Frontiers in Celiac Disease

Frontiers in Celiac Disease

Pediatric and Adolescent Medicine Vol. 12 Series Editors David Branski Jerusalem Wieland Kiess Leipzig

Frontiers in Celiac Disease Volume Editors Alessio Fasano Baltimore, Md. Riccardo Troncone Naples David Branski Jerusalem 52 figures, 19 in color, and 25 tables, 2008 Basel Freiburg Paris London New York Bangalore Bangkok Shanghai Singapore Tokyo Sydney

Prof. Alessio Fasano, MD Center for Celiac Research and Mucosal Biology Research Center University of Maryland School of Medicine Baltimore, Md., USA Prof. Riccardo Troncone, MD Department of Pediatrics and European Laboratory for the Investigation of Food-Induced Diseases University Federico II Naples, Italy Prof. David Branski, MD Division of Pediatrics Hadassah University Hospitals Jerusalem, Israel Library of Congress Cataloging-in-Publication Data Frontiers in celiac disease / volume editor, Alessio Fasano, Riccardo Troncone, David Branski. p. ; cm. (Pediatric and adolescent medicine, ISSN 1017 5989; v. 12) Includes bibliographical references and indexes. ISBN 978-3-8055-8526-2 (hard cover: alk. paper) 1. Celiac disease. I. Fasano, Alessio. II. Troncone, R. (Riccardo) III. Branski, D. IV. Series. [DNLM: 1. Celiac disease immunology. 2. Celiac Disease. W1 PE163HL v.12 2008 / WD 175 F935 2008] RC862.C44F76 2008] 616.3 99 dc22 2008007963 Bibliographic Indices. This publication is listed in bibliographic services, including Current Contents. Disclaimer. The statements, options and data contained in this publication are solely those of the individual authors and contributors and not of the publisher and the editor(s). The appearance of advertisements in the book is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements. Drug Dosage. The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Copyright 2008 by S. Karger AG, P.O. Box, CH 4009 Basel (Switzerland) www.karger.com Printed in Switzerland on acid-free and non-aging paper (ISO 9706) by Reinhardt Druck, Basel ISSN 1017 5989 ISBN 978 3 8055 8526 2

Contents VII Preface Fasano, A. (Baltimore, Md.); Troncone, R. (Naples); Branski, D. (Jerusalem) 1 Historical Perspective of Celiac Disease Guandalini, S. (Chicago, Ill.) 12 Natural History of Celiac Disease Kaukinen, K.; Collin, P.; Mäki, M. (Tampere) 18 The Changing Clinical Presentation of Celiac Disease Lebenthal, E.; Shteyer, E.; Branski, D. (Jerusalem) 23 The Global Village of Celiac Disease Catassi, C. (Ancona/Baltimore, Md.); Yachha, S.K. (Lucknow) 32 HLA and Non-HLA Genes in Celiac Disease Zhernakova, A. (Utrecht); Wijmenga, C. (Utrecht/Groningen) 46 Twins and Family Contribution to Genetics of Celiac Disease Greco, L. (Naples); Stazi, M.A. (Rome); Clerget-Darpoux, F. (Villejuif ) 57 Biochemistry and Biological Properties of Gliadin Peptides Barone, M.V.; Auricchio, S. (Naples) 66 Innate Immunity and Celiac Disease Meresse, B.; Malamut, G.; Amar, S.; Cerf-Bensussan, N. (Paris) 82 Celiac Disease: Across the Threshold of Tolerance Koning, F. (Leiden) 89 The Role of the Intestinal Barrier Function in the Pathogenesis of Celiac Disease Fasano, A. (Baltimore, Md.); Schulzke, J.D. (Berlin) 99 Diagnosis of Coeliac Disease. Open Questions Auricchio, R.; Troncone, R. (Naples) 107 Current Guidelines for the Diagnosis and Treatment of Celiac Disease Caicedo, R.A.; Hill, I.D. (Winston-Salem, N.C.)

114 Current Therapy Stern, M. (Tübingen) 123 Update on the Management of Refractory Coeliac Disease Al-toma, A.; Verbeek, W.H.M.; Mulder, C.J.J. (Amsterdam) 133 The National Institutes of Health Consensus Conference Report Cohen, M.B. (Cincinnati, Ohio); Barnard, J.A. (Columbus, Ohio) 139 Beyond Coeliac Disease Toxicity. Detoxified and Non-Toxic Grains Gilissen, L.J.W.J.; van der Meer, I.M.; Smulders, M.J.M. (Wageningen) 148 Oral Glutenase Therapy for Celiac Sprue Ehren, J.; Khosla, C. (Stanford, Calif.) 157 Inhibitors of Intestinal Barrier Dysfunction Paterson, B.M. (Baltimore, Md.); Turner, J.R. (Chicago, Ill.) 172 Development of a Vaccine for Celiac Disease Anderson, R.P. (Parkville, Vic.) 181 Regulatory T Cells in the Coeliac Intestinal Mucosa. A New Perspective for Treatment? Gianfrani, C.; Camarca, A. (Avellino/Naples); Salvati, V. (Naples); Mazzarella, G. (Avellino/Naples); Roncarolo, M.G. (Milan); Troncone, R. (Naples) 188 Strategies for Prevention of Celiac Disease Hogen Esch, C.E.; Kiefte-de Jong, J.C.; Hopman, E.G.D.; Koning, F. (Leiden); Mearin, M.L. (Leiden/Amsterdam) 198 Towards Preventing Celiac Disease An Epidemiological Approach Ivarsson, A.; Myléus, A.; Wall, S. (Umeå) 210 Animal Models of Celiac Disease Marietta, E.V.; Murray, J.A.; David, C.S. (Rochester, Minn.) 217 Author Index 218 Subject Index VI Contents

Preface Celiac disease (CD) is an immune-mediated enteropathy triggered by the ingestion of glutencontaining grains (including wheat, rye and barley) in genetically susceptible individuals. Epidemiological studies conducted during the past decade revealed that CD is one of the most common lifelong disorders worldwide. CD can manifest itself with a previously unappreciated range of clinical presentations, including the typical malabsorption syndrome and a spectrum of symptoms potentially affecting any organ system. Since CD often presents in an atypical or even silent manner, many cases remain undiagnosed and carry the risk of long-term complications, including anemia, osteoporosis, infertility or cancer. The high prevalence of the disease and its variety of clinical outcomes raise several interesting questions. Why is a disease that, if not treated, is associated with a high rate of morbidity and increased mortality yet not segregated by genetic evolution, and why does it remain one of the most frequent genetically based disorders of humankind? One possible explanation is that gluten, a protein introduced in large quantities in the human diet only after the advent of agriculture, activates by mistake of evolution mechanisms of innate and adaptive immunity that are too important for human survival to be eliminated. Another unresolved issue concerns the variable(s) that dictates the length of clinical latency and the type of symptoms experienced by CD patients when the disease becomes clinically apparent. In recent years, there have been noticeable shifts in the age of onset of symptoms and in the clinical presentation of CD, changes that seem to be associated with a delayed introduction of gluten coupled with its reduced amount in the diet. Another controversial topic concerns the complications of untreated CD. Multiple studies that have focused on the biochemistry and toxicity of gluten-containing grains and the immune response to these grains suggest that individuals affected by CD should be treated, irrespective of the presence or absence of symptoms and/or associated conditions. However, well-designed prospective clinical studies to address this point have not been performed, nor can they be conceived, given the ethical implications of such studies. Nevertheless, there is general agreement that the persistence of mucosal injury, with or without typical symptoms, can lead to severe complications in CD patients who do not strictly comply with a gluten-free diet. Another controversial issue is related to screening policies in terms of who should be screened for CD. The prevalence of the disease and the burden of

illness related to this condition, particularly if not treated, are so high as to possibly support a policy of general population screening. However, costeffective analyses and return on investment for patients, healthcare providers and policy makers keep the debate open. This book covers most of the aforementioned controversial and yet unresolved topics by capitalizing on the contribution of opinion leaders expert in CD and of its multidisciplinary ramifications. What the reader will surely find stimulating about this book is not only its exhaustive coverage of our current knowledge of CD, but also of provocative new concepts in disease pathogenesis, treatment and prevention that can be extrapolated to other immune-mediated pathologies. Indeed, given the undisputable role of gluten in causing inflammation and immunemediated tissue damage, CD represents a unique model of autoimmunity in which, in contrast to most other autoimmune diseases, a close genetic association with HLA genes (DQ2 and/or DQ8), a highly specific humoral autoimmune response (autoantibodies to tissue transglutaminase) and, most importantly, the triggering environmental factor (gluten) are known. This information provides the rationale for the treatment of the disease based on complete avoidance of gluten-containing grains from the patients diet. Therefore, CD represents the only autoimmune disorder for which a treatment is available, since the trigger(s) involved in the pathogenesis of other autoimmune diseases remain elusive at best. This also implies that CD could represent the best model to study autoimmune pathogenesis and, eventually, to develop novel therapeutic strategies for the treatment of conditions still orphan of any possible solution. We want to take the opportunity to thank all the contributors of this book who took time from their busy schedule to realize this project. This book would not have been possible without the expertise and invaluable contribution and technical support of Mrs. Donna Bethke and of the Karger editorial team. Alessio Fasano, Baltimore, Md. Riccardo Troncone, Naples David Branski, Jerusalem VIII Preface