cancer incidence was reduced by 3%. The Mediterranean diet is rich in extra-virgin olive oil (EVOO) and is associated with a lower incidence of colorectal cancer. EVOO contains phenolic extracts with potential antioxidant effect. Fini L et al. reported that pinoresinolrich EVOO extracts have potent chemopreventive properties, and specifically upregulate the tumor suppressor p53 cascade in vitro (Fini L, Hotchkiss E, Fogliano V, Graziani G, 2008). This result was achieved at substantially lower concentrations in EVOO than with purified pinoresinol, indicating a possible synergic effect between the various polyphenols in olive oil. ∗∗(http://www.doctorsfornutrition.com/) ∗∗∗Combination of phytonutrients (e.g. curcumin, green tea extract) that attenuates proinflammatory and carcinogenic cascades.

MY HEALTH PLAN FOR KRISTIN 1. Diet: continue high vegetable, high-fiber, Mediterranean-based diet∗ 2. High-potency multivitamin 3. Doctor’s green and red alert∗∗ 4. Calcium: 1,000 mg/d. Vitamin D: 2,000 i.u. 5. Foods with high ORAC value 6. Colonoscopy in 1 year then every 3 years; screen children at age 25 7. Weight-reduction program 8. Daily exercise (minimum 30 minutes per day) 9. KappArest from Biotics Research (2 bid)∗∗∗ 10. Continue yoga, mind–body work, prayer, meditation, guided imagery

Conclusion Prevention, as English clergyman Thomas Adams observed in 1618, “is so much better than healing because it saves the labor of being sick.” Preventive tools were much more sparse during the time of Thomas Adams than they are today. Despite the availability of vaccines to prevent infectious disease, and medicines to lower cholesterol and blood pressure, we are committed to discover agents that can lower the risk of developing cancer and other noncommunicable diseases.

558

INTEGRATIVE GASTROENTEROLOGY

Colon cancer is ranked as the third leading cause of cancer-related death. Cancer is a leading cause of death globally. Seventy percent of the cancer deaths occur in low- and middle-class income countries, where the resources available for prevention, diagnosis, and treatment are limited. In industrialized nations such as the United States, with rising healthcare costs and the present economic crisis leaving millions without jobs and health insurance, the disease burden from cancer, especially colorectal cancer, is bound to show an upward trend. In 2008, the World Health Organization (WHO) projected the global burden of death from noncommunicable disease to rise by 17% by the year 2018. Tackling this burden is a challenge to every nation (WHO, 2008). Preventive strategies for cancer must be considered in the context of activities that prevent other chronic diseases, especially those with which cancer shares common risk factors, such as coronary artery disease, diabetes mellitus, substance abuse, and respiratory illness. The common risk factors for the chronic diseases listed above include a sedentary lifestyle, a diet low in fiber and antioxidants, but high in fat and simple sugars, tobacco and alcohol use, and overweight and obesity. Other risk factors include environmental exposure to toxins, which can be endogenous or exogenous. Cancer, especially colon cancer, is largely preventable. For primary prevention of colorectal cancer, our strategy should aim at reducing the level of the risk factors in the population as a whole. When we reduce the risk factors associated with cancer, we not only prevent the incidence of cancer, we also prevent incidence of other chronic conditions. Overweight, obesity, and sedentary lifestyle accounts for at least 274,000 deaths worldwide. As healthcare providers, the first step we must undertake in preventing colorectal cancer is to have a systematic approach to the assessment of risk factors. Next, using the risk assessment to prioritize our actions, we need to identify:how many of the risk factors are modifiable and how many of the risk factors are attributable to avoidable exposure to carcinogens. Decision making in prevention strategies should consider social and economic factors. Incorporating a daily exercise routine of 30 minutes of walking does not require going to a gym. Likewise, including fiber-rich seasonal fruits and vegetables, and adequate calcium and vitamin D, is of the utmost importance. With regard to folic acid, though the benefits are certainly noted, the exact amount and timing of supplementation need to be determined by further studies. In conclusion, eating healthfully, engaging in regular exercise, and taking nutritional supplements tailored to meet individual needs, are likely to help keep colorectal cancer away.

47 Liver Disease MATTHEW CAVE , NAEEM ASLAM , CHRISTOPHER KULISEK , LUIS S. MARSANO , AND CRAIG J. MCCLAIN

key concepts ■

■

■

■

■

■

CAM therapy is widely used by patients with liver disease, and patients frequently do not divulge this use to their physicians. Multiple CAM agents effectively prevent and treat experimental liver injury. We frequently utilize zinc and magnesium supplementation for beneficial effects on the liver, as well as for treating muscle cramps, an often overlooked but potentially debilitating complication of liver disease. Several CAM therapies, such as silymarin and SAM, appear safe, but there are limited or conflicting human clinical data on efficacy. Hepatotoxicity is an important side effect of many CAM agents, especially weight-loss agents. CAM agents may interfere with the metabolism/disposition of traditional medications. ■

Introduction

C

omplementary and alternative medicine (CAM) is an area of rapidly growing public interest. One estimate showed that CAM is used by approximately 42% of the U.S. population (Eisenberg, Davis et al., 1998). Major reasons for CAM use include back problems, anxiety, depression, 559

560 INTEGRATIVE GASTROENTEROLOGY

headaches, and liver disease. Viral hepatitis, nonalcoholic steatohepatitis (NASH), alcoholic liver disease, (ALD) and cirrhosis of multiple etiologies have been the most studied liver disorders in clinical trials using CAM products. This high use of CAM by the general U.S. population is mirrored in the high use by patients with liver disease. This is due, in part, to lack of FDAapproved therapy for ALD and NASH, the chronic course of many types of liver diseases, and symptoms ranging from fatigue to muscle cramps. In one survey of 989 patients with liver disease seen at liver disease clinics in 6 U.S. medical centers between April 1 and August 1, 1999, 389 (39%) reported using some form of CAM at least once during the preceding month: 21% used herbal preparations (13% used herbs to treat their liver disease: milk thistle, 12%; and licorice root, 1%); 18% used self-prayer; 9%, relaxation; 8%, multivitamins; 7%, massage; 6%, chiropractic; and 6%, spiritual healing (Strader, Bacon et al., 2002). Five variables were found to be predictive of alternative therapy use: female gender, young age, high level of education, high annual income, and geographic location. Overall, 74% of patients reported using CAM in addition to medications prescribed by their physicians, yet 26% did not inform their physicians regarding their CAM use (Seeff, Lindsay et al., 2001; Strader, Bacon et al., 2002). Similarly, White and colleagues reported that 35 of 76 patients (46%) with hepatitis C (HCV) used CAM, with 24% of this group using herbal supplements.

The herb most commonly used for hepatitis C is milk thistle.

Benefits of CAM ranged from reduction in fatigue to improved gastrointestinal function, and no adverse effects of CAM were reported (White, Hirsch et al., 2007). These studies are representative of many others reporting the wide use of CAM in liver disease (Krueger, Dryden et al., 2005; Hanje, Fortune et al., 2006; McClain, Dryden et al., 2008). In this article, we will review recent reports of CAM therapy in liver disease and potential hepatic toxicity, with an emphasis on mechanisms of action and clinical applications. We will only discuss biologic therapies, as these have been the main forms of CAM studied in liver disease. We will review (1) selected minerals and vitamins; (2) products involved in the hepatic methionine pathway; (3) prebiotics/probiotics; (4) polyphenols; (5) herbals; and (6) CAM hepatotoxicity.

Liver Disease 561

1. Minerals and Vitamins ZINC

Zinc is the second most abundant trace element in the body (second only to iron). Zinc is involved in multiple aspects of cell functions including metabolism, detoxification, antioxidant defenses, signaling transduction, and gene regulation. Zinc participates in cell functions mainly through binding to thousands of zinc proteins including metalloenzymes. Zinc coordination has catalytic, structural, and/or regulatory roles in zinc proteins, and removal of zinc can exert deleterious effects on cell function, leading to cell injury/death (Goode, Kelleher et al., 1990; Kang & Zhou, 2005). Major manifestations of zinc deficiency in humans include anorexia, skin lesions, growth retardation, neurosensory defects, and immune dysfunction (McClain, Adams et al., 1988).

Zinc deficiency has been documented in multiple types of human liver diseases (Stamoulis, Kouraklis et al., 2007). Moreover, experimental zinc deficiency in animals increases susceptibility to several forms of hepatotoxicity such as lipopolysaccharide-induced liver injury (Shea-Budgell, Dojka et al., 2006). In patients with alcoholic liver disease, hepatic zinc deficiency has been found to be correlated with liver dysfunction as indicated by decreased serum albumin, increased serum bilirubin, and decreased galactose elimination capacity and antipyrine clearance (Atukorala, Herath et al., 1986; Bianchi, Marchesini et al., 2000). Major mechanisms for zinc deficiency in patients with liver disease include poor intake, decreased absorption, and increased urinary losses (McClain, Hill et al., 2006). Extensive recent research in experimental animals has shown that zinc supplementation protects against alcohol-induced liver injury. Zinc supplementation works through many mechanisms including decreasing abnormalities in gut barrier function caused by alcohol, decreasing endotoxemia, reducing proinflammatory cytokine production, reducing oxidative stress, and preserving function of critical hepatic-zinc finger proteins (Lambert, Zhou et al., 2004; Zhou, Wang et al., 2005; Kang, Song et al., 2008; Zhou, Liu et al., 2008). Zinc supplementation in humans with liver disease has been shown to reverse signs and symptoms of zinc deficiency, such as altered immune

562

INTEGRATIVE GASTROENTEROLOGY

function, skin lesions, and night vision abnormalities (McClain, Marsano et al., 1991; McClain, Hill et al., 2006). The case for zinc therapy for liver disease is best supported in Wilson’s disease, an autosomal recessive genetic disease involving abnormalities in cellular copper export.

Zinc inhibits the absorption of copper from the gastrointestinal tract by inducing enterocyte metallothionein. Metallothionein is a protein that binds metals and has a high affinity for copper. It preferentially binds copper present in the enterocyte (absorbed from the gastrointestinal tract) and prevents it from entering the portal circulation.

Zinc is used primarily as maintenance therapy in successfully treated patients, and as first-line therapy in asymptomatic patients (Brewer, Dick et al., 1998). The dose of zinc usually required to impair copper absorption and to treat Wilson’s disease is 50 mg of elemental zinc (equivalent to 220 mg zinc sulfate) three times a day. Long-term zinc supplementation in other liver diseases should be ≤ 50 mg of elemental zinc/day to avoid side effects such as copper deficiency or GI distress. Unfortunately, few human studies have been performed on zinc supplementation in other forms of liver disease. One recent study suggested that chronic zinc therapy may decrease hepatic fibrosis, as evidenced by a decrease in serum Type IV collagen levels (Takahashi, Saito et al., 2007).

The main side effects of zinc supplementation are nausea and potential copper deficiency (if given at a dose of ≥ 220 mg zinc sulfate [50 mg elemental zinc] three times per day).

We frequently give one 220mg tablet of zinc sulfate a day in an attempt to prevent oxidative stress, inflammation, and possibly decrease fibrosis. We utilize zinc for muscle cramps in patients with liver disease. Muscle cramps are an under-recognized and common complication of cirrhosis that may respond to zinc and/or oral magnesium supplementation (Kugelmas, 2000).

MAGNESIUM

Magnesium is an essential mineral involved in multiple enzyme systems, muscle function, and insulin/glucose metabolism (Wells, 2008). Alcoholics, including

Liver Disease 563

those without liver disease, and patients with cirrhosis due to many etiologies frequently have low total body magnesium levels, sometimes with normal serum magnesium levels (Koivisto, Valta et al., 2002). This is thought to be due to a combination of factors, including poor absorption in the small bowel, enhanced urinary excretion, abnormal accumulation of saturated fatty acids in cell membranes, and malnutrition (Cohen, 1985).

Hypomagnesemia has been implicated in the pathogenesis of specific disease states, especially nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Both conditions are strongly associated with insulin resistance, obesity, Type 2 diabetes mellitus, hypertriglyceridemia, and hypertension.

Magnesium levels have been shown to regulate the cellular response to insulin, with low levels of magnesium producing cellular insulin resistance (Barbagallo, Gupta et al., 1997). In a study that supports this magnesium/ insulin resistance link, six nondiabetic subjects were fed a low-magnesium diet for 4 weeks, and diet-induced magnesium deficiency increased insulin resistance (Nadler, Buchanan et al., 1993). Oral magnesium supplementation also has been shown to improve insulin sensitivity in nondiabetic subjects (Guerrero-Romero, Tamez-Perez et al., 2004). Lastly, there is a significant relation between low magnesium concentrations, and both hepatic inflammation and fibrosis in NASH (Rodriguez-Hernandez, Gonzalez et al., 2005). A study of preeclampsia patients with muscle cramps showed improvement of cramps with magnesium supplementation (Dahle, Berg et al., 1995). We regularly treat muscle cramps in patients with liver disease with magnesium oxide, 400 mg orally daily. There have been few clinical trials of magnesium supplementation for the treatment of liver disease, with one trial showing significant improvement in the liver AST with magnesium supplementation (Poikolainen & Alho, 2008).

VITAMIN E

Vitamin E is a chain-breaking antioxidant. Tumor necrosis factor alpha (TNF-α) is a proinflammatory cytokine important in the pathogenesis of many forms of liver injury including nonalcoholic and alcoholic liver disease (Hill, Barve et al., 2000; Tilg & Diehl, 2000); and nuclear factor kappa B (NF-κB) is a transcription factor for TNF-α as well as multiple other

564 INTEGRATIVE GASTROENTEROLOGY

pro-inflammatory cytokines (Schreck, Rieber et al., 1991; Schulze-Osthoff, Los et al., 1995; Hill, Barve et al., 2000; Tilg & Diehl, 2000; Arteel, Marsano et al., 2003). In vitro studies demonstrated increased binding activity of NF-κB in human monocytes treated with ethanol, and subsequent studies showed that patients with alcoholic hepatitis demonstrate increased monocyte NF-κB activation and increased production of TNF-α (Mandrekar, Catalano et al., 1997; Hill, Barve et al., 2000). In vitro vitamin E treatment of monocytes from patients with alcoholic hepatitis decreased NF-κB activation and effectively inhibited TNF-α production (Hill, Devalaraja et al., 1999). In nonalcoholic fatty liver disease (NAFLD) there also is evidence to suggest an etiologic role for TNF-α and NF-κB. Oxidative stress has been postulated to play an etiologic role in the development of many forms of liver disease including NASH (oxidative stress acts as the “second hit” to produce NASH). Vitamin E also has been shown to block in vitro activation of stellate cells, in part by decreasing NF-κB activity (Lee, Buck et al., 1995). Transforming growth factor-β1 (TGF-β1) is a pro-fibrotic cytokine that is elevated in many forms of human liver disease. Expression of TGF-β1 is increased in animal models of hepatic fibrosis, and in studies performed in rats with carbon tetrachloride (CCl4)-induced liver fibrosis, treatment with vitamin E decreased levels of TGF-β and improved liver injury and fibrosis (Parola, Leonarduzzi et al., 1992; Parola, Muraca et al., 1992; Liu, Degli, Esposti et al., 1995). Indeed, vitamin E is effective in preventing many forms of experimental liver injury.

The effects of vitamin E in human liver disease such as ALD, NAFLD, and NASH are mixed.

One of the most commonly cited studies on vitamin E and NASH is an open-label pilot study of 11 children with NASH treated with vitamin E. Patients were treated with dietary instruction and high-dose vitamin E (between 400 to 1,200 international units (IU)/day) for 4 to 10 months. Five of 11 patients showed significant improvement in ALT levels with the lowest dose (400 IU/day), 4 patients improved with 800 IU/day, and 2 patients treated with 1,200 IU/day showed improvement in ALT levels liver histology was not evaluated (Lavine, 2000). Another randomized controlled trial (RCT) studied 28 children with NASH treated with vitamin E. Groups were randomized to dietary instruction or dietary instruction plus vitamin E (400 IU/day x 2 months; 100 IU/day x 3 months), and were followed for 5 months. Vitamin E was shown to be effective in reducing and normalizing transaminases in children with NASH,

Liver Disease 565

although no effect on ultrasound liver brightness was noted (Vajro, Mandato et al., 2004). However, in the largest study to date in children/adolescents, antioxidants (vitamin E 600 IU/day + ascorbic acid 500 mg/day) provided no additional benefit to lifestyle modification as assessed by liver biopsy and liver enzymes. This randomized trial of lifestyle modification (± antioxidants) did show that lifestyle modification with weight loss and exercise positively influenced liver biopsy and liver enzymes at 2 years of intervention (Nobili, Manco et al., 2008). A nonrandomized, non-placebo-controlled pilot study of 22 adult Japanese patients examined patients with NAFLD and NASH treated with vitamin E. Patients were treated with dietary instruction for 6 months followed by vitamin E (300 IU/day) for 1 year. TGF-β1 levels were significantly higher in the patients with NASH when compared to patients with NAFLD or healthy subjects. Elevated TGF-β1 in patients with NASH improved after 1 year of vitamin E treatment and correlated with improvements in ALT levels. In the patients with NASH, 5 of 9 also showed histologic improvement with decreased inflammation and fibrosis after treatment with vitamin E (Hasegawa, Yoneda et al., 2001). We evaluated 16 adults with NASH treated with either dietary instruction alone or dietary instruction and 800 IU/daily of vitamin E for 12 weeks. Both groups demonstrated an improvement in BMI and significant improvement in ALT; however, subgroup analysis showed no further benefit in the patients treated with vitamin E and dietary instruction, when compared to the group receiving dietary instruction alone (Kugelmas, Hill et al., 2003). The PIVENS study (pioglitazone vs. vitamin E) sponsored by the National Institutes of Health (NIH) has enrolled almost 250 patients, and results from this trial should provide direction on vitamin E therapy for NASH (Chalasani, Sanyal et al., 2009). Studies in alcoholic liver disease have generally been negative concerning vitamin E therapy. A large RCT evaluated 67 patients with decompensated alcoholic cirrhosis treated with vitamin E and advised to abstain from alcohol. Patients were treated with 500 IU/day of vitamin E for 1 year; at the end of 1 year, there was no significant improvement seen in liver function tests, hospitalization rates, or overall mortality when compared to placebo (de la Maza, Petermann et al., 1995). A recent RCT studied 51 patients with mild to moderate alcoholic hepatitis treated with 1,000 IU/daily of vitamin E for 1 year. There were no significant differences in biochemical markers (serum aminotransferases, bilirubin, albumin, prothrombin time, or creatinine) or overall mortality between the treatment group and placebo group (Mezey, Potter et al., 2004). Lastly, patients with HCV generally do not have improved viral response to interferon plus ribavirin therapy with the addition of vitamin E therapy (Hanje, Fortune et al., 2006). At the current time, we do not routinely use

566

INTEGRATIVE GASTROENTEROLOGY

high-dose vitamin E therapy in liver disease (outside of clinical trials) due to conflicting data on efficacy and some theoretic risks.

2. Products of Hepatic Methionine Metabolism Abnormal hepatic methionine metabolism is well documented in many forms of liver disease including ALD, generally characterized by decreased hepatic S-adenosylmethionine (SAM) and folate levels, increased hepatic S-adenosylhomocysteine (SAH), and homocysteine accumulation (Figure 47.1). Several mechanisms have been proposed for SAM depletion in liver disease, including: inactivation of methionine adenosyltransferase (MAT – converts methionine to SAM); excessive consumption of SAM by the liver; and inhibition of endogenous methionine synthesis due to impaired homocysteine methylation (Purohit, Abdelmalek et al., 2007).

Folate deficiency is another well-characterized metabolic abnormality in liver disease, especially ALD.

Folate is a water-soluble vitamin that plays an integral role in methionine metabolism and DNA synthesis. Folate in its 5-methyltetrahydrofolate (5-MTHF) form can transfer a methyl group to homocysteine via a methionine synthase (MS)-catalyzed reaction to form endogenous methionine, which is a precursor of SAM. Thus, folate helps maintain normal concentrations of homocysteine, methionine, and SAM. Folate deficiency can impair methionine metabolism, leading to hyperhomocysteinemia as well as depletion of methionine and SAM (Purohit, Abdelmalek et al., 2007).

In contrast to decreased SAM and folate levels, increased hepatic levels of homocysteine and SAH (two other important metabolites in hepatic methionine metabolism) are observed in many liver diseases, especially ALD.

Homocysteine is formed from methionine after removal of the methyl group on SAM and hydrolysis of SAH. Substantial data support the suggestion that hyperhomocysteinemia may play an important role in the development of alcohol-induced fatty infiltration of the liver, liver injury, and hepatic fibrogenesis (Refsum, Ueland et al., 1998).

Liver Disease 567

SAH is a direct product after SAM transfers its methyl groups to various compounds, via many different methyltransferases, and SAH is a potent endogenous inhibitor of most methyltransferases. We have reported that increased SAH accumulation sensitized hepatocytes to TNF-induced cell death, and we postulated that increased SAH in liver disease may be an endogenous sensitizer to TNF hepatotoxicity (Song, Zhou et al., 2004).

SAM

SAM protects against multiple experimental toxin-induced liver diseases (Purohit, Abdelmalek et al., 2007). SAM administration attenuated alcoholinduced steatosis and restored hepatic glutathione concentrations in rats, and it attenuated ethanol-induced depletion of mitochondrial glutathione and restored mitochondrial function in hepatocytes (Feo, Pascale et al., 1986). In mice, SAM treatment significantly attenuated acute alcohol-induced liver injury characterized by attenuation of alcohol-induced steatosis, necrosis, and increased ALT activity, all of which were associated with restoration of hepatic SAM and mitochondrial glutathione concentrations, and attenuation of lipid peroxidation (Song, Zhou et al., 2003). SAM may also protect by decreasing tumor necrosis factor α (TNFα) and increasing interleukin-10. In the most comprehensive clinical study to date, the therapeutic potential of SAM was tested in a 24-month randomized, placebo-controlled, doubleblind, multicenter trial of 123 patients with alcoholic cirrhosis (Mato, Camara et al., 1999). SAM treatment improved survival or delayed the need for liver transplantation in patients with alcoholic liver cirrhosis, especially in those with less advanced liver disease. In this trial, increased hepatic concentrations of glutathione may have contributed to the beneficial effects of SAM because, in another study, oral administration of 1.2 g SAM/d for 6 months significantly increased hepatic glutathione concentrations in ALD patients (Vendemiale, Altomare et al., 1989). While this one large multicenter study showed some beneficial effects of SAM, other studies are needed to confirm these beneficial effects and to define appropriate dosing schedules. The dose we utilize in clinical trials is 400 mg 4 times daily (1,600 mg total)

FOLATE

It is clear that folate deficiency in micropigs accelerates alcohol-induced liver injury through multiple pathways. However, with folic acid fortification in the current American diet, chronic alcohol exposure may not lead to major hepatic

568

INTEGRATIVE GASTROENTEROLOGY

folate deficiency in the United States. Whether further folate administration will attenuate human ALD or other forms of liver injury is unknown. In spite of unclear indications, we frequently supplement ALD patients with folate (1 mg/day).

BETAINE

Betaine is highly effective in reducing homocysteine levels and removing fat from the liver in experimental models of alcohol-induced liver injury (Ji and Kaplowitz, 2003). Unfortunately, good RCTs in humans are lacking, as are dose-finding studies in humans. Betaine is much more stable than SAM, and its absorption is much better characterized. A pilot study of high-dose betaine therapy (10 g twice a day) in NASH showed promising results (Abdelmalek, Angulo et al., 2001), but a larger, follow-up, randomized trial in NASH did not show significant benefit (unpublished data). Thus, further human studies are warranted, but we do not clinically supplement with betaine at the current time.

3. Polyphenols The term dietary polyphenols refers to members of a large family of related organic plant molecules. Plant polyphenols frequently impart flavor and color to fruits and other plant products. Plant polyphenols can be divided into several classes, generally depending on the number of phenol rings contained in the structure. Polyphenols are the most abundant antioxidants consumed by humans, with a total intake as high as 1 g/day (Scalbert, Johnson et al., 2005).

Although many in vitro studies demonstrate robust biological effects from plant polyphenols, actual in vivo systemic effects likely may be modest, due to poor gastrointestinal absorption. Major human studies have not been performed in liver diseases, but there are exciting in vitro and animal studies. We will briefly review the effects of green tea polyphenols, resveratrol, and curcumin.

GREEN TEA

There is increasing interest in the role of tea (Camellia sinensis) in maintaining health and treating disease. Although tea consists of several components,

Liver Disease 569

research has focused on polyphenols, especially those found in green tea. These include (-)-epicatechin (EC); (-)-epigallocatechin (EGC); (-)-epicatechin3-gallate (ECG); and (-)-epigallocatechin-3-gallate (EGCG). Of these, EGCG generally accounts for more than 40% of the total (Hara, 1997). Green tea polyphenols are potent antioxidants (Salah, Miller et al., 1995). EGCG usually has the greatest antioxidant activity, and it is the most widely studied polyphenol for disease prevention (Bagchi, 1999). Many of the putative health benefits of tea are presumed to be due to its antioxidant effects. Tea may also act as an anti-inflammatory agent. We reported that mice fed an extract of green tea polyphenols had decreased TNF-α production, NF-κB activation, hepatotoxicity, and lethality, in response to an injection of lipopolysaccharide (LPS; see Yang, de Villiers et al., 1998). Similarly, green tea polyphenols have been shown to protect against experimental alcohol-induced hepatic fibrosis and concomitantly decrease endotoxin levels in rats (Li, Zhang et al., 2004). Green tea (EGCG) protected against the hepatotoxin carbon tetrachloride (Chen, Tipoe et al., 2004). Green tea from Camellia sinensis also attenuated primary graft failure after liver transplantation of fatty livers in rats (Zhong, Connor et al., 2004). These same investigators showed that Camellia sinensis attenuated experimental hepatic fibrosis in rats following bile duct ligation (Zhong, Froh et al., 2003). A recent study documented the beneficial effects of EGCG on the metabolic syndrome in mice fed a high-fat diet (Bose, Lambert et al., 2008). Supplementation with dietary EGCG in mice fed a high-fat diet reduced body weight, percent body fat, and visceral fat, compared to mice without EGCG treatment. EGCG also attenuated insulin resistance, plasma cholesterol, and monocyte chemoattractant protein concentrations, and decreased liver weight, liver triglycerides, and plasma alanine aminotransferase concentrations in mice fed a high-fat diet (Bose, Lambert et al., 2008). Of some concern, however, are recent case reports of green-tea-induced hepatotoxicity in humans (Molinari, Watt et al., 2006).

RESVERATROL

Resveratrol has been linked to both improved fitness and life extension in animal studies (Howitz, Bitterman et al., 2003; Lagouge, Argmann et al., 2006). Because it is found in red grapes and red wine, resveratrol was believed to be a potential mediator of the French paradox. However, recent studies suggest that the resveratrol levels in red wine are insufficient based on its low bioavailability to explain the French paradox. Nonetheless, resveratrol is an attractive and emerging CAM agent for liver disease. Animal models of both alcoholic and nonalcoholic fatty liver disease demonstrate that resveratrol attenuates steatosis,

570

INTEGRATIVE GASTROENTEROLOGY

oxidative stress, and proinflammatory cytokine production through mechanisms involving activation of both 5’-AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1; see Ajmo, Liang et al., 2008; Rivera, Moron et al., 2008). Furthermore, in preclinical studies, resveratrol exerted both chemotherapeutic and chemopreventive actions against hepatocellular carcinoma (Wu, Sun et al., 2004; Bishayee and Dhir, 2008). Despite this emerging therapeutic rationale, we could not find any published human clinical trials of resveratrol in liver disease. Resveratrol’s potential risk as a weak phytoestrogen is debated in the literature.

CURCUMIN

Curcumin is a yellow pigment that is found in the Indian spice turmeric, and has important inhibitory effects on inflammation, angiogenesis, and tumor formation (Anand, Thomas et al., 2008). Curcumin has multiple mechanisms of action including acting as an antioxidant, inhibiting NF-kB activation and decreasing TNF-α and TGF-β production. Curcumin has been shown to be beneficial in several models of hepatotoxicity including obesity, carbon tetrachloride, bile duct ligation, and endotoxin (Memis, Hekimoglu et al., 2008; Reyes-Gordillo, Segovia et al., 2008; Weisberg, Leibel et al., 2008). Importantly, curcumin has potent antitumor effects, including effects against hepatocellular carcinoma (Anand, Thomas et al., 2008). Unfortunately, curcumin, like many other polyphenols, has poor oral bioavailability that limits its chemoprevention efficacy (Anand, Thomas et al., 2008). Thus, novel strategies to improve bioavailability, including nano delivery systems, liposomes, pegylation, and curcuma prodrugs, are all under active investigation (Anand, Thomas et al., 2008).

4. Herbals SILYMARIN (MILK THISTLE)

Silymarin, the active ingredient extracted from Silybum marianum (also known as milk thistle), has been used by ancient physicians and herbalists to treat a variety of liver and gallbladder diseases. A large number of animal studies have reported hepatoprotection against a diverse range of toxins including acetaminophen, carbon tetrachloride, mushroom poisoning (phalloidin), radiation, iron overload, phenyl hydrazine, alcohol, cold ischemia, and thiocetamide (Jacobs & Dennehy et al., 2002).

Liver Disease 571

The elucidation of the mechanisms by which silymarin protects the liver has expanded substantially over the last two decades. Silymarin works as an antioxidant by reducing free radical production, protects against lipid peroxidation, stabilizes cell membranes, has anti-fibrotic properties, and inhibits NF-kB activation with favorable immunomodulatory effects (Dehmlow, Erhard et al., 1996; Saliou, Rihn et al., 1998; Manna, Mukhopadhyay et al., 1999; Hanje, Fortune et al., 2006). In the United States, silymarin is one of the most commonly used CAM agents in the treatment of liver disease. Large controlled trials of silymarin have been performed in Europe, with variable results, probably due to lowquality clinical trials (Hanje, Fortune et al., 2006). A recent Cochrane metaanalysis of 18 randomized trials in 1,088 patients with alcoholic and/or hepatitis B or C virus liver diseases highlights some of these issues. This study showed a significantly decreased liver related mortality when low-quality trials were included, but no significant effect was found in high-quality clinical trials on all-cause mortality, liver-related mortality, complications of liver disease, or liver histology (Rambaldi, Jacobs et al., 2005). On the other hand, a recent systematic review and meta-analysis by Saller et al. concluded that the use of silymarin is reasonable in Amanita phalloides poisoning, alcoholic liver disease (as an addition to abstinence), and Child’s A cirrhosis (Saller, Brignoli et al., 2008). Recently, the Hepatitis C Antiviral Long Term Treatment Against Cirrhosis (HALT-C) Trial survey reported that 504 (44%) of 1,145 study participants who were nonresponders to chronic hepatitis C treatment had a history of herbal supplement use either prior to or at baseline evaluation. Silymarin was a constituent in 72% of the 60 different herbals noted at enrollment, and herbal use showed no significant effects in decreasing ALT and HCV RNA levels (Seeff, Curto et al., 2008).

Despite the lack of strong evidence, silymarin is still the most commonly used complementary and alternative medicine therapy for chronic liver diseases, in part because of its good safety profile. Well-designed, multicenter RCTs of silymarin are required to prove its effectiveness in chronic liver disease, and NIH-sponsored trials are ongoing.

GLYCYRRHIZIN (LICORICE ROOT)

The active component of Glycyrrhiza glabra (licorice root) is glycyrrhizin. Licorice root has been used for centuries in traditional medicine to treat cough, bronchitis, gastritis, and liver inflammation. It is available over the counter in

572 INTEGRATIVE GASTROENTEROLOGY

liquid, powder, and pill forms in the United States (Levy, Seeff et al., 2004). Glycyrrhizin has antioxidant, immunosuppressive, and anti-inflammatory properties. It also enhances interferon production and stimulates natural killer cell activity (Shiki, Ishikawa et al., 1986; Shiki, Shirai et al., 1992; Yoshikawa, Matsui et al., 1997). Clinical trials using glycyrrhizin (intravenous-IV) have mostly involved the treatment of hepatitis C, specifically, patients who are refractory to, or intolerant of, interferon treatment. A double-blind randomized trial performed by Suzuki et al. looked at IV injections of 80 mg of Stronger Neo-Minophagan C (SNMC, the Japanese standard preparation of glycyrrhizin combined with glycine and cysteine) in patients who had histologically proven chronic active hepatitis. After 1 month of treatment in 133 patients, transaminases fell by about 40% in the treatment group versus a 2% drop in the placebo group, and no significant side effects were noted (Suzuki, Ohta et al., 1984). Arase et al. showed improvement in ALT level with glycyrrhizin in patients with hepatitis C (Arase, Ikeda et al., 1997). Very few studies have shown enhanced antiviral effects with glycyrrhizin. The main side effects of glycyrrhizin treatment include fluid retention and hypokalemia because of its mineralocorticoid effect (Hanje, Fortune et al., 2006). Licorice root should be avoided in patients with cirrhosis, and we do not utilize it in our patients with chronic liver disease.

HERBAL COMBINATIONS

Several other herbal combinations have been reported to have efficacy in chronic liver disease, especially in chronic hepatitis B and C. These studies have come mainly from the Orient and are often observational in nature. Some of the most widely used of these herbal preparations are listed in Table 47-1.

5. Prebiotics/Probiotics There are approximately 100 trillion microorganisms residing in the human bowel (Cani & Delzenne, 2007). Therefore, the human body contains more prokaryotic cells than eukaryotic cells. However, there are limited data suggesting that the composition of the bowel flora is abnormal in patients with liver disease. For example, patients with cirrhosis primarily due to viral hepatitis had a significant increase in Enterococcus, Enterobacter and Clostridium species and a significant decrease in Bifidobacterium species (Zhao, Wang et al., 2004). Work from our group demonstrated that patients with alcoholic

Liver Disease 573

Table 47.1. Blended Herbal Preparations in Liver Disease: Method of Action and Uses Blended Herbal

Method of Action

Use

TJ-9

Anti-fibrotic; inhibition of stellate cell activation; decreases hepatic lipid peroxidation; increases TNF-α and granulocyte colony stimulating factor (g-CSF)

Hepatitis B; prevention of hepatocellular carcinoma

TJ-108

Reduction in HCV-RNA, hepatoprotective

Hepatitis C

Herbal medicine 861

Blocking cyclin/cyclin-dependent kinase, facilitating remodeling of fibrotic liver tissue

Hepatitis B

CH-100

No loss in HCV-RNA; however, decreased ALT, hepatoprotective

Hepatitis C

Bing Gan

Some improvement in HCV-RNA clearance

Hepatitis C

Liv 52

Inhibits lipid peroxidation; decreases TNF activity Experimental liver injury; ALD

Preparations

liver disease have decreased numbers of bowel bifidobacteria, lactobacilli and enterococci compared to healthy controls (Kirpich, Solovieva et al., 2008). Bowel–liver interactions are well described in liver disease. Importantly, heavy alcohol use is associated with increased gut permeability, and the frequency of endotoxemia is high (McClain, Barve et al., 1999; Carithers & McClain, 2006). Lipopolysaccharide (LPS) derived from Gram-negative bowel flora stimulates proinflammatory cytokine production in Kupffer cells to mediate alcoholic hepatitis (McClain, Barve et al., 1999).

Pathological alterations in bowel flora could contribute to the development and progression of liver disease, while restoring normal bowel flora could be a viable treatment option.

Probiotics are defined as live microorganisms that, when administered in adequate amounts, confer a health benefit to the host, apart from their simple caloric value. Likewise, prebiotics, such as fermented products, soluble fiber and inulin, modulate the composition of the bowel flora to confer health benefits. Many newer commercial preparations contain both prebiotics and probiotics and are called synbiotics.

574

INTEGRATIVE GASTROENTEROLOGY

Animal studies support a variety of mechanisms of action for prebiotics and probiotics in the treatment of liver disease. Nanji et al. first demonstrated that Lactobacillus GG reduced endotoxemia and alcohol-induced liver injury in rats (Nanji, Khettry et al., 1994). Feeding oats (prebiotic) has been shown to prevent endotoxemia and liver injury in rats fed alcohol (Keshavarzian, Choudhary et al., 2001). In mice injected with LPS and d-galactosamine, pretreatment with the probiotic mixture VSL#3™ prevented a breakdown in colon barrier function, reduced bacterial translocation, reduced tissue TNF-α levels, and significantly attenuated liver injury (Ewaschuk, Endersby et al., 2007). In addition to reducing inflammation, probiotics may also reduce oxidative stress. For example, intestinal B. longum and L. acidophilus reduced in vitro plasma lipid peroxidation (Lin & Chang, 2000). Probiotics may also influence bioenergetics and metabolism to influence liver disease. In a mouse model of NASH, VSL#3™ was shown to reduce the activity of Jun-N-terminal kinase (JNK), which integrates inflammatory and metabolic signals and mediates insulin resistance (Li, Yang et al., 2003). The prebiotic, fructooligosaccharides (FOS), was recently shown to increase production of glucagon-like peptide-1 (GLP-1) by L cells in the colon, and to decrease its degradation by dipeptidyl peptidase-IV (Delzenne, Cani et al., 2007). This resulted in an increased portal vein concentration of GLP-1, with resultant hepatic insulin sensitization (Delzenne, Cani et al., 2007). Therefore, prebiotics and probiotics appear to modulate inflammation, oxidative stress, and metabolism in animal models of liver disease. These mechanisms provide the rationale supporting the need for more clinical research on prebiotics, probiotics, and synbiotics in the treatment of liver disease. Emerging human data suggest a role for both prebiotics and probiotics in the treatment of a variety of liver diseases.

Probiotics have been reported improve liver transaminases in patients with alcoholic hepatitis who were treated with Bifidobacterium bifidum and Lactobacillus plantarum 8PA3 for five days over abstinence alone (Kirpich, Solovieva et al., 2008). The reduction in liver enzymes occurred concomitantly with the restoration in numbers of bifidobacteria and lactobacilli, which were decreased prior to therapy (Kirpich, Solovieva et al., 2008). In a pilot study, the prebiotic FOS improved transaminases and insulin resistance at 8 weeks in patients with NASH (Daubioul, Horsmans et al., 2005). Cirrhotic patients treated with a synbiotic preparation had significantly reduced endotoxemia and arterial ammonia (Liu, Duan et al., 2004). Patients with alcoholic cirrhosis and NAFLD treated with VSL#3™ had significantly reduced plasma levels of

Liver Disease 575

the lipid peroxidation products, malondialdehyde, and 4-hydroxynonenal (Loguercio, Federico et al., 2005). However, only the patients with alcoholic cirrhosis had an improved plasma cytokine profile (reduced tumor necrosis factor alpha and increased interleukin-10; Loguercio, Federico et al., 2005). Probiotics, and bifidobacteria in particular, are a promising area of research in obesity and NASH. Reduced fecal bifidobacteria in normal weight human infants was predictive of the subsequent development of childhood obesity at 7 years of age (Kalliomaki, Collado et al., 2008). Likewise, in mice, high-fat feeding was associated with a significant reduction in cecal Bifidobacterium spp., with significant increases in body weight, adipose tissue mass, liver triglycerides, endotoxemia, and hepatic tumor necrosis factor alpha (Cani, Amar et al., 2007). The authors subsequently demonstrated that a prebiotic mixture of FOS restored the quantities of bifidobacteria in high-fat-fed rodents to decrease endotoxemia, proinflammatory cytokines, insulin resistance, and fatty liver (Daubioul, Taper et al., 2000; Cani, Neyrinck et al., 2007). This is a rapidly evolving area. Because of well-documented gut–liver interactions, we feel this will be an important area for research into CAM intervention in liver disease in the future.

6. CAM Hepatotoxicity Hepatotoxicity from herbal products may be difficult to diagnose and is likely underreported. Reasons for CAM toxicity include lack of well-designed RCTs to assess the safety and efficacy of the CAM products, natural variability of herbal products, differences in production methods/contamination issues and, sometimes, the addition of obscure ingredients in unknown amounts (Kaplowitz, 1997; Stedman, 2002). Herbal mixtures are not required to be standardized, and although they are expected to adhere to regulations of the Dietary Supplement and Health Education Act of 1994, they do not always conform to good manufacturing practices. Public education about how to read the labels of herbal products and understand the ingredients may reduce bad outcomes. It is recommended that the individual look for well-known manufacturers of herbal products and to look for the USP (United States Pharmacopeia) or NF (National Formulary) symbol on the label. Eisenberg et al. reported that 72% of patients using unconventional therapies failed to inform their physicians that they were doing so (Eisenberg, Davis et al., 1998). This has been a consistent problem noted in most CAM surveys. Most “conventional medicine” physicians are not trained in CAM and they are not aware of ingredients used in herbal remedies. A high index of suspicion is needed to diagnose CAM side effects (Strader, Bacon et al., 2002). Herbal products are

576

INTEGRATIVE GASTROENTEROLOGY

Table 47.2. Herbal Hepatotoxicity Herb

Type of Liver Injury

Crotalaria Heliotropium Senecio longilobus Symphytum officinale (Pyrrolizidine alkaloids)

Sinusoidal obstruction syndrome (veno-occlusive disease)

Chaparral leaf, germander

Zone 3 necrosis, cirrhosis, cholestasis, chronic hepatitis

Pennyroyal (squamit) oil

Zone 3 necrosis, microvesicular steatosis, fulminant liver failure

Jin Bu Huan

Acute and chronic cholestatic hepatitis, microvesicular steatosis, fibrosis

Mistletoe

Chronic hepatitis

Margosa oil

Microvesicular steatosis, Reye syndrome, hepatic necrosis

Usnic acid

Fulminant liver failure

Atractylis gummifera

Acute hepatitis, fulminant liver failure

Callilepis laureola

Acute hepatitis, fulminant liver failure

Impila

Acute hepatitis, fulminant liver failure

Camphor

Necrolytic hepatitis

Cascara sagrada

Cholestatic hepatitis

TJ-8, Dai saiko-toi

Autoimmune hepatitis

TJ-9, Sho-saiko-to

Acute and chronic hepatitis

Paeonia spp.

Acute hepatitis, fulminant liver failure

Greater celandine

Chronic hepatitis, cholestasis, fibrosis

Germander

Acute and chronic hepatitis, fulminant liver failure

Isabgol

Giant cell hepatitis

Kava

Acute and chronic hepatitis, fulminant liver failure

Ma Huang

Acute hepatitis, autoimmune hepatitis

Oil of cloves

Hepatic necrosis

Sassafras

Hepatocarcinogen

Saw palmetto

Mild hepatitis

Shou-wu-pian

Acute hepatitis

Valerian

Mild hepatitis

Liver Disease 577

capable of producing both intrinsic (or predictable) hepatotoxicity and idiosyncratic (unpredictable) hepatotoxicity (Chitturi & Farrell, 2000; Seeff, 2007). A prospective study supported by the National Institute of Diabetes and Digestive and Kidney Diseases, referred to as the Drug-Induced Liver Injury Network Study is currently underway. It is a multicenter study and patients with Tylenol hepatotoxicity are excluded. Initial results have shown that CAM is responsible for 6% of enrolled patients. Hepatocellular injury was seen in 53% of cases as compared to cholestatic (22%) and mixed pattern of injury (25%). A survey of the National Poison Information Service for the years 1991– 1995 documented 785 cases of possible or confirmed adverse reactions to herbal drugs, among which hepatotoxicity was the most frequent adverse reaction (Shaw, Leon et al., 1997). Table 47.2 sets forth examples of CAM-related hepatotoxicity. CAM agents can interact adversely with traditional medications. An example is the potential interaction of St. John’s wort with cyclosporine and indinavir (Ruschitzka, Meier et al., 2000). This interaction was highlighted when cardiac transplant patients underwent rejection shortly after starting St. John’s wort, presumably because of the induction of cytochrome P450 3A4 by the St. John’s wort (Piscitelli, Burstein et al., 2000). It is important to instruct all transplant patients (and other patients on immunosuppressive therapy) to inform their physician before starting any CAM agent, and not to use St. John’s wort. MEDwatch is an FDA-sponsored program available for physicians to report adverse events associated with FDA-monitored products, including special nutritional supplements (telephone: 1-800-FDA-1088). Patients can make similar reports through the FDA office of Consumer Affairs (1-800-532-4400) (Verma & Thuluvath, 2007).

Various web sites to consult for hepatotoxicity: http://www.fda.gov/medwatch http://.alhmed.od.nih.gov http://nccam.nih.gov http://www.herbmed.org http://vm.cfsam.fda.org

Conclusion CAM agents are widely used by people with liver disease (similar to the general population), and this use is frequently not reported to the patient’s physician. Silymarin, or milk thistle, is the most widely used CAM agent for liver disease.

578

INTEGRATIVE GASTROENTEROLOGY

It has an excellent safety profile, but data are conflicting concerning efficacy. It would not be unreasonable to use it as supportive therapy during Amanita phalloides mushroom poisoning, and also in alcoholic liver disease and Child’s A cirrhosis. We frequently use zinc supplementation as an anti-inflammatory and anti-fibrotic agent in multiple types of liver disease, and we utilize zinc and magnesium to treat muscle cramps complicating cirrhosis. It is important to be aware that hepatotoxicity is a major complication of CAM therapy. Moreover, CAM agents may interfere with the metabolism/disposition of traditional medications. Thus, healthcare workers and patients need to beware of both the potential benefits and risks of CAM agents.

ACKNOWLEDGMENT

Funding support: Research support was provided by the National Institutes of Health (McClain/Cave) and the Veterans Administration (McClain/Cave).

48 Integrative Approaches to Diseases of the Pancreas and Gallbladder VINAY CHANDRASEKHARA AND ANTHONY N. KALLOO

key concepts ■

■

■

■

■

■

■

■

Patients should seek immediate conventional medical treatment for suspected acute pancreatitis, as this is a serious medical condition with a significant risk of morbidity and mortality. Patients with severe acute pancreatitis should be given nutrition early during the course of disease, preferably with enteral feedings if possible. Antioxidant supplements, including polyphenols, have been shown to reduce oxidative stress in animal models, but need to be further studied before they can be recommended for treatment in humans. Gallstone disease is widely prevalent, particularly in Western countries. Cholecystectomy (surgical resection of the gallbladder) is the treatment of choice in the United States for symptomatic gallstone disease. Maintaining appropriate weight and participating in a regular exercise program can reduce the risk of developing gallstone disease. Reducing dietary fat may actually increase the risk of gallstone disease; however, substituting saturated fats with fish oil and polyunsaturated fats can lower the risk of gallstone formation. A high-fiber diet that is low in refined carbohydrates and simple sugars may reduce the risk of gallstone disease. ■

579

Pancreas

I

nflammatory disease of the pancreas may occur as an acute or chronic process. The incidence of acute pancreatitis in the United States is approximately 5,000 new cases each year, with a mortality rate of 10% (Kasper, 2005). The most common causes of acute pancreatitis are summarized in Table 48.1. The classic presentation of acute pancreatitis is epigastric abdominal pain radiating to the back, associated with nausea and vomiting, and it is relieved with sitting or leaning forward. Biochemical and radiographic evaluation usually aid the diagnosis of pancreatitis. Serum amylase is the most widely ordered test, although it is not very specific for pancreatitis. Amylase typically rises within 6 to 12 hours of onset, and has a short half-life of 10 hours. In acute uncomplicated attacks, serum amylase remains elevated for three to five days. Serum lipase has a sensitivity Table 48.1. Causes of Acute Pancreatitis Gallstone disease (including microlithiasis) Alcohol Hypertriglyceridemia Post-ERCP or biliary manipulation Trauma Medications (azathioprine, 6-mercaptopurine, estrogen, tetracycline, sulphonamides, valproic acid, didanosine, pentamidine, metronidazole, furosemide, thiazides, sulfasalazine, 5-ASA) Sphincter of Oddi dysfunction Cystic fibrosis Pancreas divisum Hereditary pancreatitis Vasculitis Renal failure Infectious causes (mumps, cytomegalovirus, varicella-zoster, coxsackie, HIV, herpes simplex virus) Pancreatic cancer

Integrative Approaches to Diseases of the Pancreas and Gallbladder 581

of 85% to 100% and is more specific than amylase for acute pancreatitis. The various radiographic studies used to evaluate the pancreas are outlined in Table 48.2. Multiple scoring systems, including the Ranson scoring system and Apache II, have been developed to help predict those patients with higher rates of morbidity and mortality associated with acute pancreatitis. These scoring systems are cumbersome to use and have not been widely incorporated as a patient assessment tool by clinicians. Risk factors that have been shown to affect survival in acute pancreatitis include organ failure, pancreatic necrosis, obesity, age above 70, hemoconcentration, and elevated C-reactive protein (Kasper, 2005). Treatment of acute pancreatitis typically consists of supportive measures, including resting the bowel by fasting the patient and administering intravenous (IV) fluids for hydration along with IV pain medications. If the patient is expected to remain fasting for an extended period of time, parenteral or postpyloric tube feedings have been traditionally used, although recent data show that prepyloric feedings do not worsen morbidity or mortality and do not exacerbate symptoms of pancreatitis (Petrov, Correia, & Windsor, 2008). IV antibiotics should be administered for acute necrotizing pancreatitis. In addition, surgery may be required for pancreatic debridement. Further treatment is based on the underlying etiology of the pancreatitis (procedures to remove gallstones, removing the offending medication or alcohol rehabilitation, etc.).

Table 48.2. Diagnostic Studies for Evaluating the Pancreas in Acute and Chronic Pancreatitis Diagnostic Test

Comment

Abdominal X-ray

Simple, noninvasive but not sensitive

Abdominal Ultrasound

Simple, noninvasive, can provide information on pancreatic pseudocysts, mass lesions, and calcifications

CT Scan

Useful for the diagnosis of pancreatic calcifications, pancreatic ducts and mass lesions in the pancreas

MRCP

Noninvasive, good for imaging the pancreatic duct, especially in patients who are at high risk for ERCP

ERCP

Invasive, but allows for diagnostic and therapeutic maneuvers for the pancreatic duct and sphincter of Oddi

EUS

Allows for excellent imaging of the head of the pancreas and for biopsies and aspiration of masses and cysts within the pancreas

582

INTEGRATIVE GASTROENTEROLOGY

Chronic pancreatitis is a condition with inflammatory changes of the pancreas that results in permanent structural damage to the organ, leading to impairment of endocrine and exocrine function. Chronic pancreatitis usually manifests as chronic abdominal pain with features similar to that of acute pancreatitis, as well as pancreatic insufficiency with steatorrhea and malabsorption of fat-soluble vitamins (Vitamins A, D, E, K) and vitamin B12. Severe cases of chronic pancreatitis can lead to glucose intolerance and diabetes mellitus. Biochemical testing is often less helpful in chronic pancreatitis, as serum amylase and lipase levels may be normal due to pancreatic fibrosis. Radiographic imaging may be useful, especially if pancreatic calcifications are noted in the organ with beading of the main pancreatic duct (Table 48.2). Treatment for chronic pancreatitis usually involves supplementation with pancreatic enzymes, pain management, and avoidance of potential triggering factors, including alcohol and fatty meals. It is important for patients to seek conventional medical treatment for acute attacks of pancreatitis, as they carry a high risk of morbidity and mortality if not treated. An integrative approach may be useful for the prevention and treatment of recurrent attacks of acute pancreatitis and chronic pancreatitis.

Nutrition Patients with severe acute pancreatitis should be fed early via the enteral route during the course of disease (McClave, Chag, Dhaliwal, & Heyland, 2006). The use of prepyloric feedings versus postpyloric feeds is debatable; however, enteral nutrition is preferred to parenteral feedings because such therapy modulates reduces oxidative stress, promotes more rapid resolution of the disease process, and is more cost effective (McClave et al., 2006). Patients who have had at least one episode of pancreatitis should avoid alcohol consumption to prevent further attacks. In cases of hypertriglyceridemia-associated pancreatitis, treatment includes weight loss to the ideal weight, lipid-restricted diet, and control of serum glucose levels in those with diabetes mellitus. Enterally administered n-3 polyunsaturated fats (including fish oil) in patients with acute pancreatitis have been shown to decrease length of hospitalization and length of requirement for jejunal feedings (Lasztity et al., 2005). For patients with chronic pancreatitis, the ideal diet should be moderate in fat, with restriction of long-chain triglycerides and increase in foods that contain medium-chain fatty acids that do not require lipase for digestion (Kasper, 2005).

Integrative Approaches to Diseases of the Pancreas and Gallbladder 583

Supplements Several studies have investigated the role of free radicals in the pathogenesis of acute pancreatitis, which has led to the use of antioxidants for the treatment of acute and chronic pancreatitis (Sanfey, Bulkley, & Cameron, 1984; Schoenberg et al., 1990). Additionally, people with acute pancreatitis have been found to have lower levels of antioxidants including vitamin A, glutathione, selenium, beta-carotene, and vitamin E compared to healthy controls (Uden et al., 1992). One small double-blind, placebo-controlled study demonstrated that oral micronutrient antioxidant therapy with vitamin C, vitamin E, beta-carotene, selenium, and methionine, during the active treatment phase of patients with recurrent acute pancreatitis, was associated with amelioration of oxidative stress (Uden et al., 1992). Some practitioners have been using intravenous antioxidant therapy for severe acute pancreatitis based on equivocal data. A recent randomized, double-blind, placebo-controlled trial of intravenous antioxidant therapy with n-acetylcysteine, selenium, and vitamin C, with 43 patients, showed that although relative serum levels of antioxidants rose and markers of oxidative stress fell, treatment with antioxidants did not result in a statistical difference in organ dysfunction or patient outcome (Siriwardena et al., 2007). It should be noted that the treatment arm had a higher rate of death due to multiorgan failure from severe pancreatitis. For chronic pancreatitis, a randomized, double-blind, placebocontrolled crossover trial of 36 patients with chronic pancreatitis demonstrated that oral antioxidant supplementation was associated with improvements in quality of life in terms of pain, physical and social functioning, and general health perception, as assessed by the SF-36 questionnaire (Kirk et al., 2006). Probiotics have also been considered in the treatment of acute pancreatitis, with the intent of preventing infectious complications. A multicenter, randomized, double-blind, placebo-controlled trial with 298 patients demonstrated that probiotic supplementation did not reduce the risk of infectious complications, and was associated with an increased risk of mortality due to ischemic bowel (Besselink et al., 2008). At this time, probiotic prophylaxis should not be administered to patients with severe acute pancreatitis.

Herbal Medications Polyphenols are plant-derived phytochemicals that have anti-inflammatory and vasculoprotective properties. Resveratrol, epigallocatechin gallate, and

584 INTEGRATIVE GASTROENTEROLOGY

curcumin are polyphenols that have been shown to attenuate acute pancreatitis in rodent models (Shapiro, Singer, Halpern, & Bruck, 2007). If given early in the course of acute pancreatitis, polyphenols may prevent the development of multiorgan dysfunction and septic shock. Prophylactic administration of polyphenols attenuates ischemia-reperfusion injury to the bowel, kidneys, liver, and heart. Polyphenols have also been shown to improve survival rates in animal models of endotoxemia (Shapiro et al., 2007). Other herbs that have been used to prevent acute pancreatitis include Indian gooseberry (Emblica officinalis see Thorat et al., 1995), grape seed extract (Vinis vinifera), and Pycnogenol (Pinus pinaster). Traditional Chinese medicine may also be useful for preventing and treating pancreatitis, but has not been validated with prospective placebo-controlled studies. Herbs that are commonly used in traditional Chinese medicine include licorice root (Glycyrrhiza glabra), ginger root (Zingiber officinale), Asian ginseng (Panax ginseng), peony root (Paeonia officinalis), and cinnamon Chinese bark (Cinnamomum verum).

Acupuncture Acupuncture has been used for the treatment of pain due to pancreatic disease; however, formal studies have shown mixed results. Electro-acupuncture stimulation, which uses electrical current on acupuncture needles, is a popular traditional therapy that has been demonstrated to have a protective effect in animal models of acute pancreatitis. (An et al., 2007)

Gallbladder Gallstones are widely prevalent in Western countries, particularly in the United States, where autopsy series have demonstrated the presence of gallstones in more than 20% of women and 8% of men over the age of 40 (Kasper, 2005). Approximately 1 million new cases of gallstone disease (cholelithiasis) develop each year, resulting in more than 500,000 cholecystectomies being performed annually in the United States (Moga, 2003). There are two major types of gallstones: cholesterol stones account for 80% of cholelithiasis, with pigment stones accounting for the remaining 20%. Cholesterol stones contain more than 50% cholesterol, whereas pigment stones are primarily composed of calcium bilirubinate (Browning & Sreenarasimhaiah, 2006). The risk of gallstone formation is increased with supersaturation of bile with cholesterol, decreased secretion of bile acids, and stasis of bile flow (Table 48.3).

Integrative Approaches to Diseases of the Pancreas and Gallbladder 585

Table 48.3. Predisposing Factors for Gallstone Formation Demographic/ Genetic Factors

Cholesterol stones – North American Indians, Northern Europe and North America Pigment stones – Asia

Increased cholesterol saturation of bile

Obesity Weight loss Estrogen Increasing age High cholesterol diet Oral contraceptive medications Fibric acid medications (clofibrinate)

Decreased bile acid secretion

Increasing age Low fiber diet Diseases/resection of the ileum resulting in chronic loss of bile salts

Biliary stasis

Gallbladder hypomotility Prolonged parenteral nutrition Fasting Pregnancy Inactivity Low fat diets

The most characteristic symptom caused by cholelithiasis is biliary colic, which presents as postprandial right upper quadrant pain lasting 30 minutes to 5 hours. Often, the patient will complain of worse pain with heavy fatty meals, or eating after a period of prolonged fasting. Nausea and vomiting are frequent symptoms that accompany the abdominal pain. Complications of cholelithiasis include acute cholecystitis, biliary obstruction, cholangitis, and pancreatitis. The diagnosis of cholelithiasis is confirmed with one of several different imaging studies listed in Table 48.4. The treatment of choice in the United States for symptomatic cholelithiasis is a laparoscopic cholecystectomy. Although complications from surgery are infrequent (3% to 6%), they can be significant, resulting in bile duct and liver injury. Additionally, 10% to 15% of patients experience post-cholecystectomy syndrome, in which they continue to have symptoms that were thought to be caused by the gallbladder, or develop new symptoms normally attributed to the gallbladder. Ursodeoxycholic acid and extracorporeal shockwave lithotripsy have also been used to help dissolve gallstones in patients who are poor surgical candidates. An integrative approach to the treatment of cholelithiasis

586

INTEGRATIVE GASTROENTEROLOGY

Table 48.4. Diagnostic Evaluation of the Gallbladder and Bile Ducts Diagnostic Test

Comment

Abdominal X-ray

Rapid, low cost, low yield Pathognomonic findings in calcified gallstones, porcelain gallbladder, emphysematous cholecystitis

Right upper quadrant ultrasound

Rapid, accurate (>95% accuracy for gallstones) with real time imaging Procedure of choice for gallstones

HIDA scan

Accurate for cystic duct obstruction or confirmation of acute cholecystitis Useful with CCK to assess gallbladder emptying

CT scan

Useful for evaluating dilated bile ducts, particularly for hepatic or pancreatic masses

Magnetic resonance cholangiopancreatography (MRCP)

Excellent sensitivity for bile duct dilatation and intraductal abnormalities

Endoscopic retrograde cholangiopancreatogram (ERCP)

Best visualization of the distal biliary tract, endoscopic sphincterotomy and treatment is a possibility

Endoscopic Ultrasound

Most sensitive method for detecting ampullary stones

not only focuses on the symptoms of gallstones, but can help dissolve gallstones and reduce the risk of gallstone formation.

Lifestyle Modification Obesity is an independent risk factor for the development of gallstones. Slow, gradual weight loss can reduce the risk of gallstone formation by reducing the amount of cholesterol secreted into bile; however, weight loss of more than 1.5 kg (3.3 lbs.) per week can trigger gallstone formation (Weinsier, Wilson, & Lee, 1995). Ursodeoxycholic acid can prevent gallstone formation during rapid weight loss by increasing the solubility of cholesterol in bile (Worobetz, Inglis, & Shaffer 1993). Exercise has been shown to be inversely related to the risk of undergoing cholecystectomy. According to the Nurses Health Study, exercising 2 to 3 hours per week was found to reduce the risk for cholecystectomy by 20% in women (Leitzmann et al., 1999). A similar study conducted in male healthcare professionals found that 34% of symptomatic gallstone disease

Integrative Approaches to Diseases of the Pancreas and Gallbladder 587

could be prevented by exercising 30 minutes a day with endurance-type training at least five times per week (Leitzmann et al., 1998). In both studies, the beneficial effects of exercise were independent of weight reduction. It has been postulated that exercise decreases late-phase postprandial gallbladder volume and increases late-phase gallbladder motility via neural or hormonal mechanisms (Sari, Balci, & Balci, 2005).

Dietary Fat Lowering total dietary fat is not an effective treatment for gallbladder disease, but a change in the type of dietary fat ingested can improve the composition of bile and reduce the risk of gallstone formation. Low-fat diets fail to stimulate gallbladder contraction and result in biliary stasis, which actually increases the risk of gallstone formation. Substituting saturated fats with fish oil and polyunsaturated fats that are rich in anti-inflammatory omega-3 fatty acids can reduce the formation of gallstones by enhancing bile flow and stabilizing the phospholipid-cholesterol vesicles (Berr et al., 1992). Patients should be instructed to reduce their intake of fried foods, red meat, and dairy products to reduce the amount of saturated fat in their diet, and replace this with diets rich in omega-3 fatty acids including coldwater fish, walnuts, and flaxseed (Rakel, 2007). Omega-3 fatty acids have also been shown to stabilize the cholesterol saturation index and nucleation time (time to cholesterol deposition) in obese patients who are rapidly losing weight, and may possibly prevent the formation of cholesterol gallstones (Méndez-Sánchez et al., 2001).

A low fat diet may actually increase the risk of gallstone disease. Substituting saturated fats with fish oil and polyunsaturated fats can lower the risk of gallstone formation.

Fiber Intake It has been shown that vegetarians have a lower risk of cholelithiasis (Nair & Mayberry, 1994). This has been attributed to a diet low in saturated fat, but also to a high-fiber diet. Fiber reduces the absorption of deoxycholic acid (DCA), which at high concentrations can act as an irritant to the gallbladder epithelium (Moga, 2003). DCA is a microbial product formed from bile acids by intestinal bacteria, which lowers the solubility of cholesterol in bile. Foods that contain water-soluble fiber have the greatest affinity for binding DCA and may

588

INTEGRATIVE GASTROENTEROLOGY

be helpful for preventing and reversing gallstones (Rakel, 2007). A Western diet low in fiber and high in fat has been associated reduced concentrations of bile acids leading to the formation of gallstones (Moerman. Smeets, & Kromhout, 1994). Fruits, vegetables, oat bran, and ground flaxseed are good sources of fiber. Although legumes are rich in fiber, they have been shown to significantly raise the concentration of cholesterol in bile.

Simple Sugars and Insulin Resistance Plasma insulin levels have been found to be elevated in nondiabetic patients with gallstone disease, despite normal serum glucose. (Misciagna et al., 2000) Hyperinsulinemia has been shown to decrease cholesterol 7-hydroxylase activity (Subbiah & Yunker, 1984), the hepatic enzyme that converts cholesterol to primary bile acids (Apstein & Carey, 1996). Additionally, diets that consist of simple sugars increase the DCA content, raise the cholesterol saturation index, and reduce the concentration of the beneficial cholic acid (Thornton, Emmett, & Heaton, 1983). A higher intake of dietary glycemic load and glycemic index has been shown to increase the risk of cholecystectomy in women (Tsai, Leitzmann, Willett, & Giovannucci, 2005). Nutritional strategies to improve insulin sensitivity and glucose tolerance may also have beneficial effects on gallstones. These include substituting saturated fats with mono- or polyunsaturated fats, decreasing trans fatty acids, increasing consumption of omega-3 fatty acids, and replacing refined carbohydrates (simple sugars) with unrefined carbohydrates found in fruits and vegetables (Lichtenstein & Schwab, 2000).

Food Allergy Some practitioners believe that food allergies may be common triggers for symptoms attributed to gallbladder attacks, based on early studies. (Breneman, 1968) It has been hypothesized that this allergic response is mediated by histamine release from mast cells present in gallbladder mucosa (Hemming et al., 2000). In one study, a food elimination diet improved all symptoms in 69 patients with gallstones or postcholecystectomy syndrome within 5 days of treatment (Breneman, 1968). Foods that were most likely to induce gallbladder symptoms included eggs, pork, onion, fowl, milk, coffee, citrus, corn, beans, nuts, apples, and tomatoes. Treatment with antihistamines resulted in faster resolution of symptoms, suggesting that the underlying mechanism was food allergy and not food intolerance; however, this has not been validated with placebo-controlled trials.

Integrative Approaches to Diseases of the Pancreas and Gallbladder 589

Coffee In a prospective cohort study that included 46,008 men, and used a 131-item food frequency questionnaire, coffee consumption was associated with a lower risk of symptomatic gallbladder disease (Leitzmann et al., 1999). This association was not found with decaffeinated coffee, leading some to believe that the benefits were attributable to caffeine. Although there was a positive association with caffeinated soft drinks and lower risk of gallbladder symptoms, the correlation was not statistically significant. Coffee stimulates cholecystokinin release and enhances gallbladder contractility (Douglas, 1999). Caffeine is secreted in bile (Holstege, Kurz, Weinbeck, & Gerok, 1993), and may decrease bile cholesterol saturation by increasing bile flow (Knodell, 1978). In animal models, caffeine has been shown to prevent cholesterol crystallization (Lillemoe et al., 1989).

Ursodeoxycholic Acid Ursodeoxycholic acid (UDCA) has been used by some practitioners for dissolution of cholesterol gallstones, although the success of laparoscopic cholcecystectomy has reduced this option to patients who wish to avoid surgery, or are poor surgical candidates. UDCA decreases the saturation of cholesterol in bile, and may also retard cholesterol crystal nucleation (Kasper, 2005). The best success for complete dissolution is with small (<5 mm) radiolucent cholesterol gallstones. Gallstone recurrence occurs 30% to 50% over 3 to 5 years after successful treatment with UDCA. UDCA has also been shown to prevent gallstone formation during rapid weight loss, particularly in those who have undergone bariatric surgery (Uy et al., 2008). Ursodeoxycholic acid (UDCA) can prevent gallstone formation in patients undergoing rapid weight loss (greater than 1.5 kg or 3.3 lbs per week).

Supplements A lack of dietary ascorbic acid (vitamin C) has been linked to gallstone disease in animal models (Jenkins, 1978). Vitamin C affects the rate-limiting step in catabolism of cholesterol to bile acids. In humans, vitamin C supplementation

590 INTEGRATIVE GASTROENTEROLOGY

has been associated with a decreased risk of gallstones, and a lower need for cholecystectomy, in postmenopausal women who consume alcohol (Simon et al., 1998). This relationship was not statistically significant in nondrinkers. Follow-up studies have confirmed this correlation in women, but this same correlation was not seen in males (Simon & Hudes, 2000). Vitamin E has been thought to be beneficial in the prevention of gallstone formation, particularly in patients who are unable to modify their lifestyle or dietary habits. In one animal study, a high-fat diet did not result in a higher rate of gallstone formation if the animals were given vitamin E supplementation (Christensen, Dam, & Prange 1953). Calcium has also been shown to have a beneficial effect on the risk of cholesterol gallstones by binding secondary bile acids, including DCA, and reducing the solubility of cholesterol in bile. In middle-aged men, the risk gallstone formation has been inversely correlated with calcium intake (Moerman et al., 1994). Lecithin and phosphatidylcholine reduce the saturation of cholesterol in bile. Studies on the supplementation of lecithin have shown higher concentrations in bile. Clinically, this has not had a significant effect on dissolving gallstones, but may be beneficial in gallstone prevention (Rakel, 2007).

Gallbladder/Liver Flush Some alternative practitioners may prescribe gallbladder flushes that typically include olive oil and lemon juice. The belief is that the monounsaturated fat in olive oil may stimulate gallbladder contraction and improve bile flow; however, this has not been clinically validated by prospective studies (Rakel, 2007). In fact, these preparations may actually trigger attacks of gallbladder pain, or even acute cholecystitis, and are therefore not currently recommended for patients with gallstone disease.

Herbal Medications Herbal medications have been used to treat multiple small stones and sludge in patients with infrequent symptoms. Herbs are found in many different preparations, but they are most commonly prepared as dry extracts used to make tea. Choleretic herbs stimulate bile flow and reduce the amount of cholesterol in bile (Table 48.5). Choleretic herbs are often used with peppermint oil, which contains a large amount of menthol and has been used to dissolve gallstones.

Integrative Approaches to Diseases of the Pancreas and Gallbladder 591

Table 48.5. Choleretic Herbs Used in the Treatment of Gallstones Herb

Precautions

Milk Thistle (Silybum marianum)

Laxative effect, allergic reaction in persons with allergies to ragweed, daisies, marigolds

Dandelion root (Taraxecum officinalis)

Gastric hyperacidity, contact dermatitis (if used topically), allergic reaction in persons with allergies to ragweed, daisies, marigolds

Artichoke (Cynara scolymus)

Contact dermatitis (if used topically)

Turmeric (Curcuma longa)

Rarely causes dyspepsia in high doses

Greater celandine (Chelidonium majus)

Dyspepsia, contact dermatitis (if used topically), hepatitis (rare)

Oregon grape (Mehonia aquifolium)

Should not be used during pregnancy or breastfeeding, as it may worsen jaundice in infants

Acupuncture Some practitioners feel that acupuncture aids in the expulsion of gallstones (Moga, 2003); however, the greatest benefit of acupuncture is relief of abdominal pain through the release of endorphins. Multiple different points have been identified for relief of symptoms attributed to gallbladder disease. In a golden hamster model of cholelithiasis, acupuncture was associated with decreased biliary cholesterol content, and increased beneficial cholic acid. (Moga, 2003)

49 An Integrative Approach to Gender-Specific Digestive Health Issues LAURA K. TURNBULL, GERARD E. MULLIN , AND SHARON DUDLEY-BROWN

key concepts ■

■

■

■

■

Women are afflicted with functional bowel disorders, microscopic colitis, collagenous colitis, autoimmune liver disease, proximal colon cancers, and gallstone disease far more than men. The purported mechanisms for women to develop the irritable bowel syndrome include: emotional life experiences, abuse, sensitivity to pain, serotonin receptor expression, hormones, and menstrual cycle, among others. Women are more inclined to utilize modalities of complementary and alternative medicine (CAM) than men. CAM modalities have been shown to be effective for functional bowel disorders, including functional dyspepsia and the irritable bowel syndrome. Men are predisposed to develop Barrett’s esophagus, achalasia, and autoimmune pancreatitis, for unknown reasons. ■

Introduction

I

n a healthcare system that is predominantly based upon a male experience of disease, the gender variations in both the symptomology and psychosocial consequences of specific disease states unique to women are often overlooked. As new research focusing on sex and gender differences in GI 592

An Integrative Approach to Gender-Specific Digestive Health Issues 593

illness emerges, it is becoming apparent that there are clear differences in how such illnesses manifest themselves physiologically, as well as how these diseases affect the emotional well-being of those affected. In order to adequately diagnose, treat, and support patients afflicted with GI illness, it is imperative to understand the variations between genders in the clinical manifestations, psychosocial experiences, and trends of healthcare-seeking behaviors.

Gender-Specific Digestive Conditions There are a number of GI illnesses with skewed gender-specific prevalences (Table 49.1.). Autoimmune liver disease, celiac disease, collagenous colitis, functional bowel disorders, gallstones, microscopic colitis, primary biliary cirrhosis, and proximal colorectal cancer afflict women more than men (Lee, Mayer, Schmulson, Chang, Naliboff, 2001).On the other hand, achalasia, autoimmune pancreatitis, Barrett’s esophagus, and all digestive cancers (e.g., pancreatic cancer) are seen in men more often than women (Silverman, 2007).

Colorectal Cancer The American Cancer Society estimates that about 108,070 new cases of colon cancer (53,760 in men and 54,310 in women) and 40,740 new cases of rectal cancer (23,490 in men and 17,250 in women) was diagnosed in 2008. Colorectal cancer is expected to cause about 49,960 deaths (24,260 men and 25, 700 women) in 2008. In the United States the incidence of colorectal cancer overall is higher in men than in women. However, when colorectal cancer is subdivided into the region of the colon affected, recent evidence suggests that women are more frequently diagnosed with cancer proximal to the splenic flexure, while men are more frequently diagnosed with cancers in the distal region (Jacobs, Thompson, & Martinez, 2007). This difference in pathology may explain the apparent variations in response to dietary influences between men and women. For instance, while further investigation is required, recent research suggests that obesity, energy intake, selenium, and fiber have more significant protective effects in men than women (Jacobs, Thompson, & Martinez, 2007; Duffield-Lillico et al., 2002).Additionally, dietary intake of red and processed meat in men has been epidemiologically tied to their predilection of distal colorectal cancers (Chao et al., 2005). Conversely, women may experience greater protective effects from higher vitamin D levels than men (Jacobs, Thompson, & Martinez, 2007). Dietary and supplemental calcium have been shown to decrease the risk of developing

Table 49.1. Gender-Specific Conditions: Prevalence, Pathogenesis and Treatment GI Illness/

U. S. Prevalence, Gender

Condition

(M:F ratio)

Pathogenesis

Integrative

Achalasia

(1:100,000) M>>>F

Progressive loss of nitrergic neurons (inhibitory; relaxation) with the relative preservation of cholinergic neurons (excitatory; contraction)in the lower esophageal sphincter (LES).

Symptomatic: dilation of LES, surgery, dietary modifications, peppermint oil to relax LES.

Autoimmune Liver Disease

1 in 31 or 3.13% or 8.5 million F>>M

Autoimmune inflammatory attack on liver parenchymal cells

Corticosteroids, immunosuppressives, ∗polyphenol bioflavonoids (curcumin, green tea extract, quercetin, boswellia, ginger), fish oils, anti-inflammatory diet.

Autoimmune Pancreatitis

USA unknown; 0.82 per 100 000 individuals in Japan M>>F

Autoimmune-inflammatory attack on pancreas

Corticosteroids, immunosuppressives, ∗polyphenol bioflavonoids (curcumin, EGCG–green tea extract, quercetin, boswellia, ginger), fish oils, anti-inflammatory diet

Barrett’s Esophagus

66

2.3% (with reflux symptoms) 1.2% (without reflux symptoms) M>>F

Prolonged exposure of the esophagus to acid reflux causing a pre-malignant transformation of the esophageal lining

Western: acid blockade –proton pump inhibition. Integrative options: licorice root, aloe vera, slippery elm (cytoprotective), Swedish bitters, ginger, D-limonene (promotility)∗∗

Celiac Disease

1:100 F>M 2:1

Autoimmune disease –gluten initiates proinflammatory attack on small bowel

Gluten withdrawal from the diet.

Collagenous Colitis

Unknown F>>M

Autoimmune, collagen deposition in subepithelial basement membrane of colonic lining

67

Treatment

Bismuth subsalicylate Boswellia serrata Budesonide Mesalamine Mesalamine + cholestyramine Probiotics

Functional 10-15% US of population Bowel Disorders F>M (all)

Motility, hormonal, visceral hypersensitivity, others

Symptomatic Herbal Hypnosis Cognitive Behavioral Therapy

Gallstones

8.5 million F>M

estrogen and progesterone multiparity increase risk

Dietary Surgical Astringent herbals

Microscopic Colitis

Unknown F>M

Autoimmune-collagen deposition in subepithelial basement membrane

Avoid NSAIDs Trial of lactose elimination) Anti-diarrhea agents or tannins Bismuth subsalicylate 5-ASA (mesalamine) compounds

Primary Biliary Cirrhosis

200,000 F>>M

Autoimmune attack of inflammatory cells on the medium-sized intrahepatic bile ducts of the liver

Immunosuppressives Bezafibrate Ursodeoxycholic acid Interferon-a Liv-5268-70 Sho-saiko-to71-73

Proximal Colon Cancer

∗∗∗41,667 F>M

Diet, vitamind D levels, calcium intake, multifactorial

Exercise74 vitamin D and calcium protective in women9-14

∗ see Chapter 46: Liver Disease ∗∗ See Chapter 39: Upper Gastrointestinal Disorders: Dyspepsia, Heartburn, Peptic Ulcer Disease, and H. Pylori ∗∗∗28% of colorectal cancers are proximal (Rim, Seeff, Ahmed, King, & Coughlin, 2009)75

596

INTEGRATIVE GASTROENTEROLOGY

colorectal cancer and precancerous adenomas (Baron et al., 1999).In this study, higher serum 25-hydroxyl-vitamin D levels were associated with a protective effect from developing colorectal cancer. Several other investigators support these findings (Martinez, Marshall, Sampliner, Wilkinson, & Alberts, 2002; Wu, Willett, Fuchs, Colditz, & Giovannucci, 2002; Kampman, Slattery, Caan, & Potter, 2000; Marcus & Newcomb, 1998).9–14 However, Martinez and Willett (1998) reviewed the epidemiological data pertaining to calcium and concluded that it is not associated with a “substantial” risk reduction from developing colorectal cancer and precancerous adenomas.15 The Women’s Health Initiative (WHI) was performed with 36,282 women who received either placebo or the combination of 500 mg of elemental calcium carbonate with 200 IU of vitamin D (Wactawski-Wende et al., 2006).16 The women who received the intervention (calcium, vitamin D) were not protected from developing colorectal cancer. Based upon epidemiological studies, these doses appear to be suboptimal for adequate chemoprevention of colorectal neoplasia (Wu, Willett, Fuchs, Colditz, & Giovannucci, 2002).12

Gallstone Disease In the United States, gallstone disease afflicts 20 to 25 million adults, with more than 700,000 cholecystectomies performed annually costing $6.5 billion (Sandler et al., 2002; Shaffer, 2006).17, 18 Thus, gallstone disease is among the most costly digestive disorders. Gallstone disease has a clear gender-specific prevalence, with women before the age of 50 being afflicted two to three times more often than men (Shaffer, 2006; Rome Group, 1988).18–20 In the United States it is estimated that 6.3 million men and 14.2 million women between the ages of 20 and 74 are affected (Everhart, Khare, Hill, & Maurer, 1999).21 Women are at greater risk of both developing gallstone disease and requiring subsequent cholecystectomy (Shaffer, 2006).18 It is thought that hormonal factors are the major contributors to this gender difference, with pregnancy and estrogen therapy being significantly implicated in the development of gallstones (Cirillo et al., 2005; Park et al., 2009).22, 23 While there is a clear difference with regard to gender, the increased incidence is only apparent in younger populations, with women of childbearing age affected most greatly (Jensen & Jorgensen, 1991).24 This phenomenon suggests the implication of both pregnancy and hormones on the formation of gallstones; specifically, the increased levels of estrogen and progesterone along with multiparity (Date, Kaushal, & Ramesh, 2008).25 Furthermore, men who have been placed on estrogen replacement therapy,

An Integrative Approach to Gender-Specific Digestive Health Issues 597

and women receiving hormone replacement therapy, are at an increased risk for gallstone formation (Novacek, 2006).26

Autoimmune Gastrointestinal and Liver Disease Women overall are predisposed to autoimmune disease (Zandman-Goddard, Peeva, & Shoenfeld, 2007).27 However, autoimmune conditions of the gut in general are not more prevalent in women than in men for unclear reasons. For example, the prevalence of inflammatory bowel disease is not different in males than females. On the other hand, Celiac disease has twice the disease prevalence in women when compared to men, and is associated with other autoimmune conditions that are more common in women (Megiorni et al., 2008).28 Thyroiditis, scleroderma, Sjörgen’s syndrome, collagenous colitis, microscopic colitis, primary biliary cirrhosis, autoimmune gastritis, and autoimmune hepatitis are far more common in women than men (Table 49.2; see also Talley, 2008a, 2008b).29, 30 Many of these conditions are associated with high titers of autoantibodies, such as antinuclear (ANA), antimitochondrial (AMA), antimicrosomal, anti-SCL-70, anti-smooth muscle antibodies, etc. The presentation of a middle-aged female with high titers of any of these autoimmune antibodies, or presence of any of the aforementioned conditions, should raise suspicion for underlying celiac disease.

Achalasia Achalasia is an uncommon (1:100,000) condition of the esophagus characterized by a progressive loss of nitrergic neurons (inhibitory; relaxation) with the relative preservation of cholinergic neurons (excitatory; contraction) early in the disease process (Kraichely & Farrugia, 2006).31 This resulting imbalance of neurotransmitters causes the lower esophageal junction to become tonically contracted and fail to relax during swallowing. Achalasia is equally distributed between men and women; however, chest pain is a female-predominant presentation of the disease (Mikaeli, Farrokhi, Bishehsari, Mahdavinia,& Malekzadeh, 2006).32 Thus, in a female who presents with progressive dysphagia along with chest pain, in the absence of gastroesophageal reflux disease, achalasia should be considered. On the flip side, there is a form of achalasia that is associated with antineuronal autoimmune antibody formation (anti-GAD-65) in the setting of a male gender bias (Kraichely & Farrugia, 2006).31 These data

598

INTEGRATIVE GASTROENTEROLOGY

Table 49.2. Autoimmune Diseases Associated with Celiac Disease Gastrointestinal-Liver • Microscopic colitis • Collagenous colitis • Autoimmune hepatitis • Primary biliary cirrhosis Endocrine • Autoimmune diabetes mellitus • Addison’s disease • Autoimmune thyroid disease Rheumatological • Sjögren’s syndrome • Systemic lupus erythematosus Dermatological • Vitiligo • Dermatitis herpetiformis • Psoriasis • Alopecia areata (adapted from Barker & Liu, 2008)

suggest that gender-specific variants of achalasia exist and require further exploration.

Barrett’s Esophagus Barrett’s esophagus is a premalignant condition of the esophagus, whereby the squamous mucosa bordering the squamous-columnar junction of the esophagus is replaced by intestinal-type columnar mucosa (Wood & Yang, 2008).33 This “specialized” intestinal type of columnar mucosa, which forms as a metaplastic reaction to chronic acid and bile reflux from the stomach, has an overall 5% chance to develop into adenocarcinoma of the esophageal cancer, also a male-predominant disease (Bresalier, 2008).34 The classic risk factors for developing Barrett’s esophagus include being male, aged 50, smoking cigarettes, and

An Integrative Approach to Gender-Specific Digestive Health Issues 599

having a history of gastroesophageal reflux disease (GERD). Any middle-aged male with chronic GERD presenting with difficulty swallowing requires an urgent endoscopy in order to rule out esophageal cancer or a stricture arising in the setting of Barrett’s esophagus. Esophageal adenocarcinoma is the fastest rising cancer of the digestive tract (Wood & Yang, 2008; Haghdoost et al., 2008).33–35

Autoimmune Pancreatitis Autoimmune pancreatitis (AIP) is the pancreatic manifestation of a fibroinflammatory systemic disorder affecting the kidney, bile ducts, retroperitoneum, lymph nodes, parotid, and lacrimal glands (Gardner & Chari, 2008).36 The aforementioned organs are populated by an IgG4-dense lymphocytoplasmic infiltrate (Chari et al., 2006).37 The prevalence of AIP in Japan is 0.82:1000, analogous to achalasia in the United States. AIP in Japan accounts for 5% to 6% of patients with pancreatitis. Males are twice as likely as females to develop AIP, and the disease typically presents in the fifth decade, though more than 85% present older than 50 years of age (Nishimori, Tamakoshi, & Otsuki, 2007).38 AIP is a condition that most commonly presents as painless jaundice, alerting an evaluation for pancreatic malignancy. Since the disease is steroid responsive, IgG4 levels should be evaluated in males presenting with painless jaundice. Supplements and diet aimed at suppressing inflammation should be considered for this condition, given its steroid responsiveness (see Chapter 31).

Non-Ulcer Dyspepsia Non-ulcer dyspepsia (NUD) is not clearly linked to gender predisposition. There are several studies showing a higher prevalence of symptoms in females (Richter, 1991; Johnsen et al., 1991; Agreus, 1993; Kay, Jorgensen, SchultzLarsen, & Davidsen, 1996; Meineche-Schmidt & Krag, 1998; Stanghellini, 1999)39-44, whereas others show either male predominance (Johnsen, Straume, & Forde, 1988)45 or no gender bias (Drossman et al., 1993; Talley, Zinsmeister, Schleck, & Melton 3rd, 1992; Bernersen et al., 1990; Jones et al., 1990; Kay & Jorgensen, 1994)46–50. One possible explanation for the wide variation in the gender-specific prevalence of individuals with non-ulcer dyspepsia, could be from the male gender being more susceptible to dyspepsia from Helicobacter pylori infection (Sasidharan, Uyub, & Azlan, 2008).51 Another possibility is that those aforementioned studies on the prevalence of sex-specific dyspepsia only performed descriptive demographics, rather than specific gender analyses.

600 INTEGRATIVE GASTROENTEROLOGY

Welen and colleagues reported that functional dyspepsia adversely affects women more than men in daily life (Welen, Faresjo, & Faresjo, 2008).52 Overall, it appears that men and women with dyspepsia appear to differ with respect to symptom patterning and pain processing. Well-designed population studies are needed to investigate the prevalence of dyspeptic symptoms.

Gastroparesis Gastroparesis is a chronic disorder caused by stomach pump failure, and is characterized by profound nausea, vomiting, and epigastric pain. Most often, the cause is unapparent and, of the known associations, diabetes is the most common. Idiopathic gastroparesis is a functional bowel disorder that is more prevalent in females than males (Stanghellini et al., 2003).53 The mean age of onset of idiopathic gastroparesis is 34 years, and the female to male ratio has been reported to be 4:1 (Patrick & Epstein, 2008).54 The reason for the sex ratio imbalance remains unknown, but Soykan et al. (1998) reported that 62% of patients with idiopathic gastroparesis revealed past history of physical or sexual abuse.55 There is also evidence of a gender difference in solid and liquid emptying between men and women, with female gastric emptying slower than men (Datz, Christian, & Moore, 1987).56

Causes of Gastroparesis: • Idiopathic • Diabetes • Gastrointestinal surgery • Gastroesophageal reflux disease • Viral infection • Scleroderma • Myotonic dystrophies • Iatrogenic (medications)

The Irritable Bowel Syndrome and Functional Bowel Disorders Irritable bowel syndrome (IBS) is a chronic functional GI disorder characterized by abdominal pain associated with alterations in defecation or stool

An Integrative Approach to Gender-Specific Digestive Health Issues 601

frequency and consistency (Mearin, 2007).57 The prevalence of IBS in Western countries is reported to be 10% to 15% with a female to male ratio of 2:1 (Ringel, Williams, Kalilani, & Cook, 2009).58 Abdominal bloating is common in patients with IBS, and its prevalence and relative severity differ on the basis of sex (Lu, Chang, Lang, Chen, Luo, & Lee, 2005).59 Of all digestive diseases, the functional bowel disorders such as IBS have been well described as to the underlying pathophysiology of their gender predilection (Tables 49.3 and 49.4). Along these lines, recent interest in gender differences in IBS has been fueled, in part, by studies suggesting that new pharmacological therapies for this syndrome are more effective in female than in male IBS patients (Chang, Heitkemper, 2002).60 The epidemiology, pathophysiology, and integrative approach to IBS are discussed by in Chapter 42 by Pickett-Blakely, Davison, and Mullin.

Table 49.3. Gender-Specific Differences in IBS Pathophysiology • Autonomic nervous system dysregulation • Afferent sensory pathway • Postinflammatory/infection Psychological status: • Greater prevalence of depression, anxiety, psychological perceived stress and somatization in women • Visceral perception to stress Response to medication Hormones Pain modulation Visceral hypersensitivity Motility Extracolonic manifestations (adapted from Ouyang and Wrzos, 2006)

602

INTEGRATIVE GASTROENTEROLOGY

Table 49.4. Summary of Key Gender-Specific Differences in IBS Epidemiology • F>M 2:1 in the community • F>M 3-4:1 in healthcare-seeking population Clinical Symptoms • Constipation: F>M • Diarrhea: M>F • Worsened IBS with extracolonic features f: F>M • Overlap pain syndromes: F>M • Timing with menstrual cycle: 50% of females Pathophysiology • GI motility: GI transit M>F • Visceral hypersensitivity: F>M • Abuse: F>M • Postinfectious: F>M • Psychological perpetuators: F>M • History of hysterectomy: 33% of F • Sexual dysfunction: F>M • Hormonal and menstrual irregularities: F>M • Chronic Stress-HPA axis dysregulation: F>M • Altered serotonin signaling of serotonin reuptake transporter (SERT)gene expression in F Response to Treatment • Pharmacological: F>M for serotonergic drugs • Hypnotherapy: F>M • Melatonin: F>M (adapted from Ouyang & Wrzos, 2006)

Bloating symptoms are more prevalent in women than men, and are associated with a decrease in the quality of life and increases in healthcare utilization and use of medications (Cain et al., 2008).

An Integrative Approach to Gender-Specific Digestive Health Issues 603

Issues of extracolonic pain syndromes (e.g., fibromyalgia), gynecological problems (e.g., dyspareunia) and hormonal imbalances (e.g., estrogen) are well described in this book in Chapter 7, Chapter 9, and Chapter 10.

Extracolonic Conditions Associated with IBS (F>M) • Interstitial cystitis • Dyspareunia • Chronic pelvic pain • Migraine headache • Temporomandibular joint disorder • Fibromyalgia • Depression or anxiety∗ • Dysmenorrhea∗ • Premenstrual syndrome∗ ∗ worse in women with IBS> those without IBS (Lee et al., 2001; Mayer et al., 1999)

Patients with a functional disease were more likely to seek alternative medical care than those with organic disease (33% vs. 7%; p<0.0001; see Verhoef, Sutherland, & Brkich, 1990).61 Kearney and Brown-Chang (2008) reported that 21% to 51% of individuals with IBS use CAM practices.62 Overall, mind– body treatments (cognitive-behavioral therapy, hypnotherapy), peppermint oil, traditional Chinese medicine, and Western-based herbs (STW 5) have been shown to be beneficial for IBS (Mullin, Pickett-Blakely, & Clarke, 2008).63 Additional modalities available to individuals with IBS are discussed in detail in in Chapter 42. Table 49.5 summarizes the type and annual cost of the most commonly utilized modalities in the United States. It is interesting to note that factors associated with CAM use in IBS have been well characterized (van Tilburg et al., 2008).64 Women are more likely than men to utilize integrative approaches to manage their IBS symptoms (van Tilburg et al., 2008).64 Koloski et al. (2003) reported that approximately one half (n=103, 49.8%) of patients with IBS or functional dyspepsia had sought conventional care, while only a fraction (n=43, 20.8%) used CAM. Furthermore, being female independently predicted CAM use.4 Smart and colleagues (1986) confirmed that in IBS subjects, younger females were predictors for CAM utilization.65 The factors associated with CAM use in IBS are shown in Table 49.6. The overall results of CAM utilization in IBS is shown in Table 49.7.

604 INTEGRATIVE GASTROENTEROLOGY

Table 49.5. Complementary and Alternative Medicine Modalities Used in IBS with Annual Costs in U.S. Dollars Mean Annual Cost (USD)

% Use

Ginger root tea

40

14.8

Massage therapy

400

12.6

80

10.0

Psychotherapy

280

8.1

Aromatherapy

40

7.2

Homeopathy

120

8.1

Acupuncture

180

3.3

Biofeedback

40

1.4

Hypnosis

80

1.4

All CAM

240

38.4

Modality

Yoga

(adapted from van Tilburg et al, 2008)

Table 49.6. Factors Associated with CAM use in IBS • Younger age • College graduate • Higher severity of symptoms • Bloating-distention • Depression • Anxiety • Somatization • Lower quality of life (adapted from Koloski et al., 2003)

An Integrative Approach to Gender-Specific Digestive Health Issues 605

Table 49.7. Complementary and Alternative Medicine (CAM) in IBS: Overall Results Herbs

Mind–Body: best results

• Peppermint oil (p-IBS), 8 studies, benefit

• Psychological

• TCM (d-IBS), STW-5, benefit

• Cognitive-behavioral therapies

Diet

• Yoga

• Elimination diet (15%–71% response, nonsustained)

• Reflexology

Supplements

• Guided imagery

• Melatonin (1 study, benefit)

• Meditation

• Probiotics (8 RCTs, 7 benefit)

• Biofeedback

Energy Medicine

• Multicomponent

• Hypnosis

• Acupuncture (2 controlled sham studies, benefit) (adapted from Mullin, Pickett-Blakely, & Clarke, 2008)

Conclusion There are several digestive disorders that have a gender-specific basis for pathophysiology, symptomology, and response to therapy. Clinicians should be aware of the proclivity of these digestive disorders as it relates to gender, to raise suspicion of underlying disease and enhance early diagnosis and treatment. Research and widespread reporting of the gender disparities of digestive disease will ultimately lead to improved patient care and physician satisfaction. Given that females utilize CAM more than males, clinicians should become familiar with the effectiveness of CAM modalities for the functional bowel disorders and consider offering alternative options, given the high satisfaction rate among patients and the results derived from clinical trials.

50 Gastrointestinal Disorders and Eating Disorders CAROLYN COKER ROSS

key concepts ■ ■

■

■

■

Gastrointestinal disorders often co-occur with eating disorders. It is important for the clinician to be aware of the signs and symptoms of eating disorders, to avoid missing the diagnosis in patients who present with GI problems. It is important for the clinician to distinguish between gastrointestinal disorders related to disordered eating, as many of these will be resolved with refeeding. The use of dietary supplements can reduce symptoms of functional bowel disorders. Integrative medicine approaches to the treatment of GI disorders offer the clinician effective alternatives to conventional therapies. ■

G

astrointestinal (GI) complaints are present in 50% of individuals diagnosed with eating disorders. It is often difficult to distinguish true GI diseases from complaints related to eating disorders (McClain et al., 1993), the majority of which resolve with refeeding. As well, certain GI diseases can present a picture that is similar to eating disorders, or can represent the inciting event that contributes to the development of an eating disorder in vulnerable individuals. In a survey of individuals with functional bowel disorders (FBDs), complementary and alternative medicine (CAM) therapies were used by 35% of patients in an HMO. Therapies included the use of ginger, massage therapy, and yoga. The use of CAM was not related to dissatisfaction with conventional therapies (van Tilburg et al., 2008). Therefore, it is important 606

Gastrointestinal Disorders and Eating Disorders

607

for gastroenterologists to be able to use the presentation of GI disorders as a means to identify eating disorders in their practice. As well, an understanding of CAM therapies may be helpful in treating these patients.

Incidence/Prevalence Eating disorders represent a spectrum of conditions including anorexia nervosa (AN), bulimia nervosa (BN) and eating disorder not otherwise specified (ED-NOS). Binge eating disorder (BED) is a new category under consideration for inclusion in the Diagnostic and Statistical Manual but is currently included under ED-NOS.

The lifetime prevalence of eating disorders as reported in a large-scale national study for AN, BN, and BED was 0.9%, 1.5%, and 3.5% for women and 0.3%, 0.5%, and 2.0% for men (Hudson, 2007).

Anorexia Anorexia has the highest mortality of any of the psychiatric diagnoses (Palmer, 2003) and is the leading cause of death in young women (15 to 24 years old). The mortality rate among those with anorexia is estimated to be 0.56% per year, 12 times higher than the annual all-cause mortality rate for females 15 to 24 years old in the general population (Sullivan, 1995). Anorexics experience an intense fear of gaining weight, and for those who are female and postmenarchal, loss of three consecutive menstrual cycles is required to meet the diagnostic criteria.

The hallmark of AN is the refusal or inability to maintain a healthy body weight, and body image distortion—individuals see themselves as being much larger in size than they are.

Anorexia has been diagnosed in children as young as seven, but is most common in adolescents and young adults. There are also many individuals who are diagnosed in midlife, either with a relapse of an eating disorder diagnosed earlier, or a new eating disorder.

608

INTEGRATIVE GASTROENTEROLOGY

There are two types of AN: the restricting type, in which the individual severely limits food intake, and the binge–purge type, in which restricting alternates with some form of purging including the use of self-induced vomiting, laxative or diuretic abuse, and compulsive exercise.

Bulimia Nervosa Behaviors associated with bulimia include recurrent bingeing, defined as eating a large quantity of food in a short period of time, followed usually by compensatory purging by self-induced vomiting, laxative, or diuretic abuse. Individuals with BN are usually normal weight or slightly overweight. The onset of bulimia parallels that of anorexia, but its prevalence is much higher than that of AN by the early adult years. Comorbid substance use disorders are also higher in BN than in AN, reaching a lifetime prevalence of up to 40% (Lilenfeld et al., 1997). Over a 7-year period, approximately one-half of those with restricting anorexia will develop binge–purge type anorexia; one-third will develop bulimia (Eddy et al., 2008).

Binge Eating Disorder (BED) and Eating Disorder not Otherwise Specified (ED-NOS) ED-NOS is the diagnosis used for individuals who do not meet the strict criteria for AN or BN. Binge eating disorder is the most well defined of the disorders included under ED-NOS. BED is characterized by the consumption of large quantities of food within a short period of time without a compensatory purging mechanism. Those with BED experience a lack of control over their eating behavior, eat beyond the point of fullness, and often eat very rapidly. Up to 25% of overweight or obese individuals seeking weight loss treatment have BED (Pull, 2004). In fact, most individuals with BED are overweight or obese. Compared with individuals with obesity who do not have BED, persons with BED have more extreme fluctuations in their weight, higher levels of body dissatisfaction (Marcus et al., 1992), and a higher incidence of psychopathology (Yanovski, 1993).

Gastrointestinal Disorders and Eating Disorders

609

Medical Complications (de Zwaan & Mitchell, 1993) The medical complications associated with anorexia, bulimia, and binge eating disorder can be serious and life-threatening. The symptoms associated with these complications, if recognized, can be used as a way to screen patients and enable them to obtain help not just for their GI symptoms but for the underlying eating disorder. For the purposes of this book, the major complications will be summarized, with more extensive focus being placed on the gastrointestinal system. Pulmonary complications: Patients who vomit regularly are at risk for aspiration pneumonia; if vigorous, vomiting can result in pneumomediastinum, pneumothorax, or subcutaneous emphysema and rib fractures. Cardiac complications: Abnormalities on the electrocardiogram (EKG) in those with AN and BN are common and include nonspecific ST-T wave changes, prolongation of the QT interval (which can indicate higher risk for sudden death syndrome), and severe bradycardia (with rates from 25 to 40 beats per minute). Other abnormalities include hypotension, orthostatic blood pressure changes (which are adaptations to starvation and should not be mistaken as secondary to physical conditioning (Palla & Litt, 1988), peripheral edema, hypoproteinemia, cardiomyopathy, and mitral valve prolapse. Skin and teeth: Anorexics develop fine baby hair (lanugo) on the face and forearms as an adaptation of starvation. Individuals with bulimia can experience loss of dental enamel due to purging. Metabolic consequences: Diabetics with an eating disorder can manipulate their use of insulin to increase glucosuria and loss of calories in the urine. Other findings include hypoglycemia secondary to restricting, hyperlipidemia in AN, BN, and BED, and loss of bone mineral density (BMD) in those with a history of anorexia and extended periods of amenorrhea. There is a sevenfold increase in fracture risk in eating disorder patients with low BMD (Rigotti et al., 1991). Thyroid function testing may show the “sick euthyroid syndrome” (normal TSH, decreased T3 and increased reverse T3), which is an adaptation to starvation and returns to normal with refeeding. Patients with BED may have metabolic syndrome. Hematologic system: In AN, leukopenia, thrombocytopenia, and in cases of extreme starvation, bone marrow atrophy (Howard et al., 1992) may occur. Electrolytes abnormalities: Hypokalemia can result from dehydration, vomiting, and laxative and diuretic abuse, and is the cause of some of the mortality in eating disorder patients. Hypophosphatemia may be exacerbated with

610

INTEGRATIVE GASTROENTEROLOGY

refeeding, increasing the risk for myocardial dysfunction and seizures (Wda et al., 1992). Gastrointestinal system: The most common complaints by patients with any eating disorder when they begin to refeed are gastrointestinal, and include early satiety, bloating, gas, abdominal pain, diarrhea, and constipation.

The prevalence of functional GI disorders in a study of patients with AN, BN, and ED-NOS reported 98% had a GI disorder, including 52% with irritable bowel syndrome, 51% with heartburn, 23% with dysphagia, and 22% with functional anorectal pain disorder; 52% had three or more coexisting disorders (Boyd et al, 2005).

Underweight, restricting individuals with anorexia can develop delayed gastric emptying (Dubois et al., 1979), which improves with refeeding and is thought to be secondary to food-restricting behaviors (Szmukler et al., 1990). In eating disorder patients who binge, more serious complications can include ulcers of the stomach and duodenum, gastrointestinal bleeding including rectal bleeding, which is associated with laxative abuse, gastric dilatation, and rupture due to binging or as a side effect of overly aggressive refeeding in those with anorexia nervosa. Individuals with BED experience significant bloating, acid regurgitation, heartburn, dysphagia, and upper abdominal pain. BED is also associated with diarrhea, urgency, constipation, and feeling of anal blockage (Cremonini et al., 2009). Superior mesenteric artery syndrome is a less common consequence in AN, and is due to the loss of fat around the superior mesenteric bundle (Sours & Vorhaus, 1981). This can cause abdominal pain and is usually alleviated by weight restoration. Those patients with eating disorders who purge or chronically vomit can develop gastroesophageal reflux disease, and hiatal hernia. Pancreatitis can be a result of pancreatic stimulation during bingeing or during refeeding. A small study of women with anorexia and chronic constipation reported 66% with slow colonic transit time and 41% with pelvic floor dysfunction. Colonic transit time normalized with refeeding (Chiarioni et al., 2000). Severe liver dysfunction has been reported as a consequence of malnutrition in AN (Furuta et al., 1999). GI diseases can coexist with eating disorders. A case report of 10 patients with celiac disease and eating disorders highlights the difficulty in diagnosing and treating individuals with both illnesses (Leffler et al., 2007).

Gastrointestinal Disorders and Eating Disorders

611

Treatment Integrative medicine therapies for eating disorders include a wide array of approaches that are founded on the principle that the body has its own self-healing capacity. Therapies used in integrative medicine can include conventional therapies, nutritional supplements, mind–body therapies, and complementary and alternative therapies such as acupuncture. There is a paucity of research that specifically examines therapies for treating GI complications in patients with eating disorders. Studies cited in this chapter will discuss results using complementary and alternative therapies for the GI symptoms common in eating disorder patients. As the studies cited show, many of the medical complications associated with eating disorders are alleviated by refeeding. Refeeding applies to AN, BN, and BED, as patients with an eating disorder—even those who binge eat—are often undernourished and may be deficient in vitamins and minerals, or may be restricting certain macronutrients such as fat or carbohydrates.

The most important first therapy for all the eating disorders should be nutritional in the form of food, and also nutritional or dietary supplements.

NUTRITIONAL SUPPLEMENTS

The use of nutritional supplements and herbs offers an alternative to, and may reduce side effects from, prescription medications.

DIGESTIVE SUPPLEMENTS

Eating disorder patients commonly suffer from digestive complaints, which may increase when they resume more normal patterns of eating. These symptoms can create challenges during the refeeding process and become distractions in the treatment process. Symptoms may include constipation, diarrhea, bloating, and abdominal cramping or pain. Integrative therapies work to restore normal bowel function and can prevent the need for stimulant or bulk laxatives, upon which patients can become dependent.

612

INTEGRATIVE GASTROENTEROLOGY

Probiotics Probiotics are products that contain the beneficial bacteria and yeast that are used to replace or enhance gut flora. Levels of probiotics can be decreased by the use of antibiotics, alcohol and drugs, stress, and chronic constipation. The most well studied probiotics are Lactobacillus rhamnosus GG and Bifidobacterium lactis, which have been effective in treating antibiotic-associated diarrhea, rotavirus diarrhea, and ectopic conditions. A preliminary study on the effects of fermented milk in individuals with anorexia and children with diarrhea (two malnourished populations) demonstrated an increase in interferon-gamma, thought to be a marker demonstrating the effect of probiotics on the immune response (Solis et al., 2002). A meta-analysis of 10 randomized controlled trials (RCTs) demonstrated good evidence to support the use of probiotics in treating irritable bowel syndrome, although it was unclear which strain was most effective (Moayyedi et al., 2008). Probiotics may be useful in decreasing constipation associated with low fiber and low caloric intake (during dieting) in overweight individuals (Amenta et al., 2006). An RCT in irritable bowel syndrome patients demonstrated that a probiotic mixture can reduce abdominal pain, distension, borborygmi, and flatulence (Kajander et al., 2005). Probiotics may also reduce the severity of constipation in individuals with chronic constipation (Koebnick et al., 2003).

Use of a preparation that has a double-walled capsule will increase the likelihood that the probiotics are not destroyed in the stomach acidity.

Digestive Enzymes Pancreatic enzymes have been used in conventional medicine for conditions related to pancreatic insufficiency and malabsorption. The use of pancreatic digestive enzymes may also be useful in other conditions associated with poor digestion, including eating disorders. Digestive enzymes help break down carbohydrates, fat, and protein. A small study done in an inpatient eating disorder unit, of patients on a combination of a plant-based pancreatic enzyme product and probiotics, resulted in a decrease in reports of GI complaints (from 15% to 5%), and a decrease in the use of conventional medications (from 15% to 2%) to treat GI complaints. The treatment group was compared to a similar group

Gastrointestinal Disorders and Eating Disorders

613

of inpatients at the same facility prior to the institution of the supplement regimen (Ross et al., 2008). Digestive enzymes are traditionally from porcine or bovine sources; however, plant-based or microbe-derived enzymes are currently available and offer the same efficacy at a much lower dose. Animal-based and plant-derived or microbe-derived enzymes may be used alone or in combination for treating malabsorption and lactose intolerance (Roxas, 2008).

Flaxseed Flaxseed taken orally or in baked goods has been used for the treatment of constipation, colon damage secondary to laxative abuse, and irritable bowel syndrome. Flaxseed is a good source of soluble fiber and has the additional benefit of providing a rich source of alpha linolenic acid and omega-3 fatty acids. A study in healthy adults who were given 50 grams of flaxseed per day for one month showed an increase in bowel movements per week by 30% (Cunnane et al., 1995).

Melatonin Melatonin is a hormone made by the pineal gland that has been used as a sleep remedy. There is an association between irritable bowel syndrome and insomnia. In one study using melatonin (3 milligrams), insomnia improved and abdominal pain associated with irritable bowel syndrome decreased. There was no effect on other symptoms of irritable bowel syndrome. However, in another study using the same dosage of melatonin for a longer period of time, patients with irritable bowel syndrome had less pain and bloating, and had improvements in bowel habits as well as decreases in headache, heartburn, and nausea (Saha et al., 2007).

ACUPUNCTURE

Acupuncture is one of the treatments used in traditional Chinese medicine (TCM) and is widely practiced in the United States. TCM is based on the principle that disease is caused by imbalances in the flow of “qi” (pronounced “chee”), which is the vital life energy that flows throughout the body in a complex system of meridians, or channels. A meta-analysis of studies on acupuncture for GI diseases found a number of RCTs demonstrating an improvement

614

INTEGRATIVE GASTROENTEROLOGY

Table 50.1. Supplement doses, Food Sources and Side Effects Food Source

Dosage

Side Effects/Drug Interactions

Probiotics

Fermented foods, kefir, yogurt

Dose varies by product. Typical doses for children: 5–10 billion; adults: 10–20 billion

No known interactions with medications. Side effects: gas and bloating.

Digestive Enzymes

Bromelain: pineapple Papain: papaya

Dose varies by product. A typical OTC plant/microbial product may contain: Cellulase: 185 GD units Amylase: 20,000 SKB units Protease: 40,000 HUT units Lipase: 9,000 Lipase units Lactase: 1400 FCC units

Allergic reactions can occur. Side effects: GI upset when taken in high doses

Flaxseed

Flaxseed

40–50 grams/day

Flaxseed may interact with antidiabetic drugs (lowers blood glucose) and anticoagulants (may theoretically increase bleeding times)

Melatonin

NONE

3–5 milligrams/day

Melatonin may interact with antidiabetic drugs (impair glucose utilization) and anticoagulants (may theoretically increase bleeding times. Caffeine decreases melatonin levels.

in health-related quality of life (although sham acupuncture was as effective here as actual acupuncture) for irritable bowel syndrome and inflammatory bowel disease. Real acupuncture was superior to sham in studies on Crohn’s disease and colitis (Schneider et al., 2007). A Cochrane review of acupuncture for irritable bowel syndrome did not find conclusive evidence for its efficacy for IBS (Lim et al., 2006).

Gastrointestinal Disorders and Eating Disorders

615

Conclusion There are few studies that focus specifically on the treatment of GI diseases in individuals with eating disorders. Studies cited in this chapter may be useful for extrapolation to this population who suffer with significant GI symptoms. CAM therapies can often reduce the risk of side effects of conventional therapies. Complementary and alternative therapies in general offer safe, possibly effective options that can be used with and in place of the usual conventional therapies.

51 Ethical Issues in Integrative Gastroenterology JULIE STONE

key concepts ■ ■

■

■

■

■

Ethical issues are at the heart of therapeutic relationships. Conventional and complementary therapists need an adequate understanding of each other’s therapeutic modalities in order to communicate, refer appropriately, and work in an integrated manner. Acting ethically involves benefiting and not harming patients, encouraging patients to make choices for themselves by providing adequate information, and treating patients fairly and without discrimination. While legal requirements vary slightly across jurisdictions, the need to obtain consent is a major ethical requirement. All practitioners must work within the limits of their competence and make appropriate referrals where necessary. Therapists should recognize that all interventions carry risks and that sometimes things go wrong. Therapists should respond to complaints constructively, putting in place mechanisms to learn from errors and near misses. ■

616

Introduction

A

gainst a backdrop of high levels of digestive diseases in the West, high numbers of patients access a range of CAM (complementary and alternative medicine) therapies for treatment of a variety of gastroenterological conditions. Some of these patients will have received a conventional medical diagnosis, whereas other patients will self-refer to CAM therapists without having first been diagnosed by a physician. This chapter will explore some of the ethical issues associated with integrative gastroenterology, including the areas of respect for patient autonomy, the competence of CAM practitioners and the need to practice within limits of competence, the duty of any healthcare practitioner not to harm patients, and ethical responsibilities in relation to justice, including the need to ensure appropriate redress in the event of a mishap. Despite some variety in the underlying philosophical bases of different codes of ethics, there is a significant degree of commonality in what is expected of a practitioner. (Stone, 2002) Core ethical responsibilities include: • Being sufficiently skilled in whatever therapies are provided and only working within the limits of competence, making referrals where necessary • Being aware of any specific contraindications to treatment and having additional skills for working with vulnerable groups, including children and mentally incapacitated patients • Keeping up to date by undertaking continuing professional development (CPD), and receiving appropriate supervision to ensure professional support and avoid burn-out • Recognizing when it is appropriate to refer the patient to another therapist, either within the same modality, or to another CAM therapist, or to a conventional physician • Ensuring the quality and safety of healthcare products prescribed, and maintaining equipment and premises to ensure that patients are not harmed • Creating and maintaining effective professional boundaries • Providing sufficient information about treatment and its side effects to ensure that patients understand what is proposed and are in a position to consent to or refuse treatment • Maintaining confidentiality and ensuring compliance with relevant data protection legislation

618

INTEGRATIVE GASTROENTEROLOGY

• Responding appropriately and effectively to complaints • Acting on concerns about other practitioners

What Do We Mean by “Ethics”? Professional ethics is about how practitioners ought to act, and the right thing to do in a contentious situation, where opinions and rights may be in conflict. Healthcare relationships are not like ordinary contractual relationships between consensual adults, and patients’ capacity to enter into voluntary arrangements may be compromised by a variety of factors, including the obvious factor of being disadvantaged by ill health. Ethics are especially important because of the disequilibrium inherent in professional relationships. This disequilibrium is based largely on the relative disparity in knowledge between the therapist and the patient. The practitioner has a wealth of technical knowledge about his or her therapy, whereas the patient may know very little about what the therapy involves and what outcomes may be realistic. This information gap may be exacerbated by the use of technical jargon or unfamiliar language by the practitioner during consultations (Stone, 2000). Ethics and law are now routinely incorporated into professional education curricula, in part reflecting an increased interest in consumer and patient rights, and in part driven by an increasingly litigious culture and the desire on the part of practitioners not to be sued. Like legal duties, ethics concerns rights and responsibilities. These may be set out in professional codes, statute and case law and organizational protocols. The regulatory framework governing conventional medicine, which incorporates many ethical obligations, also translates to CAM practice. (Cohen 1998) That said, healthcare professionals must familiarize themselves with the precise regulations that apply in a given work situation, and should seek professional legal and ethical advice if they are unsure about their responsibilities. In the past, practitioners in the United States were sanctioned for using or referring patients to CAM practitioners (irrespective of whether the referral caused harm). However, medical freedom statutes instituted in various states have removed this threat, and state boards have adopted regulations that acknowledge the growth of integrative approaches to treatment that combine conventional medicine and CAM. (Cohen, 2005)

Ethics requires practitioners to be accountable for their actions and act in accordance with professional and societal rules.

Ethical Issues in Integrative Gastroenterology

619

Nonetheless, professionals remain accountable for their actions and may need to justify departure from accepted custom and practice in a situation where the practitioner has acted outside professional norms, and in ways that no responsible body of medical opinion would advocate.

Arriving at Ethically Justifiable Decisions Because practitioners and patients may hold diverse cultural values, it is important to have a shared process for determining how to arrive at ethically justifiable decisions. This ensures a level of consistency within healthcare, so that choices are not made according to the whim of individual practitioners. This section will explore some of the main traditions of ethical thinking in healthcare.

DUTY-BASED THEORIES

Duty-based theories suggest that the right course of action is that which complies with relevant rules. Professional rules, set out in formal codes of practice, have the benefit of being drafted with profession-wide consensus, increasingly with significant input from patients and other key stakeholders. An advantage of duty-based approaches is that they provide a degree of consistency, so that professionals know what to do in difficult situations. While this is desirable for practitioners and patients, the nature of professional codes is such that they can only ever cover “headline” issues, and cannot provide sufficient detail to act as a blueprint for how professionals ought to act in every given situation. (Stone, 2002) Rather, ethical codes tend to set out a series of imperatives from which other rules in the code are derived. Table 51.1 sets out the key principles which underpin the U.K. General Medical Council’s core ethical guidance.

Ethical decisions are the best possible, in all the circumstances, taking relevant considerations into account.

Acting ethically means trying to decide the best way to act in a given situation. It is about what a practitioner ought to do. To clarify how the GMC expects doctors to work within the code, it defines what it means by the terms “must” and “should.”

620

INTEGRATIVE GASTROENTEROLOGY

Table 51.1. Good Medical Practice (2006) The duties of a doctor registered with the General Medical Council Patients must be able to trust doctors with their lives and health. To justify that trust, you must show respect for human life and you must: • Make the care of your patient your first concern • Protect and promote the health of patients and the public • Provide a good standard of practice and care • Keep your professional knowledge and skills up to date • Recognize and work within the limits of your competence • Work with colleagues in the ways that best serve patients’ interests • Treat patients as individuals and respect their dignity • Treat patients politely and considerately • Respect patients’ right to confidentiality • Work in partnership with patients • Listen to patients and respond to their concerns and preferences • Give patients the information they want or need in a way they can understand • Respect patients’ right to reach decisions with you about their treatment and care • Support patients in caring for themselves to improve and maintain their health • Be honest and open and act with integrity • Act without delay if you have good reason to believe that you or a colleague may be putting patients at risk • Never discriminate unfairly against patients or colleagues • Never abuse your patients’ trust in you or the public’s trust in the profession You are personally accountable for your professional practice and must always be prepared to justify your decisions and actions. Source: http://www.gmc-uk.org/guidance/good_medical_practice/GMC_GMP.pdf

In Good Medical Practice, the terms “you must” and “you should” are used in the following ways: • “You must” is used for an overriding duty or principle. • “You should” is used when we are providing an explanation of how you will meet the overriding duty.

Ethical Issues in Integrative Gastroenterology

621

• “You should” is also used where the duty or principle will not apply in all situations or circumstances, or where there are factors outside your control that affect whether or how you can comply with the guidance. Source: http://www.gmc-uk.org/guidance/good_medical_practice/how_gmp_ applies_to_you.asp

Practitioners may have to weigh conflicting ethical principles to resolve an ethical dilemma.

Professional codes establish a broad framework, but they do not remove the professional’s own autonomy to make whatever decision seems to be the most ethically sensitive and sensible on the basis of all available information. Neither can codes help practitioners resolve dilemmas where duties appear to conflict with each other (for example, where maintaining confidentiality would cause harm to the patient or to another person). Weighing conflicting moral obligations remains the professional’s responsibility. Arguably, to remove this autonomy would turn professionals into mere technocrats, and would remove the artistry and humanity that complement the scientific basis of the therapeutic relationship.

Outcome-Based Theories The other main group of ethical theories includes outcome-based or consequence-based theories. These theories subscribe to the notion that the right course of action is the one that is likely to promote the best outcome or consequences. Here, the aim of any action or decision is to choose the option that is likely to promote the best outcome (for the greatest number) or, turned on its head, the option that produces the least harm (for the fewest people). Appeals to this sort of decision-making are helpful in deciding how to allocate scarce resources (for example, use cheaper treatments rather than more expensive treatments if the outcome is thought to be equal). In individual practitioner–patient relationships, the theory would mandate choosing treatments where the side effects are less severe, all other factors being equal. From a theoretical perspective, outcome-based decisions are flawed in that they base the rightness or wrongness of an action on likely outcomes, which may not

622 INTEGRATIVE GASTROENTEROLOGY

materialize. In individual treatment decisions, it is impossible to predict with certainty what the outcome will be in advance.

Principle-Based Ethics Principle-based ethics distill many of the ethical imperatives outlined previously. First pioneered by Beauchamp and Childress (2001) in the United States, and Gillon (1994) in the United Kingdom, the principle-based approach involves considering ethical principles in light of the available evidence, and weighing these to arrive at an ethically defensible position. The key principles are: • Respect for autonomy • The duty to benefit and not harm • Respect for principles of justice and fairness Western ethics place a high value on individual autonomy and the freedom of rights of competent individuals to make their own decisions, rather than have others make decisions for them on the basis of what is perceived to be in their interests. Callahan (2003) notes that the principle of respect for autonomy is given a place of honor, “because the thrust of individualism, whether from the egalitarian left or the market-oriented right, is to give people maximum liberty in devising their own lives and values.” The emphasis on respect for autonomy is a relatively recent phenomenon. Previously, healthcare in the West was more paternalistic, with many patients trusting their practitioners to make decisions for them. In some Eastern traditions, practitioners still place a high value on preserving a patient’s hope, and bad news may be imparted to family members but withheld from patients. It is arguable whether this respect for autonomy is, indeed, the overriding ethical principle in CAM therapies that originate in non-Western cultures. (Stone, 2002) In culturally diverse populations, different weight will be given to each of these principles. Similarly, individual patients will give different weight to how they prioritize these principles. Subject to legal requirements that provide a baseline to ensure that each of these principles meets a given standard, practitioners and patients must negotiate an ethical basis for the relationship. Negotiating a contract of mutual expectations is an important way of minimizing misunderstandings and complaints.

Virtue- or Values-Based Theory An alternative trend in ethical teaching involves the cultivation of core values or virtues. Virtues may be described as desirable behaviors which, if practiced

Ethical Issues in Integrative Gastroenterology

623

habitually, become embedded in a person’s character and incline an individual toward making “good” ethical decisions. Values for healthcare professionals might include trustworthiness, empathy, courage, and integrity. This approach concentrates on the practitioner rather than the decision, drawing on the role of practical reasoning, emotion, and the practitioner’s motivation in making moral decisions.

Applying Ethical Frameworks There is little consensus as to how the ethical frameworks or traditions should be applied in practice. Although healthcare training increasingly emphasizes the importance of reflective practice, the process of making ethical decisions is rarely explicit and, in practice, a practitioner is likely to draw on a number of the theories and rules just discussed. Ethical implications of treatment or research do sometimes need to be consciously articulated and adjudicated; for example, when a practitioner is making an application to a research ethics committee, or when regulatory bodies are drafting guidance in an ethically contested area. In practice, however, a healthcare practitioner’s day-to-day decisions are only likely to be externally reviewed retrospectively, should they become the subject of complaint or disagreement. Accordingly, the bulk of this chapter will concentrate on the components or aspects of practice where practitioners may experience ethical uncertainty, and which may give rise to complaint.

Competence and the Duty to Benefit Patients A desire to heal is the universal ethical basis of healthcare. The overarching ethical principle of any professional relationship is that the intervention will, on balance, produce a net benefit over harm. This recognizes the fact that any therapeutic endeavor will have a risk of side effects, whether in conventional treatment or complementary therapies. Within conventional medicine, the scope of healing a patient tends to be narrowly defined as alleviating symptoms. This is in line with a mechanistic approach to health and human suffering. Of course, doctors are not a homogenous group, and individual practitioners and specialties will vary to the extent that they embrace a more biopsychosocial or holistic approach to health and healing. A holistic understanding of what healing involves might include the following: • hearing what a patient is really saying, and understanding the meaning of the illness episode to the patient (including its emotional and spiritual impact)

624

INTEGRATIVE GASTROENTEROLOGY

• understanding what sort of relief the patient is looking to gain out of the treatment; for example, gaining greater control over a long-term condition • minimizing symptoms as much as is possible • being realistic about how much the treatment is likely to benefit the patient, and not distorting the patient’s expectations by overstating the anticipated effects of treatment

Competent Practice Based on Appropriate Pre- and Post-Registration Training Therapeutic relationships depend on patient trust, specifically, the ability of the patient to trust that the practitioner is suitably skilled in his or her field and has the requisite professional competencies to treat. Ordinarily, this will mean that the practitioner has undertaken a suitable training at an appropriate level, and has obtained the relevant qualifications to state that he or she possesses certain skills. Levels of training and expertise vary widely across the complementary and alternative sector. Any professional who is considering making a referral to a nonconventional practitioner should take steps to ensure that the person to whom they are referring the patient is suitably qualified. Failure to do so could result in legal or professional sanction.

Competent practice should be underpinned by evidence that a therapy provides more benefit than harm.

Qualifications should provide a minimum guarantee that the practitioner has the requisite entry-level skills to join a profession, but practitioners should also commit themselves to lifelong learning to keep them up to date and to make sure that they continue to develop as professionals. Most licensing bodies now require professionals to demonstrate that they undertake regular continuing professional development (CPD). CPD is increasingly outcomebased, and practitioners are increasingly expected to demonstrate what they have learned from courses, and encouraged to reflect upon how this will improve their practice. Practitioners should try to ensure that their postregistration education and training involves learning with others, including opportunities to discuss ethical dilemmas and how these have been resolved in practice.

Ethical Issues in Integrative Gastroenterology

625

Evidence-Based CAM and Patient Choice One of the biggest ethical debates surrounds the extent to which any particular CAM therapy is able to deliver benefit to the patient. While this is linked, in part, to promoting research/evidence-based practice, there is a more basic question, which is related to the scope of a holistic approach. The nature of holism implies that a practitioner is able to treat all aspects of a patient’s condition (looking at the patient as a whole person, paying attention to emotion and spiritual needs and not purely physical symptoms). Arguably, every holistic therapist will consider himself or herself legitimately equipped to accept a patient for treatment, as there will invariably be some aspect of the therapeutic relationship that can offer some level of comfort to a patient. This exposes a fundamental tension in balancing the freedoms of individuals to accept treatment of their own choice, with a desire to ensure that patients are not exposed to risks of therapies that may be less effective than others. This is not solely an issue for CAM practitioners. One of the features of gastric symptoms is that they may be caused by many disease processes, including psychosomatic problems. A patient may resort to complementary and alternative medicine after having exhausted a range of conventional specialties. Nonetheless, the holistic nature of nonconventional practice means that practitioners need to be realistic with themselves and their patients as to whether their modality is likely to benefit the patient. This requires an awareness and familiarization on the part of CAM practitioners and doctors with other approaches that might better benefit a patient. It is not wholly possible to legislate this aspect of practice. Offers to treat should be based on a realistic assessment of the evidence, and reviewed after a few sessions to see if the therapy is delivering benefit. The same principle applies to practitioners who offer not just one form of treatment, but a variety of alternative therapeutic modalities. Not only must such practitioners be adequately trained in each therapy they offer, but they should also be transparent about what treatment they are offering the patient, and on what evidential basis, so that the patient can make an informed choice. A practitioner should not switch from one modality to another when symptoms are not improving, without being very explicit. All CAM practitioners should be familiar with the contraindications to their particular therapy, and the additional caution to be exercised in applying certain treatment to special groups of patients. CAM therapists should recognize the point at which they should make a referral to a physician for a conventional diagnosis.

626

INTEGRATIVE GASTROENTEROLOGY

Patient Autonomy The surge in usage of CAM in itself reflects a desire on the part of patients to opt for a treatment modality of their choice. Patients suffering from gastric conditions may choose from an array of licensed and unlicensed practitioners, with high levels of usage of acupuncture and other energy-based techniques, Ayurvedic and Western herbal remedies, homeopathy, and touch-based therapies, including osteopathy and massage. Patients have a right to choose from a diverse array of practitioners, practicing, for the main part, outside state-funded healthcare. The principle of respect for patient autonomy has a number of implications, for both CAM practitioners and mainstream physicians. Autonomy connotes the rights of individuals to make their own choices, in accordance with their own values and principles, free from coercion and interference. Patients need to be given adequate information to be able to make choices about the form of healthcare they are to receive, and to decide whether to accept or reject the treatment offered. Professional practice reflects this obligation in the duty of practitioners to make sure that they obtain patient consent. While the legal requirements for obtaining a valid consent may vary between jurisdictions, the underlying ethical premise is based on respecting autonomy, and reflects the centrality of the principle of bodily integrity and freedom from interference. This denotes the rights of individuals not to be touched by anyone unless they have expressly consented to it (other than limited exceptions, including medical emergencies). Therapists sometimes assume, incorrectly, that the principle of implied consent means that they do not require actual permission to touch or treat a patient. This is incorrect. While it is true that a patient has chosen to attend an appointment, a therapist still needs to explain the following aspects of treatment, in a way that the patient can understand: • • • •

What is involved in the therapy How many sessions are likely to be necessary What the treatment will involve The anticipated benefits of treatment, and when benefit might be expected • How long the benefits of treatment might be expected to last • Possible side effects and what the patient should do in response. Patients should be told about small but common risks, and also about less likely risks that carry a risk of significant harm

Ethical Issues in Integrative Gastroenterology

627

• Alternatives to what is proposed (both complementary and conventional treatments) A therapist should also provide an opportunity for a patient to ask questions and should respond fully to any additional questions or concerns that the patient may have. In determining precisely which risks should be disclosed, practitioners should work within their professional code of ethics and any relevant case law. Certain procedures require additional caution. Where an invasive diagnostic or therapeutic procedure is required, for example, therapists should communicate fully why this is necessary, what will happen, and explain that the patient can ask the practitioner to stop at any point. Therapists should also make sure the patient knows that they can have a chaperone present. In most situations where an invasive procedure is required, therapists should seek consent in advance; e.g., provide the information in a first session, and undertake the procedure at the next.

Respecting autonomy can be enhanced through creating specific therapeutic contracts.

This will allow patients time to reflect on what is proposed, and give them a “cooling off ” period if they do not want to go ahead. Where this is not possible because the practitioner feels that the procedure is necessary in a hurry, the patient must nonetheless be told they can ask the practitioner to stop at any point.

Contracting with Patients Some therapists find value in creating explicit “contracts” with patients. This can be particularly helpful in the private sector, where practitioners work outside organizational frameworks. Drawing up a therapeutic (as distinct from a legal) contract can be a helpful way of both respecting the patient’s autonomy and protecting practitioners from subsequent complaints, by highlighting each party’s responsibilities. While specific terms of a therapeutic arrangement may vary from patient to patient, the basic framework provided in Table 51.2 may provide a potential model for nonconventional therapists.

628

INTEGRATIVE GASTROENTEROLOGY

Table 51.2. Practitioner’s Responsibilities • Telling the patient about their background and experience and areas of expertise and qualifications • Explaining what is involved in the therapy (e.g., providing a leaflet) • Explaining what the patient can expect of each session, including any likely physical or emotional after-effects • Agreeing on fees and the position regarding missed appointments • Setting a number of sessions after which the patient’s progress will be reviewed, together with an indication of how long therapy is likely to be needed to bring about a level of improvement • Supplying the patient with a copy of notes or a résumé of treatment given at the end of therapy, so they can use this when pursuing therapies in the future Patients’ Responsibilities • To attend appointments • To be full and frank in notifying practitioners what treatments they are currently using (so as to minimize the risks of treatment and drug interactions) • To provide information honestly and in sufficient detail to allow the practitioner to make a diagnosis and provide the appropriate treatment • To follow reasonable advice given by the practitioner • To display courtesy and respect for the practitioner as an individual • To pay promptly for all sessions (including canceled sessions, subject to agreement) Contracts should set out practitioner and patient responsibilities. Practitioners must actively avoid directly or indirectly harming patients.

Not Harming Patients All ethical theories highlight the centrality of not harming patients. For the purposes of integrative therapy, harm, as described by the U.S. Federation of State Medical Boards (FSMB) has been described as conveying three discrete notions: • Economic harm that results in monetary loss but presents no health hazard; • Indirect harm that results in a delay of appropriate treatment, or in unreasonable expectations that discourage patients and their families from accepting and dealing effectively with their medical conditions; • Direct harm that results in adverse patient outcome. Practitioners have an ethical and legal imperative to refrain from causing harm and, in some jurisdictions, such as the United States, potential liability

Ethical Issues in Integrative Gastroenterology

629

can arise if a practitioner indirectly harms a patient, e.g., by delaying access to more appropriate treatment. While Stone and Matthews (1996) challenge the notion of use of CAM constituting indirect harm per se, all practitioners should ensure that patients are given adequate information to direct them to the most efficacious treatments available (CAM or conventional). This requires knowledge about the benefits and risks of conventional and nonconventional treatments.

What Factors State Boards Will Consider in Determining Appropriateness of Treatment In consideration of these potential harms, the FSMB urges state medical boards to evaluate whether or not a physician is practicing “appropriate medicine” by considering the following practice criteria, namely whether the physician is using a treatment that is: • effective and safe (having adequate scientific evidence of efficacy and/or safety, or greater safety than other established treatment models for the same condition) • effective, but with some real or potential danger (having evidence of efficacy, but also of adverse side effects) • inadequately studied, but safe (having insufficient evidence of clinical efficacy, but reasonable evidence to suggest relative safety) • ineffective and dangerous (proven to be ineffective or unsafe through controlled trials or documented evidence, or as measured by a risk/ benefit assessment) As part of his discussion of the use of CAM in children, Cohen (2005) notes that although the FSMB has clarified that using CAM therapies in itself does not constitute grounds for discipline, those guidelines nonetheless require a strong therapeutic rationale, including that the selected CAM therapies are likely to provide “a favorable risk/benefit ratio compared with other treatments for the same condition,” be “based on a reasonable expectation that it will result in a favorable patient outcome, including preventive practices,” and “be based on the expectation that a greater benefit will be achieved than that which can be expected with no treatment.”

Practitioners must refrain from intentionally causing harm, and should not continue treatment longer than is necessary and in the patient’s interests.

630

INTEGRATIVE GASTROENTEROLOGY

Intentionally Causing Harm The requirement not to cause harm goes beyond recognition of the risks inherent in therapy, and requires practitioners to refrain from intentional actions or behaviors that will cause harm to a patient, since this is anathema to the basis of healing relationships. Most professional codes include rules prohibiting practitioners from exploiting professional relationships for their own benefit. This might include: • prolonging the duration of the professional relationship for the financial benefit of the practitioner, where there is no longer an ongoing therapeutic basis for seeing the patient • allowing the patient to continue attending and paying for therapy because the patient has formed an emotional dependence on the therapist • carrying out untried or untested approaches to satisfy professional curiosity outside the confines of regulated research

Maintaining Appropriate Professional Boundaries Practitioners must maintain appropriate personal and professional boundaries, including emotional, sexual, and financial boundaries. Part of the duty to avoid harming patients requires CAM and conventional practitioners to set and maintain appropriate professional boundaries with patients, and to refrain from acting sexually, or in other ways that blur the distinction between professional and social relationships. Evidence shows that boundary violations occur across all healthcare and social care professions, and there are reported incidences of abuse by doctors as well CAM practitioners (Halter et al. 2007). It is always the professional’s responsibility to set and maintain clear boundaries (CHRE, 2008). The consequences for patients when practitioners breach acceptable boundaries can be very serious, and in the most serious cases, abuse can lead to post-traumatic stress disorder, depression, suicidal tendencies, and emotional distrust, failure to access health services when needed, and use and misuse of prescription and other drugs and alcohol. A proven allegation by a patient of boundary violation can also end a practitioner’s career. Whereas a minority of practitioners deliberately set out to abuse patients, other practitioners may find themselves on the receiving end of a complaint

Ethical Issues in Integrative Gastroenterology

631

because they lack self-awareness of how they are perceived by patients, or because they fail, for example, to act appropriately in the light of a patient’s sexual attraction or dependence. Practitioners need to learn how to differentiate between caring, empathetic relationships, including the appropriate and safe use of touch, and acting in ways that expose themselves and patients to harm. For example, some alternative therapists may be more physically demonstrative than conventional doctors, and may think it is appropriate to hug a patient. Use of touch is highly potent, and may or may not be appropriate and safe according to context. Practitioners should be particularly sensitive to the use of touch in patients who may have a history of being sexually abused, and in patients with mental health problems. (Stone, 2007) Practitioners should be aware of the particular boundary issues working in CAM may pose. In order to minimize risk, practitioners should also be aware of the vulnerabilities of working from their own homes, or treating patients in the patient’s home with no chaperone. They should also recognize some of the early warning signs that might highlight the blurring of boundaries and should, for example, be wary about giving or receiving gifts from patients, accepting or offering social invitations, and disclosing too much information about themselves, in situations where self-disclosure is more for the practitioner’s benefit than the patient’s.

Supervision A practitioner who has concerns about a particular patient should raise these in supervision. Regular supervision helps to ensure that practitioners maintain high standards of ethical practice. Unethical practice is rarely deliberate, and substandard practice is more likely to originate from inadequate training, reinforced by working in isolation from peers over a period of time. Constructive supervision may provide a necessary outlet for therapists in which technical and ethical difficulties can be discussed openly and in a supportive and non-judgmental environment.

Upholding Principles of Justice and Fairness Principles of equality, justice, and fairness should underpin therapists’ dealings with patients. Often these principles may be enshrined in statutes and

632

INTEGRATIVE GASTROENTEROLOGY

professional codes, with laws and regulations ensuring that practitioners treat all patients equally irrespective of gender, disability, sexual orientation, or age (save to the extent that differential treatment is therapeutically indicated). The principle of respect for justice is often taken to include fair distribution of resources. This is ethically problematic in the case of CAM therapy—most of which, in the West, is delivered predominantly in the private sector to relatively affluent clients who can afford to pay for treatments that are not provided as part of state-funded healthcare or reimbursed by third-party payers. While inequitable, this position is unlikely to change until there is a stronger evidence base demonstrating clinical and cost effectiveness of nonconventional techniques. (Ernst et al., 2004)

Practitioners should respond appropriately and not defensively to complaints, and take action on concerns about professional colleagues.

Respect for the principle of justice requires practitioners to anticipate that mistakes do happen (even to the most competent practitioners), and to make adequate provision for this eventuality. Most codes require practitioners to hold adequate indemnity insurance so that they can respond appropriately if complained against. Poor communication is at the heart of most patients’ complaints, and practitioners could minimize many complaints from escalating by responding appropriately to patients’ dissatisfactions. A good therapeutic relationship should allow patients to air concerns while still feeling supported, and practitioners should encourage honest feedback from patients as a means of improving their practice. Rather than feeling defensive, practitioners should regard complaints and adverse events as an opportunity to learn from their own mistakes. Where appropriate, practitioners should apologize when something has gone wrong. This is not the same as admitting liability; rather it is an acknowledgment of the patient’s sense of grievance and a demonstration of empathy and compassion. Justice considerations also require practitioners to speak out if they encounter poor practice on the part of professional colleagues, whether from their own discipline or practicing within a different modality. In this regard, practitioners have an advocacy role and duty to facilitate the appropriate highlighting of poor practice, recognizing that the role of regulation is public protection and that membership of a profession confers individual as well as collective responsibilities. Where necessary, therapists should signpost how, and to whom, patients can complain, and should report poor practice or criminal

Ethical Issues in Integrative Gastroenterology

633

activity, such as suspected child abuse, to the relevant professional body or authorities. Specific ethical issues include failure to diagnose. Issues specific to integrative gastroenterology: As well as the generic ethical issues outlined above, the practice of integrative gastroenterology gives rise to some specific ethical issues, whether treatment is offered by CAM practitioners or conventional physicians trained in CAM modalities.

Failure to Diagnose There is a risk that CAM therapists treating patients with gastroenterological conditions may fail to spot an underlying pathology that requires urgent medical treatment; e.g., failing to diagnose gastric or bowel cancer. This raises the debate around the extent to which CAM practitioners are competent and trained to make a medical diagnosis, and the point at which they should make a referral to a conventional physician. Patients are free to refuse such a referral, but the practitioner’s autonomy means that she or he can equally refuse to treat any patient felt to be in need of urgent medical attention. The issue of diagnosis becomes more vexed when the patient is consulting a therapist whose diagnosis is based on a fundamentally alternative system; e.g., a traditional Chinese medicine practitioner, in that the diagnosis would be in energetic terms and would not correspond to a conventional medical diagnosis. Nonetheless, all CAM practitioners must recognize contraindications to treatment and be aware of their potential liability if they fail to make an appropriate referral in such circumstances. Conventional practitioners should also be aware of their potential liability for malpractice if they make a referral to a CAM practitioner that delays access to treatment, resulting in a patient suffering harm. In order to minimize potential liability, practitioners should record in the notes any recommendation to seek urgent medical care that the patient has chosen to ignore. Practitioners may decide, in such circumstances, that they cannot continue to treat, in which case they should make arrangements to hand over the case appropriately.

Delivering Evidence-Based Treatments As far as possible, therapists should use evidence-based treatments. While the nature of what constitutes good evidence, or good enough evidence, is highly

634

INTEGRATIVE GASTROENTEROLOGY

contested, many therapies do have an emerging evidence base, and practitioners should keep up to date in their field and specialty to be able to treat in accordance with researched treatments. Therapists also have a collective and individual responsibility to audit their own practice and to promote a researchbased culture to the extent that this will benefit current and future patients.

Practitioners should encourage open communication with the primary care physician to ensure patient safety.

Encouraging Patients to Disclose what Treatments they are Receiving Unless patients feel confident to disclose what treatments they are receiving, there is a real risk of them suffering side effects from drug interactions. All practitioners should strive to be nonjudgmental about a patient’s treatment choices, and equip themselves with enough information to know the likely impact of different modalities. For the purposes of effective communication, and also gaining consent, conventional and CAM practitioners need to understand the basics of the different approaches to integrative gastroenterology treatments. Do as I say, not as I do… An interesting ethical question is how far practitioners should act as role models, or motivational lifestyle gurus, particularly in integrative gastroenterology, if the therapist suspects that lifestyle issues may be responsible for some or all of the patient’s symptoms. In making recommendations about lifestyle changes, practitioners must be realistic about how much change is appropriate, realistic, or safe. For example, nutritional therapists should be cautious about “prescribing” dramatic purging or highly restrictive dietary regimes, which may be dangerous for some patients and can be particularly damaging for patients with emotional issues—for example, patients with previous histories of eating disorders.

Practitioners should avoid exerting undue influence or imposing their own views on patients.

Ethical Issues in Integrative Gastroenterology

635

Practitioners should be aware of the potentially disproportionate influence they may be exerting on their patient’s life. In order to promote autonomy, practitioners should work toward fostering patients’ self-reliance and independence, rather than dependence on the practitioner. This includes reviewing how long therapy should continue, and a realistic assessment of when therapy should be terminated.

Ensuring that any Products Recommended or Sold to Patients Are in Their Best Therapeutic Interests Over-the-counter remedies are among the CAM treatments that patients pursue for gastroenterological problems (e.g., peppermint oil for irritable bowel syndrome). Some practitioners have their own range of products and remedies, and may offer these to patients as part of their treatment. Practitioners should never push their own products onto patients to the extent that patients feel compelled to purchase these as a condition of treatment. Not only must any practitioner ensure that their range of products comply with appropriate licensing and regulatory requirements, but practitioners must also ensure that any product that is prescribed is done so on the basis of the practitioner’s assessment of the patient’s interests, and is not motivated by financial reasons.

Promoting patients’ best interests underpins all ethical interventions.

Conclusion All therapeutic relationships give rise to ethical issues, and practitioners must ensure that treatments are underpinned by the patient’s best interests, and backed up by evidence, as much as possible. When a practitioner deviates from accepted professional practice, he or she should be prepared to justify this departure to a licensing board or, potentially, a court of law. While patients have a right to choose and seek out CAM approaches to treatment, professionals have a responsibility to safeguard the welfare and well-being of the patients through the use of safe and efficacious treatments. In integrative gastroenterology, where the cause of the patient’s problems may be hard to ascertain and treat, practitioners should work constructively and collaboratively with colleagues, working toward an improved evidence base in this challenging clinical area.

52 There Is No Alternative to Evidence RONALD L. KORETZ “There cannot be two kinds of medicine—conventional and alternative. There is only medicine that has been adequately tested and medicine that has not, medicine that works and medicine that may or may not work. Once a treatment has been tested rigorously it no longer matters whether it was considered alternative at the outset.” (Angell & Kassirer, 1998)

key concepts ■

■

■

■

■

■

Evidence-based medicine drives our clinical decision making, and should be practiced by all healthcare practitioners. Clinical trials have disparities in methodologies, reporting, and interpretation, which has potential bias. In evaluating the evidence, clinical decision-makers should understand the differences between expert opinion, case series, case-controlled studies, cohort studies, randomized clinical trials and systematic reviews. Lack of blinding, failure to conceal allocation, inadequate randomization scheme, lack of intent to treat analysis, involvement of vested interest (conflict of interest), early stopping, selective outcome reporting, and unequal treatment of control groups are all examples of methods that lead to bias in clinical trials. A Type I error is the term applied to the phenomenon of finding what appears to be a significant difference when one does not truly exist. A Type II error is the failure to see a difference that truly exists. Complementary and alternative medicine is frequently fraught with blinding bias because many studies are subjective and report symptoms as the primary endpoint. ■

636

Introduction

T

he intent of this chapter is to provide a perspective on evidence-based medicine, in particular evidence regarding therapeutic interventions. As is to be appreciated from the quote by Angell and Kassirer, the rules are no different for evidence collected to assess the efficacy of interventions in complementary and alternative medicine than they are for allopathic medicine. The main issue that will be considered is the use of data from the literature to assist the clinician in making therapeutic decisions. That clinician wants to make decisions that will benefit his or her patients. This is the juncture where an understanding of evidence becomes critical. More and more, clinicians are utilizing the paradigm of evidence-based medicine (Evidence-Based Medicine Working Group, 1992), a process that has been defined as “integrating individual clinical expertise with the best available external clinical evidence from systematic research” (Sackett et al., 1996). In this regard, there is a hierarchy of evidence that extends from the least to the most reliable. This hierarchy is based on how much influence bias has had in the gathering and/or interpretation of the data. “Bias” is not a pejorative term, but a statistical concept regarding the extent to which external forces influence observations. Table 52.1 details this hierarchy.

Table 52.1. Hierarchy of Evidence Regarding Interventional Decisions Ranking of Evidence

Source of Evidence1

Experience (lowest level)

Personal Local expert National expert (textbook chapter, narrative review article)

Publication of clinical observations

Uncontrolled experience Nonrandomized controls Randomized controls

Effort to find all data (highest level) 1

Systematic review of randomized trials

Reliability of evidence increases as one moves down the table.

638

INTEGRATIVE GASTROENTEROLOGY

Types of Evidence EXPERT OPINION

From a practical perspective, when one is confronted with a question to which he or she does not know the answer, the easiest path to take is to ask somebody who is believed to be an expert. This can be accomplished through a personal contact, or by seeking the answer in a textbook chapter or narrative review article. However, if the answer is not accompanied by the reason(s) that underlie it, that response becomes simple dogma. Even in our enlightened evidence-based era, dogmatic teaching pervades medicine. Like dogma everywhere else, it may or may not be based on valid information. Consider the story of the young girl who, every Christmas, watched her mother prepare a ham dinner. The mother first cut off about a quarter of the meat, threw it away, and then cooked the remainder. When the girl asked her mother why she did it that way, the mother told her that that was the way her mother did it. The young girl asked her grandmother why, and she received the same answer, namely that it was the way her mother taught her. When the young girl asked her great-grandmother why a quarter of the ham was wasted, the great-grandmother laughed. She said that she had no idea why her daughter or her granddaughter did it, but she did it because her pan was too small to hold the entire ham. Thus, at the time that a new dogmatic principle is introduced, it may be a rational approach. However, with the passage of time and the introduction of new knowledge, it can become outdated. Expert opinion becomes more reliable if the available data still support it. Unfortunately, this is often not the case (Antman et al., 1992).

Uncontrolled Experiences CASE REPORTS/CASE SERIES

In these studies, the investigators provide a description of one (or a few) patients because the case(s) represent unusual or thought-provoking features. This is typically how rare diseases, unusual presentations of more common diseases, and even new therapies first come to light. Ideally, the authors of the

There Is No Alternative to Evidence 639

paper will put their new observation into the perspective of what information is already available. These reports of one or a few patients do not provide any insight into the frequency or overall impact of the observation, because there is no denominator (the total population of patients from which the one[s] in the report arose).

The case report simply memorializes the observation. Occasionally, case reports become historically important, such as the first description of AIDS (Gottlieb et al., 1981). If the observation refers to a treatment, it can become the rationale for a subsequent interventional trial.

COHORT STUDIES (RETROSPECTIVE OR PROSPECTIVE)

These studies usually document the natural history of a particular condition. While such studies can be conducted after the construction of a protocol (patients are followed into the future), they are more often retrospective (all of the events have already happened). Typically, all eligible patients are identified from previous diagnoses and their records are reviewed. Such studies are likely to emanate from medical centers where records of patients are systematically stored. In these cases, an entire (albeit selected) population is defined, so there is a denominator available to make an estimate of the frequency of a particular outcome (e.g., death). Retrospective cohort studies are relatively easy to do; the investigator reviews a number of records. There are potential biases in these reports, including ascertainment (a more vigorous effort to find the disease in centers with interests in it) and referral (a type of selection bias).

An example of potential bias is that individuals with chronic hepatitis C who are being followed in tertiary liver clinics develop decompensated cirrhosis at a rate that is 5 to 10 times higher (Tong et al., 1995) than that observed in entire cohorts of patients who were identified at the time of infection (Seeff et al., 2001). This likely reflects the fact that tertiary centers attract sicker patients. Some investigators have employed this methodology to justify various treatment modalities. In other words, they describe the natural history of patients with a particular disease who are exposed to a particular intervention. However, this does produce a variety of interpretative problems because of the

640 INTEGRATIVE GASTROENTEROLOGY

introduction of several kinds of biases. It is usually unknown why these patients (but not others) received the therapy. Treatment in a center of excellence may not be reproducible elsewhere (“guru bias”). No blinding of therapy occurred, allowing the personal biases of both the patient and the healthcare worker to influence the apparent outcome. Finally, the absence of a control group prevents any comparison to a group who did not receive the therapy. (Reports that include controls will be considered in the next sections).

CASE-CONTROL STUDIES

This methodology was developed by epidemiologists to identify etiologies of disease. Patients with a particular disease are identified and matched to controls who do not have that disease. Exposures that are being hypothesized as being important in the etiology of the disease are then sought in the records of both groups. If the exposure occurs more often in the disease group, it is considered as a potential cause; if it is more common in the controls, it is a potential protector. Case-control studies are retrospective and can only establish associations between the exposure and the disease. Association does not prove causation.

An example of association-causation is: A and B may be associated because A causes B (a true causative association). However, if some other factor (C) causes both A and B, a noncausative association can exist between A and B. For example, malnourished patients have poorer clinical outcomes than do nourished ones (association). However, interventions that improve parameters of malnutrition do not improve clinical outcomes (Koretz, 2005), suggesting that the malnutrition does not cause the poorer outcome. Case-control studies are not well suited to make inferences about the efficacy of therapeutic interventions. Consider the inability of case-control studies to predict therapeutic efficacy with regard to hormone replacement therapy and cardiac disease. While the case-control (and other observational) studies indicated that replacement therapy would be helpful, a large randomized trial found that the treatment actually caused harm (Anderson et al., 2004).

CONTROLLED TRIALS

A controlled trial is the classic methodology to assess the impact of an intervention on a disease state. In such a study, the outcomes in a group of patients

There Is No Alternative to Evidence 641

that received an intervention are compared to the same outcomes in a group that did not receive the intervention. The control group is important because it provides insight into how the intervention altered the natural history of the disease. There are times when the outcome in a particular patient is absolutely predictable and unfavorable. In such cases, if an intervention favorably alters that prediction, efficacy is established. We do not need controlled trials to justify cardiopulmonary resuscitation for cardiac arrest or hemodialysis in end-stage renal disease. However, most clinical conditions are not so predictable. Controls can be identified in several ways. The important distinction is to know whether or not the controls were selected by a process of randomization. Nonrandomized controls can be historical (retrospectively identified from records) or be concurrent patients who, for some reason, were not treated. Since the purpose of the control is to be an individual who differs from the treated patient solely on the basis of not having received the treatment, randomization is paramount. If only the treatment variable were to be changed, any subsequent difference in outcome could be attributed to the intervention (establishing a causative relationship between the intervention and the outcome).

In a randomized trial, a homogeneous group of patients is identified and then, by chance, each one of them is either given or not given the treatment. In a randomized trial, unless the randomization scheme breaks down, only one variable is changed.

Different demographic features (gender, age, etc.) are as likely to be randomized into one arm as into the other. (Typically, reports of these studies contain a table that compares the demographic features of both groups in order to prove that a balanced distribution did occur.) Regardless of how a nonrandomized control patient is selected, such an individual must differ from the treated subject in at least two ways. The first is the non-receipt of the therapy. The second is the reason(s) why the treatment was not provided. Thus, there are now at least two variables that differentiate the two groups, so an observed difference in outcome between the groups cannot simply be ascribed to the treatment. Any such difference can be considered to be one that is associated with the treatment, but a causative relationship cannot be inferred. (The data can be used to create the hypothesis that the treatment may be effective, but a randomized trial is still necessary to prove it.) Baseline differences between the treated and control groups are known as confounders; randomization eliminates this confounding bias. Trials employing

642

INTEGRATIVE GASTROENTEROLOGY

nonrandomized controls usually overestimate the observed efficacy of the intervention (Ioannidis et al., 2001; Sacks et al., 1982).

SYSTEMATIC REVIEWS

Most clinicians are used to reading narrative review articles, ones that arise when editors ask “experts” to write articles that provide the reader with the most current information. Narrative reviews appear to suffer from at least the potential influence of bias (McAlister et al., 1999; Mulrow, 1987). In distinction, systematic reviews of interventions provide a more objective assessment of the available evidence. A systematic review begins with a protocol that defines a strategy to find all of the relevant randomized trials (in order to avoid “cherry-picking” references that happen to agree with a preconceived bias), and a description of the methodology that will be used to formulate the conclusion. The data drive the conclusions. For interventional questions, a well-done systematic review of randomized trials is now considered to be the “gold standard” for establishing efficacy (Cook et al., 1997).

Systematic reviews are often referred to as “meta-analyses,” but the two are not the same. Systematic reviewing is the process of locating and considering all of the available evidence; meta-analysis refers to the process of combining data from different trials. Any meta-analysis should be preceded by a systematic review, but systematic reviews do not necessarily have to combine the data quantitatively.

Data combination, whether by simply adding the numerators and denominators together or by first weighing each study for its statistical reliability and then adding the weighted numbers together (meta-analysis), is done to increase the power of seeing an effect or, if an effect is present, more precisely defining it. The downside of combination is the fact that disparate studies are being combined. Obviously, if the trials are too different (too heterogeneous), it makes little sense to combine them.) The process of systematic reviewing and meta-analysis has been criticized in the past because the result does not always agree with what has been observed in single large randomized trials (LeLorier et al., 1997). At least some of this criticism is more apparent than real; if one looks at the actual data in the paper by LeLorier et al., one can see that the meta-analysis almost always agreed with the outcome from the large trial with regard to the direction of the

There Is No Alternative to Evidence 643

effect; the issue was that one, but not the other, claimed that the difference was statistically significant. “Pre-filtered” collections of references that contain only randomized trials and/or systematic reviews are available. The best known of these are The Cochrane Library, Best Evidence and UpToDate.

BIASES IN RANDOMIZED TRIALS

The purpose of randomization is to eliminate biases introduced by confounding factors. However, other biases, enumerated in Table 52.2, can still occur. These biases are not just intellectual curiosities. If efforts are not taken to eliminate them, a larger treatment effect is usually observed (Kjaergard et al., 2001; Moher et al., 1998; Schulz et al., 1995). This enhanced effect in the less methodologically

Table 52.2. Biases that Arise in Randomized Trials Lack of blinding

The outcome is assessed by individuals who know into which arm the patient was assigned.

Failure to conceal allocation

The investigator (or the patient) is aware of what the arm assignment will be prior to entering the study.

Poor randomization The randomization scheme results in an unbalanced assignment. technique Lack of intent to treat analysis

Patients are lost after the randomization and not accounted for in the analysis.

Subgroup analysis

Only a portion of the total study group is analyzed.

Surrogate outcome

The outcome is a lab test or other measure of physiologic function.

Treatment of controls

The control group receives some intervention that the study group did not receive.

Selective outcome reporting

Not all outcomes that were observed were presented.

Breakdown of randomization

In spite of randomization process, confounding factors are still present.

Early stopping

Study stopped before the original protocol called for completion.

Involvement of vested interests

Individuals or groups with vested interest(s) in the outcome are involved in the conduct of the study.

644 INTEGRATIVE GASTROENTEROLOGY

rigorous trials is attributed to the presence of bias. Thus, randomized trials can be graded by the degree to which the methodology avoided bias; trials that are more rigorously designed and executed are referred to as being of “high quality” or being at “low risk of bias.”

LACK OF BLINDING

This is an easy concept to understand when the outcome is a subjective one (e.g., pain). Of course, even quantitative outcomes (e.g., duration of hospitalization, the presence or absence of infection) can be subjective judgments. While trials of surgical interventions are difficult to blind, dramatic placebo effects have been observed (Cobb et al., 1959; Dimond et al., 1960). In general, non-blinded trials produce larger treatment estimates (Kjaergard et al., 2001).

FAILURE TO CONCEAL ALLOCATION

Neither the investigator nor the patient should know into which arm the patient will be assigned until the patient actually enters the trial. This concealment of allocation is not the same thing as blinding, which refers to being unaware of the treatment during the course of the trial.

If the patient knows what he or she will be receiving, that knowledge can influence his or her decision to participate. If the investigator knows into which arm the patient will be assigned, preferential screening can occur. (For example, a patient who looks particularly sick might have a more intense evaluation looking for the presence of an exclusion criterion if assignment was to be to the treatment arm.) Failure to conceal allocation does result in larger estimates of treatment effect (Kjaergard et al., 2001; Moher et al., 1998; Schulz et al., 1995).

INADEQUATE RANDOMIZATION SCHEME

Even if the investigator does not know the allocation, a poor randomization scheme can cause problems. For example, suppose the randomization is based on the first letter of the last name; any trial in Scotland will have a disproportionate number of patients named MacDonald in one of the arms (and some of the MacDonalds may share genetic similarities).

There Is No Alternative to Evidence 645

Usually, randomization is done using tables of random numbers or computers; even coin flips or card draws are adequate. Quasi-randomization schemes (allocating patients based on a record number or day of the week) are not satisfactory. In such schemes, the investigator and/or the patient will know what treatment will be provided, so concealment of allocation is lost.

LACK OF INTENT-TO-TREAT ANALYSIS

The only time when the randomization is known to be intact is at the beginning of the trial. Thus, all of the randomized patients should be accounted for. If patients drop out of one arm for some systematic reason, the randomization will no longer be intact. Consider a trial that compared two types of enteral nutrition (Bower et al., 1995) and used length of stay in the intensive care unit as the primary outcome. The investigators were not sure how to include data from the patients who died. They did not find a significant difference in the mortality rate between the two arms, so they calculated the durations of stay only for the survivors. However, there were twice as many deaths in one arm as in the other; the “not statistically significant” p value was 0.06. The shorter length of stay in the arm with the higher mortality rate probably reflected the fact that there were a larger number of sicker patients who survived in the other arm.

SUBGROUP ANALYSES

Often investigators will undertake a comparison between only some of the patients in each arm, namely those who share a common factor. Subgroup analyses are only valid if the randomization is still intact within that subgroup. In reality, it is difficult to be sure that this is the case. Subgroup analyses can be used to generate hypotheses, but these analyses cannot prove them.

SURROGATE OUTCOMES

Surrogate (sometimes referred to as intermediate) outcomes are typically lab tests or other measures of function that do not directly reflect clinical symptoms. In order to qualify as a valid surrogate, it must be shown (1) that the

646

INTEGRATIVE GASTROENTEROLOGY

surrogate outcome correlates with the clinical one and (2) that interventions that change the surrogate outcome also change the clinical one in the same direction (Bucher et al., 1999). In most cases, surrogate outcomes do not meet this latter criterion. A classic example of this was a randomized trial of antiarrhythmic therapy for use as prophylaxis after myocardial infarction; while there were fewer arrhythmias (surrogate outcome) in the treated group, that group also had a higher mortality (Cardiac Arrhythmia Suppression Trial [CAST] Investigators, 1989).

TREATMENT OF CONTROL GROUPS

Whenever randomized trials are interpreted as testing the efficacy of a particular intervention, it is easy to assume that the control group was an untreated one. However, often two different treatment regimens are compared. In such instances, any difference in outcome only reflects the relative effect of one treatment over another, and cannot reflect the absolute value of either one. This creates a problem when the absolute effect of either is not known.

SELECTIVE OUTCOME REPORTING

There are examples of reports of trials in which the outcomes that were originally planned to be observed were not reported (Chan et al., 2004). By comparing the original protocols to the final paper, Chan et al. concluded that half of the efficacy and two-thirds of the harm outcomes were incompletely reported.

BREAKDOWN OF RANDOMIZATION

Sometimes, in spite of all good intentions, a randomization breaks down, resulting in confounding factors being introduced. For example, a randomized trial that compared two different types of enteral nutrition formulations in intensive care unit patients was confounded by the fact that significantly more patients in one group received the infusions into the stomach rather than the small intestine (Brown et al., 1994). Gastric, compared to small intestinal, infusions appear to increase the risk of complications (Critical Care Clinical Practice Guidelines Committee, 2009).

There Is No Alternative to Evidence 647

EARLY STOPPING

Randomized trials are often stopped early because of apparent benefits. However, there is concern about such decisions, especially when the original protocol did not specify explicit and rigorous criteria for such early stopping. When this issue was examined in depth (Montori et al., 2005), some typical characteristics of such trials were identified. They were often industry-sponsored drug trials in cardiology, cancer, and AIDS patients. On average, only about 60% to 65% of the intended patient population had been enrolled at the time of stopping. The trial protocol (or methods section of the paper) usually did not contain the appropriate statistical analysis to justify the early cessation.

Involvement of Vested Interest Industry (and probably other vested interests) does exert subtle (and sometimes not so subtle) influence. The problem can arise in the conducting of the trial (Bell et al., 2006; Hill et al., 2008; Miners et al., 2005). More often, the bias appears during the interpretative stage, namely how the data are presented (or “spun”; see Als-Nielsen et al., 2003; Turner et al., 2008; Yank et al., 2007).

STATISTICAL CONSIDERATIONS

Outcome Reporting Statistics Dichotomous outcomes are those that either do, or do not, happen (e.g., the incidence of death or complications). These outcomes are usually reported as absolute risk differences (for beneficial outcomes, absolute risk reductions) or relative risks (again, for beneficial outcomes, relative risk reductions). An absolute risk reduction is the difference in the incidence of the outcome between the treated arm and the control arm. The relative risk reduction is the incidence in the treated arm divided by the incidence in the control arm. While both are reported as percentages, the relative risk is a higher number than the absolute risk reduction (even though the actual effect is the same).

648

INTEGRATIVE GASTROENTEROLOGY

As an example, consider a treatment that reduces a complication rate from 10% to 5%. The absolute risk reduction is 5% (10% – 5%). The relative risk reduction is 50% (5%/10%). The intervention is then marketed with the claim that it reduces the complication rate by 50%; while this is true of the rate, it only reduced the incidence of the complication by 5%. A helpful way to put all of this into perspective is to calculate the “number needed to treat.” This is simply done by dividing 100% by the absolute risk reduction; in the above example, 20 patients would have to be treated to prevent one complication.

P Values The p value represents the probability that an outcome occurred by chance. Traditionally, great credence is given to a probability that is less than 5 out of 100 (“< 0.05”). However, this is an arbitrary distinction. After all, why believe that a p value of 0.049 means that a difference is true, but a value of 0.051 means that there was no difference? It is more appropriate to view the p value as an expression of the probability of something happening by chance rather than as a demonstration of truth.

95% Confidence Interval A trial only produces an estimate of an actual effect, not the precise truth. Thus, if the same experiment is conducted many times, a range of estimates would be obtained. The 95% confidence interval represents the range over which these observations would occur 95% of the time. While this is not the same thing as the probability that an observation was due to chance (the p value), the confidence interval can be used to define a “significant finding.” This is commonly employed in meta-analysis. Dichotomous outcomes in meta-analyses are reported as absolute risk differences, relative risks, or odds ratios (the likelihood of the outcome in the treated arm divided by the likelihood of the outcome in the control arm). If the intervention made no difference, the outcomes would be equivalent. Thus, the point of equivalence for absolute risk differences is 0.00 and that for relative risks or odds ratios is 1.00. Any 95% confidence interval that does not cross the point of equivalence is considered to be significant.

There Is No Alternative to Evidence 649

Type I Error A Type I error is the term applied to the phenomenon of finding what appears to be a significant difference when one does not truly exist. Type I errors can arise when a large number of analyses are done without correcting for the possibility of finding chance differences.

An example of a Type I error is that if 25 comparisons are made between interventions that are not truly different, there is a 62% chance of finding at least one p value of 0.04. The Type I error was even a subject of an article in the Wall Street Journal (Beck, 2009). Type I errors can also result from publication bias (Dickersin et al., 1992; Easterbrook et al., 1991; Shaheen et al., 2000; Simes, 1986). Publication bias is the term that is applied to the phenomenon of preferentially reporting dramatic differences and failing to report outcomes that were less favorable. Such a practice results in chance findings appearing in the medical literature. Furthermore, it is difficult for the reader to protect himself or herself from this problem, as no other published information is available. In general, one should be wary of small trials that demonstrate dramatic differences; if something seems too good to be true, it probably isn’t.

Type II Error A Type II error is the failure to see a difference that truly exists.

Type II errors usually occur because inadequate numbers of patients were included in a trial. It is usually incorrect to label a small trial that failed to show an effect as “negative”; rather, it should be considered to contain inadequate numbers to demonstrate an effect (Freiman et al., 1978; Moher et al., 1994). One way to try to avoid this problem is to perform an a priori sample size calculation to estimate the number of patients that will be needed in order to see a difference of a certain magnitude.

650 INTEGRATIVE GASTROENTEROLOGY

Equivalence/Non-inferiority Most trials are designed to show that an intervention is better than no treatment (superiority trials). At times, a new intervention is compared to a standard treatment that is known to be effective, and the intent is to show that the former is the same (equivalence trial), or at least not worse (non-inferiority trial). Such trials require larger numbers of patients than do superiority trials (Tinmouth et al., 2004). When trials are underpowered to establish equivalence, interpretive problems with Type II errors can arise. For example, early small trials did not find any statistically significant differences when patients with active Crohn’s disease were treated with steroids or with elemental diets, leading to the claim that the two treatments were equivalent. Larger trials and a meta-analysis (Griffiths et al., 1995) showed that steroid therapy was superior.

SPECIFIC COMMENTS ABOUT EVIDENCE IN THE COMPLEMENTARY AND ALTERNATIVE MEDICINE LITERATURE

Up until now, the topic of evidence-based medicine has not been confined to complementary and alternative medicine. However, there are some issues that are specific to this literature.

Complementary and alternative medicine largely deals with the treatment of symptoms, often without any regard to the actual underlying diagnosis. Since the symptoms are usually subjective, blinding becomes particularly important as a component of the methodology.

There are literally thousands of randomized trials in complementary and alternative medicine. The risk of bias of these trials, in spite of the need for blinding, is comparable to the risk of bias in the allopathic literature (Bloom et al., 2000). Unfortunately, the actual risk of bias in both fields is usually high, reflecting a lack of rigorous methodology in clinical science in general. Many of the randomized trials in this field come from Asia, and China in particular. In this regard, two observations should be noted about the Chinese biomedical literature. The first is that positive results appear to be far more common than in the Western world (Vickers et al., 1998). Secondly, two

There Is No Alternative to Evidence 651

investigations into the question about methods used for randomization have concluded that this term is used differently in China than in the Western world (suggesting that allegedly randomized trials are not randomized in the traditional way; see Liu et al., 2002; Taixiang et al., 2008).

Conclusion Since evidence-based medicine is now widely accepted, it behooves all healthcare workers to be familiar with its methodology. Critical reading of the literature is an important skill to develop. One way to become facile with these techniques is to read original research in a different way. Instead of looking first at the Abstract, and perhaps at the Discussion section, one should start with the Introduction in order to gain insight into what the question is. One then goes to the Methods section and decides if the methodology is capable of addressing the question. If the answer to that question is no, there is no point in reading further. If the answer is yes, one should then read the Results section and decide what the answer is. After that, one is free to read the Abstract and Discussion to see if the author agreed. Another technique to employ is to attend regular journal clubs that focus on methodology. In this model, all of the participants read the paper before the meeting and formulate their own thoughts (along the lines discussed in the preceding paragraph). The journal club then allows a collegial interaction and learning. These exercises and activities are going to be cumbersome at first. However, with practice, the process becomes easier. In fact, one can learn to read papers just as quickly this way and, in the process, make the experience much more intellectually engaging.

This page intentionally left blank

INDEX

A AAD. See antibiotic-associated diarrhea ABCB1, 274t abdominal fat deposition, 529 abdominal massage, 191 abdominal pain, 354–76 acupuncture for, 129t, 367–68 biofeedback for, 371 biologically-based therapies, 371–73 CBT for, 370 coordination of care, 373–76 defined, 355 discussion, 362 evidence-guided care, 365–66 family involvement, 362–63 fiber and, 372 guided imagery for, 371 hypnosis for, 370–71 IBS and, 356 impact of, 356 knowledge base, 361–62 NP/CAM use for, 357–59 patient education, 363 patient in, 361 peppermint for, 373, 375t physical therapies for, 368–69

placebo treatment, 374t, 375t predictors, 359–60 probiotics and, 372–73, 374t reassurance for, 370 regulation of treatment, 363–65 TENS for, 369 treatment options, 357 abdominal ultrasound, 581t abdominal wall hernia costs of, 17t prevalence of, 15t abdominal X-ray, 581t, 586t absorption Ayurvedic herbs for, 136 evaluation of, 30–32, 53t malabsorption, 34, 383, 401 physiology of, 207–8 zinc, 507 AB-yogurt, 425–26 acacia, 487 acanthosis nigricans, 107 achalasia, 594t, 597–98 achlorhydria, 56 SIBO and, 85t acid secretion-suppressing drugs, 209–10, 211

653

654 INDEX

acrodermatitis enteropathica, 104 acrokeratosis paraneoplastica. See Bazex’s syndrome ACTH. See adrenocorticotropic hormone acupuncture, 94, 123–30, 158t for abdominal pain, 129t, 367–68 acceptance of, 360t augmentation of immunity theory, 126t circulatory theory, 126t clinical studies, 423–24 complications, 424 contraindications, 130t conventional medical care and, 127 for duodenal motility, 129t for eating disorders, 613–14 electro, 124, 422–24 endorphin theory, 126t function of, 125–26 for gallbladder, 591 for gastric motility, 129t for gastric secretion, 128t, 129t gate control theory, 126t history of, 123, 127–28 for IBD, 128t for IBS, 128t, 129t mechanisms of action, 126t minor adverse events, 126–27 for nausea, 128t, 129t needles in, 124 neurotransmitter theory, 126t for pancreatitis, 584 precautions, 130t risks, 126 safety, 126 serious injury, 127 technique, 128–30 for upper gastrointestinal disorders, 422–24 usefulness of, 124–25 acute febrile neutrophilic dermatosis. See Sweet’s syndrome acute myocardial infarction, 397 acute pancreatitis, 580t adaptive immune system, 36, 37 ADDE. See American Digestive Disease Epidemic

adenovirus, 395 adrenocorticotropic hormone (ACTH), 195 Adriamycin, 323 Advasana, 353 AGA. See American Gastroenterology Association agni, 132, 138 AHA. See autoimmune hemolytic anemia alanine aminotransferase (ALT), 289 alcohol, 488 sensitivity to, 451 alcoholic liver disease, 565–66 alkaline reflux, 405 allergies. See food allergies; hypersensitivity reactions allium vegetables, 318 allocation, 644 aloe, 90, 134, 217, 324 for IBD, 521–22 Alosetron, 468 ALT. See alanine aminotransferase altered barrier function, 33–34 alternating IBS, 481–82 ama, 132, 138 pacifying, 139–40 amalaki, 135, 139 for upper GI disorders, 414 Amanita, 322 Amanita phalloides, 311, 571, 577 America Association of Poison Control Centers, 365t American Cancer Society, 544 American diet, inflammation and, 288–90 American Digestive Disease Epidemic (ADDE), 22 American Gastroenterology Association (AGA), 13, 21, 220, 345 American Psychological Association, 175 American School of Osteopathy, 142 5-aminosalicylic acid, 277t amphetamines, 540 amygdala, 117 anaerobic bacteria, 62 angelica root, 418, 471t, 518 Angostura bitters, 320 animal models, 121

INDEX 655

Anisette, 320 annamaya kosha, 132 anorexia nervosa, 404, 607–8 diagnosis of, 607 ANS. See autonomic nervous system Antabuse, 403 antacids, 378, 388–89 nutrient depletions from, 389 side effects, 388 anthraquinones, 311 antibiotic-associated diarrhea (AAD), probiotics for, 263–64 antibiotics, 31 diarrhea and, 263–64 pro-motility therapy, 89–91 RLS for, 93–94 antibody-dependent cell-mediated cytotoxicity, 453, 459 antiemetics, herbal, 314–15 anti-endomysial antibodies, 441 antigens apical periodontitis from, 397–98 dental biomaterials, 399–400 environmental, 33 from marginal periodontitis, 395–97 antigliadin antibodies, 441 anti-inflammatory diet, 489 anti-inflammatory therapy, 113 herbal, 315–16 antimicrobial agents, 31 herbal, 90, 317–18 antimony, 400 antireticulin, 441 antispasmodics, herbal, 318–19 anxiety, 165 apical periodontitis, 397–98 antigens from, 397–98 infections from, 397–98 treatment of, 398 apoptosis, 497 appendectomy, 498 appetite enhancement, Ayurvedic herbs for, 134 apple, 487 arabinogalactans, 91 arachidonic acid, 289, 510

arginine, 280 aromatherapy, peppermint, 411 Arthus reaction, 454 artichoke, 320, 321, 591t artichoke leaf extract, 417 articulations, visceral manipulation, 253t artificially-sweetened beverages, 486 asafetida, 136 asana, 349, 351 ashwagandha, 316, 416 asparagus, 489 Asparagus racemosus. See shatavari aspartame, 451 aspirin, 311, 412, 548t Crohn’s disease and, 496 asthma, 449, 451 astragalus, 284 ATG16L1, 274t Atractylis gummifera, 576t Atractylodis lanceae rhizoma, 419–20 augmentation of immunity theory, 126t Aurantii nobilis pericarpium, 420 autoimmune disease, 33, 253 gastrointestinal, 597 liver, 594t, 597 Autoimmune Epidemic (Nakazawa), 236 autoimmune hemolytic anemia (AHA), 453 autoimmune pancreatitis, 594t, 599 autonomic nervous system (ANS), 40, 152 chiropractic and, 149–51 in visceral manipulation, 253t autonomy, 626–27 awareness, 132–33 Ayurvedic medicine, 6, 29, 157 for absorption enhancement, 136 for appetite enhancement, 134 for digestion enhancement, 134 for digestive fire quieting, 134–36 for elimination encouragement, 136–37 general principles of, 131–32 herbs in, 133–38, 137t azathioprine, 276t azoreductase, 49 azulenes, 315

656

INDEX

B Bacon, Francis, 189 bacteria anaerobic, 62 enterobacteria, 44 gram-negative, 62, 396 gram-positive facultative, 44 lactic acid, 91 bacterial gastroenteritis, PPIs and, 383–85 bacterial nucleic acids, 46 bacterial overgrowth, 80, 382. See also small intestinal bacterial overgrowth intestinal permeability and, 80 urinary markers of, 63–64 bacterial signal transduction, 47 Bacteroides, 44, 68, 76 Bacteroides thetaiotamicron, 46 baking soda, 405 balsalazide, 514 bamboo shoots, 487 banana powder. See plantains barley, 489, 500t germinated, 516–17 Barrett’s esophagus, 384, 594t, 598–99 barrier function, 32–37 altered, 33–34 basil, 136 BAT. See body awareness therapy bay, 136 Bazex’s syndrome, 106–7 beans, 90, 485, 486, 499, 552 Beauchamp, 151 Beaumont, William, 165 behavior modifications. See also cognitive behavioral therapy for IBS, 480 for long-term results, 490–92 for practitioners, 492 Behçet, Hulusi, 392 Behçet’s disease, 103 soft tissue oral lesions and, 392–93 belladonna, 314 bell peppers, 485 Benson, Herbert, 160 bentiromide, 57

berberine, 31, 317 beryllium, 399 beta-carotene, 495 betaine, 568 Bhagavad Gita, 349 bias, 642 in randomized trials, 643–44 bibhitaki, 136 bicarbonate, 145 bidirectional signaling, 40–41 Bifantis, 489 Bifidobacteria, 68, 74, 91 Bifidobacteria infantis, 263 Bifidobacterium, 263, 297, 299, 513t, 572 Bifidobacterium breve, 265, 472 Bifidobacterium infantis, 265 evidence-based review of, 472 Bifidobacterium lactis, 113 Bifidobacterium longum, 265 bile acids, 49, 54t, 584 evaluation of, 53t biliary dyskinesia, 191, 422 biliary stasis, 585t binge eating, 531, 608 Bing Gan, 573t biofeedback, 329, 340, 344, 428 for abdominal pain, 371 success of, 331–31 biofield, 156 biofilm layer, 32, 35–36 biotin, 49 α-bisabolol, 315 bisacodyl, 390 bismuth subsalicylate, 263 bisphenol-A (BPA), 399 bitter candytuft plant. See clown’s mustard bitter orange peel, 320 black pepper, 134, 138, 304–5 Bland, Jeffrey, 9 Blastocystis hominis, 76 blinding, 644 bloating, 602 BMI. See body mass index body awareness therapy (BAT), 476 Body Intelligence Techniques, 133, 138 body mass index (BMI), 528, 539

INDEX 657

bogbean, 318 bone broths, 301–2 bone disease, 439–40 bone status calcium and, 507 vitamin D and, 506 vitamin K and, 506–7 Boswellia serrata, 281 for IBD, 521 boswellic acids, 315 botanicals. See herbal medicine botulinum injections, 94 bovine colostrum, 517–18 bowel-associated dermatosis arthritis syndrome, 103 bowel bypass syndrome, 103 bowel movements, normative, 29–30 BPA. See bisphenol-A Brahmi, 416 Breaking the Vicious Cycle (Gottschall), 291, 499 breast, 113 breast-feeding, 436, 496 breath hydrogen and methane test, 63 broccoli, 485 Brodmann’s area, 246 broth, 487 bone, 301–2 budesonide, 276t bulimia nervosa, 608 preventative measures, 406–7 Burkitt, Dennis, 299 C cabbage juice, 217, 302–3, 409 cactus, 487 CAD. See coronary artery disease caffeine, 480, 487, 488 sensitivity to, 451 calcitriol, 506 calcium, 279t, 503t, 548t bone status and, 507 colorectal cancer and, 549–51 dental disease and, 401 foods rich in, 483–84 gastric motility and, 483

H2 receptor antagonists and, 387 PPIs and, 385 supplements, 484, 507, 590 Callilepis laureola, 576t caloric deficits, 538 calprotectin, 278, 279 CAM. See complementary and alternative medicine Camellia sinensis, 568 camphor, 576t Campylobacter, 383 cancer. See also colorectal cancer; specific types of digestive system, 15t esophageal, 446 fear of, 328 MBSR and, 198–99 metastatic breast, 245 pancreatic, 18t Candibactin AR, 90 Candibactin BR, 90 Candida albicans, 74 Candida spp., 74 capsaicin, 413, 414 caraway seed oil, 319, 418, 471t science behind, 410–11 CARD15/NOD2, 274t, 280 cardamom, 136, 138 cardiac disease eating disorders and, 609 MBSR and, 201 social support and, 243 cardiovascular events, 381 Carethers, John M., 384 carminatives, 320 Carnegie Foundation, 143n1 Cartesian principle, 7 cascara, 421 cascara sagrada, 324, 576t case-control studies, 640 case reports, 638–39 castor oil, 390 catarrh, 301 catechins, 520 catecholamines, 246 cauliflower, 485

658

INDEX

causative homeopathy, 186 cayenne, 134 CBC. See complete blood count CBT. See cognitive behavioral therapy celecoxib, 548, 548t celery, 487 celiac disease, 81, 213, 433–48, 594t adult-onset, 437 autoimmune diseases associated with, 598t bone disease and, 439–40 clinical manifestations, 436–37 complications, 445–47 dermatologic manifestations of, 437–38 diagnosis, 440–44 disorders associated with, 438t endocrine disorders, 440 environmental factors, 436 epidemiology, 433–34 extraintestinal manifestations of, 437–40 genetic factors, 434 gluten in, 434–35 hematologic manifestations of, 437 hepatic manifestations of, 439 histological assessment, 442–43 IBS and, 436 infertility and, 440 malignancy and, 445–46 mucosal immune responses, 435–36 neurologic manifestations of, 439 osteoporosis in, 445 pathogenesis, 434–36 prevalence of, 15t, 22 refractory, 447 restless leg syndrome and, 94–95 serological testing for, 441–42, 442t as silent epidemic, 20 soft tissue oral lesions and, 394 treatment, 444–45 upper endoscopy, 442–43 Celiac Disease: A Hidden Epidemic (Green), 20 Center for Disease Control and Prevention, 450 Centor, Robert, 9 central iron deficiency, 92

central nervous system (CNS), 38, 81, 253 bidirectional signaling, 40–41 enteric flora and, 39–40 gut changes and, 39–41 mucosal immunity and, 39–40 neuroendocrine immune signaling, 41 parasympathetic tone and, 39 sympathetic nervous system and, 39–40 CF. See cystic fibrosis CFU. See colony-forming units CH-100, 573t chamomile, 134, 136, 315, 318, 320, 418, 471t chaparral leaf, 576t Chapman’s Reflexes, 144 Chavan Prash, 135 chelidonium, 422 Chelidonium majus. See greater celandine chemical compounds, 487–88 chemoprevention, 547, 548t of colorectal cancer, 550t chewing, 491 Cheyney, Garnett, 303 chi, 6 chia seeds, 487 chicory root, 489 chili powder human studies, 414 science behind, 413–14 for upper GI disorders, 413–14 chiropractic, 146–55 ANS and, 149–51 history of, 147–48 integration of, 148 medicine and disease, 151–53 Chiropractic Leadership Alliance, 150 chitin, 541 chitosan, 541 chocolate, 488 cholecystectomy, 585 cholecystokinin, 41, 56 choleretics, herbal, 321 cholestyramine, 277t chromium, 400, 541 IBD for, 508–9 chronic fatigue syndrome, 84 SIBO and, 91–92

INDEX 659

chronic inflammatory periodontal disease (CIPD), 396, 397 chronic liver disease prevalence of, 15t research expenditures, 18t chronic pancreatitis (CP), 213, 581t chronic renal failure, SIBO and, 85t chronic symptoms, 488–90 chyme, 56 chymotrypsin, 57 cimetidine, 386 Cinnamomi cortex, 420 cinnamon, 136, 138 CIPD. See chronic inflammatory periodontal disease ciprofloxacin, 264 circulatory theory, 126t cirrhosis, 59, 572 prevalence of, 15t primary biliary, 595t research expenditures, 18t cisapride, 410, 411, 468 cisplatin, 315, 323 Citrucel, 486 citrus, 488, 502 clinical trials on EFAs, 510–11 licorice, 412–13 pharmaceutical, 344 turmeric, 413 for ulcerative colitis, 510–11 clopidogrel, 381 Clostridia, 76 Clostridium difficile, 48, 50t, 120, 264, 572 PPIs for, 380 prevalence of, 15t clove oil, 576t clown’s mustard, 319, 418, 471t CNS. See central nervous system cobalamin, 402 cobalt, 400 Cochrane Library, 469 coenzyme Q10, 89 coffee, 589 cognitive behavioral therapy (CBT), 200, 329, 330–31

abdominal pain, 370 evidence-based review of, 477 in IBS, 331 limitations, 334–35 Cohn, Erich, 301 cohort studies, 639–40 prospective, 639–40 retrospective, 639–40 Colitis Foundation of America, 242 collagen, 562 collagenous colitis, 594t colon assessment difficulties, 66 conventional assessment of, 66–67 evaluation of, 54t microbe assessment in, 65–67 new technologies for assessment, 67 colonic adenomas, 15t colony-forming units (CFU), 44 colorectal cancer, 20, 23–24 calcium and, 549–51 chemoprevention, 550t curcumin and, 553–54 diet and, 23–24, 555–57 exercise and, 555–57, 558 fiber and, 23–24 folate and, 552 gender-specific, 593–96 glucosinolates and, 554–55 prevalence of, 23–24 prevention of, 547 rates of, 545–46 research expenditures, 18t risk factors, 546, 558 selenium and, 552–53 vitamin D and, 551–52 colorectal health, 544–58 colostrum, 91 bovine, 517–18 commensal flora, 27, 28–29, 37, 258 drug discovery and, 50t, 51t community-acquired pneumonia, PPIs and, 381 community connection, 244 comorbid disorders, 329

660

INDEX

compassion, 10, 351 in doctor-patient relationship, 237–38 competence, 623–24 complementary and alternative medicine (CAM), 4 for abdominal pain, 357–59 clinician concerns in, 468 defined, 468 doctor openness to, 239–40 efficacy, 468 evidence-based review of, 467–78, 625 hepatotoxicity, 575–77 for IBS, 604t–605t patient autonomy and, 626–27 patient-doctor relationship in, 361 placebo effect and, 468 predictors of, 359–60 surveys on, 362 for upper GI disorders, 409–10 complete blood count (CBC), 545t complex homeopathy, 185 complex lesions, 406–7 comprehensive stool analyses (CSA), 463 computed tomography (CT), 581t, 586t confidence intervals, 648 congestive heart failure, 201–2 Congress, 19 constipation causes of, 480 costs of, 17t economic impact of, 21 fiber and, 480 homeopathic remedies for, 186 idiopathic, 86 iron and, 484 magnesium and, 481 medication for, 390–91 prevalence of, 15t constitutional remedies, 184 Consumer Price Index (CPI), 21 contact dermatitis, 399 peppermint and, 412 contraceptives, oral, 498 contracting, 627–28 control groups, 646 controlled trials, 640–41

copper, 402 coriander, 136, 138 corn, 488 coronary artery disease (CAD), 243, 395 coronary atherosclerosis, 397 corticosteroids, 276t, 277t, 455, 465 adverse events, 523 corticotropin-releasing factor (CRF), 40 corticotropin-releasing hormone (CRH), 195, 475 cortisol, 61, 246 corydalis, 315 Cowden syndrome, 108–9 COX-2. See cyclooxygenase 2 CP. See chronic pancreatitis CPI. See Consumer Price Index C-reactive protein, 581t CRF. See corticotropin-releasing factor CRH. See corticotropin-releasing hormone Crohn’s and Colitis Foundation of America, 248 Crohn’s disease, 35, 58–59, 81, 120 aspirin and, 496 exclusion diets and, 501 fish oils and, 511–12 FODMAPS and, 499–501 functional clinical tests, 278–79 immune response in, 494 lymphocytes in, 494 malnutrition in, 279t pharmaceutical management, 276t probiotics for, 266 remission, 500 research expenditures, 18t restless leg syndrome and, 94–95 risk factors, 271–72 soft tissue oral lesions and, 392 Crotalaria, 576t cruciferous vegetables, 554 cryoglobulinemia, 103 mixed, 105 crypt hyperplasia, 443, 445 CSA. See comprehensive stool analyses CT. See computed tomography cucumber, 487

INDEX 661

cultured foods, 298 cumin, 136, 138 Curcuma amada, 413 Curcuma domestica Val, 422 Curcuma longa, 211 curcumin, 281, 315, 316–17, 548t. See also turmeric administration of, 520 colorectal cancer and, 553–54 for IBD, 520–21 cyclooxygenase 2 (COX-2), 372, 510, 547 cyclosporine, 577 cystic fibrosis (CF), 213 cytochrome P450, 553, 577 cytokines, 84 inflammatory, 289 D DA. See d-arabinitol dACC. See dorsal anterior cingulate cortex dairy, 483–84, 488, 499 Dandasana, 352 dandelion, 134 dandelion root, 320, 591t DANS. See descending antinociceptive system d-arabinitol (DA), 65 Davison, Kathryn P., 249 DCs. See dendritic cells deamidation, 435 death rates, 243 de Chauliac, Guy, 189 defense factors, 458–59 deglycyrrhizinated licorice (DGL), 211, 412 dehydration, 485 dehydroepiandrosterone (DHEA), 61, 517 delayed food allergies symptoms, 460 testing, 460–61 delayed hypersensitivity reactions, 455t Demodex folliculorum, 96 demulcent foods, 301, 487 herbal, 321–22 dendritic cells (DCs), 36, 46 dental biomaterials, 399–400 dental disease, 392–407

bulimia nervosa, 404 calcium and, 401 clinical nutritional considerations, 400–401 complex lesions, 406–7 copper and, 402 eating disorders and, 609 folic acid and, 402 GERD and, 405 hard tissue lesions management, 405–7 iron and, 401 magnesium and, 401 malabsorption and, 401 systemic management of immunodysfunction, 394–95 vitamin A and, 402 vitamin B12 and, 402 vitamin C and, 402 vitamin D and, 402 vitamin K and, 402 zinc and, 402 depletions, 391 depression, 200 obesity and, 531 social support and, 243 dermatitis herpetiformis (DH), 104, 437 Descartes, Rene, 7 descending antinociceptive system (DANS), 118 detoxification, 114–15 devil’s claw, 518 DGL. See deglycyrrhizinated licorice DH. See dermatitis herpetiformis dharana, 349 DHEA. See dehydroepiandrosterone Dhunurasana, 351 dhyana, 349 diabetes mellitus, 49, 213, 396, 440 type 1, 29 type 2, 201 diagnostic considerations, 29–30 diaphragm, 351 diarrhea, 464 antibiotic-associated, 263–64 causes of, 481 diet and, 481

662

INDEX

diarrhea, (continued ) homeopathic remedies for, 186 infectious, 16t traveler’s, 263 diet, 270. See also elimination diet American, 288–90 anti-inflammatory, 489 assessment, 535–36 change, 360t colorectal cancer and, 23–24, 555–57 diarrhea and, 481 eucaloric, 538 exclusion, 501–3 gluten-free, 444t, 446t IBD and, 496, 498–503 IBS and, 480 low sulfur, 501 obesity and, 534–36 types of, 538–39 very-low-caloric, 539 Westernization of, 22–23 yeast elimination, 502–3 Dietary Supplement and Non-Prescription Drug Consumer Protection Act, 364 Dietary Supplement Health and Education Act (DSHEA), 364 digestifs, 320 digestion Ayurvedic herbs for, 134 evaluation of, 30–32 Indian spices and, 306t maldigestion, 31–32 mind-body interactions in, 132–33 physiology of, 207 yoga and, 350–51 digestive disease in American households, 19 battle against, 20–22 burden of, 15t–18t costs of, 20–21 epidemic, 5 facts, 13–14 growth of, 19–20 prevalence of, 14–19, 19–20 research expenditures, 18t

silent epidemics, 20 support groups, 248 Western-based, 25 digestive enzymes, 458, 614t eating disorders and, 612–13 digoxin, 49, 311 dill, 136 disease susceptibility, 243 disulfiram, 403 diuretics, 540 diverticular disease costs of, 17t fiber and, 23 prevalence of, 15t, 22–23 diverticulosis, 23 prevalence of, 15t d-lactic acid, 64 DLG5, 274t DNA analysis, 67 doctor-patient relationship, 9–11, 236–40, 327–30 behaviors affecting, 341t of CAM users, 361 establishment of, 340 hope in, 240 knowledge in, 238–39 openness to CAM in, 239–40 product recommendations, 635 professional boundaries, 630–31 treatment disclosure, 634–35 in Western medicine, 9 docusate, 391 don tien, 6 dopamine, 49 dorsal anterior cingulate cortex (dACC), 246 double-blind challenge test, 457 Drossman, Douglas, 338, 343, 346 drug-induced interstitial nephritis, 381 drug-induced nutrient deficiency, 277t drug interactions antacids, 389 H2 receptor antagonists, 387 herbal medicine and, 313 laxatives, 391 drug resistance genes, 74–75

INDEX 663

DSHEA. See Dietary Supplement Health and Education Act Duke, W.W., 449 duloxetine, 118, 122 duodenal motility, 129t duty-based theories, 619–20 dynamic qi gong, 222 dysbiocide, 90 dysbiosis, 62, 77, 92 fermentation, 302 management, 489 probiotics for, 489 dyspepsia functional, 179–81, 208, 464 non-ulcer, 599–600 visceral manipulation for, 255 E E. Coli, 48, 62, 82, 259, 318, 513t EAACI. See European Academy of Allergy and Clinical Immunology earth, 28 East Anglia Multicenter Controlled Trial, 501–2 eating disorders, 606–15. See also specific disorders acupuncture for, 613–14 cardiac complications, 609 digestive enzymes and, 612–13 electrolytes in, 609–10 flax seeds for, 613 incidence of, 607 medical complications, 609–10 melatonin for, 613 metabolic consequences, 609 not otherwise specified, 608 probiotics for, 612 pulmonary complications, 609 skin and teeth in, 609 supplements for, 611 treatment, 611–13 eating mechanics, 491 ECF-A, 453t ecosystem diversity, 77 ECs. See enterochromaffin cells eczema, 451

edge-to-edge attrition, 407 Edison, Thomas, 11 EED. See erythema elevatum diutinum EFA. See essential fatty acids egg allergies, 450, 502 elastase, 32 elderly, pneumonia in, 382 electro-acupuncture, 124 clinical studies, 423–24 complications, 424 for upper GI disorders, 422–24 electrolyte abnormalities, 609–10 electromyography, 150 elimination diet, 90, 462 case studies, 292t–295t implementing, 290–91 research on, 291 yeast, 502–3 ELISA. See enzyme-linked immunoassays EMBASE, 469 Emblica officinalis, 414 emotional factors FMS and, 118 IBS and, 111–12 emotional motor system (EMS), 39, 478 empathy, 9 EMS. See emotional motor system enamel demineralization, 404 Enbrel, 276t endometrium, 113 endomysium, 435 endorphin theory, 126t endoscopic retrograde cholangiopancreatogram (ERCP), 586t endoscopic sampling, 56 endoscopy, upper, 442–43 energy flow. See qi energy manipulation, 474 energy medicine, 156–63 anatomy and, 159–60 definition of, 156–59 evidence for, 161–62 healing and, 159–60 illness development and, 159–60 prevalence of, 156–59

664

INDEX

energy medicine, (continued ) research evidence for, 160–61 side effects, 162–63 systematic reviews of, 161 techniques, 158 Entamoeba histolytica, 317, 318 enteric flora, 39–40 enteric infections costs of, 17t intestinal permeability and, 80 enteric nerve terminals (ENTs), 38 enteric nervous system, 27, 38–39, 253 gut homeostasis and, 38 gut microbiota and, 38–39 enteritis, 17t Enterobacter, 572 enterobacteria, 44 enterochromaffin cells (ECs), 38, 41, 228 Enterococcus, 572 ENTs. See enteric nerve terminals environmental antigens, 33 enzyme immunoassays, 75 enzyme-linked immunoassays (ELISA), 457, 460–61, 464 scientific validity of, 461 ephedra, 540 epigallocatechin, 281, 583–84 epinephrine, intramuscular, 465 Epstein, Ronald, 9 equivalence, 650–51 ERCP. See endoscopic retrograde cholangiopancreatogram erythema elevatum diutinum (EED), 101 erythema nodosum, 103–4 Esomeprazole, 18t esophageal adenocarcinoma, 384 esophageal cancer, 446 esophageal disorders, 426–27 essential fatty acids (EFA), 91. See also omega-3 fatty acids; omega-6 fatty acids clinical trials on, 510–11 enteric-coated, 511 IBD and, 509–12 physiology, 509–10 supplementation, 509–12

ulcerative colitis and, 510–11 essential nutrients, 289 estrogen, 113–14, 548t ethanol consumption, 58 ethics, 616–35 competence and, 623–24 decision making, 619–20 defining, 618–19 duty-based theories, 619–20 frameworks, 623 law v., 618 outcome-based theories, 621–22 principle-based, 622 responsibilities, 617–18 virtue-based, 622–23 eucaloric diet, 538 European Academy of Allergy and Clinical Immunology (EAACI), 461 evidence, 636–51 hierarchy of, 637t in literature, 650–51 types of, 638 vested interest, 647–49 evidence-based review of abdominal pain, 365–66 of BAT, 476 of Bifidobacterium infantis, 472 of CAM, 467–78, 625 of CBT, 477 of energy manipulation, 474 of herbal medicine, 469–71 of hypnosis, 476–77 of meditation, 475 methods, 469 of mind-body interventions, 475–78 of probiotics, 472–74 study selection criteria, 469 of support groups, 477–78 of yoga, 475–76 evidence-based treatments, 633–34 exclusion diets, 501–3 Crohn’s disease and, 501 exercise, 219–20 assessment, 536–37 benefits of, 220, 536 colorectal cancer and, 555–57, 558

INDEX 665

regimen, 536 sessions, 536 exocrine pancreatic insufficiency, 212–14 causes, 213–14 diagnosis, 213 intervention, 214 expert opinion, 638 expressive writing. See self-care journaling extraintestinal disorders, 48–49 F Faecalibacterium prausnitzii, 48 failure to diagnose, 633 fairness, 631–33 familial adenomatous polyposis (FAP), 548t, 553–54 family involvement, 362–63 famotidine, 386 FAP. See familial adenomatous polyposis Fasano, Alessio, 33 fast food, 25, 289–90 IBD and, 496 fasting-induced adipocyte factor (FIAF), 49 fasting plasma amino acids, 53t fat bugs, 76 FC Cidal, 90 FDA. See Food and Drug Administration fecal chymotrypsin, 53t, 57 fecal fats, 57 evaluation of, 53t fecal fibers, 58 fecal pancreatic elastase, 57 fecal pH, 68 fecal sampling, 66 fecal short-chain fatty acids, 69 fecapentaenes, 69–70 Federal State Medical Boards (FSMB), 628 Federal Trade Commission (FTC), 365t fennel, 136, 320 fenugreek, 518 Fermentable Oligo-,Di- and Mono Saccharides and Polyols. See FODMAPS fermentation dysbiosis, 302

fermented foods, 298, 489 soy, 489 FGID. See functional gastrointestinal disorder FIAF. See fasting-induced adipocyte factor fiber, 540–41 abdominal pain and, 372 chart, 300t colorectal cancer and, 23–24 constipation and, 480 dehydration and, 485 diverticular disease and, 23 foods rich in, 486 gallstones and, 587–88 GI function and, 299 increasing, 481 insoluble, 299 intake basics, 485 motility and, 485–86 soluble, 299 supplements, 486 Fiber Choice, 486 fibromyalgia, 84 symptoms, 117 true, 117 fibromyalgia syndrome (FMS), 116–22 diagnosis of, 118 emotional disorders and, 118 IBS and, 119–20 mood disorders and, 118 PTSD and, 120 SIBO and, 120–21 symptoms, 117 fire, 28 FISH. See fluorescence in situ hybridization fish oils, 282, 587 Crohn’s disease and, 511–12 ulcerative colitis and, 511t 5-HT, 314 flagellin, 46 flax seeds, 323, 486, 487, 489, 614t for eating disorders, 613 Flexner Report, 143n1 flora. See commensal flora; enteric flora; gut flora Floradix, 320

666 INDEX

flow cytometry, 45–46 fluorescence in situ hybridization (FISH), 45 FMS. See fibromyalgia syndrome FODMAPS (Fermentable Oligo-,Di- and Mono Saccharides and Polyols), Crohn’s disease and, 499–501 folate, 49, 279t, 503t, 548t colorectal cancer and, 552 deficiency, 566, 567–68 IBD and, 504t folic acid dental disease and, 402 prolonged use of, 524 supplements, 503–4 foods. See also diet; nutrition strategies; specific foods calcium in, 483–84 cultured, 298 demulcent, 301, 321–22, 487 fast, 25, 289–90, 496 fermented, 298, 489 fiber in, 486 magnesium in, 484 medical, 90, 296 migraines and, 452t minerals in, 483–84 portion sizes, 536 prebiotics in, 296–98, 489 preferences, 536 probiotics in, 296–98, 489 water based, 487 food allergies, 216, 290. See also hypersensitivity reactions; specific foods classification of, 452–55 clinical presentation of, 450–51 common, 451t costs of, 450 delayed, 460–61 egg, 450, 502 epidemiology of, 450 gallstones and, 588 GALT in, 459 IgG and, 459–60 interstitial cystitis and, 95

long-term management, 465–66 migraine and, 452t milk, 450 organ systems involved in, 450–51 peanut, 450 short-term management, 465 symptoms, 460 testing, 460–61 Food and Drug Administration (FDA), 312, 365t foodborne illness, 18t food challenge testing, 457–58 food reactions, 449–66 history of, 449–50 Foot-Yangming meridian, 423 formula feeding, IBD and, 496–97 4R GI Restoration Program, 281–82 Four “R” Program, 59t free radical injury, 281 Friedman, Gerald, 296, 489 fructans, 90, 297 fructooligosaccharides, 297, 516, 574 fructose, 90 FSMB. See Federal State Medical Boards FTC. See Federal Trade Commission functional bowel disorders, 595t Functional Brain-Gut Research Group, 346 functional dyspepsia, 208, 464 hypnosis and, 179–81 functional foods, 287–308 functional gastrointestinal disorder (FGID), 20, 338 categories for, 356t management of, 342t functional MRI, 166, 196, 344 G Galen, 449 gallbladder, 579–93 acupuncture for, 591 coffee and, 589 diagnostic evaluation of, 586 evaluation of, 53t, 56–58 flush, 590 herbal medications, 590 homeopathy for, 187

INDEX 667

research expenditures, 18t supplements for, 589–90 ursodeoxycholic acid and, 589 gallstones, 539, 584, 595t costs of, 17t dietary fat and, 587 disease, 596–97 factors in formation of, 585 fiber and, 587–88 food allergies and, 588 lifestyle modification and, 586–87 prevalence of, 15t, 24 GALT. See gut-associated lymphoid tissue gamma-interferon (γ-IFN), 494 Gardner’s syndrome, 107–8 garlic, 318 gas, intestinal, 86–87 gas discharge visualization (GDV), 159 gas production, 50 gastric acid evaluation of, 53t suppression of, 30–31 gastric bypass, 541 gastric emptying, enhancement of, 421t gastric motility. See motility gastric secretion, acupuncture for, 128t, 129t gastrin, 384 gastritis costs of, 17t prevalence of, 15t gastroduodenal disorders, 427 Gastroenterology (magazine), 346, 384 gastroesophageal (GE) junction, 30 gastroesophageal reflux disease (GERD), 13, 29, 359 costs of, 17t dental management, 405 evaluation of, 30–31 hard tissue lesions and, 402–3 PPIs for, 379–86 prevalence of, 15t, 25 structural causes of, 256t visceral manipulation for, 255–56 gastrointestinal malignancy, 17t gastrointestinal motility, SIBO and, 84–85 gastrointestinal tract

diagnostic considerations, 29–30 fiber and, 299 healthy, 270–71 immune system in, 35, 459 laboratory evaluations, 53t restoration program, 281–84 stress and, 195 in TCM, 28–30 gastroparesis, 600 gate control theory, 126t GBF. See germinated barley foodstuff GDH. See gut-directed hypnotherapy GDV. See gas discharge visualization GE junction. See gastroesophageal junction gelatin, 301–2 gender-specific issues, 592–605 colorectal cancer, 593–96 IBS, 600–605 Genesis Today 4 Fiber, 486 gentian, 134, 320, 421 Gentiana lutea. See gentian GERD. See gastroesophageal reflux disease germander, 576t germinated barley foodstuff (GBF), 516–17 Giardia lamblia, 75, 317, 318 ginger, 134, 138, 303–4, 548t peppermint and, 421 science behind, 417 tea, 139 for upper GI disorders, 417 Gingko biloba, 518 Ginseng radix, 420 gliadin, 435, 448 GLP-1. See glucagon-like peptide-1 glucagon-like peptide-1 (GLP-1), 574 glucagonoma syndrome, 104, 106 glucose, 86t glucosinolates, 548t colorectal cancer and, 554–55 β-glucuronidase, 67–68 glucuronidation, 115 glutamine, 90, 217, 280 IBD and, 512 supplementation, 512 glutathione, 217, 399, 508, 567

668 INDEX

gluten celiac disease and, 434–35 intolerance, 290 introduction of, 436 gluten-free diet, 444t poor response to, 446t glycocalyx, 458 glycosides, 68 Glycyrrhizae radix, 420 Glycyrrhiza glabra, 422 glycyrrhizin, 315–16, 571 GnRH. See gonadotropin-releasing hormone goldthread, 317 gonadotropin-releasing hormone (GnRH), 195 Goodheart, George J., 153 Good Medical Practice, 620t Goodpasture’s syndrome, 454 Gordon, James S., 247 Gorei-san, 420 Gottschall, Elaine, 291, 499 gram-negative bacteria, 62, 396 gram-positive facultative bacteria, 44 greater celandine, 319, 418, 471t, 576t, 591t clinical studies, 417 science behind, 416 for upper gastrointestinal disorders, 416 Green, Peter, 20 green bananas, 301 green beans, 485 green tea, liver and, 568–69 guided imagery, 164–73, 332–33 for abdominal pain, 365–66, 371 applications of, 166, 168–69 contraindications to, 172t defining, 166 function of, 167–68 hypnosis v., 167 for IBS, 165 questions, 171t research studies, 166 risks, 171–72 sessions, 169t–171t use of, 169–71 Guillain-Barré syndrome, 82, 237, 240

gut-associated lymphoid tissue (GALT), 37, 216 food allergies and, 459 gut-directed hypnotherapy (GDH), 476 gut flora, 34–35, 216, 494 pathological alterations in, 573 gut-gynecological axis, 114 gut homeostasis, enteric nervous system and, 38 gut immunology, 36–37 gut microbiota, 38 assessment techniques, 72–73 dysbiosis, 77 ecosystem diversity, 77 influence of, on health, 71–78 insulin resistance and, 76–77 obesity and, 76–77 specimen integrity, 73–74 transport issues, 73–74 gynecological health IBS and, 113 nutritional interventions for, 113–14 H H2 receptor antagonists, 378, 386–88, 405 calcium and, 387 drug interactions, 387 iron and, 387 nutrient depletions, 387 side effects, 386 vitamin B12 and, 387 zinc and, 387 Haas, Sydney Valentine, 499 Hahnemann, Samuel, 183 halitosis, 403–4 Helicobacter pylori and, 403 Hange-koboku-to, 420 hard tissue lesions dental systemic management of, 405–7 GERD and, 402–3 haritaki, 136–37, 139 Hashimoto’s thyroiditis, 29 Hawkins, David, 153 HBD-2, 274t HBD-3, 274t HBD-4, 274t

INDEX 669

HCl supplementation, 212 healing touch, 158t, 162 health-related quality of life (HRQOL), 120 Healthy Aging (Weil), 489 heartburn, 31 PPIs for, 379 Heidelberg capsule, 54t test, 55–56 Helicobacter pylori, 44, 106, 210, 304, 317 discovery of, 409 halitosis and, 403 mastic and, 415 peppermint and, 411 prevalence of, 15t rosacea and, 96–97 Heliotropium, 576t HEMA. See hydroxy methylmethacrylate hematocrit, 160 hemoglobin, 160 hemorrhoids costs of, 17t prevalence of, 16t henbane, 314 hepatics, herbal, 322–23 hepatitis A, 16t hepatitis B, 16t hepatitis C, 105, 248, 322, 560 milk thistle for, 560 prevalence of, 16t research expenditures, 18t as silent epidemic, 20 hepatitis D, 16t herbal medicine, 309–25, 570–72. See also specific herbs actions of, 314–24 adverse effects, 313 antiemetic, 314–15 anti-inflammatory, 315–16 antimicrobial, 90, 317–18 antispasmodics, 318–19 in Ayurvedic medicine, 133–38 bitters, 211, 320 choleretics, 321 combinations, 418–22 demulcents, 321–22 digestifs, 320

drug interactions, 313 evidence-based review of, 469–71 for gallbladder, 590 hepatics, 322–23 for IBD, 518 for IBS, 471t introduction to, 309–10 laxatives, 323–24 for obesity, 540–41 for pancreatitis, 583–84 quality of, 312 randomized trials, 470 safety of, 312–13 for upper GI disorders, 410–18 Hering, Constantine, 183 Hering’s Law of Cure, 183 hernia abdominal wall, 15t, 17t hiatal, 31 herpes simplex, 395 Herter, C.A., 301–2 hex, 163 hiatal hernia, 31 HIDA scan, 586t hing, 136 hip fracture, 382–83 hippocampus, 117 Hippocrates, 7, 10–11, 157, 165, 183, 449 histamine, 453t histocompatibility antigen (HLA), 394, 395 HIV, 202 HLA. See histocompatibility antigen HLA-DQ2, 444, 445 HLA-DQ8, 444, 445 Hoelen, 420 homeopathy, 158t, 182–88 acceptance of, 360t causative, 186 clinical studies, 185 complex, 185 for constipation, 186 for diarrhea, 186 for gallbladder disorders, 187 history of, 183 mechanism of action, 184–85 for nausea and vomiting, 187

670

INDEX

homeopathy, (continued ) remedy samples, 186–87 scientific confirmation, 185 for upper GI disorders, 428–29 homocysteine, 566 honey, 304 raw, 489 Hoodia gordonii, 541 hope, 240 hops, 318, 320 hormone replacement therapy (HRT), 498 hormones. See also specific hormones gut and health of, 114 IBS and, 112 host-microbe communication, 47–48 HPA axis. See hypothalamic-pituitaryadrenal axis HRQOL. See health-related quality of life HRT. See hormone replacement therapy Human Genome Project, 269 human lactoferrin (Lf), 60 Humira, 276t hunger, 534 hydrogen, 31 hydrogen-methane breath test, 54t hydroxy methylmethacrylate (HEMA), 399 5-hydroxytryptamine (5-HT), 314 hyperadrenalism, 531 hypercalcemia, 506 hyperhomocysteinemia, 505 hyperparathyroidism, 401 hyperpermeability, 58, 458–59 hypersensitivity reactions, 290. See also food allergies delayed, 455t pharmacologic mediators of, 453t type I, 452 type II, 453 type III, 454 type IV, 454–55 hyperthyroidism, 401 hypertriglyceridemia, 582 hypnosis. See hypnotherapy hypnotherapy, 91, 165, 329, 332–33, 427 abdominal pain, 370–71 acceptance of, 360t

definition of, 175 evidence-based review of, 476–77 follow-ups, 177 fourteen day diary symptom scores, 178t functional dyspnea and, 179–81 guided imagery v., 167 gut-directed, 476 for IBD, 181 for IBS, 176–79 mechanisms of, 175–76 patient response, 177t physiological parameters, 179t randomized controlled trials on, 333 reviews, 178–79 hypoalbuminemia, 83–84 hypochlorhydria, 55–56, 58, 209–12 causes, 209–10 diagnosis, 209 iatrogenic, 30–31 intervention, 210–12 hypothalamic-pituitary-adrenal (HPA) axis, 81, 91, 117, 122 hypothalamus, 117 hypothyroidism, 531 I I3C. See indole-3-carbinol IAT. See Integrative Assessment Technique iatrogenic hypochlorhydria, 30–31 IBD. See inflammatory bowel disease Iberogast, 319 IBS. See irritable bowel syndrome IC. See idiopathic constipation; interstitial cystitis ICAM-1. See intercellular adhesion molecule 1 iceberg lettuce, 487 ICU. See intensive care unit ICV. See ileocecal valve idiopathic constipation (IC), 86 IFFGD. See International Foundation of Functional Gastrointestinal Disorders γ-IFN. See gamma-interferon IgA. See immunoglobulin A IgE. See immunoglobulin E IgG. See immunoglobulin G

INDEX 671

IgM. See immunoglobulin M ileocecal valve (ICV), 192 immune barrier, evaluation of, 54t immune enhancers, 91 immune-inflammatory connection, 272–73 immune system adaptive, 36, 37 in digestive tract, 35, 459 maturation, 51t ImmunoCAP, 457 immunodysfunction, systemic dental management of, 394–95 immunoglobulin A (IgA) deficiency, 441 secretory, test, 61 serologic tests, 441, 442t immunoglobulin E (IgE), 54t, 291 long-term management, 465–66 quantification of, 457 short-term management, 465 testing, 452, 464 immunoglobulin G (IgG), 54t, 91, 291, 400 food allergies and, 459–60 in IBS, 462 protective roles for, 466t testing for, 461–62 immunoglobulin M (IgM), 105, 400 immunology, gut, 36–37 immunosuppressants, 276t inadequate randomization scheme, 644–45 increased intestinal permeability, 80, 214–18 causes, 215 diagnosis, 215 IBD and, 497 Indian spices, 305 digestive stimulation from, 306t indinavir, 577 indole, 63–64 indole-3-carbinol (I3C), 554–55 infections apical periodontitis from, 397–98 enteric, 17t, 80 from marginal periodontitis, 395–97 respiratory, 396 systemic illness and, 81–82

infectious diarrhea, 16t infertility, 440 inflammation, 95–96 American diet and, 288–90 anti-inflammatory diet, 489 anti-inflammatory therapy, 113, 315–16 causes of, 489 in IBD, 495 in IBS, 112–13 intestinal permeability, 80–81 management, 489–90 metastatic, 396 mucosal, 60–61 in premenstrual IBS, 112–13 inflammatory bowel disease (IBD), 29, 48, 214, 261, 493–525 acupuncture for, 128t adverse events, 523 aloe for, 521–22 alternative therapies, 498–509 Boswellia serrata for, 521 bovine colostrum and, 517–18 calcium supplementation, 507 catechins for, 520 chromium supplementation, 508–9 costs of, 17t curcumin for, 520–21 current medical management, 276–77 dietary associations and, 496 ecosystem diversity in, 77 EFAs and, 509–12 fast food and, 496 folate and, 504t folic acid supplements, 503–4 formula feeding and, 496–97 gene variants in, 273–75 glutamine and, 512 herbal medicine for, 518 hypnosis and, 181 inflammation in, 495 intestinal permeability and, 497 iron supplementation, 509 isotretinoin and, 498 Lactobacillus rhamnosus and, 515 magnesium supplementation, 508 malnutrition and, 495, 503t

672

INDEX

inflammatory bowel disease (IBD), (continued ) melatonin and, 518 mind-body medicine for, 522–23 NAG and, 513 nutritional genomics and, 271–72 nutritional influences in, 279–81 pathogenesis, 275 polyphenols for, 519 prebiotics and, 516–17 precursors, 498 prevalence of, 16t, 24 preventive prescription, 524–25 probiotics for, 264–65, 513–16 remission, 523 resveratrol for, 519–19 reversible symptoms, 495 Saccharomyces boulardii and, 515 selenium supplementation, 508 self-management, 522 smoking and, 498 special diets for, 498–503 stress and, 522 supplements, 503–9 susceptibility genes, 274t treatment considerations, 254t visceral manipulation for, 254 vitamin A supplementation, 505 vitamin B6 supplementation, 505 vitamin B12 supplementation, 504 vitamin C supplementation, 505 vitamin D3 and, 497–98 vitamin E supplementation, 505 VSL-3, 514–15 zinc supplementation, 507 inflammatory cytokine pathways, 33, 289 Insight Subluxation Station, 150 insoluble fiber, 299 insulin, 409, 556 resistance, 76–77, 588 Integrative Assessment Technique (IAT), 146, 153–55 integrative gastroenterology, roots of, 5 integrative medicine goals in, 10

principles of, 4–5 Western medicine v., 8t Integrative Medicine, 229 intensive care unit (ICU), 380–81 intentional harm, 630 intent-to-treat analysis, 645 intercellular adhesion molecule 1 (ICAM-1), 372 interkingdom signaling, 40 interleukin-2, 494 interleukin-4, 273 interleukin-6, 246 interleukin-8, 246, 425 interleukin-12, 273 interleukin-13, 181 internal transcribed spacer (ITS) regions, 73 International Foundation of Functional Gastrointestinal Disorders (IFFGD), 13, 14, 21, 345 interstitial cystitis (IC) food allergies and, 95 SIBO and, 95 intestinal gas, 86–87 intestinal hyperpermeability, 58, 458–59 intestinal microbiota, 43–51 absence of, 46 assessment, 65–67 assessment difficulties, 66 conventional assessment of, 66–67 development of, 258–59 as disease contributor, 48 drug discovery and, 50 environmental modifiers, 45 evaluation of, 54 extraintestinal disorders and, 48–49 as health asset, 48 host-microbe communication, 47–48 lifestyle modifiers, 45 metabolic activity of, 49–50 new technologies for assessment, 67 population assessment, 61–62 studying, 45–46 transduction of bacterial signals, 47 intestinal permeability, 33–34, 41 bacterial overgrowth and, 80 decreased, 34

INDEX 673

diagnoses of, 33t enteric infections and, 80 genetics and, 80–81 increased, 80, 214–18, 497 inflammation and, 80–81 intramuscular epinephrine, 465 inulins, 297, 500t iron, 279t, 503t constipation and, 484 deficiency, 92 dental disease and, 401 H2 receptor antagonists and, 387 motility and, 484 supplements, 484, 509 irritable bowel syndrome (IBS), 13, 14, 29, 60 abdominal pain and, 356 acceptable treatments, 360t acupuncture for, 128t, 129t alternating, 481–82 awareness, 491 behavior modifications and, 480 CAM modalities for, 604t–605t CBT in, 331 celiac disease and, 436 chronic symptom management, 488–90 costs of, 17t, 21 definition, 480 diagnosis of, 208 diet and, 480 economic impact of, 368 emotional factors, 111–12 evidence-based review of, 467–78 extracolonic conditions associated with, 603 FMS and, 119–20 gastric motility and, 482–88 gender-specific differences, 600–605 guided imagery for, 165 gynecological manifestations of, 113 herbal medicine for, 471t hormones and, 112 hypnosis and, 176–79 IgG in, 462 inflammation and, 112–13 menstrual exacerbation of, 110–15

nutrition strategies for, 479–92 pathophysiological mechanisms, 343 peppermint for, 470t personalization for, 491 postinfectious, 82t, 262 premenstrual exacerbation of, 110–15 prevalence of, 16t, 24–25 probiotics for, 262–63 research expenditures, 18t Rome III diagnostic criteria for, 468t SIBO and, 86t stress and, 111 Symptom Severity Score, 368 types, 480–81 visceral manipulation for, 254–55 isabgol, 576t isotretinoin, 498 ITS regions. See internal transcribed spacer regions J Janssen Clinical Investigator Awards, 345 Janu Sirsasana, 352 jejunoileal bypass, 541 Jerusalem artichoke, 489 jimson weed, 314 Jin Bu Huan, 576t jiva, 349 JNK. See Jun-N-terminal kinase Johns Hopkins, 10, 338 Joh Rei, 158t Journal of General Internal Medicine, 9 Jun-N-terminal kinase (JNK), 574 justice, 631–33 K kale, 485, 509 Kampo, 157 kapha, 140t, 350 katuka, 322 kava, 576t kefir, 489 kelp, 487 keratinized gingiva, 394 kimchi, 489

674

INDEX

kininogenase, 453t knowledge, 238–39 Konsyl, 486 Koop, C. Everett, 232 Kupffer cells, 573 L LAB. See lactic acid bacteria laboratory evaluation, 53t Lack, Gideon, 451 lactic acid bacteria (LAB), 91 Lactobacillus, 64, 76, 211 trials, 425 Lactobacillus acidophilus, 31, 64, 265 Lactobacillus bulgaricus, 425 Lactobacillus casei, 31, 265 Lactobacillus delbrueckii, 265 Lactobacillus gasseri, 425 Lactobacillus paracasei, 263 Lactobacillus plantarum, 113, 265, 574 Lactobacillus reuteri, 425 Lactobacillus rhamnosus, 425, 472, 612 IBD and, 515 trials, 473t Lactobacillus salivarius, trials, 473t lactose intolerance prevalence of, 16t probiotics for, 260–61 lactulose, 31, 33t, 86t lactulose hydrogen breath testing (LHBT), 120–21 lactulose-mannitol challenge, 53t, 54t, 58–59 lamina propria, 41 l-amino acid decarboxylase, 64 Lansoprazole, 18t law, ethics v., 618 law of totality, 183 laxatives, 323–24, 379, 389–90 drug interactions, 391 nutrient depletions, 391 osmotic, 391 l-dopa, 49 leafy greens, 484, 552 leaky guy, 32 lecithin, 590

lectins, 290 Leishmania donovani, 317 lemon balm, 318, 319, 320, 418, 471t lemon juice, 485 lemon verbena, 136 Leptospermum scoparium, 304 Leptospirosis, 186 leukotriene B4, 453t leukotriene C4, D4, 453t levofloxacin, 263 Lewis, Pearl, 247–48 Lf. See human lactoferrin l-glutamine, 34, 282 LHBT. See lactulose hydrogen breath testing licorice, 135–36, 139, 284, 315, 316, 388, 471t, 518 clinical trials, 412–13 deglycyrrhizinated, 211, 412 for liver disease, 571–72 science behind, 412 for upper GI disorders, 412–13 Lillard, Harvey, 147 limbic structures, 117 Lin, Henry, 261 lipase, 49 evaluation of, 53t lipopolysaccharide (LPS), 46, 372, 396 lipoteichoic, 50t Liu-Jun-Zi-Tang, 419–20 Liv 52, 573t liver, 559–78 alcoholic disease, 565–66 autoimmune disease, 594t, 597 CAM toxicity, 575–77 celiac disease and, 439 chronic disease, 15t, 18t detoxification pathways, 296 disease costs, 17t disease research expenditures, 18t evaluation of, 53t flush, 590 green tea and, 568–69 licorice for, 571–72 magnesium for, 562–63 minerals and vitamins for, 561–66

INDEX 675

nonalcoholic fatty, disease, 16t, 20 prebiotics and, 572–75 probiotics and, 572–75 resveratrol and, 569–70 silymarin for, 570–71 vitamin E for, 563–66 zinc for, 561–62 long pepper, 134, 136, 138 lower esophageal incompetence, 405 low sulfur diet, 501 LPS. See lipopolysaccharide lubricants, motility and, 487 lymphatic system, 145 lymphocytes in Crohn’s disease, 494 in ulcerative colitis, 494 lymphokines, 455 M macronutrient balance, 490–91 magnesium, 323, 495 constipation and, 481 deficiency, 563 dental disease and, 401 food sources of, 484 gastric motility and, 483 for liver, 562–63 PPIs and, 385 supplements, 484, 508, 562–63 magnetic resonance cholangiopancreatography (MRCP), 586t magnetic resonance imaging (MRI), 150 functional, 166, 196, 344 magnetism, 157 Ma Huang, 576t major histocompatibility complex (MHC), 274t malabsorption, 34 dental disease and, 401 PPIs and, 383 malaise, 396 maldigestion, 31–32 malignancy-associated disorders, 106–9 malignant melanoma, 245 malnutrition

in Crohn’s disease, 279t IBD and, 495, 503t MALT. See mucosa-associated lymphoreticular system managed care, 7 mannitol, 33t, 59 MAP. See Mycobacterium avium subspec paratuberculosis marginal periodontitis antigens from, 395–97 infections from, 395–97 margosa oil, 576t Marichyasana, 352 Marjariasana, 351 Marks, Loren, 153 marshmallow, 321 massage, 189–93 abdominal, 191 benefits, 190 contraindications, 193 digestive tract technique, 191–92 effects of, 190 gastric motility and, 191 history, 189–90 thermovibromassage, 191 mastic clinical studies, 415 H. pylori and, 415 science behind, 415 for upper GI disorders, 415 MAT. See methionine adenosyltransferase Mayo Clinic, 223 MBSR. See mindfulness-based stress reduction McDonald’s, 25 mechanical dialogue, 252 Medicaid, 21 medical foods, 90, 296 meditation brain changes in, 196 evidence-based review, 475 mindfulness, 196 relaxation response, 475 Mediterranean diet, 557 MEDLINE, 469 medroxyprogesterone acetate, 548t

676

INDEX

MedScape, 250 MEDwatch, 577 megalovirus, 395 melanoma, 446 melatonin, 614t for eating disorders, 613 IBD and, 518 Mendelian traits, 273 menstrual IBS, 110–15 Mentha piperita L. See peppermint 6-mercaptopurine, 276t mercury, 399 meridian, 159 small intestine, 36 meridians, 6 mesalamine, 18t, 276t, 513t meta-analyses, 642 metabolic syndrome, 48, 556 metal, 28 metastasis, 396–97 metastatic breast cancer, 245 metastatic inflammation, 396 methionine adenosyltransferase (MAT), 566 methionine metabolism, 566–68 methionine synthase (MS), 566 methotrexate, 276t, 318, 509 metoclopramide, 419 metronidazole, 264, 277t MGUS. See monoclonal gammopathy of undetermined significance MHC. See major histocompatibility complex miasmatic remedies, 184 microbial metabolic markers, 67–70 microbiota. See gut microbiota; intestinal microbiota microscopic colitis, 595t migraine, 451 foods linked to, 452t Military Appropriations Act, 143 milk, 409, 449, 502 allergies, 450 skim, 535 milk thistle, 311, 322, 418, 471t, 591t for hepatitis C, 560

milnacipran, 118, 122 mind-body interactions dietary recommendations for, 139t–140t in digestion, 132–33 evidence-based review of, 475–78 prescription for, 138–39 mind-body medicine, 326–36, 337–48 for abdominal pain, 369–71 for IBD, 522–23 limitations, 334–35 practicing, 328 mindfulness-based stress reduction (MBSR), 195–96, 475. See also stress benefits of, 197, 199 cancer and, 198–99 congestive heart failure and, 201–2 healthcare utilization, 202 in healthy adults, 197–98 heart disease and, 201 HIV and, 202 limitations of, 203 pain and, 198 in practice, 196–97 psychiatric conditions and, 199–201 transplant patients and, 201 type 2 diabetes and, 201 mindfulness meditation, 196 mineral deficiencies, 31 mineralocorticoid excess syndromes, 412 mineral oil, 391 minerals. See also specific types clinical studies, 429–30 foods rich in, 483–84 for liver, 561–66 motility and, 482–85 science behind, 429 supplements, 484 for upper GI disorders, 429 mistletoe, 576t mixed cryoglobulinemia, 105 monoclonal gammopathy of undetermined significance (MGUS), 101 monosodium glutamate, 451 Monotoux test, 455 mood disorders, FMS and, 118 morbid obesity, 539

INDEX 677

morphine, 311 motilin, 423 motility acupuncture for, 128t, 129t calcium and, 483 chemical compounds and, 487–88 disruption of, 482 duodenal, 129t fiber and, 485–86 IBS and, 482–88 iron and, 484 lubricants and, 487 magnesium and, 483 massage and, 191 minerals and, 482–85 optimizing, 482–88 potassium and, 484 SIBO and, 84–85 sodium and, 484 vitamin C and, 485 water and, 486–87 mouth guards, 405, 406 MRCP. See magnetic resonance cholangiopancreatography MRI. See magnetic resonance imaging MS. See methionine synthase mucosa-associated lymphoreticular system (MALT), 273, 459 mucosal immunity, 39–40 mucosal inflammation, 60–61 Mullin, Gerard, 247 must, 620, 621 musta, 139 myasthenia gravis, 238 Mycobacterium avium subspec paratuberculosis (MAP), 48 myelodysplastic syndrome, 101–2 myeloma, 101–2 myocardial infarction, 395 acute, 397 N N-acetylglucosamine (NAG), 513 NAFLD. See non-alcoholic fatty liver disease NAG. See N-acetylglucosamine

National Center for Complementary and Alternative Medicine (NCCAM), 157, 160, 357 National Institutes of Digestive Diseases, Diabetes and Kidney Diseases (NIDDK), 14 National Institutes of Health (NIH), 14, 19, 565 National Poison Information Service, 577 natto, 487 naturopathic medicine, 205–18 nausea, 128t, 129t, 187 NCCAM. See National Center for Complementary and Alternative Medicine NCV. See nerve conduction velocity necrotizing enterocolitis, 261 needles, acupuncture, 124 negative nitrogen balance, 279t, 503t Neiguan point, 129 neomycin, 121 nerve conduction velocity (NCV), 150 nerve impingement syndrome, 149 neuroendocrine immune signaling, 41 neuroendocrine system, 117 neurotransmitter theory, 126t neutrophilic dermatoses, 100–103 Newton, Isaac, 7 nickel, 399, 400 nicotine, 487 NIDDK. See National Institutes of Digestive Diseases, Diabetes and Kidney Diseases NIH. See National Institutes of Health 95 confidence interval, 648 niyama, 349 nizatidine, 386 non-alcoholic fatty liver disease (NAFLD) prevalence of, 16t as silent epidemic, 20 non-alcoholic steatohepatitis, 29, 215, 560, 563, 564–65 non-Hodgkin’s lymphoma, 446 non-inferiority, 650–51

678

INDEX

nonsteroidal anti-inflammatory drugs (NSAIDs), 58, 215, 271, 548t colorectal cancer and, 547–49 non-ulcer dyspepsia, 599–600 nonverbal behaviors, 341t Novartis Pharmaceuticals Corporation, 21 NSAIDs. See nonsteroidal antiinflammatory drugs nuclear factor κB, 47, 517 nutmeg, 136, 139 nutraceuticals, 296 nutrient depletions, 389 nutrient supply, 490 nutritional genomics, 9, 268–86 functional clinical tests, 278–79 inflammatory bowel disease and, 271–72 management, 277 nutrition strategies. See also diet; foods chronic symptoms, 488–90 for gynecological health, 114–15 for IBS, 479–92 motility, 482–88 in pancreatitis, 582 O oats, 489 oat bran, 486, 487, 500t obesity, 48, 526–43 behavioral assessment, 532–35 behavioral factors, 533–34 depression and, 531 dietary assessment, 535–36 dietary modification for, 534 drugs for, 540–41 epidemic of, 527 exercise assessment, 536–37 genetic factors, 529 gut microbiota and, 76–77 health risks of, 528 herbal medications for, 540–41 integrative assessment, 531–32 laboratory examination, 532 medical assessment, 530–32 morbid, 539 mortality and, 527 physical examination, 532

sarcopenic, 528 surgery for, 540–41 treatment for, 529–30 treatment maintenance, 542 treatment success, 543 obstetric complications, 396 okra, 487 olive oil, 487, 557 omega-3 fatty acids, 217, 496, 587 omega-6 fatty acids, 509 Omeprazole, 18t, 384 Omnivore’s Dilemma (Pollan), 288 Ondansetron, 315 onions, 489 online support groups, 249–50 opioid pathway, 423 opportunistic overgrowth, 62 oral contraceptives, 498 oral desensitization, 466 oral signs, 401–2 oral tolerance, 27, 36 mechanics of, 458 orange, 485 orange peel, 134 oregano, 136 Oregon grape root, 317, 591t orlistat, 540 Ornish program, 245 orthobiosis, 62 Osler, William, 10–11 osmotic laxatives, 391 osteopathic medicine, 141–45 application of, 144–45 history of, 142–43 introduction to, 142–44 osteoporosis, 506 in celiac, 445 outcome-based theories, 621–22 outcome reporting statistics, 647–48 over-the-counter remedies, 377–91 oxalate, 49 oxidative stress, 495 P PABA index, 53t Padhastasana, 351

INDEX 679

Paeonia, 576t pain. See also abdominal pain MBSR for, 198 pelvic, 95–96 palladium, 399 Palmer, B.J., 147–48 Palmer, D.D., 147 palmoplantar keratoderma, 107 PAM. See pathogen-associated molecular patterns pancreas, 579–93 evaluation of, 53t, 56–58, 581t pancreatic cancer, 18t pancreatic insufficiency, 31–32 pancreatic panniculitis, 104–5 pancreatitis, 58–59 acupuncture for, 584 acute, 580t autoimmune, 594t, 599 chronic, 213, 581t herbal medicine for, 583–84 nutrition in, 582 prevalence of, 16t probiotics for, 583 supplements for, 583 Pantoprazole, 18t papillomatosis, 109 Paracelsus, 183 parasitology, 75–76 parasympathetic tone, 39 Pare, Ambroise, 189 Parkinson’s syndrome, 92 parsley, 485 Paschimottanasana, 351, 352 Pasteur, Louis, 151, 318 pathogen-associated molecular patterns (PAM), 37 patient. See also doctor-patient relationship in abdominal pain, 361 autonomy, 626–27 education, 363 harm, 628–30 hypnotherapy, 177t in self-care journaling, 230t transplant, 201

pattern-recognition receptors (PRR), 27, 36–37 Pauling, Linus, 9, 269 Pawanmuktasana, 351 PCR. See polymerase chain reaction peanut allergies, 450 pectin, 409 Peginterferon alfa-2a, 18t pelvic floor dyssynergia (PFD), 331, 371 pelvic pain, 95–96 PEMF. See pulsed electromagnetic field pemphigus, 453 pennyroyal oil, 576t peppermint, 136, 305, 319, 418, 471t for abdominal pain, 373, 375t aromatherapy, 411 clinical data on, 411–12 contact dermatitis and, 412 ginger and, 421 for IBS, 470t science behind, 410–11 trials, 411 for upper GI disorders, 410–11 pepsin, 53t Pepticare, 422 peptic ulcer disease, 409 costs of, 17t prevalence of, 16t research expenditures, 18t peptidoglycans, 46 peripheral edema, 83–84 peristalsis, 44 peroxisome proliferator-activated receptor-γ (PPAR-γ), 47 personalization, 491 PET. See positron emission tomography Peumus boldus, 421 Peutz-Jeghers syndrome, 108 Peyer’s patches, 33, 37 PFD. See pelvic floor dyssynergia PG. See pyoderma gangrenosum pH, fecal, 68 pharbitis seed, 315 pharmaceutical trials, 344 phase I detoxification, 114–15 phase II detoxification, 114–15

680

INDEX

phenolic flavonoids, 451 phenylalanine, 451 philosophy, Western, 7 phosphatidylcholine, 590 p-hydroxyphenylacetic aciduria, 64 physical abuse, 329 physical barrier, 54t physical therapy, 368–69 physiological systems approach, 207–8 function restoration, 208–9 pineapple, 485 Pinelliae tuber, 420 pioglitazone, 565 piperine, 304 Piper longum, 422 pitta, 139t, 350 pituitary extract, 409 placebo response, 9–10, 161 in abdominal pain, 374t, 375t CAM and, 468 plantago ovata seed, 500t plantains, 301 clinical studies, 415 science behind, 415 for upper GI disorders, 415 plasma fatty acids, 53t PMN-e. See polymorphonuclear neutrophil-elastase PMS. See premenstrual syndrome pneumonia community-acquired, 381 in elderly, 382 polarity therapy, 158t Pollan, Michael, 288 polymerase chain reaction (PCR), 45, 73, 121 advantages of, 78t polymorphonuclear neutrophil-elastase (PMN-e), 60 polyphenols, 299–301, 568–70, 583–84 IBD and, 519 Polyporus, 420 polysaccharides, 302 portion sizes, 536 positron emission tomography (PET), 176, 344

post-traumatic stress disorder (PTSD), 229 FMS and, 120 potassium, 279t, 503t motility and, 484 potatoes, 289, 499 pouchitis, 264 Power Vs. Force (Hawkins), 153 PPAR-γ. See peroxisome proliferatoractivated receptor-γ PPIs. See proton-pump inhibitors pranayama, 349, 351 pratyahara, 349 prebiotics characteristics of, 297 definition of, 259, 516–17 food sources, 296–98, 489 IBD and, 516–17 liver and, 572–75 in ulcerative colitis, 500t prednisolone, 502 prednisone, 276t preeclampsia, 563 prematurity, 498 premenstrual IBS, 110–15 emotional factors, 111–12 hormones and, 112 inflammation and, 112–13 premenstrual syndrome (PMS), 111 pressures, 253t Prevotella, 76 Prilosec, 379 primary biliary cirrhosis, 595t principle-based ethics, 622 ProAdjuster, 150 probiotics, 34, 257–67, 614t. See also specific probiotics abdominal pain and, 372–73, 374t clinical applications of, 260 clinical studies, 425 for Crohn’s disease, 266 definition of, 259 drug discovery and, 50t, 51t for dysbiosis, 489 for eating disorders, 612 evidence-based review of, 472–74 food sources, 296–98, 489

INDEX 681

for IBD, 264–65, 513–16 for IBS, 262–63 immunoregulatory roles of, 514 for lactose intolerance, 260–61 liver and, 572–75 mechanism of action, 259–60 for necrotizing enterocolitis, 261 for pancreatitis, 583 randomized trials on, 473t regimen construction, 472 safety of, 266 science behind, 424–25 SIBO and, 89–90 strains, 472 for ulcerative colitis, 265 upper gastrointestinal disorders for, 424–26 product recommendations, 635 professional boundaries, 630–31 promotility antibiotic therapy, 89–91 Propionibacterium freudenreichii, 472 trials, 473t Pro Solutions, 150 prospective cohort studies, 639–40 prostaglandins D2, 453t protease, 53t protease inhibitors, 301 protein-calorie malnutrition, 395 proton-pump inhibitors (PPIs), 209–10, 378, 405 calcium deficiency and, 385 cardiovascular events and, 381 Clostridium difficile, 380 community-acquired pneumonia and, 381 complications of, 380–85 for frequent heartburn, 379–80 for GERD, 379–86 hip fracture and, 382–83 magnesium deficiency and, 385 malabsorption and, 383 nutrient depletion and, 385–86 side effects, 380 protozoa, 72 proximal colon cancer, 595t PRR. See pattern-recognition receptors

psychiatric conditions, MBSR for, 199–201 psychological treatments, 340 rationale behind, 426 for upper GI disorders, 426–28 psyllium, 136, 486 PTSD. See post-traumatic stress disorder pulsed electromagnetic field (PEMF), 159 p values, 648 pyoderma gangrenosum (PG), 101–2 pyostomatitis vegetans, 392 pyrexia, 396 Q qi, 124 qi gong, 158t, 221–22 dynamic, 222 QOL. See quality of life quality of life (QOL), 464, 467 quercetin, 217, 281, 553–54 quinine, 311 quorum-sensing, 36, 40–41 R Rabeprazole, 18t radioallergosorbent test (RAST), 452, 457 Raji cell test, 454 Rakel, David, 229 randomized trials, 640 biases in, 643–44 breakdown of, 646 controlled, 640–41 of herbal therapy, 470 on hypnosis, 333 Lactobacillus, 425 Lactobacillus rhamnosus, 473t Lactobacillus salivarius, 473t peppermint, 411 on probiotics, 473t Propionibacterium freudenreichii, 473t Shermanii, 473t TCM, 470 Ranitidine, 18t, 386, 416 RAST. See radioallergosorbent test raw honey, 489 Raynaud’s arthralgia, 401 rDNA. See ribosomal DNA

682

INDEX

reassurance, 370 reductionism, 7–8 reflexology, 474 refractory celiac disease, 447 regulatory T cells, 36 reiki, 158t, 160, 162, 225–26 benefits of, 225 history of, 226 relaxation, 165 for esophageal disorders, 426–27 stress and, 475 training, 168, 333–34 relaxation response meditation (RRM), 475 Remicade, 276t reproducibility, 461 respiratory infections, 396 restless leg syndrome (RLS) alternative therapies for, 94 antibiotics, 93–94 celiac and, 94–95 Crohn’s disease and, 94–95 medical therapy for, 93t secondary, 92–93 SIBO, 92 resveratrol, 281, 315, 583–84 for IBD, 519–19 liver and, 569–70 retrospective cohort studies, 639–40 rhabdomyolysis, 385 Rhamnus purshiana. See cascara Rheum. See rhubarb rheumatoid arthritis, 202 SIBO and, 85t rhinitis, 451 rhubarb, 421 ribavirin, 18t, 565 riboflavin, 296 ribosomal DNA (rDNA), 67 rice bran, 486 rifaximin, 121, 263 for SIBO, 87–89 studies, 88t right upper quadrant ultrasound, 586t RLS. See restless leg syndrome Rome Foundation Research Committee, 345

Rome II criteria, 291 Rome III criteria, 468t root canal, 397–98 rosacea, 96 H. pylori and, 96–97 SIBO and, 97 RRM. See relaxation response meditation S Saccharomyces boulardii, 91, 259, 265, 266, 513t IBD and, 515 Saccharomyces cerevisiae, 502 S-adenosylhomocysteine (SAH), 566 S-adenosyl methionine (SAMe), 357, 566, 567 SAH. See S-adenosylhomocysteine Salmonella, 82 Salmonella, 318, 383 Samadhi, 349 SAMe. See S-adenosyl methionine Samhita, Sushruta, 5, 6, 7 Sandler, Robert S., 13 sarcopenic obesity, 528 sassafras, 576t saturated fat, 23–24 sauerkraut, 489 Savasana, 352 saw palmetto, 576t SCFAs. See short-chain fatty acids Schilling test, 53t Schweitzer, Albert, 318 scleroderma, SIBO and, 85t scopolamine, 314 secondary restless leg syndrome, 92–93 secretin, 56 selective outcome reporting, 646 selenium, 495, 548t colorectal cancer and, 552–53 supplementation, 508 selenoproteins, 552 self-care journaling, 227–31 clinical practice, 229 medical literature on, 228–29 patient handout, 230t self-help groups, 249

INDEX 683

Senecio longilobus, 576t senna, 324, 390 serotonin, 41, 122 serotonin and norepinephrine reuptake inhibitors (SNRIs), 118 sesame oil, 487 sesame seeds, 485 sexual abuse, 329 Shandong Provincial Hospital, 464 Shanka bhasma, 422 Shashankasana, 351 shatavari, 134–35, 139 for upper GI disorders, 416 Shenxiahewining, 420 Shermanii, 472 trials, 473t Shigella, 82 shogaols, 315 short-chain fatty acids (SCFAs), 258 fecal, 69 should, 620, 621 Shou-wu-pian, 576t SIBO. See small intestinal bacterial overgrowth Sigma Instruments, 150 silent epidemics, 20 silibinin, 322 silymarin, 315, 323 for liver disease, 570–71 safety of, 571 simple sugars, 588 Singh, Gurkirpal, 21 single nucleotide polymorphisms, 269, 270 skepticism, 361 skim milk, 535 skin, 99–109 in eating disorders, 609 prick testing, 456–57 SLC22A4, 274t, 275 SLE. See systemic lupus erythematosus sleep apnea, 539 slippery elm, 321, 518 small bowel adenocarcinoma, 446 small bowel aspirate, 121 small intestinal bacterial overgrowth (SIBO), 31, 83–84, 261

achlorhydria, 85t animal models, 121 chronic fatigue syndrome and, 91–92 chronic renal failure and, 85t common causes, 85t gastrointestinal motility and, 84–85 IBS and, 86t interstitial cystitis and, 95 intestinal gas and, 86–87 lesser known causes, 85t probiotics and, 89–90 protection against, 83 restless leg syndrome and, 92–93 rheumatoid arthritis and, 85t rifaximin for, 87–89 rosacea and, 97 scleroderma and, 85t systemic consequences of, 91–95 therapy, 87 small intestine evaluation, 53t, 58–60 small intestine meridian, 36 small ribosomal subunit RNA, 45 SmartPill GI Monitoring System, 56 smoking, 480, 527 IBD and, 498 perinatal exposure to, 498 Sneddon-Wilkinson syndrome, 102 SNMC. See Stronger Neo-Minophagen C SNRIs. See serotonin and norepinephrine reuptake inhibitors SNS. See sympathetic nervous system social isolation, 241 sodium, motility and, 484 sodium nitrate, 451 soft palate, 394 soft tissue oral lesions Behçet’s disease and, 392–93 celiac disease and, 394 Crohn’s disease and, 392 diseases producing, 392 soluble fiber, 299 somatostatin, 41 sound therapy, 158t sourdough, 298 soy, fermented, 489 Specific Carbohydrate Diet, 291, 498–99

684

INDEX

specimen integrity, 73–74 specimen transport, 73–74 spinal manipulative therapy, 152 spirituality, 232–35 care, 233–35 importance of, 234 SQUID. See superconducting quantum interference devices St. John’s wort, 577 Staphylococcus aureus, 74 statistics, 647–49 outcome reporting, 647–48 type I error, 649 type II error, 649–50 steatorrhea, 57 Still, Andrew Taylor, 142 stomach, 53t, 55 stool assessment difficulties, 66 comprehensive analyses, 463 conventional assessment of, 66–67 fecal pH, 68 fecapentaenes in, 69–70 β-glucuronidase in, 67–68 microbe assessment in, 65–67 microbial metabolic markers, 67–70 new technologies for assessment, 67 short-chain fatty acids in, 69 wetting agents, 391 strawberries, 485 Streptococcus thermophilus, 263, 265 Streptomyces, 259 stress. See also mindfulness-based stress reduction definition of, 194–95 GI disease and, 195 IBD and, 522 IBS and, 111 oxidative, 495 post-traumatic, 120, 229 reduction, 168, 194–204, 219–20 relaxation and, 475 Stronger Neo-Minophagen C (SNMC), 572 STW 5, 471t clinical studies of, 419 science behind, 418

tolerability of, 419 for upper GI disorders, 418–19 subcutaneous immunotherapy, 465 subgroup analyses, 645 subtle body, 156 sucrose, 499 sugar, 488 sulfasalazine, 49, 277, 277t sulforaphane, 548t, 554–55 sulfur, 501 sulindac, 548t sunshine, 548t, 551 superconducting quantum interference devices (SQUID), 159 superior mesenteric artery syndrome, 610 Supersize Me (film), 289 supervision, 631 supplements calcium, 484, 590 for eating disorders, 611 EFA, 509–12 fiber, 486 folic acid, 503–4 for gallbladder, 589–90 glutamine, 512 HCl, 212 iron, 484, 509 lecithin, 590 magnesium, 484, 508, 562–63 minerals, 484 for pancreatitis, 583 phosphatidylcholine, 590 selenium, 508 vitamin A, 505 vitamin B6, 505 vitamin B12, 504 vitamin C, 505, 589–90 vitamin D3, 506 vitamin E, 505, 563–66, 590 vitamin K, 506–7 zinc, 507, 561–62 support groups, 241–50 benefits of, 244 cardiac disease and, 243 community connection, 244 death rates and, 243

INDEX 685

depression and, 243 digestive disease, 248 disease susceptibility and, 243 evidence-based review of, 477–78 online, 249–50 surrogate outcomes, 645–46 Surya Nadi, 351 susceptibility genes, 274t Sweet’s syndrome, 102–3 sympathetic chain, 144t sympathetic nervous system (SNS), 39–40 Symphytum officinale, 576t symptom monitoring control, 477–78 synbiotics, 573 definition of, 259 systematic reviews, 642–43 systemic illness, infections triggering, 81–82 systemic lupus erythematosus (SLE), 454 systemic signs, 79–98 T Tack, Jan, 384 Tai Chi, 158t components of, 221–24 form, 223 health improvement from, 223 tangweikang, 418 Taylor, Charles, 189 Taylor, George, 189 T-cell lymphoma, 447 TCM. See traditional Chinese medicine T effector responses, 37 Tegaserod, 18t, 468 TENS. See transcutaneous electrical nerve stimulation terminalia, 417–18 Terminalia arjuna, 417–18 Terminalia chebula, 417–18, 422 TGF-β1. See transforming growth factor β1 thalassemia, 307 T-helper 1, 424 atypical type, 494 proinflammatory activity, 272–73 T-helper 2, 424 anti-inflammatory activity, 272–73

atypical type, 494 therapeutic touch, 158t, 160 thermovibromassage, 191 thrombocytopenia, 386 thyme, 136 thyroid disease, 440 Hashimoto’s thyroiditis, 29 hyperthyroidism, 401 hypothyroidism, 531 thyroid-stimulating hormone (TSH), 532 tienchi ginseng, 284 titanium, 399 TJ-8, 576t TJ-9, 573t, 576t TJ-108, 573t TNF-α. See tumor necrosis factor alpha α-tocopherol, 505 toll-like receptors, 27, 37, 46, 274t tomatoes, 487, 502 toothbrush, 404 traditional Chinese medicine (TCM), 6–7, 28, 123–24, 157. See also herbal medicine gastrointestinal tract in, 28–30 gut immunology in, 36–37 trials, 470 transcription factor, 47 transcutaneous electrical nerve stimulation (TENS), 369 transforming growth factor β1 (TGF-β1), 564 transglutaminase (TTG), 435 transitional gut, 62–63 transplantation, 201 traveler’s diarrhea, 263 trials. See clinical trials; randomized trials Trichomonas vaginalis, 317 triggers, 488 Trikonasana, 351 triphala, 136, 324 tryptase, 453t tryptophan, 63 TSH. See thyroid-stimulating hormone TTG. See transglutaminase tumor necrosis factor alpha (TNF-α), 84, 96, 246, 372, 399, 494, 502, 567 turkey rhubarb, 324

686 INDEX

turmeric, 305–6, 315, 316, 422, 591t. See also curcumin clinical trials, 413 effects of, 306 science behind, 413 for upper GI disorders, 413 type 2 diabetes, MBSR for, 201 tyramine, 64, 290 sensitivity to, 451 tyrosine, 64 U UC. See ulcerative colitis ulcerative colitis (UC), 35, 60, 494 clinical trials, 510–11 EFAs and, 510–11 fish oils and, 511t low sulfur diet, 501 lymphocytes in, 494 prebiotics in, 500t probiotics for, 265 remission, 500 research expenditures, 18t risk factors, 271–72 ulcerative proctitis, 500 ultrasound abdominal, 581t right upper quadrant, 586t umeboshi plums, 307 UNC Center for Functional GI and Motility Disorders, 337–38 academic training, 346–47 clinical program, 340–41 international activities, 346 mentored learning, 347 public education, 346–47, 347 research infrastructure, 345–46 research program, 343–44 research team, 344–45 structure of, 339 training seminars, 347 uncontrolled experiences, 638–39 unidirectional signaling, 39 Unity, 349 upper endoscopy, 442–43

upper gastrointestinal disorders, 408–31. See also specific disorders acupuncture for, 422–24 amalaki for, 414 artichoke leaf extract, 417 ashwagandha for, 416 Brahmi for, 416 CAM for, 409–10 electro-acupuncture for, 422–24 ginger for, 417 Gorei-san for, 420 greater celandine for, 416 Hange-koboku-to for, 420 herbal combinations for, 418–22 herbal medicine, 410–18 historical perspective, 409 homeopathy for, 428–29 licorice for, 412–13 Liu-Jun-Zi-Tang for, 419–20 mastic, 415 minerals for, 429–30 peppermint for, 410–11 plantains for, 415 preventative strategies, 430–31 probiotics for, 424–26 psychological therapies, 426–28 shatavari for, 416 Shenxiahewining for, 420 STW 5 for, 418–19 tangweikang, 418 turmeric for, 413 vitamin C for, 430 vitamin E for, 430 zinc and, 429 urinary d-lactate, 64 urinary indican, 63–64 urinary markers, 63–64 of bacterial overgrowth, 63–64 of yeast overgrowth, 65 urinary metabolic markers, 54t urinary phenolic compounds, 64 ursodeoxycholic acid, 548t, 585 gallbladder and, 589 Ushtrasana, 351 usnic acid, 576t Usui, Mikao, 226

INDEX 687

V Vajrasana, 351 valerian, 318–19, 576t varicella zoster virus, 395 vascular disease, 401 vata, 139t, 350 verbal behaviors, 341t Vermont, 143 very-low-caloric diet (VLCD), 539 vested interest, 647–49 villous atrophy, 443t Viparta Karani, 352 viral hepatitis, 16t virtue-based ethics, 622–23 visceral hypersensitivity, 119 visceral manipulation, 251–56 ANS in, 253t articulations in, 253t clinical relevance, 254–56 for dyspepsia, 255 for GERD, 255 goals of, 253t for IBD, 254 for IBS, 254–55 mobility in, 252, 253t parameters, 252 pressure sin, 253t viscerosomatic reflex, 144 vitalism, 157 vitamin A, 279t, 495, 503t dental disease and, 402 supplementation, 505 vitamin B6, 505 vitamin B12 deficiency, 209–10, 279t, 503t dental disease and, 402 H2 receptor antagonists and, 387 supplementation for, 504 vitamin C, 403 dental disease and, 402 motility and, 485 supplementation, 505, 589–90 for upper GI disorders, 430 vitamin D3, 279t, 503t, 524, 548t bone status and, 506 colorectal cancer and, 551–52 dental disease and, 402

IBD and, 497–98 supplementation, 506 vitamin E for liver, 563–66 plasma levels, 495 supplementation, 505, 563–66, 590 for upper GI disorders, 430 vitamin K, 49, 524 bone status and, 506–7 dental disease and, 402 supplementation, 506–7 VLCD. See very-low-caloric diet vomiting, 404 homeopathic remedies for, 187 VSL-3, in IBD, 514–15 W water, 28 beverages, 487 dehydration, 485 foods based in, 487 motility and, 486–87 taste of, 486 watermelon, 487 weight control programs, 530t Weil, Andrew, 4, 9, 489 wellness care, 150–51 Wells, H.G., 458 Westernization of diet, 22–23 Western medicine, 7 doctor-patient relationship in, 9 integrative medicine v., 8t Western philosophy, 7 wheat, 488, 502 wheat bran, 485 wheatgrass juice, 307–8 Wheatley, Margaret, 234 Whipple’s disease, 103, 401 Whitehead, William, 338, 345, 346 WHO. See World Health Organization wild celery seeds, 134, 136, 138 Williams, Roger, 269 Wolinella, 397 Women’s Health Initiative, 597 wood, 28

688

INDEX

World Health Organization (WHO), 124 World War I, 143 X xerostomia, 405 Y yama, 349 Yang & Li, 464 yeast elimination diet, 502–3 yeast overgrowth, 65 Yersinia, 82 yoga, 158t, 349–53 acceptance of, 360t digestive health and, 350–51 evidence-based review of, 475–76 postures, 351–53

yogurt, 425–26, 489 yuj, 349 Z Zelnorm, 21 zero balancing, 158t, 162 zinc, 90, 279t, 495, 503t absorption, 507 deficiency, 561 dental disease and, 402 H2 receptor antagonists and, 387 for liver, 561–62 supplementation, 507 upper GI disorders and, 429 zinc carnosine, 34, 282 Zingiberis rhizoma, 420 Zizyphi fructus, 420 Zusanli point, 129