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Digestive Involvement in Systemic Autoimmune Diseases Handbook of Systemic Autoimmune Diseases Volume 8 1st Edition Manel Ramos-Casals Digital Instant Download Author(s): Manel Ramos-Casals, Joan Rodes, Josep Font, Ronald Asherson ISBN(s): 9780444531681, 0444531688 Edition: 1 File Details: PDF, 4.80 MB Year: 2008 Language: english

Handbook of Systemic Autoimmune Diseases Volume 8

Digestive Involvement in Systemic Autoimmune Diseases

Handbook of Systemic Autoimmune Diseases Series Editor: Ronald A. Asherson

Volume 1

The Heart in Systemic Autoimmune Diseases Edited by: Andrea Doria and Paolo Pauletto

Volume 2

Pulmonary Involvement in Systemic Autoimmune Diseases Edited by: Athol U. Wells and Christopher P. Denton

Volume 3

Neurologic Involvement in Systemic Autoimmune Diseases Edited by: Doruk Erkan and Steven R. Levine

Volume 4

Reproductive and Hormonal Aspects of Systemic Autoimmune Diseases Edited by: Michael Lockshin and Ware Branch

Volume 5

The Skin in Systemic Autoimmune Diseases Edited by: Piercarlo Sarzi-Puttini, Andrea Doria, Giampiero Girolomoni and Annegret Kuhn

Volume 6

Pediatrics in Systemic Autoimmune Diseases Edited by: Rolando Cimaz and Thomas Lehman

Volume 7

The Kidney in Systemic Autoimmune Diseases Edited by: Justin C. Mason and Charles D. Pusey

Volume 8

Digestive Involvement in Systemic Autoimmune Diseases Edited by Josep Font, Manuel Ramos-Casals, and Juan Rodés

Handbook of Systemic Autoimmune Diseases Volume 8

Digestive Involvement in Systemic Autoimmune Diseases Edited by:

Josep Fontw Department of Autoimmune Diseases, ‘‘Instituto de Investigaciones Biomédicas August Pi I Sunyer (IDIBAPS)’’, Hospital Clinic, Barcelona, Spain

Manuel Ramos-Casals Laboratory of Autoimmune Diseases ‘‘Josep Font’’, ‘‘Instituto de Investigaciones Biomédicas August Pi I Sunyer (IDIBAPS)’’, Hospital Clinic, Barcelona, Spain

Juan Rodés Liver Unit, ‘‘Instituto de Investigaciones Biomédicas August Pi I Sunyer (IDIBAPS)’’, Hospital Clinic, Barcelona, Spain Series Editor

Ronald A. Asherson

Amsterdam – Boston – Heidelberg – London – New York – Oxford Paris – San Diego – San Francisco – Singapore – Sydney – Tokyo

Elsevier Radarweg 29, PO Box 211, 1000 AE Amsterdam, The Netherlands Linacre House, Jordan Hill, Oxford OX2 8DP, UK

First edition 2008

Copyright r 2008 Elsevier B.V. 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 electronic, mechanical, photocopying, recording or otherwise without the prior written permission of the publisher Permissions may be sought directly from Elsevier’s Science & Technology Rights Department in Oxford, UK: phone (+44) (0) 1865 843830; fax (+44) (0) 1865 853333; email: permissions@elsevier.com. Alternatively you can submit your request online by visiting the Elsevier web site at http://www.elsevier.com/locate/permissions, and selecting Obtaining permission to use Elsevier material Notice No responsibility is assumed by the publisher for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions or ideas contained in the material herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library ISBN: 978-0-444-53168-1 ISSN: 1571-5078 For information on all Elsevier publications visit our website at books.elsevier.com

Printed and bound in The Netherlands 08 09 10 11 12

10 9 8 7 6 5 4 3 2 1

Dedication

This book is one of the last projects led by Josep Font before his unexpected death, and the remaining Editors wish to dedicate these lines as a means of paying a deeply felt homage. Dr. Josep Font (Barcelona, 1953–2006) devoted his professional career to the care of patients with systemic autoimmune diseases (SAD). Dr. Font trained in Internal Medicine at the Hospital Clinic of Barcelona from 1978 to 1982 and obtained his PhD in 1984 for his thesis on systemic lupus erythematosus (SLE). His post-doctoral experience was closely linked with the Lupus Research Unit at St. Thomas’ Hospital in London. His research output was prodigious, with a total of over 500 scientific articles published in 25 years. In addition, he designed and coordinated many international projects including the Eurolupus, Europhospholipid, CAPS Registry, SS-HCV Registry, and HISPAMEC, and was an active member of some of the most prestigious international research groups such as the Eurolupus Nephritis Trial and the SLICC. In 1995, Josep Font created the Department of Autoimmune Diseases at the Hospital Clinic, a pioneering unit in Europe specifically dedicated to the clinical management of patients with SAD. Dr. Font played a leading role in creating a network of different specialists at the Hospital Clinic dedicated to the care of these patients. A key characteristic of his clinical research was its multidisciplinary design and the close collaboration between different medical specialities, of which this book is an excellent example.

Josep Font was working actively until the last days of his life, and died like a soldier ‘‘with his boots on’’.

His integrity, intelligence, and loyalty made him a formidable physician and a wonderful colleague and friend. He was undoubtedly one of the foremost figures in the field of autoimmune diseases in recent decades, and the immense human and professional legacy that he leaves must be maintained and continued by all who had the great fortune to know and work with him.

Manuel Ramos-Casals and Juan Rodés

v

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Foreword I was pleased to be asked to write the Foreword for this new volume which aims to bring together knowledge on a group of auto-immune disorders involving the digestive tract with systemic involvement.

It is surely going to be an important volume and one fulfilling a long-felt need by intensivists, rheumatologists, as well as hepatologists and gastroenterologists who are involved in the care of patients suffering from this fascinating group of disorders.

Much is known about the nature of immunological reactions that underlie auto-immune disorders, with cytoxic CD8 T cells, NK cells, and b-cell auto-antibody production interacting in the disease process.

However, what initiates these processes and gives rise to a particular organ or system involvement is still in most instances uncertain, involving as it may infectious agents, environmental toxins, and with an underlying constitutional predisposition. The overlap syndromes between them are particularly fascinating.

Thus PBC and auto-immune hepatitis are usually quite distinct disorders in terms of clinical manifestations and in response to immunosuppressive therapy—highly effective in auto-immune hepatitis, little effect in primary biliary cirrhosis, yet occasional cases have features of both disorders. Primary sclerosing cholangitis in adults is characterised by a progressive fibrosing obliteration of intra and extrahepatic bile ducts but in children there is often an initial phase of an auto-immune hepatitis-like picture with a response to corticosteroids. Arthropathies are common in auto-immune hepatitis and rheumatoid arthritis in primary biliary cirrhosis. Sjögren’s syndrome too is a feature of PBC and there are many other overlap associations.

However, lupid hepatitis which was the term applied—because of the finding of LE cells in the serum to what later became known as active chronic hepatitis and then presently auto-immune hepatitis, is not part of disseminated lupus erythematosus in which hepatic involvement is mild or non-existent.

Separate chapters in the volume are devoted to the extrahepatic manifestations of chronic hepatitis consequent on HBV and HVC infection, including glomerulonephritis, thyroiditis, arthropathies, and attributable to the development of an auto-immune reactivity. One of the mechanisms involved maybe molecular mimicry in which antigens of external organisms, bacterial or viral which show homology with self-molecules trigger auto-immunity in an attempt to neutralise the infectious organisms.

With outstanding editorship and the acknowledged expertise of the writing contributors this will be an exciting volume to read.

Professor Roger Williams, CBE

vii

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List of Contributors

Rupert Abdalian Division of Gastroenterology, Department of Medicine, Toronto Western Hospital, University Health Network, Toronto, Ont., Canada

Salvatore De Vita Rheumatology Clinic, Azienda OspedalieroUniversitaria ‘‘S. Maria della Misericordia’’, DPMSC, University of Udine, Udine, Italy

Graciela S. Alarcón Department of Medicine, Division of Clinical Immunology and Rheumatology, 510 20th Street South, FOT 830, The University of Alabama at Birmingham, Birmingham, AL 35294, USA

Luis Donoso Diagnostic Imaging Centre, Hospital Clinic, University of Barcelona, IDIBAPS, Villarroel 170, 08036 Barcelona, Spain

Carmen Ayuso Radiology Department, Diagnostic Imaging Centre, Hospital Clinic, University of Barcelona, Abdomen Unit (CT and MRI), IDIBAPS, Villarroel 170, 08036 Barcelona, Spain John M. Cafardi Department of Medicine, Division of Clinical Immunology and Rheumatology, 510 20th Street South, FOT 830, The University of Alabama at Birmingham, Birmingham, AL 35294, USA Ricard Cervera Department of Autoimmune Diseases, Hospital Clı́nic, Villarroel 170, 0836 Barcelona, Catalonia, Spain Roger Chapman Department of Gastroenterology, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK Albert J. Czaja Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA Lara Dani Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Solna, Karolinska Institutet, SE-171 76 Stockholm, Sweden

Gerard Espinosa Department of Autoimmune Diseases, Hospital Clı́nic, Villarroel 170, 0836 Barcelona, Catalonia, Spain Gianfranco Ferraccioli Division of Rheumatology, School of Medicine, Catholic University of the Sacred Heart, Rome, Italy Xavier Forns Liver Unit, ICMD, Ciberehd, ‘‘Instituto de Investigaciones Biomédicas August Pi I Sunyer (IDIBAPS)’’, Hospital Clinic, Barcelona, Spain Elisa Gremese Division of Rheumatology, School of Medicine, Catholic University of the Sacred Heart, Rome, Italy Loı̈c Guillevin Department of Internal Medicine, National Referral Center for Necrotizing Vasculitides and Systemic Sclerosis, Hôpital Cochin, Université Paris 5 – René Descartes, 27 rue du faubourg Saint-Jacques, 75679 Paris cedex 14, France Jenny Heathcote Division of Gastroenterology, Department of Medicine, Toronto Western Hospital, University Health Network, Toronto, Ont., Canada Iain R.L. Kean Biomedical Research Centre, Sheffield Hallam University, Sheffield S1 1WB, England, UK ix

x

List of Contributors

Walter F. Kean Department of Medicine, McMaster University Faculty of Health Sciences, Suite #401, 1 Young Street, Hamilton, Ont., Canada L8N 1T8 Dinesh Khanna Division of Rheumatology, Department of Medicine, David Geffen School of Medicine, 1000 Veterans Avenue, Rm 32–59, Rehabilitation Building, Los Angeles, CA 90095, USA Ingrid E. Lundberg Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Solna, Karolinska Institutet, SE-171 76 Stockholm, Sweden Michael P. Manns Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany Giorgina Mieli-Vergani Institute of Liver Studies, King’s College London School of Medicine at King’s College Hospital, Denmark Hill, London SE5 9RS, UK Heiko Mix Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany Josep Ordi-Ros Internal Medicine Department, Vall D’Hebron General Hospital, Universitat Autonoma de Barcelona, 08035 Barcelona, Spain Mario Pagés Radiology Department, Diagnostic Imaging Centre, Hospital Clinic, University of Barcelona, Abdomen Unit (CT and MRI), IDIBAPS, Villarroel 170, 08036 Barcelona, Spain Christian Pagnoux Department of Internal Medicine, National Referral Center for Necrotizing Vasculitides and Systemic

Sclerosis, Hôpital Cochin, Université Paris 5 – René Descartes, 27 rue du faubourg Saint-Jacques, 75679 Paris cedex 14, France Neophytos P. Papageorgiou Center for Autoimmune Diseases, Department of Medicine B, Chaim Sheba Medical Center (Affiliated to Tel-Aviv University), Tel-Hashomer 52621, Israel Luca Quartuccio Rheumatology Clinic, Azienda Ospedaliero-Universitaria ‘‘S. Maria della Misericordia’’, DPMSC, University of Udine, Udine, Italy K.D. Rainsford Biomedical Research Centre, Sheffield Hallam University, Sheffield S1 1WB, England, UK Herbert Rakatansky Department of Medicine, Division of Gastroenterology, Warren Alpert School of Medicine, Brown University Providence, RI, USA Manuel Ramos-Casals Laboratory of Autoimmune diseases ‘‘Josep Font’’, ‘‘Instituto de Investigaciones Biomédicas August Pi I Sunyer (IDIBAPS)’’, Hospital Clinic, Barcelona, Spain Juan Rodés Liver Unit, ICMD, Ciberehd, ‘‘Instituto de Investigaciones Biomédicas August Pi I Sunyer (IDIBAPS)’’, Hospital Clinic, Barcelona, Spain Juanita Romero-Dı́az Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México Jorge Sánchez-Guerrero Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México

List of Contributors

Jose-Maria Sanchez-Tapias Liver Unit, ICMD, Ciberehd, ‘‘Instituto de Investigaciones Biomédicas August Pi I Sunyer (IDIBAPS)’’, Hospital Clinic, Barcelona, Spain

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Athanasios G. Tzioufas Department of Pathophysiology, School of Medicine, University of Athens, Greece

Albert Selva-O’Callaghan Internal Medicine Department, Vall D’Hebron General Hospital, Universitat Autonoma de Barcelona, 08035 Barcelona, Spain

Diego Vergani Institute of Liver Studies, King’s College London School of Medicine at King’s College Hospital, Denmark Hill, London SE5 9RS, UK

Yehuda Shoenfeld Center for Autoimmune Diseases, Department of Medicine B, Chaim Sheba Medical Center (Affiliated to Tel-Aviv University), Tel-Hashomer 52621, Israel

Miquel Vilardell-Tarrés Internal Medicine Department, Vall D’Hebron General Hospital, Universitat Autonoma de Barcelona, 08035 Barcelona, Spain

Elke Theander Department of Rheumatology, Malmo University Hospital, Malmo, Sweden

Claudio Vitali Department of Internal Medicine and Rheumatology, Ospedale Villamaria, Piombino, Italy

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Contents Dedication Foreword List of Contributors

v vii ix

I Introduction Digestive System and Autoimmunity Heiko Mix, Michael P. Manns

3

Imaging Techniques in Digestive Diseases Carmen Ayuso, Mario Pagés, Luis Donoso

15

II Systemic Autoimmune Diseases Systemic Lupus Erythematosus Miquel Vilardell-Tarrés, Albert Selva-O’Callaghan, Josep Ordi-Ros

31

Antiphospholipid Syndrome Gerard Espinosa, Ricard Cervera

39

Gastrointestinal Involvement in Systemic Sclerosis Dinesh Khanna

51

Inflammatory Myopathies Lara Dani, Ingrid E. Lundberg

63

Digestive Involvement in Primary Sjögren’s Syndrome Manuel Ramos-Casals, Elke Theander, Athanasios G. Tzioufas, Claudio Vitali

71

Gastrointestinal Involvement in Systemic Vasculitis Salvatore De Vita, Luca Quartuccio, Elisa Gremese, Gianfranco Ferraccioli

83

Mixed Connective Tissue Disease Juanita Romero-Dı´az, Jorge Sánchez-Guerrero

101

Gastrointestinal Manifestations of Rheumatoid Arthritis John M. Cafardi, Herbert Rakatansky, Graciela S. Alarcón

109

III Autoimmune Liver Diseases Immunopathogenesis of Autoimmune Liver Damage Albert J. Czaja

121

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xiv

Contents

Primary Biliary Cirrhosis Rupert Abdalian, Jenny Heathcote

141

Autoimmune Hepatitis Diego Vergani, Giorgina Mieli-Vergani

153

Primary Sclerosing Cholangitis Roger Chapman

169

IV Autoimmunity and Viral Hepatitis Systemic and Autoimmune Manifestations of Hepatitis B Virus Infection Christian Pagnoux, Loı¨c Guillevin

191

Extrahepatic Manifestations in Patients with Chronic Hepatitis C Virus Infection Manuel Ramos-Casals, Xavier Forns, Jose-Maria Sanchez-Tapias, Juan Rodés

209

V Other Conditions Autoantibodies in Gastrointestinal Autoimmune Diseases Neophytos P. Papageorgiou, Yehuda Shoenfeld

231

Gastrointestinal Complications of Anti-Rheumatic Drugs K.D. Rainsford, Iain R.L. Kean, Walter F. Kean

243

Subject Index

277

Colour Plate Section

PART I:

Introduction

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Handbook of Systemic Autoimmune Diseases, Volume 8 Digestive Involvement in Systemic Autoimmune Diseases Josep Font, Manuel Ramos-Casals and Juan Rodés, editors

CHAPTER 1

Digestive System and Autoimmunity Heiko Mix, Michael P. Manns Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany

1. The digestive system and gut-associated immunity Mammals depend on feeding and digestion. While single-celled organisms can directly take in nutrients from their outside environment, multi-cellular organisms, with most of their cells removed from direct contact with the outside environment, have developed specialized structures for obtaining and breaking down their food. Large, complex molecules must be broken down into monomers that can then be distributed throughout the body to every cell. This vital function is accomplished by a series of specialized organs that comprise the digestive system. The human digestive system is a coiled, muscular tube about 6–9 m in length when fully extended, stretching from the mouth to the anus. Several specialized compartments occur along this length: mouth, pharynx, esophagus, stomach, small intestine, large intestine, and anus.

Accessory digestive organs are connected to the main system by a series of ducts, including salivary glands, the pancreas, and the liver with the biliary system. Like the skin, the digestive tract is situated at the interface between external and internal milieus. In order to maintain homeostasis, physical and chemical mechanisms as elements of the innate immune response are utilized to protect against exogenous, potentially noxious agents. The

Corresponding author.

Tel.: +49-511-532-3305; Fax: +49-511-532-4896 E-mail address: manns.michael@mh-hannover.de r 2008 Elsevier B.V. All rights reserved.

DOI: 10.1016/S1571-5078(07)00001-3

membranes of the digestive tract provide a physical barrier against invading pathogens. A huge number of chemical factors, including low pH in the stomach, pepsin, lysozyme, anti-microbial substances like cryptidins and defensins, limit the growth and invasion of microorganisms (Dann and Eckmann, 2007) (Table 1).

In addition to innate defense mechanisms, the digestive system is lined by mucosal lymphatic tissues. It consists of diffuse lymphocytic infiltrates throughout the epithelium and lamina propria of the mucosa or nonencapsulated lymphoid nodules in the submucosa of the intestinal tract. Peyer’s patches are the prototypical mucosal lymphatic tissue, specialized to sample environmental antigens. The Peyer’s patches contain lymphoid compartments that are analogous to the cortex and follicles of lymph nodes. Each follicle is covered by a single-layered follicle-associated epithelium, and a more diffuse area immediately below, called subepithelial dome. The follicle-associated epithelium is interrupted by specialized membraneous cells (M cells) that have luminal microfolds instead of microvilli and lack the normal thick layer of mucus. The M cells differentiate from enterocytes under the influence of membranebound lymphotoxin-a1b2 present on local lymphoid cells (Debard et al., 2001; Kernéis et al., 1997; Golovkina et al., 1999). These cells endocytose and transport various materials (Nicoletti, 2000). Antigen is delivered to lymphocytes, mononuclear phagocytes, and dendritic cells immediately beneath M cells. The germinal centers contain B cell blasts, follicular dendritic cells, macrophages, and

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H. Mix, M.P. Manns

Table 1 Mechanisms to minimize self-reactive lymphocyte differentiation and activation Clonal deletion

Induction of apoptosis by inhibition of pro-survival pathways (BIM induction) or by activation of death receptors (FAS activation)

Receptor editing

Receptor editing through V(D)J recombination in primary lymphatic tissues (in T cells and B cells) or by somatic hypermutation in secondary lymphatic tissues (in B cells)

Clonal anergy and tuning

Intrinsic regulation by B or T cell receptor downregulation Induction of inhibitory receptors (CD5, CTLA4) Induction of phosphatases (SHP1, SHIP) Induction of ubiquitin ligases (cbl, GRAIL, Itch, Roquin)

Extrinsic regulation

Limitation of survival factors (BAFF, IL-7) Limitation of costimulation (CD40L, TLR ligands, B7 molecules) Active suppression (regulatory T cells)

unique T cells. B cells undergo immunoglobulin class switching from expression of IgM to IgA under the influence of several local factors, including transforming growth factor-b (TGF-b), interleukin-10 (IL-10), and other cellular signals that are delivered by dendritic cells and T cells (McIntyre and Strober, 1999). Lymphocytes exit the Peyer’s patches through the draining lymphatics to the mesenteric lymph nodes, from where they migrate into the bloodstream and finally home to the mucosa. The exit of lymphocytes from the bloodstream into the mucosa is mediated by loss of L-selectin expression and selective upregulation of a4b7 integrin. The ligand for a4b7 integrin, mucosal addressin cell-adhesion molecule 1 (MADCAM1), is highly expressed by the vasculature of mucosal surfaces and mediates the emigration from the bloodstream (Butcher et al., 1999). In addition, expression of the chemokine receptor CCR9 is induced in gut-derived T cells, allowing them to respond to the chemokine CCL25, which is exclusively expressed by small-bowel epithelial cells (Bowman et al., 2002; Campbell and Butcher, 2002). In contrast, T cells primed in peripheral lymphoid organs acquire the a4b1 integrin very late antigen 4 (VLA4) and the chemokine receptor CCR4 and do not migrate to mucosal surfaces (Campbell and Butcher, 2002).

Lymphocytes that home into the mucosa of the gut redistribute into distinct compartments. IgAproducing plasma cells remain in the lamina propria. CD4+ T cells are distributed more evenly

throughout the villus–crypt unit within the lamina propria. CD8+ T cells preferentially reside in the epithelium. A memory phenotype of CD4+ and CD8+ T cells predominates in both the epithelium and the lamina propria, indicating that the cells have been exposed to antigen. CD4+ T cells in the lamina propria are of particular importance to local immune regulation. They produce large amounts of cytokines, particularly interferon-g (IFN-g), but also IL-4 and IL-10 (Braunstein et al., 1997; Carol et al., 1998; Hurst et al., 1999).

Lamina propria CD8+ T cells can have potent cytotoxic T lymphocyte (CTL) activity (Lefranc- ois et al., 1999). Many of the properties of the lamina propria CD4+ T cells are similar to those of regulatory T cells in other systems (Read and Powrie, 2001; Shevach, 2002). The unresponsiveness of lamina propria T cells to commensal bacteria can be reversed by the depletion of IL-10 or TGF-b (Khoo et al., 1997).

Mesenteric lymph nodes have a crucial role in the induction of mucosal immunity and tolerance.

Antigen recognition in the mesenteric lymph nodes occurs within a few hours of feeding protein antigen (Gütgemann, 1998; Van Houten and Blake, 1996; Blanas et al., 2000; Lee et al., 2000).

More importantly, induction of oral tolerance is not possible in lymphotoxin-a-deficient or lymphotoxin-a-deficient TNF-deficient mice, which lack mesenteric lymph nodes (Spahn et al., 2002).

Furthermore, total and specific IgA-antibody responses are absent in mice lacking mesenteric

Digestive System and Autoimmunity

lymph nodes, while responses to parenterally administered antigens are preserved in these mice (Kang et al., 2002; Yamamoto et al., 2000).

Generally, immune responses to most tissue antigens are initiated in the draining lymph nodes.

Recent evidence has suggested that naı̈ve intestinal T cells first encounter antigen in the mesenteric lymph nodes and not in Peyer’s patches (MacPherson and Liu, 1999; Huang et al., 2000).

While priming of T cells selectively in Peyer’s patches would lead to efficient local immune responses or tolerance, priming of T cells in the mesenteric lymph nodes could explain the fact that intestinal antigens are able to induce systemic immunity or tolerance.

Peyer’s patches harbor distinctive subsets of dendritic cells, which have unusual phenotypic and functional characteristics (Ruedl et al., 1996).

Conventional subsets of CD8a CD11b+ (myeloid) and CD8a+CD11b (lymphoid) dendritic cells are present next to a large number of CD8a CD11b dendritic cells. Currently, little information is available about this subset of dendritic cells.

They can be found outside the organized lymphoid areas, especially in the dome region, which is immediately beneath the follicle-associated epithelium, together with CD8a CD11b+ dendritic cells.

Their presence is dependent on the production of macrophage inflammatory protein 3a (MIP3a), or CCL20, by local epithelial cells (Iwasaki and Kelsall, 2000, 2001). The predominant CD8a CD11b+ dendritic cell subset is distinctive in that it secretes IL-10. Interestingly, after ligation of the costimulator molecule receptor activator of NF-kB (RANK), the dentritic cells of Peyer’s patches respond by secretion of IL-10. Outside Peyer’s patches, i.e. in the spleen, the same conditions result in the production of IL-12 (Williamson et al., 2002). Dendritic cells in Peyer’s patches are also able to stimulate antigen-specific T cells to produce T helper type 2 (TH2) cytokines and IL-10. Collectively, these observations underscore an important role of Peyer’s patch dendritic cells in maintaining a state of tolerance against food antigens and commensal bacteria in the digestive system.

In addition, intestinal epithelial cells (IECs) have recently been identified as key elements in the development and regulation of mucosal

5

immunity (Zaph et al., 2007). These cells have been implicated in the regulation of innate immunity and chronic inflammation before (Neish et al., 2000; Rimoldi et al., 2005); however, supporting data from in vivo experiments were lacking. The authors could show that mice, deficient in IkB kinase-b (IKK-b), produce reduced levels of the epithelial-cell-restricted cytokine thymic stromal lymphopoietin. The mice were unable to mount an efficient CD4+ TH2 response against the parasite Trichuris. Severe intestinal inflammation was the result of exacerbated dendritic-cell-derived IL-12/23p40 and tumor necrosis factor-a production, as well as increased levels of CD4+ T-cell-derived IFN-g and IL-17. The results were proof that the balance of IKK-bdependent gene expression in the intestinal epithelium is crucial in intestinal immune homeostasis in addition to established pathways involved in pathogen recognition and initiation of immune responses in the gastrointestinal tract, which include M cells and specialized dendritic cell subsets that directly sample the luminal environment.

The nervous innervation of the gastrointestinal tract is extensive, including Peyer’s patches, and the diversity of adrenergic, cholinergic, and peptidergic nerve endings in patches is greater than for any other peripheral lymphatic tissue.

Noradrenergic fibers form interfollicular plexuses that ramify through the diffuse T-dependent areas near high endothelial venules (HEV). It is likely that the extensive innervation of Peyer’s patches is involved in regulating traffic and reactivity of mucosal immune cells. The nervous system, through the vagus nerve, was shown to significantly and rapidly inhibit the release of macrophage-derived tumor necrosis factor-a, thereby attenuating systemic inflammatory responses (Borovikova et al., 2000; Bernik et al., 2002; Tracey, 2002). It could be demonstrated that this cholinergic anti-inflammatory pathway of acetylcholine-mediated vagus nerve signals was mediated via the nicotinic acetylcholine receptor a7 subunit (Wang et al., 2003).

The liver as a member of the accessory digestive organs plays an important role in systemic immunity (Racanelli and Rehermann, 2006). It contains large amounts of professional antigen-presenting

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cell, including liver sinusoidal endothelial cells, Kupffer cells, and dendritic cells. Potential antigen-rich blood is filtered and pathogens are quickly eliminated by phagocytes or by the huge population of natural killer cells or natural killer T cells present in liver. The liver has a high capacity to induce antigen-specific tolerance. It acts as a central regulator in systemic immune responses by synthesizing and secreting acute-phase proteins and other mediators.

2. Self-tolerance and autoimmunity Adaptive immune responses are essential for normal health. In some cases, adaptive immune responses are elicited by antigens not associated with infectious agents. The responses are essentially identical to adaptive immune responses to infectious agents; however, the antigens are different. Autoimmunity is the response to selfantigens in the absence of infection.

The mammalian immune system is able to mount a response to any chemical structure imaginable. B cells and T cells express receptors with huge receptor diversity able to achieve specificity that differentiates molecules at the atomic level. This huge receptor diversity is encoded in the mammalian genome and is possible through two processes of somatic genome modification that occurs selectively in lymphocytes. In central lymphoid organs, i.e. bone marrow for B cells and the thymus for T cells, V(D)J recombination assembles unique receptor genes for B and T cells. In peripheral lymphoid tissues, B cell receptor genes can further be modified by singlenucleotide substitutions through somatic hypermutation. The random processes of V(D)J recombination and somatic hypermutation generate huge amounts, i.e. between 20 and 50%, of self-reactive B cells and T cells (Ignatowicz et al., 1996; Zerrahn et al., 1997; Laufer et al., 1996; Wardemann et al., 2003). Remarkably, only 3–8% of the population develops an autoimmune disease (Jacobson et al., 1997).

Currently, four mechanisms have been identified that limit the number of self-reactive lymphocytes.

First, clonal deletion is used to trigger apoptosis of cells with self-reactive receptors. Second, cells with self-reactive receptors can edit their specificity by further V(D)J recombination or somatic hypermutation until the receptor does not bind to selfantigens (Nemazee and Hogquist, 2003). Third, clonal anergy or tuning is the unresponsiveness of cells to signals from self-reactive receptors by changes in intrinsic biochemical processes and gene expression (Healy and Goodnow, 1998; Schwartz, 2003; Grossman and Paul, 2000).

Collectively, these first three mechanisms are called immunologic ignorance. When cells have evaded all the three mechanisms, extrinsic controls can limit the potential of an autoimmune response by limiting the supply of growth factors, costimuli, pro-inflammatory mediators and other factors, or through active suppression by regulatory T cells.

3. Tolerance mechanisms for autoreactive B cells in the bone marrow A series of events has been identified that occurs if an immature B cell displays a self-reactive receptor in the bone marrow. The immature B cell internalizes the self-reactive receptor when the strength of receptor crosslinking and intracellular signaling exceeds a certain threshold (Hartley et al., 1993; Fields and Erikson, 2003). As a result, homing receptors like CD62 ligand (CD62L), required to enter the lymph nodes, are not expressed (Hartley et al., 1993). In addition, B-cell-activating factor (BAFF) receptors are only poorly induced (Mackay et al., 2003). BAFF is required to sustain peripheral B cell survival.

Furthermore, recombination-activating gene 1 (RAG1) and RAG2, which encode the core enzymes for V(D)J recombination, continue to be expressed, allowing further editing of B cell receptors by rearranging a replacement B cell receptor light chain (Jankovic et al., 2004). If the receptor cannot be edited to be less self-reactive, cell death is induced, either by withdrawal of growth factors and/or through increasing levels of BCL-2-interacting mediator of cell death (BIM), a pro-apoptotic factor that inhibits essential B cell

Digestive System and Autoimmunity

survival proteins of the BCL-2 family (Strasser and Bouillet, 2003). Interestingly, BIM-deficient mice spontaneously produce anti-DNA autoantibodies (Strasser and Bouillet, 2003).

4. Tolerance mechanisms for autoreactive T cells in the thymus While B cells are designed to recognize native antigen, T cell receptors bind to peptide fragments of antigen displayed on MHC molecules. An array of self-peptides is displayed on cortical thymic epithelial cells, and T cells that weakly bind to these ligands receive maturation signals that inhibit further RAG gene expression. They increase the level of surface receptor expression and upregulate homing receptors for chemokines found in the thymic medulla and the peripheral lymphoid tissues. This so-called positive selection is unique to the thymic cortical epithelium. Selfreactive T cells are further edited by downregulating the self-reactive receptor, and RAG expression continues until the self-reactive T cell receptor a-chain is replaced with another, less self-reactive chain.

In the thymic medulla, the process of testing for self-reactivity continues with the help of medullary thymic epithelial cells and dendritic cells. The cells in the medulla express costimulatory molecules, including CD80 (B7.1) and CD86 (B7.2), the ligands for CD28. Here, T cell receptors that bind strongly to self-peptide-MHC complexes are triggered to induce cell death (negative selection). In animals, deficient in this process either through lack of medullary MHC expression or B7 expression, huge amounts of self-reactive T cells reach the periphery, causing pathologies resembling graft-versus-host disease (Gao et al., 2002). It can be speculated that the well-established association between particular MHC molecules and susceptibility to specific autoimmune diseases may stem from inefficient presentation of particular selfpeptides during this phase of T cell receptor deletion (Kanagawa et al., 1998; Wicker et al., 1995).

7

Negative selection requires the tyrosine kinase x-chain-associated protein kinase of 70 kDa (ZAP70). Mice deficient in ZAP70 develop a systemic inflammatory disorder resembling rheumatoid arthritis (Sakaguchi et al., 2003). In addition, the following factors have been identified as being essential for negative selection: growthfactor-receptor-bound (GRB) protein 2 (Gong et al., 2001), misshapen-Nck-interacting kinase (NIK) related kinase (MINK) (McCarty et al., 2005), extracellular signal-regulated kinase (ERK), and p38 and Jun kinase (JNK) activation (Palmer, 2003). Induction of cell death of autoreactive T cells requires BIM expression, which antagonizes BCL-2 and related proteins to release proapoptotic BAX and BAK. Furthermore, members of the Nur77 family of orphan nuclear receptors are induced during negative selection. T cell receptor-induced thymocyte death is blocked in the absence of Nur77 (Zhou et al., 1996).

5. Clonal anergy and tuning The intrinsic cellular mechanisms of anergy are particularly well studied in B cells with selfreactive receptors (Benschop et al., 2001). Selfreactive B cell receptors can be internalized through accelerated endocytosis, resulting in reduction of up to 99% of the initial surface expression of a self-reactive receptor. Similarly, the transport of new receptors to the surface can be blocked (Bell and Goodnow, 1994). It has been reported that self-reactive B cell receptors activate tyrosine kinase signaling poorly, which limits cell survival because of weak NF-kB1 activation. In parallel, weak signaling induces BIM expression to promote cell death (Lesley et al., 2004) and ERK pathways that block Toll-like receptor 9 (TLR9)-induced differentiation into plasma cells (Rui et al., 2003).

So-called biochemical tuning can be achieved by increasing the threshold of B cell receptor activation, regardless of its specificity. Recruitment of the SH2-domain-containing protein tyrosine phosphatase 1 (SHP1) through the surface proteins CD22 and PD1 to the activated B cell receptors

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increases its threshold for signaling (Healy and Goodnow, 1998). Another example is the recruitment of the lipid phosphatase SH2-domaincontaining inositol-5-phosphatase (SHIP) to the activated B cell receptor through Fc receptor-g (Ravetch and Lanier, 2000). Spontaneous autoantibody production can occur if either one of these mechanisms is defective.

Tuning of self-reactive T cells is achieved by increased expression of the inhibitory receptor CD5 (Wong et al., 2001; Smith et al., 2001).

Cytotoxic T-lymphocyte antigen 4 (CTLA4) is another inhibitory receptor that acts through competition with CD28 for ligation with B7 molecules and transmitting inhibitory signals.

CTLA4 was found to be upregulated in selfreactive T cells (Sharpe and Freeman, 2002; Walker and Abbas, 2002). Massive accumulation of self-reactive T cells occurs in peripheral lymphoid and nonlymphoid tissues in the absence of CTLA4. Functional variants of the CTLA4 gene can lead to thyroid autoimmunity and type 1 diabetes in humans and mice (Ueda et al., 2003).

The ubiquitin ligases cbl-b, GRAIL and Itch have been identified to be highly expressed in chronic T cell receptor signaling in vitro (Heissmeyer et al., 2004; Anandasabapathy et al., 2003; Jeon et al., 2004). Ubiquitinylation of T cell receptors, CD28 and cytokine receptor signaling molecules can alter intracellular trafficking, promote proteolytic degradation or can allosterically interfere with signaling (Naramura et al., 2002; Liu, 2004). Their importance for preventing autoimmunity in rodents has been clearly demonstrated: cbl-b deficiency coupled with a particular MHC haplotype causes type 1 diabetes in the Komeda diabetes prone (KDP) rat strain (Yokoi et al., 2002). Large numbers of activated T cells and high titers of autoantibodies can be found in mice lacking Itch, or cbl-b and its close relative c-cbl (Naramura et al, 2002; Liu, 2004).

6. Extrinsic controls of self-reactive lymphocytes A well-documented extrinsic control mechanism of autoreactive B cells is their dependence on BAFF,

which is produced in limiting quantities by lymphoid stromal cells (Mackay et al., 2003). Binding of BAFF to its receptor increases NF-kB2 activity maintaining peripheral B cell survival through induction of BCL-2 expression (Claudio et al., 2002). It also induces the expression of PIM2, a serin-threonie kinase, which has pro-survival effects by interfering with the pro-apoptotic protein BAD (Fox et al., 2003). On the one hand, given the large numbers of circulating B cells with strong receptor signaling through high affinity to antigen, the selfreactive B cells do not receive enough BAFF and are competitively deleted (Thien et al., 2004). On the other hand, in states of B cell lymphopenia or in phases when BAFF synthesis is high, i.e. during infection, self-reactive B cells are more likely to survive (Mackay et al., 2003; Lesley et al., 2004).

As with B cells, T cell survival in the periphery depends on continuous signaling through contact with MHC ligands and exposure to IL-7 (Sprent and Surh, 2002; Marrack and Kappler, 2004; Barthlott et al., 2003). Under normal circumstances, IL-7 levels are low and maintain T cells in interphase. However, in lymphopenia, IL-7 levels rise and amplify T cell receptor signaling and proliferation. This so-called homeostatic proliferation may also activate self-reactive T cells causing autoimmune diseases in extralymphatic sites, a common feature seen in people after T lymphopenia. Lymphopenia and defective T cell function in Wiskott–Aldrich syndrome is leading to an array of autoimmune and inflammatory conditions (Dupuis-Girod et al., 2003).

7. Limitation of costimuli In order to secrete antibodies, B cells must receive two signals: First, an antigen must bind to the B cell receptor; second, T helper cells must signal through CD40 ligand (CD40L) and cytokines IL-2, IL-4, IL-5, and IL-21 to initiate B cell proliferation and differentiation into plasma cells (Foy et al., 1996; Kovanen and Leonard, 2004).

Since negative selection in the thymus should have reduced the number of self-antigen-specific T cells, the latter signal to self-reactive B cells is limited.

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However, self-reactive B cells may receive signals from T helper cells responding to foreign antigens during infections, so-called bystander activation.

More importantly, infections only rarely trigger autoantibody diseases, like Guillain–Barré syndrome. Efficient B cell intrinsic tolerance mechanisms must be responsible for the fact that only 1 in 1000 people infected with Campylobacter pylori develops autoantibodies that cross-react with components of peripheral nerves (Ang et al., 2004).

Interestingly, antibody production can be partially independent of T cell help, when B cells receive stimulatory signals from bacterial flagellins, cell-wall lipopolysaccharides, and unmethylated CpG dinucleotides, which are recognized by Toll-like receptors (TLR) (Beutler, 2004). How this potentially dangerous pathway is dampened is not known in detail. Dysregulated activity of the TLR9 pathway leads to pathological accumulation of circulating IgG–self-DNA complexes, and is a potent driver of the production of autoantibodies against IgG and DNA (Leadbetter et al., 2002).

Inadequate clearance of apoptotic cells with exposed CpG DNA and other nuclear antigens may account for the striking association between systemic lupus erythematosus (SLE) and genetic deficiencies in classical complement pathway components (Taylor et al., 2000).

Mature T cells are activated by T cell receptor ligation and costimulation. Without costimulation, tolerance is favored. The most important costimulus is the interaction of CD28 on T cells and the B7 proteins CD80 and CD86 on antigen-presenting cells. TLR signaling induces expression of B7 molecules and enhances the survival and clonal expansion of T cells. Therefore, blocking B7–CD28 interactions may be an attractive way to induce tolerance. However, this treatment may also decrease thymic deletion and interfere with regulatory T cell function and intrinsic T cell regulation

by CTLA4.

9

organs (Radic and Weigert, 1994; Ray et al., 1996).

Antibodies created by this process can have markedly increased affinities for self-antigens.

Follicular B cell differentiation generates longlived plasma and memory cells, which are able to secret antibodies indefinitely (Slifka et al., 1998).

Autologous DNA, an important self-antigen target in systemic lupus erythematosus (SLE), is abundantly presented by numerous apoptotic cells in germinal centers (Rosen and Casciola-Rosen, 2001), where it represents a powerful potential stimulus for autoantibody production. It has been found that anti-double-stranded DNA antibodies are somatically mutated in animal models of SLE (Radic and Weigert, 1994).

In addition to CD40L, follicular T cells display high levels of ICOS, which is required for germinal center antibody responses in mice and humans (Sharpe and Freeman, 2002; Kroczek et al., 2004).

Follicular T cells are also dependent on costimulation through OX40L (Walker et al., 2000). T cell entry into follicles is not induced in the absence of microbial TLR agonist (Kearney et al., 1994).

Since self-antigens usually do not stimulate TLR signaling, this strict regulation of follicular T helper cell differentiation may block self-reactive T cells from delivering help to germinal center B cells.

9. Tolerance at the effector phase The mechanisms involved in preventing autoimmunity at target organs are only just beginning to be elucidated. Often pathology is limited to focal areas, like circumscribed skin lesions in pemphigus or single-joint inflammation in rheumatoid arthritis. Pathology depends on multiple factors, including immunologic cascades involving Fc receptors, mast cells, neutrophils, and complement (Wipke et al., 2004; Monach et al., 2004).

8. Regulation of self-reactive lymphocytes in follicles

10. Conclusions

Somatic hypermutation occurs in the periphery in germinal center follicles of secondary lymphoid

The mucosa of the gastrointestinal tract is a major site of pathogen entry. The gut-associated immune

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system needs to remain hyporesponsive to food antigens and commensal bacteria while mounting an efficient response against pathogens. Immune responses must be exactly coordinated and regulated in order to effectively cure an infection and to avoid chronic inflammation. Autoimmune diseases can be considered as immune responses with defects in mechanisms that control selftolerance. Every organ of the digestive system can be the target of an autoimmune response, either in systemic or in organ-specific autoimmune diseases. Although many self-tolerance mechanisms exist, defects in a single checkpoint can lead to autoimmune disease. Clinical manifestations of autoimmune diseases are often seen only after a latent period of many years and then only against a few proteins or organs. There seems to be hundreds of genes involved in the checkpoints of self-tolerance. Common analysis of DNA polymorphisms will not be effective in identifying predisposing defects, rather exon resequencing of individuals with autoimmune disease will be required.

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Handbook of Systemic Autoimmune Diseases, Volume 8 Digestive Involvement in Systemic Autoimmune Diseases Josep Font, Manuel Ramos-Casals and Juan Rodés, editors

CHAPTER 2

Imaging Techniques in Digestive Diseases Carmen Ayusoa, Mario Pagésa, Luis Donosob, a

Radiology Department, Diagnostic Imaging Centre, Hospital Clinic, University of Barcelona, Abdomen Unit (CT and MRI), IDIBAPS, Villarroel 170, 08036 Barcelona, Spain b Diagnostic Imaging Centre, Hospital Clinic, University of Barcelona, IDIBAPS, Villarroel 170, 08036 Barcelona, Spain

1. Introduction Gastrointestinal (GI) manifestations are common in patients with autoimmune diseases and can involve any part of the GI tract or the hepatobiliary system.

Furthermore, abdominal symptoms may overlap those due to other factors related to the special circumstances of autoimmune disease, such as sideeffects of medication. Imaging techniques have an important role in the diagnosis and management of pathologic abdominal conditions in these patients.

Recent technological advances have brought about considerable improvement in abdominal imaging.

This chapter provides an overview of the imaging modalities available in the diagnosis of GI involvement in the context of autoimmune diseases. A brief description of the basic principles underlying each technique is provided and the advantages and limitations of the different imaging techniques, including the newest contrast agents for ultrasound (US) and magnetic resonance (MR), are discussed.

2. Imaging modalities 2.1. Plain abdominal film and barium studies Plain abdominal films are currently mostly indicated in the clinical context of acute abdominal Corresponding author.

Tel.: +34-93-227-5412; Fax: +34-93-227-9323 E-mail address: ldonoso@clinic.ub.es r 2008 Elsevier B.V. All rights reserved.

DOI: 10.1016/S1571-5078(07)00002-5

disorders. Plain films can depict bowel distension or abnormalities in the distribution of abdominal gas, such as free intraperitoneal air, pneumatosis intestinalis, ileus or pseudo-obstructive pattern, or pylephlebitis. Although the imaging examination based on plain films of the abdomen sometimes provides enough definitive information to indicate a particular surgical or conservative treatment, it more often represents the first step in a more complex diagnostic imaging process.

Endoscopic procedures for the study of the GI pathology have dramatically decreased the indications for contrast-enhanced bowel radiographs.

However, barium studies carried out using dynamic techniques such as videofluoroscopy are increasingly used to study the functional disorders of the pharynx and esophagus.

2.2. Ultrasound or ultrasonography The commercial availability of high-resolution ‘gray scale’ equipment since 1974 has made US one of the mainstays in the study of the abdomen and particularly the hepatobiliary system. The basic principle underlying US is the transmission of sound waves into the abdominal organs from a transducer, which converts electrical energy into sound waves and vice versa. As the US wave passes through the abdominal tissues, it is affected by changes in tissue type and is refracted and reflected at interfaces between tissues with

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differing acoustic impedance. The transducer is able to detect the reflected sound waves and uses the time delay from the transmission to calculate depth within the body. The incoming vibrations are converted into electrical pulses and transformed into images by the US scanner. Current standard US of the abdomen uses state-of-the-art hardware and software together with a 3.5 or 5 MHz transducer and optional Doppler facilities.

The general availability and relatively low cost of US, together with the fact that it does not employ ionizing radiation, have ensured that it is widely used to rule out abdominal pathology.

US is often performed as the first step in the evaluation of abdominal emergencies. Moreover, it is the imaging technique of choice for screening patients with suspected focal liver lesions and also for evaluating gallbladder and biliary tree pathology.

US enables real-time studies, and the radiologist can select the most appropriate cross-sectional plane to obtain the desired information. This property enables US to guide a wide range of interventional procedures, such as aspiration biopsies, drainage of abdominal collections, or percutaneous ablative treatments of primary tumors and metastases.

There are no contraindications for US, although its effectiveness decreases in obese patients and in those with air-distended bowel loops, which make it difficult to evaluate the underlying tissues. In fact, air interposed between the transducer and the pancreas often limits the assessment of this organ.

Color, spectral, and power Doppler imaging provide a non-invasive method of measuring flow in the abdominal vessels and assessing vascularity within a lesion. Spectral Doppler provides a tracing of the Doppler wave from which it is possible to calculate various indices, including peak systolic velocity and resistive indices. Color Doppler enables the direction of blood flow to be determined. Power Doppler displays the integrated power of the color signal to depict the presence of blood flow. The pulsed Doppler technique can provide Doppler shift data selectively from a small segment along the US beam, enabling us to select a small vessel and quantify the velocity of flow through it (Fig. 1).

Tissue harmonic imaging uses secondary frequencies which are multiples of the fundamental transmitted frequency. The resulting harmonic images have fewer artifacts and better space resolution. Harmonic imaging is especially useful when contrast agents are used.

US contrast agents consist of very small gasfilled microbubbles, which are supported by a shell of biologically inert material. Microbubbles produce unique acoustic signatures that allow their signal to be separated from tissue echoes. The US system takes advantage of the strong echogenicity of the contrast agent to create an enhanced image of the area of interest. US contrast agents are especially useful for characterizing liver lesions (von Herbay et al., 2004; Burns and Wilson, 2007) and assessing the efficacy of percutaneous treatments.

2.3. Computed tomography (CT) CT shows cross-sectional views of patient anatomy. CT involves multiple X-ray transmission measurements through the patient. The information acquired is processed by a computer, which uses mathematical techniques to generate a picture of the internal structures in cross-section. Body CT was introduced in 1974. Rapid development led to the early abandonment of the initial dual-slice scanner in favor of single-detector row scanners and incremental technology. At the end of 1980s, improvements in tube technology and computing led to the advent of helical CT. This faster volumetric acquisition allowed better quality image reconstructions to be obtained in different planes. The development of multidetector CT (MDCT) began in earnest in 1998 when four-slice scanners were introduced. Systems with 6-, 8-, 10-, 16-, 40-, and 64-detector arrays have since become available.

The simultaneous acquisition of multiple (16, 64, or even more) continuous slices during one sub-second gantry rotation has improved acquisition speed, resulting in faster imaging protocols. Furthermore, improvements in the z-axis coverage speed have enabled nearly isotropic

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Figure 1. Doppler ultrasound demonstrates patency of portal vein. Doppler is displayed in images (Color Doppler) and graphically (Spectral Doppler). (See Colour Plate Section.)

image acquisition, providing high-resolution multiplanar reformations (MPR) and making excellent three-dimensional (3-D) displays possible (Prokop 2005). The advantages of MDCT are a consequence of (1) shorter scan duration, which reduces motion artifacts and enables a well-defined solid parenchymal phase of contrast enhancement and thus better adjustment of contrast medium injection rate, volume, and concentration; (2) longer scan ranges that permit very good quality CT angiographic studies of the whole body; and (3) thinner sections that permit arbitrary imaging planes, MPR (Fig. 2), and 3-D rendering (Fig. 3).

A challenge presented by multidetector-row CT is posed by the substantial increase in the number of reconstructed cross-sections (easily more than 1000 axial images) that are rapidly created and in need of analysis. This situation requires more sophisticated visualization techniques for the assessment of volumetric data, not only in terms

of 3-D workstations but also in fast automated processing and user interfaces to replace the analysis of transverse reconstructions by other alternatives. The large data load means that new ways of viewing, processing, archiving, and displaying images are necessary, and more time is needed to analyze the data than with single-slice helical CT. Images obtained with MDCT show increased image noise as the section collimation is reduced.

To keep the noise low, thicker sections have to be reconstructed. Special attention has to be paid to avoid a dramatic increase in the radiation dose to the patients using MDCT protocols, and acquisition protocols must be carefully adjusted to reduce the radiation dose.

The indications for abdominal CT in patients with autoimmune diseases cover a wide spectrum ranging from inflammatory conditions, such as abdominal sepsis or acute pancreatitis, to

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Figure 2. Computed tomography angiogram. (a) Arterial phase: MPR in a sagittal view shows the normal anatomy of the abdominal aorta and the superior mesenteric artery. (b) Portal phase: MPR in an oblique-coronal plane shows the regular patency of the portal, and superior mesenteric veins.

Imaging Techniques in Digestive Diseases

Figure 3. Computed tomography angiogram provides exquisite detail of the anatomic distribution of the celiac artery and superior mesenteric artery. The hepatic artery and its segmental branches are also displayed. (a) Maximum intensity projection image. (b) Volume-rendered image.

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neoplastic diseases, such as lymphoma or other solid tumors, where CT is a useful tool to define the tumor extension. One of the most important indications for CT is to rule out vascular complications that are fairly common in this context, such as Budd–Chiari syndrome; however, the most common and most challenging diagnostic and therapeutic problem is acute abdominal pain.

Ischemic bowel disease is a very common and severe complication in patients with autoimmune diseases, and it has a very poor prognosis when the diagnosis is delayed.

CT can also be used to direct percutaneous interventional diagnostic procedures such as fine-needle biopsy of solid focal lesions (Fig. 4), tru-cut biopsies of solid organs (liver, kidney) to rule out diffuse parenchymal disease, or percutaneous therapeutic procedures such as the drainage of abdominal fluid collections. Low-dose CT fluoroscopy allows continuous control of the tip of the needle in real-time mode to avoid damage to vital structures during interventional procedures.

MDCT angiography has become a valuable minimally invasive tool for the visualization of normal vascular anatomy and its variants, as well as pathologic conditions of abdominal vessels. As abdominal pain is a frequent clinical problem in patients with autoimmune diseases and bowel ischemia has to be ruled out, the discussion of MDCT angiography in this chapter will focus on the mesenteric vessels. Although mesenteric MDCT angiography can be specifically performed as a single study, it is often carried out in combination with studies of solid organs or more generalized abdominal imaging. In patients with suspected mesenteric ischemia, CT may help detect ischemic changes in the affected small bowel loops and mesentery, such as bowel wall thickening, submucosal hemorrhage, increased or decreased enhancement of the bowel wall, or even pathologic changes in the mesenteric vasculature like atherosclerotic stenosis, thrombosis, or occlusion (Fig. 5).

To depict these findings, both unenhanced and biphase CT abdominal studies (arterial and venous phases) are usually performed. Bowel opacification should be avoided to improve vascular visualization in 3-D imaging post-processing. A total of

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Figure 4. CT-fluoroscopy-guided fine-needle biopsy. Irregular thickening of the bladder wall can be seen secondary to a primary bladder neoplasm. A 20-gauge needle is placed in an enlarged left iliac lymph node. Metastatic tumor nests were found in the pathologic study of the sample.

100–150 ml of non-ionic iodinated contrast material (300–370 mg of iodine per milliliter) is usually administered with a power injector at a rate of 2–4 ml/s. Three-dimensional imaging postprocessing of data sets from the arterial and venous phases in the workstation allows real-time viewing of axial and multiplanar images and provides additional sophisticated rendering options, such as thick and curved MPR, thin-slab maximum intensity projection (MIP), and volume rendering (VR) reconstructions (Fig. 6). The sensitivity of CT in detecting bowel ischemia has reached 82% (Klein et al., 1995) and is comparable to that of angiography. For this reason, the indications for angiography are moving from diagnostic to therapeutic aspects. Angiography enables endovascular treatment, such as percutaneous transluminal angioplasty or stent placement, in selected patients with acute mesenteric ischemia caused by vascular occlusion (Resch et al., 2005).

2.4. Magnetic resonance MR is based on the relaxation properties of hydrogen atoms when they are subjected to a strong magnetic field, and the power of MR equipment is quantified by Teslas (T), a measurement of magnetic flux density. The first commercial MR scanners became available in the early 1980s. MR applications in relatively motionless body parts, such as the brain, spine, or musculoskeletal system, quickly took hold in the field of medical diagnosis, because high-quality images not conditioned by artifacts due to bone structures were obtained, with far better contrast resolution than CT. However, abdominal MR imaging was limited by long acquisition times that produced severe motion artifacts due to respiratory and peristaltic movements. These limitations were overcome through technical advances such as the development of ultrafast single-shot sequences, and images providing excellent anatomic detail can

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Figure 5. Acute intestinal ischemia due to nearly total occlusion of the superior mesenteric artery (SMA). (a) Axial CT section at the level of the SMA origin shows a very significant reduction in the patent lumen of the artery. (b) A small amount of gas can be seen in the superior mesenteric vein. (c) There is some gas collection in the wall of the right colon and also in the wall of the terminal ileum due to intestinal pneumatosis.

now be obtained routinely. Abdominal MR is currently a widely accepted imaging technique for the study of multiple pathologies of the GI, including pancreatic and hepatobiliary diseases.

Technical improvements have led to the development of new MR techniques, such as MR cholangiopancreatography (MRC) or MR angiography.

2.4.1. MR technique MR abdominal studies are routinely obtained with a torso phased-array surface coil. MR examinations

consist of the acquisition of different sequences according to particular study protocols, depending on the abdominal organ studied or the suspected pathology. However, most of the abdominal protocols include T1-weighted sequences (in-phase/ opposed phase to detect fatty infiltration, and/or fat-suppressed sequences), T2-weighted sequences (useful in tumor characterization), and a dynamic contrast-enhanced sequence (to demonstrate the enhancing vascular pattern of the lesions).

MR’s multiplanar capacity is one of the most interesting characteristics of this imaging

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Figure 6. Acute embolic intestinal ischemia. (a) CT topogram shows dilated small bowel loops. (b) MPR demonstrates multiple filling defects into the SMA. (c) Volume-rendered image of the same patient showing an almost complete occlusion of the SMA.

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modality: MR images can be acquired in any sectional plane. This property was initially one of the main advantages of MR over CT, although currently MDCT also allows high-quality reconstructions in any orientation.

MR has higher contrast resolution than CT, although it has less spatial resolution. In other words, there are more signal intensity changes between tissues, although less definition in limiting structures.

2.4.2. Contrast agents The most common MR contrast agents are the chelates of gadolinium, which are non-specific extracellular contrast agents. After intravenous administration, they are initially distributed in the intravascular space, but they are rapidly cleared into the interstitial space, filtered through the capillaries into the extracellular space, and are eventually excreted by the kidneys. The main indications of contrast-enhanced MR include the study of neoplastic lesions to assess tumor vascularity, vascular pathologies, and MR angiography. One advantage of these contrast agents versus the iodinated contrast media used in CT examinations is their lower or non-existent nephrotoxicity, and gadolinium contrast-enhanced

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MR studies have long been a viable alternative in patients with renal failure or iodine allergy.

However, a new severe entity which seems to be related to some gadolinium chelates has recently been reported in patients with renal failure: nephrogenic systemic fibrosis (Marckmann et al., 2006). Thus, the chelates of gadolinium should only be administered in these patients when it is essential.

Hepatobiliary contrast agents partially pass from blood through the hepatobiliary system with partial excretion through the kidneys and the bile ducts. These liver-specific contrast agents are selectively uptaken by the hepatocytes, leading to an increase in signal intensity on T1-weighted sequences of the normal liver parenchyma and also of the focal hepatocellular liver lesions. Some of the hepatobiliary contrast agents can be rapidly injected and dynamic hepatic studies can be performed to assess the anatomy of the biliary tree, to detect bile leaks, and also to detect and characterize hepatic tumors (Fig. 7).

Reticuloendothelial contrast agents are removed from the blood by the reticuloendothelial cells of the liver and the spleen. These tissue-specific contrast agents consist of small particles of iron oxide. They are injected intravenously and cleared by the reticuloendothelial system, located

Figure 7. Focal nodular hyperplasia studied by MR imaging. (a) T1-weighted gradient-echo MR image with fat suppression. The lesion exhibits homogeneous intense enhancement in the arterial phase (20 s following the injection of hepatobiliary contrast agent). (b) 20 min after injection (same sequence as (a)), the lesion is slightly hyperintense in comparison to normal liver parenchyma due to its hepatocellular nature.

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predominantly in the Kupffer cells of the liver.

Reticuloendothelial contrast agents produce a negative enhancement by decreasing signal intensity in T2-weighted sequences. Iron is added to the iron pool and excreted by the kidneys. These contrast agents are useful in characterizing some focal hepatic lesions, such as focal nodular hyperplasia.

2.4.3. Indications and limitations Absolute contraindications for MR studies are pacemakers and other ferromagnetic implants, such as cochlear implants, vagus nerve stimulators, or insulin pumps. Although other modern medical devices are mainly manufactured without ferromagnetic materials, the magnetic properties of valvular prostheses and stents must be evaluated before a patient can undergo MR. Patients must be queried about possible ferromagnetic foreign bodies, and a plain film X-ray is sometimes necessary to rule out their presence.

Liver MR is an excellent imaging technique to characterize non-specific focal lesions previously detected in US or CT studies. Among other indications, hepatic MR is widely used to stage primary hepatic tumors, to evaluate potential living liver donors, and to evaluate complications after liver transplantation. It is also usually performed in patients with liver metastasis prior to surgical resection.

MRC is a non-invasive technique to depict the biliary tree and the pancreatic ducts. The images obtained are comparable to endoscopic retrograde cholangiography (ERC). MRC is performed using heavily T2-weighted sequences that demonstrate the fluid-containing bile ducts as high-signal-intensity structures. This technique has demonstrated high sensitivity and specificity in the diagnosis of the location and etiology of biliary obstruction (Fig. 8) to the extent that ERC is usually indicated only when a therapeutic approach is needed.

MR enteroclysis is an emerging technique for the evaluation of small bowel diseases. It combines the study of luminal, mural, and extramural abnormalities. It can evaluate not only bowel wall ulcers but also transmural complications in inflammatory bowel disease (Wiarda et al., 2006). (Fig. 9)

Figure 8. MR cholangiography depicts the biliary tree and pancreatic ducts. Multiple filling defects typical of stones are shown in the lumen of the common bile duct.

Figure 9. MR enteroclysis shows anatomic demonstration of the small bowel. Coronal MR image clearly depicts fluid-filled bowel loops and provides excellent contrast between the bowel wall and surrounding structures.

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Figure 10. Images for staging an anaplastic lymphoma. PET/CT images. (a) Axial CT image at the pelvis shows an enlarged external iliac lymph node. (b) Corresponding axial maximum intensity projection image showing intense FDG uptake in the external iliac lymph node. (c) PET/CT fused image at the same pelvic level confirms the coincidence of both pathologic images. (See Colour Plate Section.)