Diagnostic Modalities in Crohn's Disease [1 ed.] 9781617283666, 9781606927014

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Copyright © 2008. Nova Science Publishers, Incorporated. All rights reserved. Girelli, Carlo M., and Luca G. Crespit. Diagnostic Modalities in Crohn's Disease, Nova Science Publishers, Incorporated, 2008. ProQuest Ebook Central,

Copyright © 2008. Nova Science Publishers, Incorporated. All rights reserved. Girelli, Carlo M., and Luca G. Crespit. Diagnostic Modalities in Crohn's Disease, Nova Science Publishers, Incorporated, 2008. ProQuest Ebook Central,

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DIAGNOSTIC MODALITIES IN CROHN'S DISEASE

No part of this digital document may be reproduced, stored in a retrieval system or transmitted in any form or by any means. The publisher has taken reasonable care in the preparation of this digital document, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information Girelli, contained Carlo M., and Luca G.This Crespit. Diagnostic Modalities in Crohn's Disease, Science Publishers, Incorporated, herein. digital document is sold with the clearNova understanding that the publisher is not engaged in

Copyright © 2008. Nova Science Publishers, Incorporated. All rights reserved. Girelli, Carlo M., and Luca G. Crespit. Diagnostic Modalities in Crohn's Disease, Nova Science Publishers, Incorporated,

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DIAGNOSTIC MODALITIES IN CROHN'S DISEASE

CARLO M. GIRELLI AND

LUCA G. CRESPI EDITORS

Nova Biomedical Books New York

Girelli, Carlo M., and Luca G. Crespit. Diagnostic Modalities in Crohn's Disease, Nova Science Publishers, Incorporated,

Copyright © 2009 by Nova Science Publishers, Inc.

Copyright © 2008. Nova Science Publishers, Incorporated. All rights reserved.

All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical photocopying, recording or otherwise without the written permission of the Publisher. For permission to use material from this book please contact us: Telephone 631-231-7269; Fax 631-231-8175 Web Site: http://www.novapublishers.com NOTICE TO THE READER The Publisher has taken reasonable care in the preparation of this book, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained in this book. The Publisher shall not be liable for any special, consequential, or exemplary damages resulting, in whole or in part, from the readers’ use of, or reliance upon, this material. Any parts of this book based on government reports are so indicated and copyright is claimed for those parts to the extent applicable to compilations of such works. Independent verification should be sought for any data, advice or recommendations contained in this book. In addition, no responsibility is assumed by the publisher for any injury and/or damage to persons or property arising from any methods, products, instructions, ideas or otherwise contained in this publication. This publication is designed to provide accurate and authoritative information with regard to the subject matter covered herein. It is sold with the clear understanding that the Publisher is not engaged in rendering legal or any other professional services. If legal or any other expert assistance is required, the services of a competent person should be sought. FROM A DECLARATION OF PARTICIPANTS JOINTLY ADOPTED BY A COMMITTEE OF THE AMERICAN BAR ASSOCIATION AND A COMMITTEE OF PUBLISHERS. LIBRARY OF CONGRESS CATALOGING-IN-PUBLICATION DATA Girelli, Carlo M. Diagnostic modalities in Crohn's disease / authors, Carlo M. Girelli, Luca G. Crespi. p. ; cm. Includes bibliographical references and index. ISBN H%RRN 1. Crohn's disease--Diagnosis. I. Crespi, Luca G. II. Title. [DNLM: 1. Crohn Disease--diagnosis. 2. Diagnostic Imaging--methods. WI 512 G524d 2009] RC862.E52G57 2009 616.3'44075--dc22 2008050191

Published by Nova Science Publishers, Inc. Ô   New York

Girelli, Carlo M., and Luca G. Crespit. Diagnostic Modalities in Crohn's Disease, Nova Science Publishers, Incorporated,

CONTENTS

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Preface

vii

Section I: Crohn’s Disease

1

Chapter I

Etiopathogenesis Carlo M. Girelli

3

Chapter II

Epidemiology Carlo M. Girelli

21

Chapter III

Pathology and Clinical Features Carlo M. Girelli

35

Section II: Endoscopic Diagnosis

51

Chapter IV

Ileocolonoscopy Carlo M. Girelli

53

Chapter V

Enteroscopy Carlo M. Girelli

69

Section III: Radiologic Diagnosis

93

Chapter VI

Contrastographic Radiological Imaging F. F. Francone, L. G. Crespi and S. Zaid

95

Chapter VII

Computed Tomography Imaging L. G. Crespi, F. F. Francone and S. Zaid

107

Girelli, Carlo M., and Luca G. Crespit. Diagnostic Modalities in Crohn's Disease, Nova Science Publishers, Incorporated,

Contents

vi Chapter VIII

Magnetic Resonance Imaging S. Zaid, F. F. Francone and L. G. Crespi

123

Chapter IX

Intestinal Ultrasound Carlo M. Girelli

133 147

Index

149

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Contributing Authors

Girelli, Carlo M., and Luca G. Crespit. Diagnostic Modalities in Crohn's Disease, Nova Science Publishers, Incorporated,

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PREFACE Inflammatory bowel disease is a heterogeneous group of chronic, idiopathic, immune-mediated, inflammatory disorders of the gastrointestinal tract, including Crohn’s disease and ulcerative colitis. They have to be distinguished from other inflammatory conditions of the gastrointestinal tract, namely: acute self-limiting colitis and infectious enterocolitides, collagenous and lymphocytic colitis, ischemic colitis, radiation colitis, diversion colitis, diverticular colitis, Behçet disease, and eosinophilic colitis, relying on clinical, pathological, microbiological, biochemical, endoscopic and radiological findings. In contrast to ulcerative colitis, the inflammation of Crohn’s disease is typically patchy, transmural (i.e. all layers of the viscus are involved) and may be located in any segment of the gastrointestinal tract; hence in severe and refractory colonic Crohn’s disease, proctocolectomy is never curative. Yet, for the colonic localization, overlapping features between ulcerative colitis and Crohn’s disease may create diagnostic difficulty, and a differential diagnosis is unfeasible in up to 10% of cases at disease onset; now, unclassified inflammatory bowel disease (IBDU; formerly indeterminate colitis) is the preferred term for this condition. Although rarely fatal, Crohn’s disease is a rather common, long-life disease, mainly affecting young and productive people in western countries, so its psychosocial and economic burden for the individual patient and society is substantial. In the last few years, impressive advances in human genetics, basic science and technology, and new insight from clinical trials of new drugs, have greatly improved our understanding of the mechanism of the disease with important implications for the characterization and the management of inflammatory bowel disease. For example, genetic studies using genome-wide-association and the

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viii

Carlo M. Girelli and Luca G. Crespit

results of clinical trials using targeted cytokine blockade are beginning to shed light on disease heterogeneity and genotype-phenotype relations, clarifying key pathogenetic events of Crohn’s disease, and paving the way to new concepts, such as the pathophysiologic role of cellular autophagy and innate immunity. From a clinical standpoint, new endoscopic and radiologic techniques have revolutionized the diagnostic approach to patients with suspected, known and operated Crohn’s disease. Recently, two endoscopic devices, capsule endoscopy and double balloon enteroscopy have quickly entered the diagnostic arena, the former allowing for safe and patient-friendly visualization of the lumen and mucosa of the entire small bowel, the second for tissue sampling and endoscopic treatment of small bowel lesions. On the other hand, sectional radiologic imaging by computerized tomography (CT), magnetic resonance (MR) and ultrasound has assumed a critical role in the management of Crohn’s disease. Multiplanar reformatted views offered by multidetector technology and the development of new techniques such as enteroclysis or oral administration of polyethylenglycol solution give to CT, at present, an unparalleled capability to depict abnormalities of the bowel wall, mesentery, abdominal and pelvic viscera, and the surrounding soft tissue and osseous structures, by far improving the diagnostic yield of conventional radiologic examination. More recently, MR new time resolving sequences have been shown to provide diagnostic details comparable to CT in the diagnosis of Crohn’s disease without the potential harm of ionizing radiations. Besides, MR spectroscopy — a new molecular-based imaging method — opens a new way in differential diagnosis of Crohn’s disease and ulcerative colitis. Finally, continuous advances in the field of diagnostic ultrasonography and improved skills of operators have increased the importance of sonography of the gastrointestinal tract in the diagnostic workup and medical decision making for many gastrointestinal disorders, especially for Crohn’s disease. For its noninvasiveness, wide availability, accuracy and repeatability, bowel sonography fits very well for follow-up assessment of known and/or resected Crohn’s disease, minimizing costs, radiations and patient discomfort. In this book, the reader will find a preliminary section on the etiopathogenesis, epidemiology, and clinical-pathologic aspects of Crohn’s disease, and — bearing in mind that the best therapeutic choice begins with an accurate diagnosis — an attempt to provide an updated, comprehensive view of the state-of-the-art endoscopic and radiologic procedures used in the diagnosis, staging and management of Crohn’s disease with special emphasis on test appropriateness in the various clinical settings.

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SECTION I: CROHN’S DISEASE

Girelli, Carlo M., and Luca G. Crespit. Diagnostic Modalities in Crohn's Disease, Nova Science Publishers, Incorporated,

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In: Diagnostic Modalities in Crohn's Disease ISBN 978-1-60692-701-4 Editors: C. M. Girelli and L. G. Crespi © 2009 Nova Science Publishers, Inc.

Chapter I

ETIOPATHOGENESIS Carlo M. Girelli

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Hospital of Busto Arsizio (VA), Italy

INTRODUCTION The etiology of Crohn’s disease is unknown, but in the last few years considerable advances in its pathogenesis have been achieved. It is now clear that Crohn’s disease is an immune-mediated disorder that derives from a breakdown of the normal homeostasis among the mucosal barrier, the immune system and the luminal milieu, including commensal bacteria. This homeostatic imbalance leads to the development of aberrant reactivity against intraluminal antigens, triggering a complex cascade of immunologic events ultimately leading to tissue injury, repair and remodeling [1-4]. This dangerous liaison of genetic, environmental and immunologic factors leading to the development of Crohn’s disease (Figure 1.1) will be described in the next pages.

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4

Carlo M. Girelli

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GENETICS Genetic factors are clearly involved in the development of Crohn’s disease, as suggested by familial aggregation and twin studies. The concordance rate of Crohn’s disease in monozygotic twins is up to 50%. Multiple studies have suggested that first-degree relatives of an affected patient carry a risk of inflammatory bowel disease that is 4-20 times as high as that among the control population and the absolute risk of inflammatory bowel disease is estimated around 7% among first-degree family members [5-7]. In addition, there is usually concordance on behavior and location of the disease among subjects of families with multiple affected members. A major breakthrough in the genetics of Crohn’s disease has been the simultaneous discovery from two independent groups of a single nucleotide polymorphism in the chromosome 16 [8,9], the CARD15/NOD2 (caspase recruitment domain family/nucleotide oligomerization domain) gene. There are three mutations found within the region of CARD15/NOD2 that encodes a C-terminal leucine-rich-repeat (LRR) which has a key role for bacterial recognition by cells of the innate immune system. Along with other peptides of the nucleotide oligomerization domain-like receptors (NLR) family — NOD1 (CARD4), CARD12, NALP3, NALP1 — CARD15/NOD2 has a direct function as intracellular pattern recognition receptor(s) (PRRs) of many pathogenassociated molecular patterns (PAMPs) [10], a heterogeneous group of microbial by-products such as lipopolisaccaride, peptydoglican, lipoproteins and flagellin. In particular, CARD15/NOD2 specifically detects muramyl dipeptide (MDP), the immunologically active moiety of the cell wall of Gram positive and Gram negative bacteria [11]. The downstream signaling pathway of CARD15/NOD2 is complex, including nuclear factor kB (NF-kB) activation, a rate-limiting step of pro-inflammatory cascade. Interestingly, CARD15/NOD2 is largely synergistic with toll like receptors (TLR), a family of surface receptors largely represented in the innate immune cells (neutrophils, macrophages, dendritic cells) which are essential in recognizing bacterial antigens [12]. CARD15/NOD2 stimulation contributes to antimicrobial effects through a variety of mechanisms, including cytokine response, production of reactive oxygen species (ROS), intracellular trafficking and maintenance of epithelial barrier integrity [13-17]. Studies in humans and mice have shown that normal CARD15/NOD2 function is required for optimal defensin expression [18,19] and hence, impaired defensin regulation may be a key feature of Crohn’s disease pathogenesis. Human defensin is a

Girelli, Carlo M., and Luca G. Crespit. Diagnostic Modalities in Crohn's Disease, Nova Science Publishers, Incorporated,

Etiopathogenesis

5

bactericidal peptide and its ileal expression is decreased in the affected bowel of patients with Crohn’s disease.

Genetic susceptiblity

Smoking, diet NSAIDs, oral contraceptive

Crohn

Immune response

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Luminal antigens

Figure 1.1. Interaction of factors involved in chronic bowel inflammation in genetically prone host in Crohn’s disease. NSAID, non steroidal anti-inflammatory drugs.

At least one mutation of the CARD15/NOD2 gene is present in near 25-35% of Crohn’s disease patients of European ancestry, but not in Asian or African American patients. CARD15/NOD2 mutations are associated with ileal, stricturing/penetrating disease in young patients [20]. Interestingly, the same mutation has been found in Blau syndrome, a very rare monogenic, highly penetrant, chronic, systemic granulomatous disease [21]. In more recent years, the development of genome-wide association (GWA) technique has fuelled the research of other putative genes in inflammatory bowel disease. Briefly, GWA consists of scanning the genome of people affected by a disease for hundreds of thousands of markers of genetic variations for a comparison with healthy controls. If a genetic variant is significantly more frequent in people with the disease, it is said to be associated and highlights this region of the genome as one likely to bear a susceptibility gene that predisposes to the disease being studied. By this genomic approach new candidate genes have

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Carlo M. Girelli

been associated with Crohn’s disease, the best studied being ATG16L1 and IRGM. ATG16L1 variants rs2241879 and T300A have been recently detected in a German population of patients with Crohn’s disease without epistatic interaction with other susceptibility genes [22], confirming the results of the preliminary report from Hampe et al. [23] and the following replication studies [24]. ATG16L1 encodes a protein called autophagy related 16 like-1 (ATG16L1) and the T300A mutation consists in the replacement of the amino acid threonine with alanine in position 300. IRGM — a gene pending more replication studies — encodes another key component of autophagy, and its variants have been associated with Crohn’s disease [24-25]. Autophagy is a catabolic process enabling the eukaryotic cells to capture cytoplasmatic components for degradation within lysosomes and this mechanism is involved in many physiological and pathological conditions including growth, morphogenesis, cancer and infectious disease. Taken together, these genomic studies suggest that defective autophagy – a previously unsuspected process – may have a prominent role in the pathophysiology of Crohn’s disease. IL23R polymorphism has been associated with Crohn’s disease in one of the first GWA scans [26] and it was rapidly replicated [24]. IL-23 is a pivotal cytokine in the differentiation of T helper cells, especially in the differentiation into Th17 lineage. In animal models the Th17 T cell subset has been shown to mediate chronic autoimmune inflammatory conditions with a central role for IL23 in the development of intestinal disease, as it will be shown in the following section. Other putative genes, namely IBD5 locus (also known as SCL22A4 and SCL22A5 mutations) — controlling the expression of organic cation transporter (OCTN1 and OCTN2) on chromosome 5 which are thought to play a critical role in elimination of organic cations and environmental toxins by the intestinal epithelial layer [27-29] — TNFSF15 on chromosome 9, gene desert (on chromosomes 5p13, 10q21, and 1q), PHOX2B, and NCF4 have been associated with Crohn’s disease, pending more replication studies for confirmation [25,26,30,31] (Table 1.1). In summary, in the last few years many new susceptibility genes for Crohn’s disease have been identified, shedding light on new, previously unsuspected, pathogenetic pathways and determining a shift in our understanding of the mechanism of the disease towards the primary role of innate immunity. In particular, the identification of NOD2/CARD15 and ATG16L1 susceptibility gene for Crohn’s disease created a paradox because these mutations result in loss of function, suggesting that Crohn’s disease may be a primary immunodeficiency

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Etiopathogenesis

7

condition with secondary overactivation of the adaptive immune system. We are waiting for replication studies on putative susceptibility genes and meta-analyses to improve our knowledge in this area.

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Table 1.1. Genes involved in Crohn’s disease from single nucleotide polymorphism (SNP) and genome wide association(GWA) studies and their implications on pathogenesis and therapy Gene

Chromosome

Evidence

CARD15/NOD2

16q12

+++

ATG16L1

2q37.1

+++

IL23R IRGM

1p31 5p33

++ ++

SLC22A4/SLC22A5 PHOX2B

5 4p13

+ +

NCF4

22q24

+

Putative mechanism Altered microbial “sensing”/↓αdefensin Impaired autophagy IL-23 receptor Impaired autophagy OCT defective Neuroendocrine cell regulation ROS regulation

Phenotype

Target drugs

Ileal disease, young people Ileal disease Unknown Unknown

Innate immunity manipulation

Unknown Unknown

Innate immunity manipulation Ustekimumab/ABT874 Innate immunity manipulation Rosiglitazone, 5-ASA -

Unknown

-

CARD, caspase recruitment domain; NOD, nucleotide oligomerization domain; ATG16L1, autophagy related 16 like 1; IL23R, interleukin 23 receptor; SLC22A4/SLC22A5, solute carrier family 22; OCT, organic cation transporters; NFkB, nuclear factor kB; IRGM, immunity related GTPase family M; PPARG, peroxisome proliferative activated receptor γ; ROS, reactive oxygen species; PHOH2B; NCF4, 5-ASA, mesalazine.

THE LUMINAL ENVIRONMENT AND THE INTESTINAL EPITHELIAL BARRIER The commensal intestinal flora is made up of more bacteria than cells in the human body (1014 vs 1013) and the number of genes expressed by this intestinal microbiota is estimated to be more than 100 times that of the somatic cells of the human body [32], many of which contribute to essential functions such as development of the mucosal immune system, digestion and uptake of fat and complex carbohydrates, and production of vitamins [33,34]. This huge intestinal bacterial mass consists of over 500 different species, mainly anaerobic bacteria

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Carlo M. Girelli

that had not been fully identified by standard culture techniques. Each individual harbors a distinct composition of bacteria that appears to remain constant over time and is defined by both genetics of the individual and maternal organisms to which the individual is exposed at the time of weaning [35]. It is not surprising that healthy individuals have developed a tolerance to intestinal microbiota and it is now clear that a breakdown of this tolerance can lead, in susceptible individuals, to the development of inflammatory bowel disease [36]. This conclusion is supported by the fact that germ-free animals do not develop intestinal inflammation, with the exception of the SAMP1/YitFc mouse, which develops spontaneous ileitis similar to Crohn’s disease [37]. Furthermore, Crohn’s disease occurs more commonly in the terminal ileum and colon, areas of the bowel with the highest bacterial burden and improves with surgical fecal stream diversion or the use of antibiotics [38]. Several mechanisms have been identified by which tolerance to commensal microbiota is induced and maintained. Innate mechanisms include the preservation of a protective mucosal barrier, which excludes bacteria and their products from contact with immune cells in the intestinal lamina propria; once this barrier is breeched, innate immune responses by inflammatory cells result in bacterial clearance. Adaptive immune responses that maintain tolerance to commensal bacteria include the induction of mucosal IgA antibodies and the differentiation of regulatory T cells (Treg) against bacterial antigens, preventing the clonal differentiation of potentially destructive Th1 and Th17 cells [39]. Maintenance of the physical barrier function of the intestine is likely a mechanism for the prevention of abnormal intestinal inflammation. Evidence for increased intestinal permeability is found in inflamed tissue from patients with Crohn’s disease [15, 40]; it can predict relapse after clinical remission and is found in unaffected first-degree relatives of Crohn’s disease patients [41,42]. These observations are supported by experimental data on animal models [43]. The bowel epithelial cells are joined by tight junctions that functionally exclude large molecules and micro-organisms. Tight junctions are made up of a variety of proteins, including occluding, junctional-adhesion molecules (JAM), claudins and tricelliulin [44] that collectively determine which molecules can transverse the paracellular space. Tight junction production and distribution by epithelial cells is regulated by neuroendocrine and immunological factors and defects in tight junction have been identified in Crohn’s disease patients [45]. Both interleukin 13 and TNFα will increase the expression of the tight junction pore-forming protein, claudin2 [46] that can directly enhance permeability. In addition, TNFα, IFNγ and ethanol activates myosin light chain kinase (MLCK) in epithelial cells. MLCK

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Etiopathogenesis

9

activation results in the phosphorylation of myosin and a disruption of the cytoskeletal components of the tight junctions [47]. As reported in the previous paragraph, further evidence for the role of intestinal barrier dysfunction in Crohn’s disease is provided by genetic susceptibility studies regarding the mutations in the IBD5 locus. Table 2.1 Molecular pattern recognition of TLRs

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Receptor TLR1 TLR2 TLR3 TLR4 TLR5 TLR6 TLR7/TLR8 TLR9 TLR11

Microbial motif ligand Triacyl-lipopeptides Lipoproteins, lipopeptides dsRNA LPS Flagellin Diacyl-lipopeptydes ssRNA Non-methylated CpG DNA Components of uropathogenetic bacteria

THE IMMUNE RESPONSE Both innate (neutrophils, macrophages, dendritic cells, Paneth cells) and adaptive (T and B cells) immune response is activated in Crohn’s disease. Most of the recent research suggests that innate immune cells dysfunction may be a primary event in the pathogenesis of Crohn’s disease [48]. Understanding of innate immunity has accelerated greatly with the discovery of several microbial sensors, the PRRs. Toll-like receptors (TLR) along with NLR family of PRRs seem to play essential roles in intestinal mucosa homeostasis and their alteration may be critical in Crohn’s disease development [49-50]. The mammalian TLR family consists of 13 members, each TLR having its intrinsic signaling pathway and inducing specific biological responses against microorganisms. Recognition of microbial components by TLR triggers activation of signal transduction pathways, which then induce dendritic cells maturation and cytokine production, resulting in development of adaptive immunity. Table 2.1 summarizes the principal TLR and their specific microbial motif ligand. The mammalian NLR family comprises more than 20 members whose defining molecular characteristics

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are a C-terminal leucine-rich repeat (LRR) domain and an N-terminal proteinprotein interaction domain composed of a CARD. Many studies have shown that several NLRs are necessary sensors of specific PAMPs, such as peptidoglycan, lipopolisaccaride, and flagellin. NLRs include NOD1 and NOD2 which are essential for the detection of MDP, the largest molecular motif common to Grampositive and Gram-negative bacteria [51]. The signaling pathway downstream of NLRs include the NF-kB pathway and activation of mitogen activated protein kinase (MAPK) which upregulates proinflammatory cytokines and adhesion molecules expression and activate the caspase 1 inflammasome [52]. Activation of NK-kB stimulates expression of several molecules relevant to the pathogenesis of Crohn’s disease, such as cytokines, chemokines, adhesion molecules and costimulatory molecules (CD40, CD80, CD86 and the inducible T-cell co-stimulator ICOS) [53-54] (Figure 2.1). The production of cytokines is enhanced in Crohn’s disease from cells of either the innate or adaptive immune system (table 3.1). Regarding adaptive immune response, Crohn’s disease has traditionally been considered a prototypical T-helper-1 (Th1) condition, mediated by the interleukin-12/interferon-γ/TNF cytokine axis and the successful treatment with anti-TNF therapy has strengthened this hypothesis [2]. Yet, a recently discovered pathway, namely interleukin-23 (IL-23)/interleukin-17 (IL-17) may have a prominent pathogenetic role in Crohn’s disease [55,56]. IL-23 drives a population of T cells that produce IL-17, IL-6 and TNFα, (Th17 cells). There is now a considerable amount of evidence from experimental studies that the Th17 pathway is critical for the development of intestinal inflammation in animal models. Bacterial colonization stimulates IL-23 expression by ileal dendritic cells and the levels of IL-23 and IL-17 are increased in Crohn’s disease tissue. The discovery of IL23 susceptibility gene for Crohn’s disease has further corroborated this hypothesis [26]. Interestingly, the IL-12 – IFNγ and IL-23 – IL-17 pathways seem to be mutually exclusive since IFNγ suppresses IL-17 and vice versa [20]; this fact might explain the relatively high rate of refractoriness to TNFα blockade in patients with Crohn’s disease. Furthermore, defective apoptosis of T cells — a well described event in Crohn’s disease — may help to self-perpetuate the inflammatory process [57]. Finally, regulatory T cells (Treg), originally called suppressor cells for their capability of inhibiting the outgrowth of antigen-reactive Th and natural killer T cells, have been shown to reverse experimental colitis in animal models [58] but results in human studies are scarce and conflicting.

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Etiopathogenesis

PDG

dsRNA

11

lipopolysaccaride flagellin

IL-1

CpG DNA

TLR2

TNF

TLR3

TLR4 TLR5 TLR9

IL-1R TNFR

NLRs

MAPK

NF-kB

MDPP

transcription

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Adhesion molecules Caspase-1 inflammasome

Pro-inflammatory cytokines, ICOS

Figure 2.1. Binding of pro-inflammatory citokines (TNF and IL-1) by specific receptors (TNFR, IL-1R) and binding of microbial products by pattern recognition receptors (TLR and NLR) on the cell membrane and in the cytoplasm activates NF-kB and MAPK that, in turn, stimulate the transcription of many pro-inflammatory and anti-inflammatory cytokines. TNF, tumor necrosis factor; IL-1, interleukin 1; IL-1R, interleukin 1 receptor; TLR, toll like receptor; PDG, peptidoglycan; CpG DNA, DNA containing cytosineguanine repeats; NLRs, NOD like receptors; MDP, muramyl dipeptide; MAPK, mitogen activated protein kinase; ICOS, inducible T-cell co-stimulator.

CELL TRAFFICKING Circulating effector and regulatory cells enter the intestine through a highly selective mechanism that involves interaction with the vascular endothelium, diapedesis through the vessel wall and migration to the lamina propria. Adhesion molecules such as intercellular adhesion molecule 1 (ICAM 1) are necessary for circulating cells to be able to stick to the activated endothelium, which is the first step in the extravasation of mononuclear cells and polymorph nuclear cells into

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Carlo M. Girelli

12

the inflamed tissue. Circulating T cells that bear α4β7 integrin bind to the endothelium of the bowel post capillary venules that selectively express mucosal vascular addressin cell adhesion molecule (MadCAM) [59]. Furthermore, inflammatory cytokines such as TNF, Il-1β and IL-6 upregulate endothelial expression of vascular cell adhesion molecules (VCAM1), very late antigen 4 (VLA4) and ICAM1 that cause circulating neutrophils and monocytes to adhere to the inflamed endothelium [60]. This better understanding of cellular trafficking in the bowel has provided new molecular targets for blocking inflammation in inflammatory bowel disease patients. Natalizumab, a monoclonal antibody which binds the α4β7 integrin and integrin α4β1 (the MadCAM and VLA4 ligands, respectively) is effective in treating Crohn’s disease [61].

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Table 3.1. Cytokine tissue levels in Crohn’s disease. IL, interleukin, TNF, tumor necrosis factor, IFN, interferon, TH, T helper; N, normal. Arrow indicates increase Cytokine IL-1b TNF IL-6 IL-5 IL-6 IL-8 IL-12 IL-13 IL-17 IL-18 IL-21 IL-23 IL-27 IFN-γ

Immune response TH17/innate TH17/innate TH17/innate TH1/adaptive TH17/innate TH17/innate TH17/innate TH1/adaptive TH1/adaptive TH17/innate TH1/adaptive TH17/innate TH17/innate TH1/adaptive

Tissue levels ↑ ↑↑ ↑ N ↑ ↑ ↑ N ↑ ↑ ↑ ↑ ↑ ↑

THE INFECTIOUS THEORY From many years, the investigators’ interest has been focused toward the existence of a specific micro-organism as possible culprit of Crohn’s disease and,

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13

paradoxically, the above reported, new data on Crohn’s disease pathogenesis have renewed the interest in this research area. Several lines of evidence support the infectious theory. First, from a pathological standpoint, Crohn’s disease closely resembles intestinal tuberculosis, with development of granuloma, the pathological hallmark of failure of the cellular immune response to remove foreign material; second, bacterial DNA has been demonstrated in Crohn’s granulomata [62]; third, Crohn’s disease is similar to Johne’s disease in the cattle, a chronic intestinal granulomatous disease caused by Mycobacterium Avium Paratuberculosis (MAP); fourth, many studies have shown a higher frequency of MAP in tissue specimens of patients with Crohn’s disease; last, antibiotic regimens are effective in the short term management of the disease. The Mycobacteria hypothesis in the etiopathogenesis of Crohn’s disease has been neither refused nor accepted. Several constraints limit the tissue detection of MAP species, such as the slow growth and the need for specific cultural adjuvants [63]. A recent study using MAP DNA insertion sequence in resected gut specimens of Crohn’s disease patients detected MAP in 52% versus 5% of controls [64], and a meta-analysis of 28 case-control studies [65] has confirmed the association of MAP with Crohn’s disease. Yet, the most compelling observation of these studies has been that the study methods lack sufficient standardization to generate reproducible prevalence estimates and strengths of association. A causal association of MAP would have important implications for the processing of milk and dairy products. The occurrence of MAP in the milk of livestock is well documented, and viable MAP organisms can survive standard pasteurization methods and the processes used for cheese production if high numbers of bacteria are present [66].

ENVIRONMENTAL FACTORS Several studies have implicated environmental factors in the pathogenesis of Crohn’s disease, the most notable being smoking, oral contraceptives, non steroidal anti-inflammatory drugs (NSAIDs), psychological stress and intercurrent infection. Unfortunately, the mechanisms by which these factors trigger the onset of the disease are largely unknown and only speculative. Among these factors, smoking is the most documented and, intriguingly, it has an opposite effect on ulcerative colitis. From a broad perspective, these factors may alter the intestinal mucosal barrier by ischemic changes (smoking and oral contraceptives) or by tiny

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epithelial breaks (NSAIDs, infection). These events could then lead to enhanced uptake of commensal bacterial antigens that stimulate T-cell mediated intestinal inflammation in the genetically susceptible host. Although Crohn’s disease patients often implicate psychological stress and diet in their illness, roles for these factors are poorly understood and results of studies in this setting have been disappointing [67,68].

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CONCLUSIVE REMARKS AND A PEEK TO THE FUTURE Many different mechanisms can lead to intestinal inflammation in Crohn’s disease, accounting for heterogeneity at genetic, phenotypic, microbiologic, immunologic and therapeutic levels. Crohn’s disease may result from failure to downregulate any inflammatory response triggered by noxious agents, such as an acute self-limiting gastrointestinal infection, NSAIDs mucosal injury or a hitherto unraveled environmental factor. Normal hosts clear infection, downregulate innate immune system and quickly heal the intestinal mucosa without stimulating adaptive, effector T-cell responses. Conversely, genetically susceptible hosts who are unable to clear a pathogenic microbe or generate a tolerance to commensal microorganisms are prone to mount a pathogenic T-cell response resulting in chronic intestinal inflammation. One of the most provocative insights from recent research is that Crohn’s disease – a condition previously considered as resulting from overly aggressive immune response and treated accordingly with immunosuppressive drugs – might be considered a complex immunodeficiency defect of the innate immune system. To this purpose, recent therapeutic attempts to enhance the innate immune system by granulocyte-monocyte colony stimulating factor (GM-CSF) and stem cells delivery have been promising [69,70]. In summary, the key factor responsible for Crohn’s disease is a complex interplay of the environment, genotype, commensal enteric flora and immune response. More detailed studies on their composition, functions and interaction are needed, but with the impressive pace of research and achievements in this area, we can foresee that phenotype patients classification at the molecular level and pathway-specific tailored therapies may soon become realities.

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[15] Buhner S, Buning C, Genschel J et al. Genetic basis for increased intestinal permeability in families with Crohn’s disease. A role of CARD15 3020insC mutation? Gut 2006; 55: 342-7 [16] Kim JG, Lee SJ, Kagnoff MF. NOD1 is an essential signal transducer in intestinal epithelial cells infected with bacteria that avoid recognition by toll-like receptors. Infect Immun 2004; 72: 1487-95. [17] Strober W, Murray PJ, Kitani A et al. Signaling pathways and molecular interactions of NOD1 and NOD2. Nat Rev Immunol 2006; 6: 9-20. [18] Kobayashi KS, Chamaillard M, Ogura Y et al. NOD2-dependent regulation if innate and adaptive immunity in the intestinal tract. Science 2005; 307: 731-4. [19] Wehkamp J, Harder J, Weichental M et al. NOD2 (CARD15) mutations in Crohn’s disease are associated with diminished mucosal alpha-defensin expression. Gut 2004; 53: 1658-64. [20] Bamias G, Cominelli F. Immunopathogenesis of inflammatory bowel disease: current concepts. Curr Opin Gastroenterol 2007; 23: 365-9. [21] Miceli-Richard C, Lesage S, Rybojad M et al. CARD15b mutations in Blau syndrome. Nat Genet 2001; 29: 19-20. [22] Glas J, Konrad A, Schmechel S et al. The ATL16L1 gene variants rs 2241879 and rs2241880 (T300A) are strongly associated with susceptibility to Crohn’s disease in the German population. Am J Gastroenterol 2007; 102: 1-10. [23] Hampe J, Franke A, Rosenstiel P et al. A genome wide association scan of nonsynonimous SNPs identifies a susceptibility variant for Crohn’s disease in ATL16L1. Nat Genet 2007; 39: 207-11. [24] Wellcome Trust Care Control Consortium. Genome wide association study of 14.000 cases of seven common disease and 3.000 shared controls. Nature 2007; 447: 661-78. [25] Parkes M, Barrett JC, Prescott NJ et al. Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn’s disease susceptibility. Nat Genet 2007; 39: 830-2. [26] Duerr RH, Taylor KD, Brant SR et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 2006; 314: 1461-3. [27] Ma Y, Ohmen JD, Li Z, et al. A genome-wide search identifies potential new susceptibility loci for Crohn’s disease. Inflamm Bowel Dis 1999; 5: 271-8.

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[28] Rioux JD, Daly MJ, Silverberg MS et al. Genetic variations in the 5q31 cytokine gene cluster confers susceptibility to Crohn’s disease. Nat Genet 2001; 29: 223-8. [29] Latiano A, Palmieri O, Valvano RM et al. Contribution of IBD5 locus to clinical features of IBD patients. Am J Gastroenterol 2006; 101: 318-25. [30] Yamazaki K, McGovern D, Ragoussis J et al. Single nucleotide polymorphisms in TNFSF15 confer susceptibility to Crohn’s disease. Hum Mol Genet 2005; 14: 3499-506. [31] Libioulle C, Louis E, Hansoul S et al. A novel susceptibility locus for Crohn’s disease identified by whole genome association maps to a gene desert on chromosome 5p13.1 and modulates the level of expression of the prostaglandin receptor EP4. PloS Genetics 2007; 3: e58. [32] Backhed F, Ley RE, Sonnenburg JL et al. Host-bacterial mutualism in the human intestine. Science 2005; 307: 1915-20. [33] Hooper LV, Midtvedt T, Gordon JL. How host-microbial interactions shape the nutrient environment of the mammalian intestine. Annu Rev Nutr 2002; 22: 283-307. [34] Gill SR, Pop M, Deboy RT et al. Metagenomic analysis of the human distal gut microbiome. Science 2006; 312: 1355-9. [35] Eckburg PB, Bik EM, Bernstein CN et al. Diversity of the human intestinal microbial flora. Science 2005; 308: 1635-8. [36] Scaldaferri F, Fiocchi C. Inflammatory bowel disease: Progress and current concepts of etiopathogenesis. J Digest Dis 2007; 8: 171-8. [37] Kosiewicz MM, Nast CC, Krishan A et al. Th-1 type responses mediate spontaneous ileitis in a novel murine model of Crohn’s disease. J Clin Invest 2001; 107: 695-702. [38] Sartor RB. Microbial influences in inflammatory bowel disease: role in pathogenesis and clinical implications. In Kirsner’s inflammatory bowel diseases, eds Sartor RB, Sandborn WJ, 2004, 138-62. Philadelphia, Elsevier. [39] Kelsall BL. Innate and adaptive mechanisms to control of pathological intestinal inflammation. J Pathol 2008; 214: 242: 59. [40] Hollander D. Crohn’s disease – a permeability disorder of the tight junction? Gut 1988; 29: 1621-4. [41] Arnott ID, Kingstone K, Ghosh S. Abnormal intestinal permeability predicts relapse in active Crohn’s disease. Scand J Gastroenterol 2000; 35: 1163-9.

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[42] Katz KD, Hollander D, Vadheim CM et al. Intestinal permeability in patients with Crohn’s disease and their healthy relatives. Gastroenterology 1989; 97: 927-31. [43] Kitajima S, Takuma S, Morimoto M. Changes in colonic mucosal permeability in mouse colitis induced with dextran sulfate sodium. Exp Anim 1999; 48: 137-43. [44] Gonzalez-Mariscal L, Betanzos A, Nava P et al. Tight junction proteins. Progr Biophys Mol Biol 2003; 81: 1-44. [45] Zeissig S, Burgel N, Gunzel D et al. Changes in expression and distribution of claudin2, 5 and 8 lead to discontinuous tight junctions and barrier dysfunction in active Crohn’s disease. Gut 2007; 56: 61-72. [46] Heller F, Florian P, Bojarski C et al. Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis and cell restitution. Gastroenterology 2005; 129: 550-64. [47] Clayburgh DR, Musch MW, Leitges M et al. Coordinated epithelial NHE3 inhibition and barrier dysfunction are required for TNF-mediated diarrhea in vivo. J Clin Invest 2006; 116: 2682-94. [48] Korzenik JR. Is Crohn’s disease due to defective immunity? Gut 2007; 56: 2-5. [49] Abreu MT, Fukata M, Arditi M. TLR signalling in the gut in health and disease. J Immunol 2005; 174: 4453-60. [50] Inohoue N, Nimuz G. Nods: intracellular proteins involved in inflammation and apoptosis. Nature Rev 2003; 3: 371-82. [51] van Heel DA, Ghosh S, Butler M et al. Muramyl dipeptide and toll-like receptor sensitivity in NOD2-associated Crohn’s disease. Lancet 2005; 365:1794-6. [52] Hommes D, van den Blink B, Plasse T, et al. Inhibition of stress-activated MAP kinases induces clinical improvement in moderate to severe Crohn's disease. Gastroenterology 2002; 122:7-14. [53] Olson TS, Bamias G, Naganuma M et al. Expanded B cell population blocks regulatory T cells and exacerbates ileitis in a murine model of Crohn disease. J Clin Invest 2004; 114: 389-98. [54] Sartor RB, Hoentjen F. Proinflammatory cytokines and signalling pathways in intestinal innate immune cells. In: Mucosal Immune Cells. 2005; 681701. Mestecky J et al. (eds.). Philadelphia. Elsevier. [55] Iwakura Y, Ishigame H. The Il-23/IL-17 axis in inflammation. J Clin Invest 2006; 116: 1218-22.

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[56] Fujino,A, Andoh S, Bamba A et al. Increased expression of interleukin 17 in inflammatory bowel disease, Gut 2003; 52: 65–70. [57] Boirivant M, Marini M, Di Felice G et al. Lamina propria T cells in Crohn's disease and other gastrointestinal inflammation show defective CD2 pathway-induced apoptosis. Gastroenterology 1999; 116: 557-65. [58] Kullberg MC, Jankovic D, Gorelick PL et al. Bacteria-triggered CD4+ T Regulatory Cells Suppress Helicobacter hepaticus–induced Colitis. J Exp Med 2002; 196: 505-15. [59] Souza HS, Elia CCS, Spencer J et al. Expression of lymphocyte-endothelial receptor-ligand pairs, α4β7/MAdCAM-1 and OX40/OX40 ligand in the colon and jejunum of patients with inflammatory bowel disease. Gut 1999; 45: 856-63. [60] Jones SC, Banks RE, Haidar A et al. Adhesion molecules in inflammatory bowel disease. Gut 1995; 36:724-30. [61] Ghosh S, Goldin E, Gordon FH et al. Natalizumab for Active Crohn's Disease. N Engl J Med 2003; 348:24-32. [62] Ryan P, Kelly RG, Lee G et al. Bacterial DNA within granulomas of patients with Crohn’s disease – detection by laser capture microdissection and PCR. Am J Gastroenterol 2004; 99: 1539-43. [63] Behr MA. Mycobacteria in Crohn’s disease: a persistent hypothesis. Inflamm Bowel Dis 2006; 12:1000-4. [64] Naser SA, Ghobrial G, Romero C et al. Culture of Mycobacterium avium subspecies paratuberculosis from the blood of patients with Crohn’s disease. Lancet 2004; 364: 1039-44. [65] Feller M, Huwiler K, Stephan R et al. Mycobacterium avium subspecies and Crohn’s disease. A systematic review and meta-analysis. Lancet Infect Dis 2007; 7: 607-13. [66] Lund BM, Gould GW, Rampling AM. Pasteurization of milk and the heat resistance of Mycobacterium avium subsp. paratuberculosis: a critical review of the data. Int J Food Microbiol 2002; 77: 135-45. [67] Reif S, Klein I, Lubin F et al. Pre-illness dietary factors in inflammatory bowel disease. Gut 1997; 40: 754-60. [68] North CS, Alpers DH, Helzer JE et al. Do life events or depression exacerbate inflammatory bowel disease? Ann Intern Med 1991; 114: 381-6. [69] Korzenik JR, Dieckgraefe BK, Valentine JF et al. Sargramostin for active Crohn’s disease. N Engl J Med 2005; 352: 2193-201.

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[70] Cassinotti A, Annaloro C, Ardizzone S et al. Autologous haematopoietic stem cell transplantation without CD34+ cell selection in refractory Crohn’s disease. Gut 2008; 57: 211-7.

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In: Diagnostic Modalities in Crohn's Disease ISBN 978-1-60692-701-4 Editors: C. M. Girelli and L. G. Crespi © 2009 Nova Science Publishers, Inc.

Chapter II

EPIDEMIOLOGY Carlo M. Girelli

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Hospital of Busto Arsizio (VA), Italy

INTRODUCTION Epidemiology refers to the study of distribution of a disease around the world, and of factors affecting the health and illness of populations, and serves as a foundation for interventions made in the interest of public health. It is considered a keystone methodology of research, and is highly considered in evidence-based medicine for identifying risk factors for disease and determining optimal health resource allocation. The study of inflammatory bowel disease (IBD) poses special problems which must be kept in mind when we evaluate any epidemiological report in this setting. First, the IBD onset is often insidious, and it may precede by months or years the full-blown clinical picture, making it difficult to determine possible etiologic agents that operate at the start of the disease. Second, the spectrum of IBD severity is wide and some patients with mild disease may be overlooked and underreported. Third, there is no diagnostic hallmark for IBD, and hence no universally accepted diagnostic criteria; although diagnostic guidelines are available [1], we don’t know if they are uniformly applied worldwide. Fourth, there may be significant misclassification and diagnostic confusion among acute

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self limiting colitis, unclassified inflammatory bowel disease, ischemic colitis, and so on. Last, temporal trends of IBD — a fundamental aspect of the epidemiological insight — could be biased by the rapidly developing diagnostic modalities. In spite of these limitations, there is no shortage of published epidemiological studies for IBD that will be reviewed in the next pages.

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INCIDENCE Incidence refers to the number of new cases of disease that develop in a time interval, generally one year. As shown in table 1.2, the incidence of Crohn’s disease ranges from 0.5 to 16.5 cases per 100.000 inhabitants [2-21]. Although the most reliable data are limited for certain regions, there is little doubt that Crohn’s disease is more common in North America, Canada and North Europe than southern Europe, Africa and Asia, representing the so-called “north to south gradient”. As shown by population-based registries, we have witnessed a striking rise in disease incidence from the end of the second world war to the 1980s, followed by a plateau (figure 1.2). Although the rising incidence may in part represent better disease recognition, most experts believe that it is genuine. Interestingly, recent reports from geographical areas where Crohn’s disease incidence is traditionally low, show an increased incidence of the disease that parallels the adoption of a western lifestyle and diet by their populations [21-24]. More recent data show a trend for increasing incidence of Crohn’s disease, including the pediatric subgroup, and a changing pattern of disease location, being the colonic involvement increasingly reported in the last series [25-29].

PREVALENCE Prevalence refers to the number of people with a specific condition at a given time, and in general prevalence is almost equal to incidence of a disease multiplied by its duration. For short-lived, self-limiting diseases, prevalence is the same as incidence; conversely, for chronic disease, prevalence may be higher than incidence by several folds. Prevalence figures are essential to policy makers who need to know the number of people affected so that they can allocate health care funds properly. Once again, to determine the true prevalence of Crohn’s disease is a difficult task for the variability of its clinical course and individuals having a

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mild disease and/or long periods of clinical remission are undercounted in registries from which crude data are extrapolated. In addition, the ethnic composition of the population being studied is variable, accounting for the striking differences in prevalence ranging from 5.8 to 198.5 cases per 100.000 inhabitants, as shown in table 1.2. Loftus and co-workers, in their systematic review based on strict selection criteria of published epidemiologic studies, suggest that between 400.000 and 600.000 people in North America actually have Crohn’s disease [30].

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Table 1.2. Incidence and prevalence of Crohn’s disease in different countries from selected registries since 1980 Author

Year(s)

Place

Bernstein

1989-94

Loftus

1984-93

Pinchbeck Kurata

1981 1987-88

Shivanada

1991-93

Trallori Rubin Kyle MatèJimenez Munkholm Odes Fireman Morita Abdul-Baki

1990-92 1985-95 1985-88 1981-88

Manitoba (CAN) Olmsted C.(US) Alberta (US) California (US) Central Europe Italy UK UK Spain

1980-87 1987-92 1980 1991 2000-04

Denmark Israel Israel Japan Lebanon

Jacobsen

19982002 2004-05

Denmark

Gearry

Canterbury (NZ)

Study design Population

Incidence* 14.6

Prevalence * 198.5

5

Population

6.9

144.1

4

Population Outpatients

10 3.6

44.4 26

2 3

Population

7

NA

19

Population Population Population Hospital

3.4 8.3 9.8 1.6

40 144 147 19.8

11 9 7 10

Population Population Population Survey Hospital/ Outpatients Population

4.1 4.2 NA 0.5 1.4

NA NA 19.5 5.8 53.1

6 12 13 14 24

9.6

151

20

Population

16.5

155.2

21

*N° cases per 100.000 persons.

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Carlo M. Girelli

24 12,00 10,00

Olmsted County

I n c id e n c e

8,00

Stockholm 6,00

Malmo Copenhagen

4,00

Alberta Tubingen

2,00

Helsinki 0,00 1955

1960

1965

1970

1975

1980

1985

1990

1995

Years

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Figure 1.2. Temporal trends of incidence of Crohn’s disease in North American and European countries.

MORTALITY IBD mortality statistics are extremely difficult to interpret for several reasons. First, IBD is an uncommon cause of death and small errors in classification can have big effects on death rates. Second, International Classification of Disease (ICD) codes for IBD have changed, and it may be difficult to plot trends over time. Third, differences in the age of different populations make comparison of mortality rates potentially erroneous and age-standardized mortality data have not been available. These limitations could account for conflicting results from many published studies; some studies show mortality in Crohn’s disease to be similar to that in the general population, while others have noted a lower life expectancy [31-36]. A recent meta-analysis showed that age-adjusted mortality risk from Crohn's disease is greater than the general population for people over 40 years old [37]. However, looking at trends over time, the mortality from Crohn’s disease increased in England and the United States from the end of the second world war to the early 1970s and then decreased [38].

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SEX AND AGE DISTRIBUTION Although some studies conducted at different times with variable methods showed a slight excess of Crohn’s disease in females, we can assume that the ratio for both sexes is close to the unit, suggesting no major gender-related risk factors. Crohn’s disease is more frequent in young people, with a median age of diagnosis in the third decade. Observers have seen a bimodal age distribution of incidence with a second, lesser peak later in life [30]. However, it is not clear whether this variation in age distribution represents a genuine difference in the age of onset of Crohn’s disease or whether it reflects a difference in classification of various entities that might be confused with Crohn’s disease, such as ischemic colitis, diverticula-associated-colitis, and drug-induced colitis. More recently, a population-based study in a well characterized French region has shown that agespecific incidence of Crohn’s disease in the over-60 age group is not different from that in younger people [39].

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ETHNICITY There are substantial differences of disease distribution in various ethnic groups. Crohn’s disease is prevalent in Caucasians, and a rare condition among Hispanics and Asians, as suggested by geographic distribution of the disease. Although, in the past, African-Americans were considered at low risk of disease, studies were conducted in areas where non-white minorities were underrepresented and more recent data have shown no difference of occurrence of the disease between whites and blacks [40,41]. Crohn’s disease is more common in Jews than non-Jews, with considerable variation in disease rate in different countries [42]. Yet, migration and globalization have provided new intriguing insight on disease etiology showing that south Asian migrants to the United Kingdom are at increased risk of developing inflammatory bowel disease [43,44], once again suggesting that environmental factors are important in the etiopathogenesis of the disease.

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RISK FACTORS Because IBD is an enteric condition, it is logical to consider diet as a possible culprit for disease development. In addition, bowel rest and elemental diet improve the flare of disease [45]. There have been several studies of diet and IBD relationship, but, unfortunately, these have not proven as helpful as one might have expected. Much of the confusion may arise from the difficulty in the reconstruction of the diet in case and control studies and there is no uniform agreement on the best method. Although several dietary factors such as margarine, coffee, alcohol, fruits, vegetables, fat, food additives, have been investigated with conflicting results, more studies have shown a higher consumption of refined sugar in Crohn’s disease patients, but many investigators believe that increased sugar and low fruit and vegetable intake may be a consequence of the disease rather the cause [46,47]. To study a pediatric population may theoretically overcome this drawback, and recently Amre et al. showed that an imbalance in consumption of fatty acids, vegetables, and fruits is associated with increased risks for Crohn’s disease among Canadian children of the Manitoba cohort [48]. In sharp contrast to the protective effect of cigarette smoking on ulcerative colitis [49], several studies have clearly demonstrated that smoking increases the risk of Crohn’s disease, with relative risk for current smokers in the range of 1.8– 3.7 [50,51]. Smoking may also influence the clinical course of the disease as suggested by studies which found that patients who smoke are more likely to have ileal rather than colonic disease [52]. In addition, continued smoking following surgical resection for Crohn’s disease increases the risk of early recurrence, especially in women [53]. Non-steroidal anti-inflammatory drugs (NSAIDs) have a broad spectrum of noxious effect on the gastrointestinal tract, ranging from mild, asymptomatic mucosal inflammation to stricture, perforation and severe bleeding [54]. They act by blocking the ciclo-oxygenase pathway of arachidonic acid metabolism, the rate limiting step for the integrity of the protective mucus of the mucosal layer. Orally administered NSAIDs have been reported to trigger relapse in patients with quiescent inflammatory bowel disease [55] and animal models support these observations [56]. A recent study from Maiden and co-workers, using state-ofthe-art imaging of the small bowel by capsule endoscopy, showed that small bowel mucosal breaks are present in up to 62% of asymptomatic people taking NSAIDs [57].

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Several cohort studies have shown an increased risk of Crohn’s disease in women using oral contraceptives. In a large prospective British study from the Oxford Family Planning Association, the relative risk for Crohn’s disease was 1.7 with a dose-response effect [51]. Other cohort studies have confirmed this association [58], whereas case-control studies, which are numerically less consistent, did not [59,60]. Taken together, these studies suggest that oral contraceptives are associated with a slight risk of developing Crohn’s disease, but, in clinical practice, women need not be advised to discontinue oral contraceptive use when a diagnosis of Crohn's disease is made. The well-known thrombogenic properties of oral contraceptives have been proposed as a possible explanation of their detrimental effect on IBD, as supported by some morphological studies which identified small microvascular infarctions in the resected bowel wall from patients with Crohn’s disease [61].

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THE “HYGIENE HYPOTHESIS” Taken together these epidemiological data have raised the possibility that improved environmental hygiene could overprotect the child from exposure to common infectious agents. If the child comes into contact with a pathogenic infectious agent later in life, an inappropriate immunologic response is triggered that could lead to the development of an abnormal or ineffective inflammatory process and possibly even Crohn’s disease. This theory, also known as “hygiene hypothesis”, is further supported by several pieces of indirect evidence, namely (i) a lower Helicobacter pylori seroprevalence in patients with IBD [62], (ii) a higher incidence of Crohn’s disease in urban areas, a more hygienic setting for nurturing children [63], (iii) preliminary data on clinical efficacy of Trichiuris suis ova in IBD patients [64]. However, direct evidences from prospective studies are lacking and this theory is up to now only speculative.

CONCLUSION In spite of uncertainty on the etiology of Crohn’s disease, epidemiological data are sufficient to state that the disease is more common in the developed countries of Scandinavia, Europe and North America and uncommon in South America, Asia and Africa. Yet, the incidence of Crohn’s disease seems to increase

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in less developed countries as they become more industrialized and adopt a western diet and lifestyle. The incidence of Crohn’s disease has risen sharply from the second world war to the 1970s, followed by a plateau. Crohn’s disease typically affects young people, but it is increasingly recognized in the elderly. Exposure to tobacco smoke, oral contraceptives, NSAIDs and possibly diet may influence disease expression. Changes in incidence rates over time and increasing detection of inflammatory bowel disease in migrants from areas of low incidence further support that environmental factors play a significant role in the etiopathogenesis of the disease.

REFERENCES [1] [2]

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[3]

[4]

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Carter MJ, Lobo AJ, Travis SP et al. Guidelines for the management of inflammatory bowel disease in adults. Gut 2004; 53 (Suppl 5): V1-16. Pinchbeck BR, Kirdeikis J, Thompson AB. Inflammatory bowel disease in Northern Alberta. An epidemiological study. J Clin Gatsroenterol 1988; 10: 505-15. Kurata JH, Kanto-Fish S, Frankl H et al. Crohn’s disease among ethnic groups in a large health maintenance organization. Gastroenterology 1992; 102: 1940-8. Loftus EV Jr; Silverstein MD, Sandborn WJ et al. Crohn’s disease in Olmsted County, Minnesota, 1940-93: incidence, prevalence and survival. Gastroenterology 1998; 114: 1161-8. Bernstein CN, Blanchard JF, Rawstone P et al. Epidemiology of Crohn’s disease and ulcerative colitis in a central Canadian province: a populationbased study. Am J Epidemiol 1999; 149: 916-24. Munkholm P, Langholz E, Nielsen OH et al. Incidence and prevalence of Crohn’s disease in the County of Copenhagen, 1962-87: a sixfold increase in incidence. Scand J Gastroenterol 1992; 27: 609-14. Kyle J. Crohn’s disease in the northeastern and northern Isles of Scotland: an epidemiological review. Gastroenterology 1992; 103: 392-99. Yapp TR, Stenson R, Thomas GAO et al. Crohn’s disease incidence in Cardiff from 1930: an update for 1991-1995. Eur J Gastroenterol Hepatol 2000; 21: 907-11.

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[10]

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Rubin GP, Hungin APS, Kelly PJ et al. Inflammatory bowel disease: epidemiology and management in an English general practice population. Aliment Pharmacol Ther 2000; 14: 1553-9. Mate-Jimenez J, Munoz S, Vicent D et al. Incidence and prevalence of ulcerative colitis and Crohn’s disease in urban and rural areas of Spain from 1981 to 1988. J Clin Gastroenterol 1994; 18: 27-31. Trallori G, Palli D, Saieva C et al. A population-based study of inflammatory bowel disease in Florence over 15 years (1978-92). Scand J Gastroenterol 1996; 31: 892-99. Odes HS, Locker C, Neumann L et al. Epidemiology of Crohn’s disease in southern Israel. Am J Gastroenterol 1994; 89: 1859-62. Fireman Z, Grossman A, Lilos P et al. Epidemiology of Crohn’s disease in the Jewish population of central Israel, 1970-1980. Am J Gastroenterol 1989; 84: 255-58. Morita N, Toki S, Hirohashi T et al. Incidence and prevalence of inflammatory bowel disease in Japan: nationwide epidemiological survey during the year 1991. J Gastroenterol 1995; 30 (Suppl 8): 1-4. Lapidus A, Bernell O, Hellers G et al. Incidence of Crohn’s disease in Stockholm County, 1955-1989. Gut 1997; 41: 480-6. Gower-Rousseau C, Salomez JL, Dupas JL et al. Incidence of inflammatory bowel disease in northern France (1988-1990). Gut 1994; 35: 1433-8. Tragnone A, Corrao G, Miglio F et al. Incidence of inflammatory bowel disease in Italy: a nationwide population-based study. Gruppo Italiano per lo Studio del Colon e del Retto (GISC). Int J Epidemiol 1996; 25: 1044-52. Ekbom A, Helmic C, Zack M et al. The epidemiology of inflammatory bowel disease: a large, population-based study in Sweden. Gastroenterology 1991; 100: 350-8. Shivananda S, Lennard-Jones J, Logan R et al. Incidence of inflammatory bowel disease across Europe: is there a difference between north and south? Results of the European collaborative Study on Inflammatory Bowel Disease (EC-IBD). Gut 1996; 39: 690-7. Jacobsen BA, Fallingborg J, Rasmussen HH et al. Increase in incidence and prevalence of inflammatory bowel disease in northern Denmark: a population-based study, 1978-2002. Eur J Gastroenterol Hepatol 2006; 18: 601-6. Gearry RB, Richardson A, Frampton CMA et al. High incidence of inflammatory bowel disease in Canterbury, New Zeland: results of an epidemiologic study. Inflamm Bowel Dis 2006;12:936-43.

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[22] Zheng JJ, Zhu XS, Huangfu Z et al. Crohn’s disease in mainland China: a systematic analysis of 50 years of research. Chin J Digest Dis 2005; 6: 17581. [23] Desai HG, Gupte PA Increasing incidence of Crohn’s disease in India: is it related to improved sanitation? Indian J Gastroenterol 2005; 24: 23-4. [24] Abdul-Baki H, ElHajj I, El-Zahabi LM et al. Clinical epidemiology of inflammatory bowel disease in Lebanon. Inflamm Bowel Dis 2007; 1: 47580. [25] Turunen P, Kolho KL, Auvinen A et al. Incidence of inflammatory bowel disease in Finnish children, 1987-2003. Inflamm Bowel Dis 2006; 12: 67783. [26] Kugathasan S, Judd RH, Hoffmann RG et al. inflammatory bowel disease in Wisconsin: a statewide population-based study. J Pediatr 2003; 143: 52531. [27] Hildebrand H, Finkel Y, Grahnquist L et al. Changing pattern of paediatric inflammatory bowel disease in northern Stockholm 1990-2001. Gut 2003; 52: 1432-4. [28] Vind I, Riis L, Jess T et al. Increasing incidences of inflammatory bowel disease and decreasing surgery rates in Copenhagen City and County, 20032005: a population-based study from the Danish Crohn colitis database. Am J Gastroenterol 2006; 101: 1274-82. [29] Thomas GA, Milar-Jones D, Rhodes J et al. Incidence of Crohn’s disease in Cardiff over 60 years: 1986-1990 an update. Eur J Gastroenterol Hepatol 1995; 7: 401-5. [30] Loftus EV, SchoenfeldP, Sandborn WJ The epidemiology and natural history of Crohn’s disease in population-based patient cohorts from North America: a systematic review. Aliment Pharmacol Ther 2002; 16: 51-60. [31] Jess T, Winther KV, Munkholm P et al. Mortality and causes of death in Crohn’s disease: follow-up of a population-based cohort in Copenhagen County, Denmark. Gastroenterology 2002; 122: 1808-14. [32] Farrokhyar S, Swarbrick ET, Grace RH et al. Low mortality in ulcerative colitis and Crohn’s disease in three regional centers in England. Am J Gastroenterol 2001; 96: 501-7. [33] Probert CS, Jayanthi V, Wicks AC et al. Mortality fron Crohn’s disease in Leicestershire, 1972-1989.: an epidemiological community based study. Gut 1992; 33: 1226-8.

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[34] Persson PG, Bernell O, Leijomarck CE et al. Survival and cause-specific mortality in inflammatory bowel disease : a population-based cohort study. Gastroenterology 1996; 110: 1339-45. [35] Ekbom A, Helmich CG, Zack M et al. Survival and causes of death in patients with inflammatory bowel disease: a population-base study. Gastroenterology 1992; 103: 954-60. [36] Wolters FL, Russel MG, Sijbrandij J et al. Crohn's disease: increased mortality 10 years after diagnosis in a Europe-wide population based cohort. Gut 2006; 55: 510-8. [37] Canavan C, Abrams KR, Mayberry JF. Meta-analysis: mortality in Crohn's disease. Aliment Pharmacol Ther 2007; 15; 25: 861-70. [38] Sonnenberg A. Mortality from Crohn’s disease and ulcerative colitis in England-Wales and the US from 1950 to 1983. Dis Colon Rectum 1986; 29: 624-9. [39] Hereshbach D, Alexandre JL, Bretagne JF et al. Crohn’s disease in the over-60 age group: a population based study. Eur J Gastroenterol Hepatol 2004; 16: 657-64. [40] Stowe SP, Redmond SR, Stormont JM et al. An epidemiologic study of inflammatory bowel disease in Rochester, New York. Hospital incidence. Gastroenterology 1990; 98: 104-110. [41] Sonnenberg A, Wasserman IH. Epidemiology of inflammatory bowel disease among US American veterans. Gastroenterology 1991; 101: 122-30. [42] Gilat T, Grossman A, Fireman Z et al. Inflammatory bowel disease in Jews. Front Gastrointest Res 1986; 11: 135-40. [43] Montgomery SM, Morris DL, Pounder RE et al. Asian ethnic origin and the risk of inflammatory bowel disease. Eur J Gastroenterol Hepatol 1999; 11: 543-6. [44] Jayanthi V, Probert CS, Pinder D et al. Epidemiology of Crohn’s disease in Indian migrants and the indigenous population in Leicestershire. Q J Med 1992; 82: 125-38. [45] Fell JM, Paintin M, Arnaud-Battandier F et al. Mucosal healing and a fall in mucosal pro-inflammatory cytokine mRNA induced by a specific oral polymeric diet in paediatric Crohn's disease. Aliment Pharmacol Ther 2000; 14: 281-9. [46] Järnerot G, Järnmark I, Nilsson K. Consumption of refined sugar by patients with Crohn's disease, ulcerative colitis, or irritable bowel syndrome. Scand J Gastroenterol 1983; 18:999-1002.

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[47] Thornton JR, Emmett PM, Heaton KW. Diet and Crohn's disease: characteristics of the pre-illness diet. Br Med J 1979; 2: 762-4. [48] Amre DK, D'Souza S, Morgan K et al. Imbalances in dietary consumption of fatty acids, vegetables, and fruits are associated with risk for Crohn's disease in children. Am J Gastroenterol 2007; 102: 2016-25. [49] Jick H, Walker AM. Cigarette smoking and ulcerative colitis. N Engl J Med 1983; 308: 261-3. [50] Silverstein MD, Lashner BA, Hanauer SB et al. Cigarette smoking in Crohn's disease. Am J Gastroenterol 1989; 84:31-3. [51] Vessey M, Jewell D, Smith A et al. Chronic inflammatory bowel disease, cigarette smoking, and use of oral contraceptives: findings in a large cohort study of women of childbearing age. Br Med J (Clin Res Ed). 1986; 292: 1101-3. [52] Lindberg E, Järnerot G, Huitfeldt B. Smoking in Crohn's disease: effect on localisation and clinical course. Gut 1992; 33: 779-82. [53] Sutherland LR, Ramcharan S, Bryant H et al. Effect of cigarette smoking on recurrence of Crohn's disease. Gastroenterology 1990; 98: 1123-8. [54] Bjarnason I, Hayllar J, MacPherson AJ et al. Side effects of nonsteroidal anti-inflammatory drugs on the small and large intestine in humans. Gastroenterology 1993; 104: 1832-47. [55] Felder JB, Korelitz BI, Rajapakse R et al. Effects of nonsteroidal antiinflammatory drugs on inflammatory bowel disease: a case-control study. Am J Gastroenterol 2000; 95: 1949-54. [56] Yamada T, Deitch E, Specian RD et al. Mechanisms of acute and chronic intestinal inflammation induced by indomethacin. Inflammation 1993; 17: 641-62. [57] Maiden L, Thjodleifsson B, Seigal A et al. Long-term effects of nonsteroidal anti-inflammatory drugs and cyclooxygenase-2selective agents on the small bowel: a cross-sectional capsule enteroscopy study. Clin Gastroenterol Hepatol 2007; 5: 1040-5. [58] Lesko SM, Kaufman DW, Rosenberg L et al. Evidence for an increased risk of Crohn's disease in oral contraceptive users. Gastroenterology 1985; 89: 1046-9. [59] Lashner BA, Kane SV, Hanauer SB. Lack of association between oral contraceptive use and Crohn's disease: a community-based matched casecontrol study. Gastroenterology 1989; 97: 1442-7.

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[60] Logan RF, Kay CR. Oral contraception, smoking and inflammatory bowel disease-findings in the Royal College of General Practitioners Oral Contraception Study. Int J Epidemiol 1989; 18: 105-7. [61] Wakefield AJ, Sawyerr AM, Dhillon AP et al. Pathogenesis of Crohn's disease: multifocal gastrointestinal infarction. Lancet 1989; 2:1057-62. [62] Halme L, Rautelin H, Leidenius M, et al. Inverse correlation between Helicobacter pylori infection and inflammatory bowel disease. J Clin Pathol 1996; 49: 65-7. [63] Blanchard JF, Bernstein CN, Wajda A, et al. Small area variations and socio demographic correlates for the incidence of Crohn's disease and ulcerative colitis. Am J Epidemiol 2001; 154: 328-35. [64] Summers RW, Elliott DE, Urban JF Jr, et al. Trichuris suis therapy in Crohn's disease. Gut 2005; 54: 87-90.

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In: Diagnostic Modalities in Crohn's Disease ISBN 978-1-60692-701-4 Editors: C. M. Girelli and L. G. Crespi © 2009 Nova Science Publishers, Inc.

Chapter III

PATHOLOGY AND CLINICAL FEATURES Carlo M. Girelli

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Hospital of Busto Arsizio (VA), Italy.

PATHOLOGY Crohn’s disease is macroscopically characterized by aphtoid ulceration and nodularity (the so-called cobblestoning), by a chronic inflammatory process that varies from mucosal to transmural disease, the latter being composed of lymphoid hyperplasia in aggregates and sometimes non-caseating granulomata, by fissures, abscesses and fistulous tracks. In the resolving phase, fibrosis develops, resulting in strictures. Crohn’s disease is typically a multi-focal disease and the lesions are patchy, spaced by apparently spared mucosa (skip lesions). From a histological standpoint, there is no pathognomonic hallmark of the disease, but the pathologist can help in differential diagnosis if he or she is fully aware of the clinical history, drug therapy, epidemiological context, macroscopic appearance of the mucosa and location from which the specimens are taken. Some histological features suggest inflammatory bowel disease rather than acute self-limiting colitis and, in the same way, some features are more suggestive for Crohn’s disease rather than ulcerative colitis. Diffuse crypt architectural distortion is the strongest pointer towards inflammatory bowel disease, in particular ulcerative colitis [1]. Other histological aspects suggestive, but not specific, for inflammatory bowel disease

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are basal lymphoid aggregates, mucin depletion and crypt abscesses. Features typically present in Crohn’s disease helping in differential diagnosis with ulcerative colitis are skip lesions, focal inflammatory infiltrate, granuloma, depth of inflammation, fissuring ulcers, lymphadenitis and mesenteric fat wrapping. Although skip lesions have been considered an indicator of Crohn’s disease, it has been recognized recently in ulcerative colitis in two distinct circumstances. One is the appendiceal skip lesion [2] and the other is the cecal patch lesion [3]. Mucin depletion has often been quoted as a hallmark of ulcerative colitis in comparison with histological appearance of Crohn’s disease. However, paradoxically, mucin may be preserved in the case of acute fulminant colitis associated with toxic megacolon. Focality of inflammatory infiltrate has been regarded as a hallmark of Crohn’s disease rather than ulcerative colitis, but it has been recognized that some patchiness of inflammation may be apparent in the healing stage of ulcerative colitis, in particular after medical therapy [4]. When granulomas are seen away from the crypt within the mucosa, they provide a stronger pointer towards a diagnosis of Crohn’s disease. However, granuloma may be encountered in other conditions, in particular in diverticula-associated-colitis, tuberculosis, vasculitides and occasionally in infectious colitis [5]. Unfortunately, this important feature is represented in only 20-30 % of biopsy specimens of patients with Crohn’s disease, but if present, it has a high positive predictive value for Crohn’s disease. Table 1.3 summarizes the most important pathological features encountered in inflammatory bowel disease and in acute self-limiting colitis. Importantly, it must be emphasized that many biopsy specimens should be taken at the time of diagnostic endoscopy in order to help the pathologist to perform a correct diagnosis. Although Crohn’s disease can be localized anywhere through the gastrointestinal tract from mouth to anus, more than 90% of cases at the onset is ileocolonic. It can be detected isolated in the small bowel, more commonly in the terminal ileum, (11-48%), isolated colonic (19-51%) and combined ileal-colonic (26-48%). Esophageal, gastric and duodenal disease account for less than 5% of cases and mostly in association with ileocolonic disease. Ano-perianal location consisting in tags, fissure, ulcer, fistula, abscess or stricture, is an important and disfiguring feature of Crohn’s disease being present in up to 25% of patients at the onset or during the course of their disease [6].

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Table 1.3. Pathological findings helpful in the differential diagnosis of Crohn’s disease. ASLC, acute self-limiting colitis Finding Crypt distortion Lymphoid aggregates Mucin depletion Crypt abscesses Skip lesions Focal inflammation Transmural inflammation Granuloma Lymphoadenitis Fissuring ulcers Mesenteric fatty changes

Crohn’s disease + ++ + + ++ ++ ++ ++ ++ ++ ++

Ulcerative colitis ++ + ++ ++ ± ± ± ± ± -

ASLC ± ± ± ± ± + -

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CLINICAL PICTURE Clinical symptoms are related to the location and behavior of the disease, and to systemic and extra-intestinal manifestations. Abdominal pain and diarrhea are the more commonly encountered feature, being present in near 70% of patients at the onset [7]. Typically, colonic disease presents with diarrhea with or without gross blood, while ileal disease usually presents with right lower abdominal pain and diarrhea, mimicking acute appendicitis. Pathophysiology of diarrhea is multifactorial, including decreased water reabsorption in colonic disease, malabsorption and bacterial overgrowth in small bowel disease. Upper location may present with dysphagia, dyspepsia and secondary pancreatitis when the esophagus, stomach and duodenum are respectively involved. Fever is common and may be the only symptom of Crohn’s disease from the outset [8]. Fatigue, anorexia, weight loss are very common symptoms leading to protein-calories malnutrition, and failure to thrive in children.

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38

Table 2.3. Principal extraintestinal manifestation of Crohn’s disease grouped for organ system involvement and bowel disease characteristics

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Articular

Axial arthritis Peripheral arthritis Osteoporosis Ocular Iritis/uveitis Episcleritis Retinal vascular disease Cutaneous/oral Pyoderma gangrenosum Erythema nodosum SAPHO Aphtous stomatitis Pyostomatitis vegetans Metastatic Crohn Hepato-biliary PSC NAFDL Gallstone Renal Stones Glomerulopathy Miscellanea Thromboembolic disease Pulmonary disease

Frequenc y

Disease location

+ ++ ++

Colon Colon SB/colon

Association with bowel flare no yes no

Response to therapy for CD no yes no

Severit y + ± +

+ + ±

colon colon colon

yes yes unknown

yes yes no

+ ± ++

+

SB/colon

no

yes

++

+ ± + ± ±

SB/colon SB/colon SB/colon SB/colon SB/colon

yes no no no no

yes unknown no no yes

+ + ± + +

+ ++ +

colon SB/colon SB

no no no

no no no

++ ± ±

+ ±

SB unknown

no unknown

no no

± ++

+

SB/colon

yes

no

+

±

unknown

unknown

unknown

±

CD, Crohn’s disease; SB, small bowel; PSC, primary sclerosing cholangitis, NAFDL, non alcoholic fatty liver disease; SAPHO, synovitis, acne, palmo-plantar pustolosis, hyperostosis, osteitis.

Extra-intestinal manifestations are present in up to half of patients, reflecting the systemic nature of inflammatory bowel disease [9]. They may precede or follow the diagnosis and may or may not be related to a clinical flare of the disease. Not uncommonly, when extra-intestinal manifestations ensue, these may

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dominate the clinical picture, dictating the quality of life and prognosis more than the intestinal disease. Articular involvement is the most common extraintestinal manifestation of Crohn’s disease. Classically, two patterns are recognized, peripheral arthritis, and axial arthritis (i.e.ankilosing spondilitis and sacro-ileitis). Peripheral arthritis is migratory, often located in large joints (knees, ankles, elbows and wrists), and it is mostly associated with active colonic inflammation. Osteoporosis is very common (up to 50% of patients of males and females) and is multi-factorial, including low intake and/or malabsorption of calcium and vitamin D, corticosteroid therapy, chronic inflammation, and low physical activity [10]. Eye disease includes anterior chamber inflammation (iritis/uveitis), episcleritis and, rarely, retinal vascular disease, the last one probably related to hypercoagulable state accompanying inflammatory bowel disease. Oral and cutaneous lesions are common, occurring in up to 25% of patients with Crohn’s disease, including apthous stomatitis, erythema nodosum, and pyoderma gangrenosum; less common manifestations include metastatic Crohn’s disease, pyostomatitis vegetans and SAPHO syndrome (synovitis, acne, palmoplantar pustulosis, hyperostosis, and osteitis), a rare form of axial arthritis associated with skin disease [11,12]. Primary sclerosing cholangitis is a chronic inflammatory disease associated with colonic inflammatory bowel disease, that shows progressive fibrosis of intra- and extra-hepatic bile ducts with a high risk of developing cholangiocarcinoma. Hypercoagulable state of inflammatory bowel disease may result in vascular complication such as stroke and pulmonary thromboembolism. More recently, some subsets of glomerular nephropathy have been associated with Crohn’s disease (membranous nephropathy, IgA nephropathy, and IgM nephropathy ) [13]. Finally, gallstone and urolithiasis are more common in Crohn’s disease probably for defective entero-hepatic absorption of bile acid and oxalate, respectively. The wide array of extraintestinal manifestations reported in Crohn’s disease are summarized in table 2.3.

LABORATORY MARKERS Laboratory markers are useful and should be integrated in the overall management of the inflammatory bowel disease patient. They have been investigated for diagnostic purposes, for assessment of disease activity and risk of complications, for prediction of relapse, and for monitoring the effect of therapy. C reactive protein (CRP) is one of the most important acute phase proteins in

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Carlo M. Girelli

humans. Under normal circumstances CRP is produced by the liver in low quantities. However, following an acute stimulus such as inflammation, the liver rapidly increases production of CRP under the influence of cytokines (mainly interleukin -6 and tumor necrosis factor α). CRP has a short half life (19 hours) compared with other acute phase proteins and will therefore rise early after the onset of inflammation and rapidly decrease during the recovery phase. Although CRP is upregulated in most inflammatory diseases, including IBD, there is remarkable heterogeneity in the CRP response between Crohn’s disease and ulcerative colitis. Whereas Crohn’s disease is associated with a strong CRP response, ulcerative colitis has only a modest to absent CRP response [14]. Erythrocyte sedimentation rate (ESR) is the rate at which erythrocytes migrate through the plasma by gravity. Hence, ESR will depend on the plasma concentration and on the number and size of the erythrocytes. Conditions such as anemia, polycythemia, and paraproteinemia invariably affect ESR. Compared with CRP, ESR will peak much less rapidly and may also take several days to decrease, even if the clinical condition of the patient or the inflammation is improved. For these reasons ESR is less useful than CRP in the management of inflammatory bowel disease. White blood cell count will increase as part of the acute phase response. Leukocytosis is therefore not a specific feature of IBD and may be seen in other inflammatory conditions. White blood cell count is also influenced by some treatments used in Crohn’s disease, such as glucocorticoids (increased) or azathioprine and 6-mercaptopurine (decreased). Platelet count will also increase and is therefore an indicator of inflammation. Albumin is a negative acute phase reactant and decreased levels may be found during inflammation. However, other conditions such as malnutrition and proteinlosing enteropathy also cause low albumin levels in patients with Crohn’s disease. If serum markers may be increased by various conditions other than gut inflammation, fecal markers would have a higher specificity for IBD in the absence of gastrointestinal infection. A number of neutrophil derived proteins present in stools have been studied, including fecal lactoferrin, lysozyme, myeloperoxidase, and calprotectin. Calprotectin, a calcium binding protein of the S100 family (S100A8, S100A9), is probably the most promising marker. It represents 60% of cytosolic proteins in granulocytes. The presence of calprotectin in feces can therefore be seen as directly proportional to neutrophil migration to the gastrointestinal tract. Although calprotectin is a sensitive marker for detection of inflammation in the gastrointestinal tract, it is not a specific marker and increased levels are also found in neoplasia, infections, and polyps. Early studies using fecal calprotectin in inflammatory bowel disease have shown a good

Girelli, Carlo M., and Luca G. Crespit. Diagnostic Modalities in Crohn's Disease, Nova Science Publishers, Incorporated,

Pathology and Clinical Features

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correlation with 111In labeled leukocyte excretion and intestinal permeability [15]. Fecal calprotectin has been shown to be a useful non invasive tool in discriminating active Crohn’s disease from irritable bowel syndrome [16]. More recently, in one study, fecal S100A12 has been shown to be more specific than calprotectin for active inflammatory bowel disease, pending confirmation studies [17]. Table 3.3. The Vienna and Montreal Classification of Crohn’s disease Vienna Age at diagnosis

A1 40 y

Location

L1 ileal L2 colonic L3 ileocolonic L4 upper B1 non-stricturing, nonpenetrating B2 stricturing B3 penetrating

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Behavior

Montreal A1 16, 40 y L1 ileal L2 colonic L3 ileocolonic L4 isolated upper disease B1 non-stricturing, non-penetrating B2 stricturing B3 penetrating P perianal disease

Several autoantibodies have been described in inflammatory bowel disease. The two most intensively studied are autoantibodies to neutrophils, i.e. atypical perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCAs) and antiSaccharomyces cerevisiae antibodies (ASCAs). Atypical p-ANCAs and ASCAs are markers for ulcerative colitis and Crohn’s disease, respectively, but their sensitivity is lower than 50% in most studies [18]. The combined use of atypical p-ANCA and ASCA may affect post-test probability in distinguishing ulcerative colitis from Crohn’s disease. The p-ANCA+/ASCA- combination is more specific for ulcerative colitis, whereas the ASCA+/p-ANCA- combination is more specific for Crohn’s disease. However, their diagnostic role appears to be limited, mainly because of their low sensitivity. When the pre-test probability of inflammatory bowel disease is quite low, such as in screening testing, a positive test result for either p-ANCAs or ASCAs only modestly influences post-test probability, and a negative test result has no clinical value. In addition, the discriminative value of ASCAs and p-ANCAs to predict definitive diagnosis (Crohn’s disease or ulcerative colitis) in patients with unclassified colitis is modest, and almost half of

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Carlo M. Girelli

these patients do not develop ASCA or p-ANCA antibodies. Finally, serial measurement of p-ANCAs and ASCAs is not useful because titers of both antibodies are stable over time and do not correlate with disease activity. Novel serum antimicrobial antibodies include the CD-related protein from Pseudomonas Aeruginosa (anti-I2), Escherichia Coli outer membrane porin C (anti-OmpC) and the flagellin-like antigen (anti-Cbir1) [20]. These antibodies are detectable in up to 50% of patients, once again reflecting the heterogeneous nature of Crohn’s disease. For the time being, their clinical significance is uncertain, and larger studies are needed to better define their diagnostic role.

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COMPLICATIONS A complication may be defined as a serious, unexpected development related to the disease itself or to its treatment. Complications of Crohn’s disease are summarized in table 4.3. Not infrequently, fistula and abscess development is the first manifestation of the disease calling for medical help. In the management of Crohn’s disease, fistula formation from the ill intestinal segment to a neighboring organ (urinary bladder, vagina, another bowel segment) or to pelvic floor and retroperitoneum (pelvic and psoas abscess, respectively) represents the most common complication requiring surgery. Intestinal obstruction may be due to inflammatory stenosis or fibro-stenotic changes in long-standing disease and may be managed conservatively in most cases. Although uncommon, massive gastrointestinal bleeding mandating urgent surgery is reported in Crohn’s disease as well. Accordingly, toxic megacolon – a life-threatening, acute, paretic distension of the large bowel with systemic toxicity – is uncommon in Crohn’s disease. It is mandatory to recognize promptly any disease-related complication in order to avoid extensive surgical resection. Finally, as in ulcerative colitis, Crohn’s disease carries an increased risk of colorectal cancer that is estimated at 18-19 fold in patients with long-standing disease of more than 20 years when compared to the expected cancer incidence [21]. Treatment related complications are summarized in table 4.3.

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Table 4.3. The most common complications observed at diagnosis and during the course of Crohn’s disease. GSC, glucocorticosteroid, AZA, azathioprine; MTX, methotrexate; anti-TNF, infliximab Disease related Entero-enteric fistula Entero-vaginal fistula

Disease location Ileum, sigmoid colon Ileum, sigmoid colon

Frequency Common Uncommon

Entero-vescical fistula Gastro-colic fistula

Ileum, sigmoid colon Transverse colon

Uncommon Rare

Abscess Toxic megacolon

Ileum, colon Colon

Common Rare

Obstruction

Small bowel, left colon

Common

Cancer Anemia

Colon Any

Thromboembolic disease Treatment related Aseptic femoral necrosis Diabetes mellitus Osteoporosis

Any

Uncommon Very common Uncommon

Psychosis Cataract, glaucoma Infection Interstitial nephropathy Leukopenia Pancreatitis

GSC GSC GSC, AZA, anti-TNF, MTX mesalazine AZA, MTX AZA, mesalamine

Rare Common Uncommon

Hepatitis Lymphoma

AZA, MTX AZA, MTX, anti-TNF (?)

Uncommon Rare

Drug GSC GSC GSC

Frequency Uncommon Common Common Uncommon Uncommon Common

Clues to diagnosis Diarrhea, malabsorption Fecaloid vaginal discharge Pneumaturia Maldigestion, undigested food in feces Pain, fever Abdominal distension, toxic state Abdominal distension, vomiting, fluid levels at x-rays Dysplasia Fatigue, pallor, tachycardia Deep vein thrombosis, pulmonary embolism Clues to diagnosis Hip pain Polydypsia, polyuria Bone pain, pathological fractures Hallucinations, delirium Blurred vision, eye pain Fever, organ-specific symptoms Renal failure Blood test Abdominal pain, blood test Liver tests Nodes enlargement, fever, weight loss

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ACTIVITY AND SEVERITY ASSESSMENT The spectrum of disease severity is wide and its objective assessment is essential. In the last four decades, a variety of scales have been developed and validated. The most popular is the Crohn Disease Activity Index (CDAI), developed in the early 1970s by the National Cooperative Crohn’s disease Study. The CDAI is determined by eight items, including the number of liquid stools, general wellbeing, the extent of abdominal pain, the occurrence of complications and extraintestinal manifestations, hematocrit, the need for antidiarrheal drugs, the presence of abdominal mass and change in body weight; each item has a numerical weighted multiplier and the sum of the eight items quantifies the overall disease severity of the disease. A score less than 150 and more than 250 indicates clinical remission and severe disease, respectively. An intermediate score between 150 and 250 indicates mild-moderate disease (table 5.3). Table 5.3. Crohn Disease Activity Index

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Items No.liquid stools Abdominal pain

Wellbeing

No complications

Antidiarrheal drugs Abdominal mass Hematocrit Weight loss Total

Scores N1: sum in the last seven days N2: sum of the last seven days ratings (0=none, 1=mild, 2=moderate; 3=severe) N3: sum of the last seven days ratings (0=well, 1=slightly under par, 2=poor, 3=very poor, 4=terrible) N4: No. of complications (arthritis; iritis/uveitis; erythema nodosum; pyoderma gangrenosum; aphthous stomatitis; anal fissure or fistula/abscess; fever >37.8°C) N5: 0=no; 1=yes

Weight 2 5

Weighted scores N1x2 N2x5

7

N3x7

20

N4x20

30

N5x30

N6: 0=no; 2=doubt; 5=definite N7: 47-Ht (male); 42-Ht (female) N8: % change of usual body weight (add or subtract according to sign)

10 6 1

N6x10 N7x6 N8x1 sum of weighted scores

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The main limitations of CDAI are its subjective nature and poor inter-rater agreement; in addition, CDAI doesn’t cover important issues such as quality of life and psychosocial aspects of the disease. Other indexes have been developed and validated (simple index, Cape Town index, Van Hees index, Present-Korelitz index) [22], but CDAI remains the most used in clinical trials. Special clinical indexes are available for pediatric populations and for perianal disease assessment. Endoscopic scores of disease severity will be discussed in the next section. Although the importance of these scales in clinical trials is unquestionable, their role in daily clinical practice is limited and many clinicians adopt the American College of Gastroenterology working definitions of Crohn’s disease activity to identify patients with severe disease [23] (table 6.3).

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CLASSIFICATION OF CROHN’S DISEASE Classification of disease by phenotypes would have benefits with respect to patient management, counseling, choice of medical or surgical therapy, and prognosis. In the last two decades, three classifications have been proposed at as many Working Parties, the Rome (1991), Vienna (1998) and Montreal (2005) classification, respectively [24]. Each classification represents a further evolution based on new insights from therapeutic trials and from a better knowledge of serotypes, genetic and clinical course of the disease. The Vienna Classification considered three items, i.e. (i) age at onset (A140yrs), (ii) location of disease (L1, ileal; L2, colonic; L3, ileocolonic; L4, upper tract), and (iii) disease behavior (B1, non-stricturing, non-penetrating; B2, stricturing; B3, penetrating). The Montreal classification has not changed the three parameters, but further modifications within each of the categories have been made, regarding the age of disease onset in three categories, A1, below 16 yrs; A2, between 17 and 40 yrs; A3 more than 40 yrs and the adjunct of perianal disease (p) as disease modifier in the behavior item (table 3.3). The last change arises from the substantial evidence that perianal fistulizing disease is not necessarily associated with intestinal fistulizing behavior and requires separate subclassification and treatment.

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Table 6.3. American College of Gastroenterology working definitions for Crohn’s disease activity (modified)

Remission

Mild-moderate

Moderate-severe

Severefulminant

Definition Patients who are asymptomatic, including those who have responded to medical intervention or have undergone surgical resection without evidence of residual disease Ambulatory patients able to tolerate oral alimentation without dehydration, toxicity, abdominal tenderness, painful mass, obstruction or >10% weight loss Patients who failed to respond to treatment for mild-moderate disease or those with symptoms of fever, weight loss, abdominal pain or tenderness, intermittent nausea and vomiting (without obstruction) or moderate-severe anemia Patients with persisting symptoms despite steroid therapy as outpatients or those presenting high fever, vomiting, obstruction, rebound tenderness, cachexia or evidence of abscess

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CLINICAL COURSE Crohn’s disease is a condition with a broad spectrum of clinical course, ranging from mild disease with several years of clinical remission to severe, complicated, life-threatening disease. Many factors may influence the course of the disease, such as spontaneous healing, response to medical therapy, relapse after surgery, smoking, comorbidity, drugs and disease behavior. The matter is further complicated by the different end-points used in clinical trials as clinical remission, reduction in CDAI, and mucosal healing. Bearing in mind these limitations, two main different temporal patterns of the disease are described, remitting-relapsing or intermittent disease, and, more rarely, chronic continuous symptoms. Furthermore, it is impossible to draw the natural history of Crohn’s disease, as almost no patient remains untreated for several years of observation. Even the course of patients allocated to placebo in randomized controlled trials is biased, because it is well known that the mere act of participating in a study, with frequent interaction with health care professionals may change the disease course of a chronic condition (the so-called Hawthorne effect) [25]. Long-term studies have shown that Crohn’s disease has a chronic course with an unpredictable relapsing rate. From placebo-treated patients in clinical trials we have learned that

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25-50% of patients with active disease go into remission spontaneously within three months, but after 12 months, only 15% of patients are still in remission [26]. Table 7.3. Conditions frequently confused with inflammatory bowel disease Both ileal and colonic disease IBS

Malignancy Vasculitis Drugs (NSAID’s)

Ileal disease

Colonic disease

Infectious enteritis (most common: Campylobacter spp, Yiersinia spp, tuberculosis)

Infectious colitis (most common: Salmonella spp, Shigella spp, E. coli spp, tuberculosis, amoebiasis, Cytomegalovirus) Diverticular disease SRUS Radiation colitis Pseudomembranous colitis Ischemic colitis

Acute appendicitis Endometriosis Pelvic Inflammatory Disease

IBS, inflammatory bowel disease; NSAID’s non steroid anti inflammatory drugs; SRUS, solitary rectal ulcer syndrome.

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DIFFERENTIAL DIAGNOSIS Like most organ systems, the gut manifests a response to injury in a limited number of ways. Infectious, neoplastic, ischemic and inflammatory processes may imitate inflammatory bowel disease for their similar clinical presentation. In addition, very few diseases have pathognomonic features. Therefore a wide array of conditions have to be considered in differential diagnosis of inflammatory bowel disease. Among the most common conditions listed in table 7.3, irritable bowel syndrome poses a clinical challenge to the gastroenterologist for various reasons. First, both inflammatory bowel disease and irritable bowel syndrome manifest chronic, relapsing abdominal pain and diarrhea. Second, young people are equally affected in both conditions. Third, irritable bowel syndrome is at least 250 fold more common than inflammatory bowel disease. Fourth, diagnostic delay of inflammatory bowel disease may eventually lead to inappropriate surgery for complicated disease. In an attempt to better identify people with Crohn’s disease within those having chronic abdominal pain and diarrhea, a Consensus Conference from a panel of experts [27] have suggested standardizing the clinical suspicion of Crohn’s disease by criteria indicated in table 8.3. Although these

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criteria have never been formally validated, they can be useful to select subjects for invasive and costly investigations.

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Table 8.3. Patients with characteristic gastrointestinal signs and symptoms of Crohn’s disease. Criteria of suspicion include at least one item of group A with at least one item under groups B, C or D. Celiac disease must to be ruled out by negative serology A. Gastrointestinal symptoms a. Chronic abdominal pain b. Chronic diarrhea c. Weight loss d. Growth failure (children) B. Extraintestinal symptoms a. Unexplained (recurrent) fever b. Arthritis/arthralgias c. Erythema nodosum/pyoderma d. Aphtous stomatitis e. Perianal disease f. Primary sclerosing cholangitis C. Laboratory markers a. Iron deficiency anemia b. Thrombocytosis/leukocytosis c. Elevated CRP/ESR d. Hypoalbuminemia e. Fecal markers (calprotectin, lactoferrin, fecal occult blood) f. Positive ASCA serology D. Non-diagnostic abnormal imaging CRP, C reactive protein; ESR, erythrocyte sedimentation rate; ASCA, anti Saccharomices Cerevisiae antibodies.

REFERENCES [1]

G Schumacher, B Kollberg, B Sandstedt. A Prospective Study of First Attacks of Inflammatory Bowel Disease and Infectious Colitis: Histologic

Girelli, Carlo M., and Luca G. Crespit. Diagnostic Modalities in Crohn's Disease, Nova Science Publishers, Incorporated,

Pathology and Clinical Features

[2] [3]

[4]

[5] [6]

[7]

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[8] [9] [10] [11]

[12]

[13]

[14]

49

Course during the 1st Year after Presentation. Scand J Gastroenterol 1994; 29: 318-332. Davison AM, Dixon MF. The appendix as a skip lesion in ulcerative colitis. Histopathology 1990; 16: 93-5. D'Haens G, Geboes K, Peeters M, et al. Patchy cecal inflammation associated with distal ulcerative colitis: a prospective endoscopic study. Am J Gastroenterol 1997; 92: 1275-9. Kleer CG, Appleman HD. Ulcerative colitis: patterns of involvement in colorectal biopsies and change with time. Am J Surg Pathol 1998; 22: 9839. Sheperd NA. Diverticular disease and chronic idiopathic inflammatory bowel disease: association and masquerades. Gut 1996; 38: 801-2. Munkholm P, Langholz E, Nielsen CH, eta al. Incidence and prevalence of Crohn’s disease in the County of Copenhagen. Scand J Gastroenterol 1992; 27: 609-14. Gashe C, Scholmeric J, Brynskov J et al. A simple classification of Crohn’s disease: report of the working party for the world congress of gastroenterology Vienna 1998. Inflamm Bowel Dis 2000; 6: 8-15. Cunha BA. Fever of unknown origin: clinical overview of classic and current concepts. Infect Dis Clin North Am 2007; 21: 867-915. Danzi JT. Extraintestinal manifestations of idiopathic inflammatory bowel disease. Arch Intern Med 1988; 148: 297-302 Bernstein CN, Leslie WD. Review article: Osteoporosis and inflammatory bowel disease. Aliment Pharmacol Ther 2004; 19: 941-52. Girlich C, Bogenrieder T, Palitzsch KD, et al. Orofacial granulomatosis as initial manifestation of Crohn's disease: a report of two cases. Eur J Gastroenterol Hepatol 2002; 14: 873-6. Dharancy S, Talbodec N, Asselah T, et al. The synovitis-acne-pustulosishyperostosis-osteitis (SAPHO) syndrome, a rare extra-digestive manifestation of Crohn's disease. Presentation of 1 case and review of the literature. Gastroenterol Clin Biol 1998; 22: 240-3. Shaer AJ, Stewart LR, Cheek DE, et al. IgA antiglomerular basement membrane nephritis associated with Crohn's disease: a case report and review of glomerulonephritis in inflammatory bowel disease. Am J Kidney Dis 2003 May;41(5):1097-109. Saverymuttu SH, Hodgson HJ, Chadwick VS, et al. Differing acute phase responses in Crohn’s disease and ulcerative colitis. Gut 1986;27:809–13.

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[15] Roseth AG, Schmidt PN, Fagerhol MK. Correlation between faecal excretion of indium-111-labelled granulocytes and calprotectin, a granulocyte marker protein, in patients with inflammatory bowel disease. Scand J Gastroenterol 1999;34:50–4 [16] Tibble J, Teahon K, Thjodleifsson B, et al. A simple method for assessing intestinal inflammation in Crohn’s disease. Gut 2000;47:506–13. [17] Kaiser T, Langhorst H, Wittkowski H et al. Faecal S100A12 as non invasive marker distinguishing inflammatory bowel disease from irritable bowel syndrome. Gut 2007; 56:1706-13 [18] Papp M, Norman GL, Altorjay I, Lakatos PL. Utility of serological markers in inflammatory bowel diseases: gadget or magic? World J Gastroenterol 2007; 13: 2028-36. [19] Dotan I, Fishman S, Dgani Y, et al. Antibodies against laminaribioside and chitobioside are novel serologic markers in Crohn’s disease. Gastroenterology 2006; 131: 366-78. [20] Papadakis KA, Yang H, Ippoliti A, et al. Anti-flagellin (CBir1) phenotypic and genetic Crohn's disease associations. Inflamm Bowel Dis 2007; 13: 52430. [21] Gillen CD, Walmsey RS, Prior P, et al. Ulcerative and Crohn’s disease: a comparison of the colorectal cancer risk in extensive colitis. Gut 1994; 35: 1507-8. [22] W. Sandborn, B. Feagan, S. Hanauer, et al. A review of activity indices and efficacy endpoints for clinical trials of medical therapy in adults with Crohn's disease . Gastroenterology 2002; 122: 512-30. [23] Hanauer SB, Sandborn W, The practice parameters committee of the American college of gastroenterology. Management of Crohn’s disease in adult. Am J Gastroenterol 2001; 96: 635-43. [24] Satsangi J, Silverberg MS, Vermeire S, Colombel JF. The Montreal classification of inflammatory bowel disease: controversies, consensus, and implications. Gut 2006; 55: 749-53. [25] Parsons HM. What Happened at Hawthorne?: New evidence suggests the Hawthorne effect resulted from operant reinforcement contingencies. Science 1974; 183: 922-932. [26] Faubion WA Jr, Loftus EV Jr, Harmsen WS, et al. The natural history of corticosteroid therapy for inflammatory bowel disease: a population-based study. Gastroenterology 2001; 121: 255-60. [27] The 5th International Conference on Capsule Endoscopy. Paris, June 9-10, 2006.

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SECTION II: ENDOSCOPIC DIAGNOSIS

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In: Diagnostic Modalities in Crohn's Disease ISBN 978-1-60692-701-4 Editors: C. M. Girelli and L. G. Crespi © 2009 Nova Science Publishers, Inc.

Chapter IV

ILEOCOLONOSCOPY Carlo M. Girelli

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Hospital of Busto Arsizio (VA), Italy

INTRODUCTION The development of fiberoptic and videoendoscopy has greatly improved the diagnosis and management of inflammatory bowel disease. Direct mucosa visualization of the bowel in conjunction with biopsy for histological evaluation allows the correct diagnosis in most patients. Moreover, endoscopy has a role in the management of patients with known inflammatory bowel disease in order to detect recurrence, refractoriness to medical therapy, and complications. Endoscopic treatment of stricture and bleeding is another opportunity for endoscopy. Attempts to perform endoscopic intubation of the ileociecal valve and subsequent examination of the terminal ileum are mandatory when there is a clinical suspicion of Crohn disease (see table 8.3). Although considered safe in experienced hands, colonoscopy can be painful, needing conscious sedation and it carries a substantial risk of perforation in the severely inflamed bowel. The aim of this chapter is (i) to define the indications for ileocolonoscopy in various clinical settings, such as suspect Crohn’s disease at the onset, disease recurrence after medical or surgical therapy, detection of complications and surveillance for cancer in long-standing disease, (ii) to depict the main endoscopic features of

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Crohn’s disease and differential diagnostic criteria with ulcerative colitis, (iii) to describe the endoscopic management of the disease. Limitations of the feasibility of endoscopy will be highlighted, introducing the need for integration with radiologic evaluation, the subject of the following section.

CLINICAL INDICATION

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Current indications for ileocolonoscopy are chronic diarrhea, blood in the stools, abdominal pain with or without signs and findings listed in table 8.3, in order to rule in, or to exclude the diagnosis of inflammatory bowel disease. Other indications, in the setting of known inflammatory bowel disease, are differentiating ulcerative colitis and Crohn’s disease; assessment of disease extent, activity or recurrence; assessment of mucosal healing after medical therapy; assessment of disease complications or radiologic abnormalities; surveillance for dysplasia and cancer in long-standing disease; therapeutic endoscopy for amenable complications. Differentiation between Crohn’s disease and ulcerative colitis has important consequences for medical therapy, surgical options and prognosis. This distinction can be made accurately in at least 90% of patients and up to 95% during the course of scheduled follow up [1,2].

SAFETY Endoscopy carries a generic risk of perforation that is increased in the severely inflamed bowel; for this reason many clinicians believe that endoscopy is contraindicated in severe disease. However, the experienced endoscopist can safely perform a gentle lower endoscopy with minimal previous bowel cleansing and slight insufflation, withdrawing the endoscope when loop angulation, pain, blood and fecal content may cause harm to the patient. Carbonnel et al. performed colonoscopy without complications – except for one colonic dilatation – in 85 consecutive patients with acute flares of ulcerative colitis, 46 of whom had severe endoscopic colitis characterized by extensive deep colonic ulcerations [3]. In many instances, a glance to the distal 25-35 cm of the large bowel in the severely ill patient is sufficient to assess the severity and grasp tissue samples for culture and histological evaluation, waiting for a second look, complete colonoscopy for disease extent assessment after improvement by medical therapy [4].

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BOWEL CLEANSING Bowel cleansing represents an unresolved issue in the endoscopic evaluation of patients having inflammatory bowel disease. Patients with active diarrhea and abdominal pain should not be submitted to standard bowel cleansing with large volume of the polyethyleneglycol (PEG) solution. In this setting, this type of preparation is often unsuccessful for subsequent vomiting and carries a substantial risk of dehydration, electrolyte imbalance and worsening abdominal cramps. In addition, osmotic laxatives like phosphate preparations should be avoided because they may cause transient aphthous mucosal lesions mimicking early Crohn’s disease, creating diagnostic confusion. In most instances a strict low residual diet, a judicious use of PEG solution and enemas can allow a bowel cleansing adequate for a good endoscopic examination without risk and discomfort to the patient.

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REASONS FOR INCOMPLETE EXAMINATIONS Limitations in bowel cleansing, severity of mucosal ulcerations and strictures are the main reasons for incomplete bowel examination in patients with suspect and known inflammatory bowel disease [5]. In the management of Crohn’s disease, these situations are the rule and integration of endoscopy with radiologic imaging studies are needed for a complete, careful bowel assessment (see next chapters).

(a)

(b)

(c)

Figure 1.4. Colonoscopic aspect of normal colon with a well represented vascular pattern (a); mild inflammatory changes with disappearance of vascular pattern, erythema, mucosal fragility (b); severe inflammatory changes with deep ulcers, cobblestone and spontaneous bleeding (c). Histological confirmation of Crohn’s disease in both (b) and (c).

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(a)

(b)

(c)

(d)

Figure 2.4. Lesional pattern in small bowel Crohn’s disease. Aphthae (a); linear, serpiginous ulcer (b); shallow irregular edged ulcer (c); and deep irregular ulcer with cobblestone (d).

LESIONAL PATTERN IN CROHN’S DISEASE In Crohn’s disease the endoscopic lesions are patchy, asymmetrical and heterogeneous. Normal colon, mild colonic inflammation and severe mucosal lesions are shown in figure 1.4. Ulcers whether aphthoid, superficial or deep, linear, serpiginous, oval or round are often surrounded by normal mucosa (figure 2.4). The rectum is spared in near 50% of cases. The presence of ulcerations on the ileociecal valve or in the terminal ileum is highly suggestive for Crohn’s disease (Figure 3.4). While fistulous tracks are better identified by radiology, sometimes colonoscopy may reveal a fistulous tract as a discrete nodularity in an area of relatively spared mucosa. There is no agreement about the best biopsy site to increase the yield of diagnostic histopathology. Whereas some authors recommend up to four biopsies of endoscopically normal rectal mucosa [6], a

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study demonstrated that biopsies on the rim of the ulcers were more likely to demonstrate nearly diagnostic granulomas [7]. The value of retrograde ileoscopy has been clearly shown in a prospective study of 110 patients with a radiologic diagnosis of Crohn’s disease of the terminal ileum subsequently evaluated by ileoscopy. Up to a quarter of patients were found to have other causes of their radiologic abnormality, including lymphoid nodular hyperplasia (Figure 4.4), a poorly understood, benign condition of the terminal ileum [8].

Figure 3.4. Ileocolonoscopic feature of Crohn’s disease of the terminal ileum.

ENDOSCOPIC DIFFERENTIAL DIAGNOSIS Ileocolonoscopy and biopsies also help differentiate between ulcerative colitis and Crohn’s disease. However in up to 10-15% of cases, Crohn’s colitis and ulcerative colitis may look very similar. The main different endoscopic patterns between these entities are summarized in table 1.4. Granularity of the mucosa with continuous involvement (figure 5.4) is typical of ulcerative colitis. In the interpretation of these endoscopic findings, we must bear in mind that the effect of therapy, in particular with topic enemas, may determine substantial changes of the typical distribution pattern of colorectal lesions. In the large published prospective series by Pera and co-workers the global accuracy of endoscopy was 89%. Diagnostic errors occurred in 4% of cases and they were

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more frequent in patients with severe inflammatory changes. The most useful endoscopic features distinguishing Crohn’s disease from ulcerative colitis were discontinuous involvement with skip lesions, anal lesions, and cobblestone of the mucosa for Crohn’s disease, and erosions, micro-ulcers and granular mucosa for ulcerative colitis [9]. In a large Norwegian cohort of patients with a new diagnosis of inflammatory bowel disease followed up for two years, the initial diagnosis of ulcerative colitis and Crohn’s disease was confirmed in 88% and 91%, respectively [10].

Figure 4.4. Lymphoid nodular hyperplasia of the terminal ileum.

The classic endoscopic features of inflammatory bowel disease can sometimes be mimicked by several forms of infectious colitis as well as non infectious conditions including ischemic colitis, radiation injuries, and non steroidal inflammatory drugs (NSAIDs) colitis. Among the infectious colitides the most common micro-organisms involved are Clostridium Difficile, Salmonella, Shigella, Campylobacter, Yersinia, Klebsiella, Treponema pallidum, Entamoeba histolytica, Herpes simplex, Cytomegalovirus. Although each entity may have a characteristic endoscopic feature (figure 6.4), the correct diagnosis can be established with the aid of a culture, serology and a thorough history (drugs, travels, anal intercourse, human immunodeficiency virus exposure). Finally, the differential diagnosis between Crohn’s disease and intestinal tuberculosis deserve

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a particular comment for various reasons. First, although uncommon in industrialized countries, intestinal tuberculosis is increasing in incidence; second, the preferred intestinal location of tuberculosis is the same as Crohn’s disease (terminal ileum, ileociecal valve and ciecum); third, medical therapy with glucocorticosteroids and anti-TNF therapy of an unrecognized intestinal tuberculosis may be potentially fatal to the patient [11]. In the series from Lee and co-workers, four clinical-endoscopic variables were associated with intestinal tuberculosis, namely involvement of fewer than four bowel segments, transverse ulcers, a patulous ileociecal valve, scarring and pseudopolyps; conversely, four variables were more commonly associated with Crohn’s disease, i.e. anorectal lesions, longitudinal ulcers, aphthous ulcers and cobblestone [12]. If doubts do persist, I recommend sampling the intestinal mucosa for culture and detection of Mycobacterium tuberculosis by polymerase chain reaction (rt-PCR).

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Table 1.4. Ileocolonoscopic features useful in distinguishing Crohn’s disease (CD) from ulcerative colitis (UC) Type of lesions Erythema Blurred vascular pattern Granularity Mucosal friability Cobblestone Aphthae Linear /serpiginous ulcers Pseudopolyps Stricture Distribution of lesions Rectal involvement Continuous involvement Patchiness Skip lesions Ileal involvment

CD ++ + + + ++ +++ +++ ++ ++

UC +++ +++ +++ +++ +++ +

+ + +++ +++ +++

+++ +++ + -

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Figure 5.4. Granular mucosa in ulcerative colitis. The vascular pattern is no longer visible.

Figure 6.4. Herpes proctitis in a homosexual HIV positive man.

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ENDOSCOPIC ASSESSMENT OF DISEASE EXTENT AND SEVERITY Assessment of disease extent and severity is of paramount importance in Crohn’s disease management. There are two validated indexes for endoscopic assessment severity, namely CDEIS and SES-CD [13,14]. CDEIS (Crohn Disease Endoscopic Index of Severity) was formerly developed by GETAID (Groupe d’etudes Therapeutiques des Affection Inflammatories du tube Digestif) French study group (table 2.4). To calculate CDEIS the bowel is divided into five segments (rectum, sigmoid-left colon, transverse colon, right colon and terminal ileum) and a numerical score based on surface involvement by disease or ulceration, and the presence of deep or superficial ulcers, of ulcerated or nonulcerated stricture is assigned. SES- CD (Simple Endoscopic Score- Crohn Disease) groundwork is similar to CDEIS, but it is less cumbersome to calculate and more suitable for daily clinical practice (table 3.4).

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ENDOSCOPIC ASSESSMENT OF DISEASE RECURRENCE Clinical relapse of Crohn’s disease after respective surgery has been reported in 33% and 44% at five and ten years respectively [15]. However, the classical study of Rutgeerts et al. on 114 patients who underwent ileocolonic resection showed endoscopic recurrence in up to 70% of patients within one year of surgery, and, in accordance with previous knowledge, nearly half of these patients were asymptomatic [16]. Up to 90% of the recurrences were in proximity of the anastomosis. Furthermore, the GETAID study reported a 60% incidence of endoscopic anastomotic relapse only three months postoperatively [17]. Importantly, these studies also identified a subgroup of patients in the postoperative period at high risk for early recurrence in which an aggressive medical therapy may be indicated. The Rutgeerts’ score for assessing postoperative endoscopic recurrence of Crohn’s disease is reported in table 4.4.

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Table 2.4. Crohn Disease Endoscopic Index of Severity (CDEIS). Total score is obtained by the sum of the total scores of the six variables. Each bowel segment includes rectum, sigmoid-left colon, transverse colon, ascending colon and terminal ileum Variable N° 1

2

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3

4

5 6

Description Number of colorectal segments in which deep ulcers are seen is divided by the number of segments examinated Number of colorectal segments in which superficial ulcers are seen is divided by the number of segments examinated Segmental surfaces involved by disease. The degree of disease involvement in each segment is determined by examining each segment for the following lesions (pseudopolyps, scars, erythema, edema, aphthae, superficial ulcers, deep ulcers, non ulcerated stricture, ulcerated stricture) and estimating the number of cm of involvement in a representative 10 cm portion from each segment. The average segmental surface involved by disease is calculated by dividing the sum of each of the individual segmental surfaces involved by disease by the number of segments examinated Segmental surfaces involved by ulcerations. The degree of ulceration in each segment is determined by examining each segment for ulceration (aphthoid ulcers, superficial ulcers, deep ulcers, ulcerated stricture) and estimating the number of cm of intestine involved by ulceration in a representative 10 cm portion from each segment. The average segmental surface involved by ulceration is calculated by dividing the sum of each of the individual segmental surfaces involved by disease by the number of segments examined Presence of a non-ulcerated stricture in any of the segments examined Presence of an ulcerated stricture in any of the segments examined

Weight 12 X

Total …….

6X

…….

1X

…….

1X

…….

3X

…….

3X

…….

Total

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Table 3.4. Simple Endoscopic Score for Crohn’s Disease (SES-CD) Variable Size of ulcers Ulcerated surface Affected surface Narrowing of the lumen

0 None None

1 Aphthous ulcers 2 cm >30%

Unaffected segment None

75%

Single, can be passed

Multiple, can be passed

Cannot be passed

Table 4.4. Rutgeerts’ score for postoperative recurrence of Crohn’s disease

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Score 0 1 2 3 4

Type of lesion No lesions < 5 aphthous lesions >5 aphthous lesions or lesions confined to the anastomosis Diffuse aphthous ileitis, diffusely inflamed mucosa Diffuse inflammation, large ulcers, nodules, narrowing

ENDOSCOPIC DETECTION AND MANAGEMENT OF COMPLICATIONS Stricture Crohn’s disease invariably recurs after surgical resection. Fibro-stenosing disease no more amenable by medical therapy can require further surgical intervention. In the last quarter of the century, in order to avoid repeated bowel resections (potentially leading to the dreaded short bowel syndrome) bowelsparing surgical techniques such as strictureplasty and endoscopic dilation have been proposed and successfully introduced in clinical practice. Successful endoscopic dilation of anastomotic recurrence using through-the-scope (TTS) balloons has emerged as an alternative to strictureplasty for selected patients. Careful patient selection is paramount to improve the clinical outcome. TTS dilation is indicated for short (< 4-5 cm), symptomatic strictures of the anastomotic recurrence and for colonic fibro-stenosing disease. Therefore, the procedure must be preceded by careful radiologic imaging to assess the length

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and angulations of the targeted lesion and the presence of pre-anastomotic viscus dilation. As shown in a recent systematic review, immediate and long-term benefits of the procedure are accomplished in 86% and 58% of patients, respectively [18]. In experienced hands, major complications (bleeding and perforation) are uncommon (2%) and generally amenable conservatively. If the stricture relapses, a further endoscopic TTS dilation is warranted, but if the symptom-free interval shortens after each procedure, surgery is recommended. The dilation technique is not standardized. Number (one to three), duration (less than two minutes or more than three minutes), balloon size used in each endoscopic session are variable in published series. Although it was never tested in formal randomized controlled trials, a pilot study of concomitant perilesional injection of glucocorticosteroids was disappointing [19], while low dose infliximab perilesional endoscopic injection was promising [20], calling for further investigation.

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Bleeding Acute lower gastrointestinal bleeding is more frequently associated with severe active ulcerative colitis. In contrast, most patients with Crohn’s disease have chronic low-grade bleeding leading to secondary iron deficiency anemia. Gross bleeding in Crohn’s disease is rare and it is often the result of deep ulceration penetrating in a large submucosal vessel. The largest published, retrospective, series in this setting consists of 34 patients [21]. The bleeding was more frequent in colonic disease (84%) and the point of bleeding, consistent with an ulcer in 95% of cases, was identified endoscopically in 60%. Most patients of this series stopped their bleeding with medical therapy, but an endoscopic hemostasis could be attempted in selected patients.

Cancer Surveillance Although the recognition of dysplasia as a precursor to cancer in inflammatory bowel disease supports the rationale for performing colonoscopic surveillance, there is considerable debate regarding the utility and costeffectiveness of surveillance programs [22, 23]. Despite published guidelines and the consensus of experts that patients with extensive ulcerative colitis for 8 years and left-sided colitis for 15 years should be enrolled in surveillance programs,

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evidence from randomized controlled clinical trials of the appropriateness of these recommendations is still lacking [24, 25]. Yet, in the setting of long-standing inflammatory bowel disease, mass lesions or strictures are ominous and must be considered malignant until proven otherwise by histological sampling. Although some mass lesions are pseudopolyps without malignant potential, a dysplasia associated lesion or mass (DALM) is often associated with carcinoma and represents a clear indication for resection. However, in most instances dysplasia and neoplasia develop in flat mucosa so it can easily be overlooked during colonoscopy. Four random biopsies for each quadrant at 3-6 cm interval of the colon are recommended in addition to targeted biopsies of suspect lesions. Despite these time-consuming efforts, dysplasia and neoplasia are frequently missed. New endoscopic techniques aim to facilitate the detection of dysplastic areas in the colonic mucosa. Chromoendoscopy and magnification endoscopy have proven to increase the detection of neoplasia in ulcerative colitis enabling pit-pattern analysis for an accurate endoscopic classification [26]. Novel endoscopic techniques incorporated in a single endoscope, the ETMI prototype (Endoscopic Tri-Modal Imaging) (Olympus Inc, Tokio, Japan) show promise in early detection of dysplastic flat mucosa in long-standing ulcerative colitis [27]. Briefly, the ETMI system consists of three modal light sources; (i) the conventional high resolution white light endoscopy with magnification, (ii) narrow band imaging (NBI), and (iii) autofluorescence imaging (AFI). For NBI the relative intensity of blue light is increased; since the blue light penetrates the mucosa only superficially and is the main color absorbed by hemoglobin, this setting enhances surface and capillary details. In the AFI mode, blue light is used for excitation and green light for reflection. A barrier filter is used to detect autofluorescence and reflection light with wavelengths of 500-630 nm only. The sequentially detected images of autofluorescence and green reflections are integrated by the processor into real-time and pseudo-color images. During AFI, normal mucosa appears green while neoplastic changes appear purple. Especially AFI technique seems promising in targeting neoplastic changes in long-standing inflammatory bowel disease from the initial published experiences [27]. Clinical trials are ongoing, but it is conceivable to guess that these new techniques will be the standard of care in the next few years in the endoscopic surveillance of longstanding inflammatory bowel disease.

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REFERENCES

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[1]

Joossens S, Reinisch W, Vermeire S et al. The value of serologic markers in indeterminate colitis: A prospective follow-up study. Gastroenterology 2002; 122: 1242-47. [2] Meucci G, Bortoli A, Riccioli FA, Girelli CM et al. Frequency and clinical evolution of indeterminate colitis: a retrospective multi-centre study in northern Italy. GSMII (Gruppo di Studio per le Malattie Infiammatorie Intestinali). Eur J Gastroenterol Hepatol 1999; 11: 909-13. [3] Carbonnel F, Lavergne A, Lémann M, et al. Colonoscopy of acute colitis. A safe and reliable tool for assessment of severity. Dig Dis Sci 1994; 39: 1550-7. [4] Daperno M, Sostegni R, Pera A et al. The role of endoscopic assessment in ulcerative colitis in the era of infliximab. Dig Liv Dis 2008; 40S: S220-4. [5] Bat L, Pines A, Ron E et al. Colonoscopy without prior preparation in mild to moderate active ulcerative colitis. J Clin Gastroenterol 1991; 13: 46-8. [6] Surawicz CM, Meisel JL, Ylvisaker T, et al. Rectal biopsy in the diagnosis of Crohn's disease: value of multiple biopsies and serial sectioning. Gastroenterology 1981; 80: 66-71. [7] Pötzi R, Walgram M, Lochs H et al. Diagnostic significance of endoscopic biopsy in Crohn's disease. Endoscopy 1989; 21: 60-2. [8] Coremans G, Rutgeerts P, Geboes K et al. The value of ileoscopy with biopsy in the diagnosis of intestinal Crohn's disease. Gastrointest Endosc 1984; 30: 167-72. [9] Pera A, Bellando P, Caldera D et al. Colonoscopy in inflammatory bowel disease. Diagnostic accuracy and proposal of an endoscopic score. Gastroenterology 1987; 92: 181-5. [10] Moum B, Ekbom A, Vatn MH et al. Inflammatory bowel disease: reevaluation of the diagnosis in a prospective population based study in south eastern Norway. Gut 1997; 40: 328-32. [11] Keane J, Gershon S, Wise RP et al. Tuberculosis Associated with Infliximab, a Tumor Necrosis Factor –Neutralizing Agent. N Engl J Med 2001; 345: 1098-104. [12] Lee YJ, Yang SK, Byeon JS et al. Analysis of colonoscopic findings in the differential diagnosis between intestinal tuberculosis and Crohn’s disease. Endoscopy 2006; 38: 592-7.

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[13] Mary JY, Modigliani R. Development and validation of an endoscopic index of the severity for Crohn's disease: a prospective multicentre study. Groupe d'Etudes Thérapeutiques des Affections Inflammatoires du Tube Digestif (GETAID). Gut 1989; 30: 983-9. [14] Daperno M, D'Haens G, Van Assche G et al. Development and validation of a new, simplified endoscopic activity score for Crohn's disease: the SESCD. Gastrointest Endosc 2004; 60: 505-12. [15] Bernell O, Lapidus A, Hellers G. Risk factors for surgery and postoperative recurrence in Crohn's disease. Ann Surg 2000; 231: 38-45. [16] Rutgeerts P, Geboes K, Vantrappen G et al. Natural history of recurrent Crohn's disease at the ileocolonic anastomosis after curative surgery. Gut 1984; 25: 665-72. [17] Florent C, Cortot A, Quandale P et al. Placebo-controlled clinical trial of mesalazine in the prevention of early endoscopic recurrences after resection for Crohn's disease. Groupe d'Etudes Thérapeutiques des Affections Inflammatoires Digestives (GETAID). Eur J Gastroenterol Hepatol 1996; 8: 229-33. [18] Hassan C, Zullo A, De Francesco V et al. Systematic review: Endoscopic dilatation in Crohn's disease. Aliment Pharmacol Ther 2007; 26: 1457-64. [19] East JE, Brooker JC, Rutter MD et al. A pilot study of intrastricture steroid versus placebo injection after balloon dilatation of Crohn's strictures. Clin Gastroenterol Hepatol 2007; 5: 1065-9. [20] Biancone L, Cretella M, Tosti C et al. Local injection of infliximab in the postoperative recurrence of Crohn's disease. Gastrointest Endosc 2006; 63: 486-92. [21] Belaiche J, Louis E, D'Haens G et al. Acute lower gastrointestinal bleeding in Crohn's disease: characteristics of a unique series of 34 patients. Belgian IBD Research Group. Am J Gastroenterol 1999; 94: 2177-81. [22] Lindberg J, Stenling R, Palmqvist R et al. Efficiency of colorectal cancer surveillance in patients with ulcerative colitis: 26 years' experience in a patient cohort from a defined population area. Scand J Gastroenterol 2005; 40: 1076-80. [23] Rutter MD, Saunders BP, Wilkinson KH et al. Thirty-year analysis of a colonoscopic surveillance program for neoplasia in ulcerative colitis. Gastroenterology 2006; 130: 1030-8. [24] Itzkowitz SH, Present DH; Crohn's and Colitis Foundation of America Colon Cancer in IBD Study Group. Consensus conference: Colorectal

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cancer screening and surveillance in inflammatory bowel disease. Inflamm Bowel Dis 2005; 11: 314-21. [25] Collins PD, Mpofu C, Watson AJ, Rhodes JM. Strategies for detecting colon cancer and/or dysplasia in patients with inflammatory bowel disease. Cochrane Database Syst Rev 2006; 19: CD000279. [26] Matsumoto T, Iwao Y, Igarashi M et al. Endoscopic and chromoendoscopic atlas featuring dysplastic lesions in surveillance colonoscopy for patients with long-standing ulcerative colitis. Inflamm Bowel Dis 2008; 14: 259-64. [27] Van den Broek FJ, Fockens P, van Eeden S et al. Endoscopic tri-modal imaging for surveillance in ulcerative colitis: Randomized comparison of high resolution endoscopy and autofluorescence imaging for neoplasia detection; and evaluation of narrow band imaging for classification of lesions. Gut 2008; doi:10.1136/gut.2007.144097.

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In: Diagnostic Modalities in Crohn's Disease ISBN 978-1-60692-701-4 Editors: C. M. Girelli and L. G. Crespi © 2009 Nova Science Publishers, Inc.

Chapter V

ENTEROSCOPY Carlo M. Girelli

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Hospital of Busto Arsizio (VA), Italy

INTRODUCTION Up to one third of Crohn’s disease lesions are located in the small intestine out of the reach of conventional endoscopy, and therefore a substantial number of patients could be undiagnosed or misdiagnosed if the clinician relies only on the indirect imaging obtained from radiologic investigations. Although it is a muchneeded procedure, the endoscopic evaluation of patients with suspected or proven small bowel disorders is among the most difficult of the medical tasks because the small bowel is located quite far from the natural orifices. In addition, the intestinal loops are long, elastic, unbounded and free in the abdominal cavity and attempts to negotiate them by an endoscope invariably result in viscus stretching and endoscope looping with inevitable failure of forward insertion of the endoscope. For this reason, push-type enteroscopy allows only the visualization of 60-80 cm of the proximal small bowel, leaving to radiologic investigation the 4-5 meters of the remainder of the small intestine. The time-honored sonde-type enteroscopy was cumbersome, unpleasant and poorly accurate and stopped being performed many years ago [1]. Therefore, until a few years ago, the diagnosis of small bowel Crohn’s disease was made on indirect radiologic imaging (small

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bowel follow-through and double-contrast enteroclysis; see the next chapters). From 2001, two endoscopic devices, namely wireless capsule endoscopy and double-balloon enteroscopy, entered the diagnostic arena with clear implications for the diagnosis and management of Crohn’s disease. Wireless capsule endoscopy is a merely diagnostic, non-invasive procedure, whereas doubleballoon enteroscopy is invasive, but allows for biopsy and therapy like every other conventional endoscopic procedure. In this chapter, available data from the literature on capsule endoscopy and double-balloon enteroscopy will be reviewed, focusing on the complementary role of the two procedures in the diagnosis and management of Crohn’s disease.

CAPSULE ENDOSCOPY

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How does it Work? The main purpose of the wireless capsule was to examine what has been called the last frontier of endoscopy: the small bowel, which is difficult to reach with standard endoscopes. The wireless capsule, introduced in clinical practice from the beginning of the new millennium [2], has rapidly become recognized as a highly useful method for painless imaging of the entire small intestine. Although the device has been particularly helpful in the evaluation of gastrointestinal bleeding of obscure origin, it clearly has an application to many other small bowel diseases, in particular Crohn’s disease of the small bowel. The first version of the video capsule was the M2A (Mouth-to-Anus) (givenimaging Yoqneam, Israel), a 26X11 mm sized, rigid plastic coated capsule which was equipped with four light-emitting diodes (LEDs) as a light source (Figure 1.5). Images were obtained every 0.5 seconds via a CMOS (complementary metal oxide semiconductor) chip, and these were transmitted at radio frequency via an eight-point sensor array placed on the abdominal surface, to a recording device worn on a special belt, and powered by a battery pack. The battery life was six hours. The field of view was 140°, and the device magnified 1:8, significantly more than the conventional endoscope. The latest developed device, the Pillcam SB2 is the same size and is equipped with six LEDs for better illumination, a battery lasting eight hours which enables the device to take up to 55.000-60.000 jpg images. The field of view has been amplified at 156°. The recorder downloads the images to a dedicated workstation for image processing in

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two hours. The RAPID® software (givenimaging, Yoqneam, Israel) provided with the work station is remarkably versatile (Figure 2.5). In the down side of the screen is a colored scroll bar, which allows the operator to move with the aid of a computer mouse to any part of the recorded video instantaneously. The bar is annotated whenever a thumbnail is selected and edited, allowing for instant return to that frame and for incorporation in the final report. Three different modes of viewing are currently available, single, double and four images, each separated by a single frame. The speed of view are in different modes; manual, automatic, slow, fast (up to 40 frames per second) and quickview. The last mode is a very fast view of the film (a few minutes) allowing for landmarks detection (stomach, duodenal cap, ciecum). The automatic mode, provided with the last RAPID® 5 version, has been enhanced by allowing for elimination of frames with repetitive images; this minimizes the time lost in viewing images while the capsule hangs up for long periods without the risk of missing significant findings. The workstation is equipped with a 17-inch computer monitor set at 800 x 600 pixels. This gives an excellent image about 4-inches across. The availability of the RAPID® reader software allows for reading on any home or office computers. Once the study has been read and reported, it can be saved to a hard disk or to a CD.

Figure 1.5. Pillcam SB and its components. 1. Optical dome, 2. Lens support, 3. Lens, 4. Light source (light emitting diodes), 5. Complementary Metal Oxide Semiconductor, 6. Batteries, 7. ASIC (Application Specific Integrated Circuit) transmitter, 8. Antenna.

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Figure 2.5. RAPID software and its components for viewing and reporting a capsule procedure.

The technique for viewing the video is personal and is a function of experience and confidence. The novice should read the video at 12-15 frames per second. An expert can read at 20 frames per second in automatic mode. With experience, the mean time of reading and report does not exceed 50 minutes. Once a lesion has been found on the video and captured as a thumbnail, the next question is its location. To this purpose, a localization software has been provided. This software is activated at the time the capsule is swallowed. For it to function, it requires delineation of the first image of the stomach, the first image of duodenum, and the first image of the ciecum. With these points defined, a twodimensional trace of where the capsule is at any time is provided. The location of a lesion is helpful in order to plan the antegrade or retrograde approach of balloon-assisted enteroscopy for its treatment or better definition. After swallowing, the capsule continues on by intestinal peristalsis until its natural excretion. Obviously, disorders of swallowing, of intestinal motility and hurdles of intestinal patency are limitations of the method. Currently there are four marketed devices of capsule endoscopy, namely the Pillcam SB (givenimaging), the EndoCapsule (Olympus, Tokyo, Japan), the MiroCam-Miroview (Intromedic, Seoul, Korea) and OMOM capsule. The conceptual differences among these four devices consist in the optical chip and the transmission mode: the EndoCapsule uses a CCD (charge coupled device) chip similar to those of conventional videoendoscopy and the MiroCam employs

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an electro-magnetic field for signal transmission to the recorder, instead of radiofrequency [3]. Their main characteristics are summarized in table 1.5. Recently, a prospective study compared the Pillcam SB and EndoCapsule systems in 20 patients with obscure gastrointestinal bleeding, concluding that both systems provided excellent images and they were equally accurate in the evaluation of the small bowel in bleeding patients [4]. Conversely, very few data are available for the remainder of the capsules in independent peer-reviewed literature. Table 1.5. Main characteristics of the marketed capsule endoscopes Name

Producer

Size

PillCam SB

Givenimaging (Israel) Olympus (Japan) Miramax (Korea) Jianshan Science & Technology (China)

EndoCapsule MiroCam

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OMOM

Field of view 156°

Frames rate

Signal transmission

11x26

Battery life (hours) 8

2/sec

RF

Year of licence 2001

11x26

8

140°

2/sec

RF

2006

11X2 4 13X2 8

10

150°

3/sec

EMF

2008

8

-

2

RF

2004*

RF, radiofrequency; EMF, electro-magnetic field (Characteristics drawn from the Producers). * Only in China.

Accuracy of Capsule Endoscopy in Crohn’s Disease Suspect and Established Crohn’s Disease Capsule Endoscopy has been a particularly promising tool for the evaluation of Crohn’s disease because of its ability to carefully examine the mucosa for subtle lesions. Several retrospective studies and case series have looked at the utility of capsule endoscopy in suspected small bowel pathology, including Crohn’s disease. In the studies looking at patients with suspected Crohn’s disease, most of these patients had either symptoms (diarrhea, abdominal pain, anemia, weight loss, fever, arthritis) or biochemical evidence of inflammatory bowel disease. Most of these patients had negative upper endoscopy, ileocolonoscopy and small bowel follow-through. All these studies showed a superiority of capsule endoscopy in diagnosing Crohn’s disease [5-8]. Several prospective comparative

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studies looking at capsule endoscopy in the diagnosis of established Crohn’s disease have also been carried out. A meta-analysis by Triester and co-workers focused on 11 prospective comparative studies comparing capsule endoscopy to other modalities for the diagnosis of established or suspected non-stricturing Crohn’s disease. A total of 228 patients were studied and capsule endoscopy was compared with multiple modalities including ileocolonoscopy, push enteroscopy, small bowel radiography, enteric-computerized tomography, and enteric-magnetic resonance imaging. The yield for capsule endoscopy versus barium radiography was 63% vs 23%, respectively. The yield of capsule endoscopy versus ileocolonoscopy was 64% and 46%, respectively. The yield of capsule endoscopy versus enteric-computerized tomography was 69% and 30%, respectively. The incremental yield of capsule endoscopy over other modalities in the diagnosis of Crohn’s disease ranged from 15% to 44% [9]. A sub-analysis of patients with known Crohn’s disease showed that capsule endoscopy had a higher yield compared to the other modalities, while patients with suspected Crohn’s disease did not show a significant yield for capsule endoscopy, but a type II error due to the smaller sample size has been suggested [10]. In another, independent metaanalysis, Marmo et al., comparing capsule endoscopy with radiologic techniques, calculated that the number needed to diagnose (NND) Crohn’s disease is 2 (95% CI 2-3) for the subgroup of patients with suspected Crohn’s disease [11]. Unfortunately, most of the studies aimed at evaluating the role of capsule endoscopy in patients with suspected Crohn’s disease included a heterogeneous group of patients seldom verified over time. This issue is particularly important in Crohn’s disease, a condition in which the final diagnosis could be made with confidence over a long period of clinical observation. Only one, small sized, prospective study, with a long-term follow up, tried to overcome this drawback. In this paper, Girelli and co-workers used as a gold standard the final diagnosis obtained after a long follow up (median, 21 months) and confirmed that capsule endoscopy is effective in diagnosing small bowel Crohn’s disease with positive and negative likelihood ratio of 5.8 and 0.08 respectively, underlining the high negative predictive value of capsule endoscopy in this subset of patients [12]. Unclassified Colitis Unclassified colitis (formerly indeterminate colitis) is defined as a chronic colitis without endoscopic and pathologic diagnostic features for either Crohn’s disease or ulcerative colitis. Unclassified colitis often poses a diagnostic and therapeutic challenge for many gastroenterologists in particular for severe disease, when restorative proctocolectomy is considered. Few studies evaluated the role of

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capsule endoscopy in unclassified colitis. Small studies found that capsule endoscopy led to a change in diagnosis in 20-40% of patients [13-15], but the implication of these findings in the clinical outcome is still unclear.

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Recurrence after Surgical Resection Clinical relapse of Crohn’s disease after surgery is preceded in most patients by endoscopic relapse, providing an attractive opportunity for intervention aimed at delaying and or preventing future complications. Though routinely used to evaluate Crohn’s disease after surgery (see Chapter 4), ileocolonoscopy requires a bowel preparation, is invasive, can be uncomfortable, and carries small but real risks. Furthermore a careful endoscopic examination of an ileocolonic anastomosis can be technically difficult and may not always be successful. Two studies evaluated the safety, accuracy and therapeutic impact of capsule endoscopy compared with colonoscopy in the postoperative evaluation of Crohn’s disease. In the first study, Bourreille et al. showed a comparable diagnostic yield of both endoscopic methods [16], while in the second study capsule endoscopy performed better showing other small bowel lesions obviously out of the reach of ileocolonoscopy; not surprisingly, patients preferred capsule endoscopy to ileocolonoscopy [17].

Advantages and Shortcomings of Capsule Endoscopy In addition to the high negative predictive value, another advantage of capsule endoscopy over other modalities is represented by the direct vision with eightfold magnification of the small bowel mucosa, accounting for its high sensitivity. Furthermore, capsule endoscopy is a painless, comfortable and a patient-friendly procedure. It doesn’t give ionizing radiations and the operatordependence seems to be quite low [18, 19]. Shortcomings are represented by the low specificity of mucosal breaks and the impossibility to take mucosal samples for histological examination. In fact, it is important to realize that the finding of mucosal breaks involving the small bowel is not by itself diagnostic of Crohn’s disease. Because there is no single gold standard diagnostic test for Crohn’s disease, the diagnosis should be formulated on a constellation of clinical, endoscopic, pathologic, and radiological and biochemical findings. In addition, there is evidence to suggest that mucosal breaks and other subtle lesions can be found on capsule endoscopy in up to 13% of normal asymptomatic subjects [20]. Other causes of mucosal breaks include infectious, ischemic, and drug-induced

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etiologies. In particular, non-steroidal anti inflammatory drug (NSAID) enteropathy is common and may create diagnostic confusion. Although it has not been universally adopted, a minimum standard terminology system for capsule endoscopy has been compiled [21]. Recently, Gralnek et al. proposed a scoring index that includes three endoscopic variables: villous edema, ulceration, and stenosis. They divided the small bowel in three tertiles and attributed different weighting scores to each finding accounting for their number and extension. A score < 135, between 135 and 790 and > 790 points indicated insignificant mucosal inflammatory changes, mild, and moderate to severe inflammation, respectively. The initial prospective evaluation of the index showed good interobserver agreement for these variables (76%, 84%, 79% for villous appearance, ulcer and stenosis, respectively) [22]. Although this scoring system adopted for inflammatory small bowel lesions is quite cumbersome for daily clinical practice, it is critical that such a standardized scoring system be used in the future so that the data from forthcoming trials will be standardized and more comparable. More recently, a simplified score system has been reported for the capsule endoscopy Crohn’s disease activity index (CECDAI) [23]. Briefly, the CECDAI was designed for the evaluation of three main parameters of small bowel pathology of Crohn’s disease (Table 2.5): A. Inflammation, rated on a scale of 0 (none) to 5 (large ulcer); B. Extent of disease, rated on a scale of 0 (none) to 3 (diffuse); C. Presence of strictures, rated from 0 (none) to 3 (obstruction). The procedure involves determining the midpoint of the bowel by measuring the small bowel transit time (SBTT), which is the only objective measure of the length of small bowel passed by the capsule, and then adding half that value to the time it takes the capsule to reach the duodenum (first duodenal view). All three parameters are then calculated separately for the proximal and distal segments. Multiplying the inflammation score (A) by the extent of disease score (B) and adding the stricture score (C) yields the segmental score; adding the two-segmented scores yields the total CECDAI score.

The Detection of Crohn’s Disease by Capsule Endoscopy: Special Issues Gastrointestinal tract patency is the major limiting factor of capsule endoscopy. Of course, Crohn’s disease may lead to luminal strictures that jeopardize the success of the procedure. Hence, capsule retention and its endoscopic or surgical removal must be kept in mind in the decisional tree of

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performing capsule endoscopy in patients with known or suspected Crohn’s disease. Capsule retention in patients with known Crohn’s disease is reported in up to 13% of cases, a figure higher than the 2.5% rate of unselected patients undergoing capsule endoscopy [24, 25]. In addition, barium studies are unreliable to detect stricture due to the high missing rate. Unexpectedly, most capsule impactions are asymptomatic and rarely produce obstructive symptoms of colicky abdominal pain, failure to pass intestinal gas and vomiting. Some experts suggest that capsule retention in Crohn’s disease constitutes a good outcome as it can lead to surgery which can cure symptoms and provide histological definitive diagnoses [26]. Yet, in my opinion, this point of view is not tenable for patients with Crohn’s disease, because they are so adapted to their anatomic change that seldom present irreversible obstruction mandating urgent surgery. Table 2.5. The Capsule Endoscopy Crohn’s Disease Activity Index (from Gal et al., modified; ref. 22) Proximal A. Inflammation score 0 = None Copyright © 2008. Nova Science Publishers, Incorporated. All rights reserved.

1 = Mild to moderate edema/hyperemia/denudation 2 = Severe edema/hyperemia/denudation 3 = Bleeding, exudate, aphthae, erosion, small ulcer (0.5 cm) 4 = Moderate ulcer (0.5–2 cm), pseudopolyp 5 = Large ulcer ([2 cm) B. Extent of disease score 0 = None 1 = Focal disease (single segment) 2 = Patchy disease (multiple segments) 3 = Diffuse disease C. Narrowing (stricture) 0 = None 1 = Single-passed 2 = Multiple-passed 3 = Obstruction

Segmental score = A x B + C. Total score = (A1 x B1 + C1) + (A2 x B2 + C2)

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Patency Capsule Although awareness of this complication existed at any time of the introduction of capsule endoscopy in clinical practice, the risk of capsule retention at the site of previously unsuspected or unknown small bowel stricture remains the main complication of capsule endoscopy. Retention seems to be seldom predictable by conventional radiology [27]. To better predict who would be at risk of capsule retention, the patency capsule (givenimaging, Yoqneam, Israel) was developed. Briefly, the patency capsule (figure 3.5) is self-dissolving and identical in size to the Pillcam SB. It contains lactose and barium sulphate to create radio-lucency and a radio-frequency identification (RFID) tag that allows it to be detected either radiologically or by a scanning device placed near the abdominal wall (Figure 4.5). Patency capsule also has a wax timer-plug at one end, which is displaced after near 30 hours from its ingestion, allowing intestinal fluids to enter the capsule and dissolve the lactose-barium mixture, leaving behind the inert parylene coat and RFID tag. If the patency capsule is excreted intact (figure 5.5), the following capsule endoscopy will be performed safely; conversely an excreted dissolved patency capsule suggests a bowel stricture, contraindicating capsule endoscopy. However, the first clinical studies performed with patency capsule gave some conflicting results, and reports of acute irreversible intestinal occlusion in subjects with known stricture tempered the enthusiasm for this novel device [28]. Researchers speculated that impaction in the stricture of the waxy dissolvable end of the patency capsule could circumvent its dissolution, resulting in bowel occlusion. In order to overcome this drawback, the second generation patency capsule, also known as Agile patency, is provided with wax timer-plugs at both ends. This new device seems to be safer and more informative than its precursor; in a recent study on 106 patients with known small bowel strictures, only three patients experienced severe transitory abdominal pain, and only one was operated on for intestinal occlusion. Importantly, no patient who excreted an intact Agile patency capsule had retention of the subsequent Pillcam SB [29].

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Figure 3.5. First generation patency capsule. Note the single dissolving waxy plug at the end of the capsule (arrow).

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CONCLUSION In conclusion, capsule endoscopy has revolutionized the diagnostic approach to small bowel disease, including Crohn’s disease. Appropriate patient selection for this novel investigation is mandatory, excluding patients with known strictures and using Patency Capsule to screen patients with clinical suspicion of small bowel strictures. In addition, we urgently need to standardize the clinical, biochemical and radiologic criteria for “suspect” Crohn’s disease in order to select patients who really need this diagnostic approach. The trade-off between the high sensitivity and sub-optimal specificity for tiny inflammatory lesions of the small bowel must be considered in the interpretation of any capsule endoscopy film segment, especially in the setting of suspected Crohn’s disease. The use of capsule endoscopy in patients with unclassified colitis may be, for the time being, restricted to patients in whom surgery is considered, waiting for more evidence-based studies. Finally, in post-surgical patients, capsule endoscopy may be an option in patients unwilling to undergo colonoscopy or in patients in whom colonoscopy is unfeasible.

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Figure 4.5. Scanner used to detect the patency capsule in the abdomen.

Figure 5.5. A patency capsule excreted intact. The dissolving waxy plug at the end of the capsule is undamaged (arrow) and the following diagnostic capsule endoscopy was uneventful.

DOUBLE-BALLOON ENTEROSCOPY Double-balloon enteroscopy enables visualization of the small bowel and allows for biopsies and therapeutic intervention in areas previously out of the reach of push enteroscopy or ileocolonoscopy and previously accessible only to intra-operative enteroscopy, a procedure with unacceptable high mortality and morbidity. Either an antegrade or retrograde approach, which consists in the

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insertion of the endoscope from the mouth or from the anus, respectively, is allowed. By both approaches, visualization of the entire small bowel is reported in 8-86% of the published series [30-34], the wide range depending on patient selection and by the experience of the operators of this difficult and highly demanding procedure. Since capsule endoscopy could identify abnormalities that might include non specific findings, there is a growing need to evaluate directly the small bowel mucosa with bioptic sampling for histological assessment.

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The Device Currently, the double-balloon enteroscope available for the investigation of the small bowel is the EN-450TS (Fuji Tokyo, Japan) which allows endoscopic therapy. The instrument was invented by Yamamoto, a Japanese endoscopist, and the first clinical experiences are from his research group [35]. The working length is 200 cm. The external diameter is 9.4 mm and the diameter of the working channel is 2.8 mm. A channel allows for the passage of the standard biopsy forceps, snare, injection needle and the thin-type Argon Plasma catheter for diathermy coagulation. The enteroscope is used with a 145 cm sliding overtube that has an external diameter of 13.2 mm and an internal diameter of 11 mm. Two inflatable/deflatable latex balloons are placed on the tip of the scope and of the overtube, respectively, before starting the procedure (Figure 6.5).

Figure 6.5. Double-balloon enteroscope. Overtube (arrowhead), Balloon attached to the tip of the scope (dark arrow); balloon attached to the overtube (light arrow).

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Technique of Insertion (Push and Pull Enteroscopy) Double-balloon enteroscopy is performed under deep sedation both by antegrade or retrograde approach; the insertion route is chosen according to the estimated location of the suspected lesion(s). Before insertion, the overtube is back-loaded onto the endoscope with both balloons deflated. In an antegrade approach, the endoscope is initially inserted into the stomach, the overtube then being inserted over the endoscope. The endoscope is advanced into the second portion of the duodenum through the overtube, which is held by an assistant, and the balloon on the endoscope tip is inflated there. The overtube is in turn inserted into the second portion of the duodenum, and the overtube balloon is also inflated. The endoscope balloon is deflated and the endoscope is inserted further through the overtube. Because the overtube balloon effectively grips the duodenum, the tip of the endoscope can be inserted more deeply in the intestine without the endoscope shaft bowing unmanageably. After the tip of the endoscope has been inserted as far as possible beyond the ligament of Treitz, the endoscope balloon is inflated and the overtube balloon is deflated; the overtube is then advanced over the endoscope. When the distal tip of the overtube reaches the distal end of the endoscope, the overtube balloon is inflated to secure the balloon within the intestine at this location. Gentle simultaneous withdrawal of the overtube and endoscope, with both balloons inflated, causes pleating of the intestine onto the overtube. Because the intestinal wall is held by the overtube inflated balloon, the endoscope is then easily inserted further through the overtube after the endoscope balloon has been deflated. This sequence of push and pull maneuvers is repeated to advance the endoscope increasingly further into the intestine. The pleating effect of the intestine over and onto the overtube allows for the insertion of the endoscope into the small bowel well beyond the physical length of the endoscope itself. Although most of the procedures can be performed after appropriate training by experienced endoscopists without using a fluoroscope, fluoroscopic guidance is helpful to recognize the insertion shape, the advancement of the overtube and the shortening of the intestine during the pull maneuver. Figure 7.5 shows a radioscopic image of the double-balloon enteroscope in its full progression in the antegrade approach. The retrograde approach is also performed using the same principle, but it may be more demanding. The latex balloons can be inflated sufficiently to grip the colonic wall while advancing through the colon, because the balloons are very elastic and balloon inflation is controlled by pressure instead of air volume, so they can be used safely regardless of the bowel diameter. After reaching the ciecum, the

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endoscope is inserted into the terminal ileum. By gripping the intestine with the overtube balloon and the endoscope balloon in turn, the endoscope can be inserted farther and farther.

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Complications Bearing in mind that double-balloon enteroscopy experience is still limited throughout the world, the procedure seems to be relatively safe with a low complication rate. From preliminary, retrospective data, double-balloon enteroscopy carries an overall complication rate of 1.2-1.7% [36]. The reported complication rate of double-balloon enteroscopy for diagnostic purpose is only 0.8%, a figure similar to conventional upper and lower endoscopy. Acute pancreatitis is the most common complication after diagnostic double-balloon enteroscopy, occurring in 0.3% of the procedures. Pathogenesis of double-balloon enteroscopy related pancreatitis is unclear. To date, two theories have been stated. One theory is based on the principle of overpressure in the intestinal compartment between the two inflated balloons causing reflux of duodenal content into the main pancreatic duct. The other theory is based on the shortening of the duodenum and proximal jejunum by the push and pull maneuver used during the procedure. This may lead to strain to the papilla of Vater and increased intraluminal pressure in the duodenum, which may obstruct the flux of pancreatic juice. In order to minimize the risk of pancreatitis some endoscopists have suggested inflating both balloons reasonably distal to the papilla of Vater. The complication rate of therapeutic double-balloon enteroscopy is 3.4-4.3% a figure higher than therapeutic upper and lower endoscopy [33,37]. In particular, polipectomy procedures in the small bowel seems to be at high risk of perforation due to the thin wall of the small bowel compared with the thicker wall of the upper and lower gastrointestinal tract. Finally, bleeding has been described as a complication of double-balloon enteroscopy in up to 15% of the procedures. In most cases these are self-limiting mucosal bleeding due to friction of the overtube balloon on the mucosa; yet, after therapeutic double-balloon enteroscopy, more severe bleeding complications have been reported with a rate similar to therapeutic endoscopy of the upper and lower gastrointestinal tract [36].

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Figure 7.5. Radioscopic view of double-balloon enteroscopy during its maximal insertion from the oral cavity.

Role of Double-Balloon Enteroscopy in Small Bowel Crohn’s Disease Although double-balloon enteroscopy is theoretically appealing in diagnosing small bowel Crohn’s disease, the technique is still in its infancy and experience is very limited. The only full-text published paper is an unblinded study by Oshitani et al. on 38 established small bowel Crohn’s disease patients who underwent double-balloon enteroscopy by a retrograde approach; in four patients conventional barium studies failed to identify mucosal changes that were identified on double-balloon enteroscopy [38]. However, this series seems to be poorly representative of the Crohn’s disease population because 24 out of 38 patient had small bowel lesions more than 20 cm proximal to the terminal ileum without any involvement of the terminal ileum. As double-balloon enteroscopy gains wider diffusion, various groups are publishing their experience. Some of these reports include patients in whom the diagnosis of Crohn’s disease was missed by other investigations, but without randomized controlled studies, these reports are quite difficult to interpret and poorly informative. The largest published experience hitherto published on double-balloon enteroscopy is from

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May and co-workers. They performed 635 double-balloon enteroscopies in 353 patients for various indications. 18 of these patients had new or established Crohn’s disease, but the diagnostic yield of double-balloon enteroscopy for the diagnosis of Crohn’s disease, or the route used to make the definitive diagnosis is not reported [33]. Matsumoto et al. compared antegrade double-balloon enteroscopy (27 patients) with push enteroscopy (91 patients) and reported a higher diagnostic yield in antegrade double-balloon enteroscopy than in push enteroscopy (79% vs 31%, p 4 mm (which is considered the upper limit of a normal bowel wall) up to 15 mm [2]. The wall thickness of a diseased bowel segment is measured in a transverse section from the central hyper-echoic line of the lumen (representing the interface between luminal content and mucosa) to the outer hyper-echoic margin of the wall (representing the serosa) (figure 1.9). The abnormal thickening of the bowel wall is the most common ultrasound finding reported in the literature to diagnose Crohn’s disease [1-30]. In the meta-analysis by Fraquelli and co-workers, aimed at evaluating the impact of different cut-off values of bowel thickening (3 vs 4 mm) in the detection of Crohn’s disease, the authors found that when a 3mm cut-off level was used as abnormal, sensitivity and specificity were 88 and 93% respectively, while when a cut-off level of >4 mm was used, sensitivity was 75% and specificity 97% [1].

Bowel Wall Echo Pattern The affected segment in Crohn’s disease should be analyzed with respect not only to wall thickness but also to bowel wall echo pattern. Normally, the bowel wall appears stratified in five layers alternatively hypo- and hyper-echoic, each layer corresponding to mucosa, submucosa, muscularis mucosae, muscularis

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propria and serosa, respectively from the inner to the outer side of the bowel wall (figure 2.9). In Crohn’s disease the bowel wall may maintain its regular stratification or may be characterized by a partial or complete loss of normal layering. In a stratified pattern, the thickened wall displays a variable enlargement of the mucosal, submucosal or muscular layers, depending on the anatomical location of the maximum degree of inflammation. The echo-stratification may be abruptly interrupted by hypo-echoic areas with hyper-echoic spots corresponding to deep ulcers, or may completely disappear (figure 1.9). The clinical and pathological significance of bowel echo pattern and its importance in defining Crohn’s disease activity has been investigated in two studies, one of which was performed in patients with stenosing disease [31-32]. Both studies — where in vivo ultrasound features were compared with resected specimens of the bowel — showed that loss of stratification (hypo-echoic pattern) correlated with severity of inflammation and that persistence of stratification in the bowel wall suggested a high degree of fibrosis within the submucosa and muscularis mucosae.

Figure 1.9. Active Crohn’ disease of the terminal ileum. Increased bowel wall thickness, with loss of stratification. Small hypo-echoic micro-abscesses are visible within the bowel wall (round arrow). Minimal effusion (thick arrow) and a round hypo-echoic lymph node are also well represented (arrowhead).

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a

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b

Figure 2.9. (a) Longitudinal scan of a normal terminal ileum. (b) Schematization of ultrasound appearance of the bowel wall with alternation of hyper- and hypo-echoic layers.

Bowel Wall Vascularity The increased vascularity is often observed in the bowel wall with decreased echogenicity. This is likely due to hyperemia and neo-vascularization related to the increased inflammatory response. Therefore, vascularity within the thickened bowel wall assessed by power color doppler has been used as an index of Crohn’s disease activity (figure 3.9). Vascularity has been evaluated using a simple

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scoring system according to the semi-quantitative (and subjective) intensity of color signals and by analysis of Doppler curves obtained from vessels detected within the bowel wall. However, neither of these parameters correlated with clinical or biochemical activity in most studies, whereas a significant correlation was often found between vascularity and endoscopic or radiologic activity [11,26,28,33,34]. To increase the sensitivity of Doppler ultrasound in detecting vascularity of diseased bowel walls, ultrasonographic contrast agents have been introduced. Esteban and co-workers have demonstrated for the first time the usefulness of contrast agents in the detection of inflammatory abdominal masses associated with Crohn’s disease [26]. The use of power doppler was combined with intravenous administration of levovist. Levovist (Schering, Berlin Germany) is an agent made of galactose microparticles and palmitic acid. The microparticles adsorb the gas dissolved in the water forming air microbubbles. After transit in pulmonary circulation, the bubbles reach the systemic circulation where they enhance the backscattering of the signal from blood vessels. Sonovue (Bracco, Milan Italy) is a second generation ultrasound contrast agent. It contains sulphur hexafluoride, a gas with low solubility in blood for the gaseous phase of microbubbles, and a phospholipid monolayer shell. Due to the high flexibility of the shell, the microbubbles are strongly echogenic in a wide range of frequencies and acoustic pressure. The feasibility and safety of this second-generation contrast agent in the detection of active inflammation in Crohn’s disease have been assessed in 52 patients [35]. Larger studies are ongoing in order to define the current role of contrast agents in the follow-up of Crohn’s disease, but they hold promise especially in the discrimination between active inflammation and fibrosis in the affected loop [36,37].

Figure 3.9. Small bowel Crohn’s disease with increased bowel wall thickness and loss of stratification (hypo-echoic wall) before (a) and after (b) contrast agent administration. The increased vascularity supports active inflammation within the bowel wall.

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Bowel Motility Thickened bowel walls in Crohn’s disease are variably associated with reduction or absence of peristalsis in the small bowel and loss of haustrae in the colon [25]. Although this manifestation is quite subjective and difficult to assess, it has been regarded as a relevant sign in most ultrasound studies, probably for its association with intestinal stenosis.

Mesenteric Hypertrophy, Effusion and Lymph Node Enlargement

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Finally, the mesenteric hypertrophy with fibro-fatty changes is a commonly encountered ultrasonographic feature of Crohn’s disease, and it appears as a hyper-echoic dyshomogeneous area surrounding the thickened bowel wall. Enlarged mesenteric lymph nodes appear as oval, homogeneous, hypo-echoic nodules with regular edges. Very small fluid collection among the thickened loops are commonly seen and are suggestive of active inflammation (figure 1.9).

Figure 4.9. Stenosing Crohn’s disease. (a) Increased bowel wall thickness with lossed stratification and lumen narrowing (arrow). (b) Dilation of the proximal loop containing fluid.

Diagnosis of Complications: Stenosis, Fistula and Abscess As previously discussed elsewhere in this book, the clinical course of Crohn’s disease is often characterized by abdominal complication such as stenosis, fistulae or abscesses. Stenosis develops in 21% of patients with ileal Crohn’s disease [38].

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It is the most frequent indication to surgery. Bowel stenosis can be identified by ultrasound as thickened bowel walls associated with narrowed lumen and increased diameter of the proximal loop, > 2.5-3 cm, which is often hyperperistaltic and fluid filled (figure 4.9). Fistulae occur in 17-82% of Crohn’s disease patients, representing the transmural extension of the disease [39]. They may end blindly in the mesentery or adjacent organs, connect two or more adjacent bowel loops (entero-enteric fistulae), and have an external drainage (entero-cutaneous fistulae). Fistulae may appear at ultrasound as hypo-echoic tracks or areas between loops (figure 5.9); sometimes, fistulae display internal hyper-echoic spots due to the presence of air or luminal debris. Intra-abdominal abscesses occur in 12-30% of Crohn’s disease patients usually as a consequence of fistulising disease, or surgical complication [40]. At ultrasound, abscesses appear as hypo-echoic lesions with fluid collection and irregular thickened walls, sometimes containing internal echoes due to the presence of solid debris and are characterized by posterior echo-enhancement. Hypo-echoic masses, especially those of small size and located close to the bowel, may be missed or mistaken for a large sinus track and hypo-echoic lymph nodes, and phlegmonous masses. Power color doppler and the use of i.v. contrast agents may help with the differential diagnosis; in fact, phlegmonous masses show an increased vascular signal [41]. Accuracy of ultrasound in the detection of complications of Crohn’s disease is summarized in the table.

Figure 5.9. Two adjacent bowel loops (arrows) with entero-enteric fistula (arrowhead).

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Table. Accuracy of bowel ultrasound in the detection of abdominal complications in Crohn’s disease Complication

Sensitivity (%)

Specificity (%)

Refs

Stenosis

70-90

93

6, 17, 27

Fistula

97*

91*

43

Abscess

91

93

6, 27

*when combined with barium studies.

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LIMITATIONS AND COLLOCATION OF ULTRASOUND IN THE DIAGNOSIS OF CROHN’S DISEASE Intestinal ultrasound, even in experienced hands, may result in false negative and false positive findings. False positive findings rely on the fact that thickening of the bowel walls is not specific to Crohn’s disease, being present also in infectious, neoplastic and other inflammatory conditions. False negative results may be seen in overweight patients where the thick layer of subcutaneous fat hurdles the deeper progression of the sonographic beam. Minimal change mucosal lesions, typical of early Crohn’s disease, are usually missed by ultrasonography, decreasing its sensitivity. Indeed, bowel ultrasound may be less reliable if performed by operators without specific or wide experience in intestinal examination. Therefore, one should rely on the operator’s experience and skill more than with other imaging diagnostic procedures. In this regard, inter-observer agreement between sonographers with experience in bowel ultrasound has been reported in preliminary studies, showing satisfactory results, in particular for the reproducibility of bowel wall thickness, the most important sonographic sign in Crohn’s disease [2]. When ultrasound is used as a first line diagnostic tool, the diagnosis of Crohn’s disease is suggested when wall thickening involves the terminal ileum, is circumferential and segmental. The definitive diagnosis should rely on endoscopy and histological examination of pathological tissues. Therefore, ultrasound may represent a useful tool prior to other invasive and expensive diagnostic investigations which can be avoided or postponed in the case of negative ultrasound findings. In known Crohn’s disease patients the accuracy of ultrasound in detecting bowel wall thickness has been usefully employed in localizing Crohn’s disease

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lesions within the bowel, in particular for ileal lesions, which can be detected in up to 90% of cases, and in assessing the length of small bowel involvement [6,21]. Several studies attempted to establish a relationship between maximum bowel wall thickness and clinical and biochemical parameters of Crohn’s disease activity. Almost all the results of these studies produced weak, although somewhat significant, correlations, thus leaving the role of bowel ultrasonography in the assessment of Crohn’s disease activity still controversial in clinical practice [6,20]. The ultrasound assessment of bowel wall in Crohn’s disease is also in use to identify post-operative recurrence following resection. In studies comparing bowel ultrasonography to conventional or capsule endoscopy, post-operative recurrence of Crohn’s disease was correctly identified in more than 80% of patients [22,24,30]. In addition, the potential of ultrasound to accurately define transmural inflammatory changes during the course of Crohn’s disease offers the possibility to assess the behavior of the diseased bowel walls following conservative surgery (miniresection and/or strictureplasty) which has become the new standard surgery of stenosing Crohn’s disease. It has been shown that the behavior of ultrasonographic bowel thickness 6-12 months after surgery is a strong predictor of patient outcome. In fact, in patients showing improvement or return to normality of the bowel wall thickness, the recurrence rate has been lower than in those maintaining the same level of bowel wall thickening [42]. Likewise, it has been shown in a series of 174 unselected Crohn’s disease patients that bowel wall thickness more than 7 mm at ultrasound was the major risk factor for intestinal resection within the following twelve months [23]. Therefore, bowel ultrasound offers a useful alternative to invasive procedures such as ileocolonoscopy or contrast radiology in the post-surgical follow-up of Crohn’s disease patients, in particular for those submitted to conservative surgery.

CONCLUSION Bowel ultrasound is a useful tool in the management of Crohn’s disease and it has been successfully used in the screening of suspected inflammatory bowel disease, especially Crohn’s disease. In these subjects, bowel ultrasound is safe, non-invasive, cheap and well accepted by patients. The most important application of bowel ultrasound is, however, in the follow-up of patients already

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diagnosed with Crohn’s disease, in whom it may be helpful to assess the site and extent of the lesions and to detect intra-abdominal complications. Increased bowel thickness – the most important ultrasonographic sign of Crohn’s disease – is easily recognized and reproducible with high inter-observer agreement. Improving the ultrasound assessment of intramural blood flow by means of power color Doppler and intravenous contrast agents may help to differentiate fibrotic and inflammatory strictures, and to discriminate inflammatory masses from abscesses. Early results are in agreement regarding the usefulness of ultrasound in the assessment of postoperative recurrence and in monitoring the outcome of the disease after surgery. Shortage of skilled and dedicated sonographers is probably one of the main reasons why intestinal ultrasound is still regarded with skepticism by many clinicians and radiologists. Finally, when discussing the merits and flaws of bowel ultrasound, we should bear in mind that most study results are derived from old research and that the technical evolution of ultrasound equipment has probably now increased the accuracy of ultrasound detection of Crohn’s disease.

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[32] Hata J, Haruma, Yamanaka H et al. US evaluation of the bowel wall in inflammatory bowel disease: comparison of in vivo and in vitro studies. Abdom Imaging 1994; 19: 395-99. [33] Scholbach T, Herrero I, Scholbach J. Dynamic color Doppler sonography of intestinal wall in patients with Crohn’s disease compared with healthy subjects. J Pediatr Gastroenterol Nutr 2004; 39: 524-8. [34] Neye H, Voderholzer W, Rickes S et al. Evaluation of criteria for the activity of Crohn's disease by power Doppler sonography. Dig Dis 2004; 22: 67-72. [35] Robotti D, Cammarota T, Debani P et al. Activity of Crohn’s disease: value of Color-Power-Doppler and contrast-enhanced ultrasonography. Abdom Imaging 2004; 29: 648-52. [36] Kratzer W, Schmidt SA, Mittrach C et al. Contrast-enhanced wideband harmonic imaging ultrasound (SonoVue): a new technique for quantifying bowel wall vascularity in Crohn's disease. Scand J Gastroenterol 2005; 40: 985-91. [37] Kratzer W, von Tirpitz C, Mason R et al. Contrast-enhanced power Doppler sonography of the intestinal wall in the differentiation of hypervascularized and hypovascularized intestinal obstructions in patients with Crohn's disease. J Ultrasound Med 2002; 21: 149-57. [38] Fenoglio-Preiser CM, Lanz PE,Listrom MB et al. Gastrointestinal pathology: an atlas and text. 1989. Raven press, New York, NY, 427-84. [39] Oberhuber G, Stangl PC, Vogelsang H et al. Significant association of stricture and internal fistula formation in Crohn’s disease. Virchows Arch 2000; 437: 293-7. [40] Nagler SM, Poticha SM. Intra-abdominal abscesses in Crohn’s disease. Am J Surg 1979; 173: 350-4. [41] Maconi G, Sampietro GM, Russo A et al. The vascularity of internal fistulae in Crohn's disease: an in vivo power Doppler ultrasonography assessment. Gut 2002; 50: 496-500. [42] Maconi G, Sampietro GM, Cristaldi M et al. Preoperative characteristics and postoperative behaviour of bowel wall on risk of recurrence after conservative surgery in Crohn’s disease. A prospective study. Ann Surg 2001; 233: 345-52. [43] Maconi G, Sampietro GM, Parente F et al. Contrast radiology, computed tomography and ultrasonography in detecting internal fistulas and intraabdominal abscesses in Crohn's disease: a prospective comparative study. Am J Gastroenterol. 2003; 98: 1545-55.

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CONTRIBUTING AUTHORS

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Carlo Maria Girelli, MD Chief of the IBD Unit, Gastroenterology and Digestive Endoscopy Service. 1st Division of Internal Medicine. Hospital of Busto Arsizio (VA), Italy Luca Giuseppe Crespi, MD Chief of the Cross-Sectional Imaging Unit, Department of Radiology. Hospital of Busto Arsizio (VA), Italy Fabio Francois Francone, MD Department of Radiology. Hospital of Busto Arsizio (VA), Italy Soraya Zaid, MD Department of Radiology. Hospital of Busto Arsizio (VA), Italy

Girelli, Carlo M., and Luca G. Crespit. Diagnostic Modalities in Crohn's Disease, Nova Science Publishers, Incorporated,

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INDEX

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A abdomen, 80, 118, 119 abdominal cramps, 55 abnormalities, viii, 54, 81, 114, 118 absorption, 39, 110 accuracy, viii, 57, 66, 75, 89, 101, 102, 104, 117, 118, 125, 130, 132, 140, 142, 143 achievement, 85 acid, 6, 26, 39, 137 acne, 38, 39, 49 acoustic, 137 acquisitions, 130 activation, 4, 9 acute, vii, 14, 21, 32, 35, 37, 39, 40, 42, 49, 54, 66, 78, 121, 133 adaptive immune system, 7, 10 additives, 26 adhesion, 8, 10, 12 adipose, 121 adipose tissue, 121 administration, viii, 96, 97, 107, 108, 109, 110, 111, 118, 137 adult, 50 adults, 28, 50 Africa, 22, 27 African American, 5, 25

agar, 108 age, 24, 25, 31, 32, 45 agent, 27, 102, 103, 108, 109, 110, 116, 120, 125, 137 agents, 14, 27, 32, 97, 103, 108, 116, 125, 137 aggregates, 35, 37 aggregation, 4 aid, 58, 71, 108 air, 82, 95, 97, 98, 102, 117, 128, 137, 139 alanine, 6 Alberta, 23, 28 albumin, 40 alcohol, 26 algorithm, 86, 87 alimentation, 46 alpha, 16 alternative, 63, 141 amino, 6 amino acid, 6 anaerobic, 7 anaerobic bacteria, 7 anastomosis, 61, 63, 67, 75, 117 ANCA, 41 anemia, 40, 46, 48, 64, 73 Anemia, 43 angioedema, 112, 121 angiography, 117

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Index

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150

angulation, 54 animal models, 6, 8, 10, 26 animals, 8 ankles, 39 anorectal fistula, 132 anorexia, 37 antibiotic, 13 antibiotics, 8 antibodies, 50 antibody, 12 antigen, 10, 12, 42 anti-inflammatory drugs, 5, 13, 26, 32 anus, 36, 81 aphthous ulcers, 59 apoptosis, 10, 18, 19 appendicitis, 37, 47, 133 appendix, 49 application, 70, 124, 130, 141 arachidonic acid, 26 arthritis, 38, 39, 44, 73 ascending colon, 62 Asia, 22, 27 Asian, 5, 25, 31 ASIC, 71 assessment, viii, 39, 44, 45, 54, 55, 61, 66, 81, 102, 107, 115, 117, 118, 125, 130, 133, 141, 142, 143, 145 asymptomatic, 26, 46, 61, 75, 77 atypical, 41 autoantibodies, 41 autofluorescence, 65, 68 autoimmune, 6 autophagy, viii, 6, 7, 16 availability, viii, 71, 96, 102, 131, 133 awareness, 78, 124

B B cell, 9, 18 backscattering, 137 bacteria, 3, 4, 7, 9, 10, 13, 16, 117 bacterial, 4, 7, 13, 14, 17, 37

barium, 74, 77, 78, 84, 87, 96, 97, 98, 100, 102, 103, 105, 107, 108, 116, 118, 119, 120, 121, 122, 123, 125, 130, 140 barium enema, 102, 123 barium sulphate, 78 barrier, 4, 7, 8, 18, 65 basement membrane, 49 behavior, 4, 37, 45, 46, 141 benefits, 45, 64, 133 benign, 57 bile, 39 bile duct, 39 binding, 11, 40 biological responses, 9 biopsies, 49, 56, 57, 65, 66, 80 biopsy, 36, 53, 56, 66, 70, 81 bladder, 42 bleeding, 26, 53, 55, 64, 73, 83, 85, 87, 117 blocks, 18 blood, 19, 37, 40, 43, 48, 54, 137, 142 blood flow, 142 blood vessels, 137 body weight, 44 bowel infections, 124 bowel obstruction, 117 breakdown, 3, 8 broad spectrum, 26, 46 bubbles, 137 bypass, 97 by-products, 4

C C reactive protein, 39, 48 cachexia, 46 calcium, 39, 40 Canada, 22 cancer, 6, 42, 53, 54, 64, 68 cancer screening, 68 capacity, 123, 129, 131 Cape Town, 45 capillary, 12, 65

Girelli, Carlo M., and Luca G. Crespit. Diagnostic Modalities in Crohn's Disease, Nova Science Publishers, Incorporated,

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Index capsule, viii, 26, 32, 70, 72, 73, 75, 76, 78, 79, 80, 81, 85, 86, 87, 88, 89, 90, 95, 103, 105, 118, 120, 122, 129, 131, 141, 144 carbohydrates, 7 carcinoma, 65 CARD15, 4, 5, 6, 7, 15, 16 carrier, 7 caspase, 4, 7, 10 catabolic, 6 catheter, 81, 97, 109 cation, 6, 7 cattle, 13 Caucasians, 25 cecum, 98 Celiac disease, 48 cell, 4, 7, 10, 11, 12, 14, 18, 20, 40 cell adhesion, 12 Central Europe, 23 charge coupled device, 72 cheese, 13 chemokines, 10 childbearing, 32 children, 26, 27, 30, 32, 37, 48, 143 China, 30, 73 cholangiocarcinoma, 39 cholangitis, 38, 39, 48 cholelithiasis, 117 Chromoendoscopy, 65 chromosome, 4, 6, 17 chromosomes, 6 chronic disease, 22 cigarette smoking, 26, 32 circulation, 137 classes, 108 classical, 61 classification, 14, 24, 25, 45, 49, 50, 65, 68, 101 clinical presentation, 47 clinical trial, vii, 45, 46, 50, 65, 67, 87 clinical trials, vii, 45, 46, 50 clinician, 69 CMOS, 70 coagulation, 81

151

Cochrane, 68 codes, 24 coffee, 26 cohort, 15, 26, 27, 30, 31, 32, 58, 67 colic, 43, 110 colitis, vii, 10, 15, 18, 22, 25, 30, 35, 37, 40, 41, 47, 49, 50, 54, 57, 58, 64, 66, 74, 79, 88, 102, 104 colon, 8, 19, 38, 43, 55, 56, 61, 62, 65, 68, 82, 95, 96, 98, 113, 130, 138 colon cancer, 68 colonization, 10 colonoscopy, 53, 54, 56, 65, 68, 75, 79, 90, 95, 118 colorectal cancer, 42, 50, 67 common findings, 113, 116 common symptoms, 37 communication, 117, 118 community, 30, 32, 124 comorbidity, 46 complement, 127 complex carbohydrates, 7 compliance, 97, 125 complications, 39, 42, 43, 44, 53, 54, 63, 64, 75, 83, 90, 101, 103, 107, 115, 117, 118, 123, 124, 133, 138, 139, 140, 142, 143, 144 components, 6, 9, 71, 72, 96 composition, 8, 14, 23, 97 computed tomography, 107, 145 computer mouse, 71 concentration, 40, 112 concordance, 4, 15 confidence, 72, 74, 87 confusion, 21, 26, 55, 76 consensus, 50, 64 constraints, 13 consumption, 26, 32 contraceptives, 13, 27, 28, 32 contrast agent, 102, 108, 109, 110, 116, 119, 120, 125, 137, 139, 142 control, 4, 13, 17, 26, 27, 32 controlled studies, 84

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Index

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152 controlled trials, 46, 64 Copenhagen, 28, 30, 49 correlation, 33, 41, 103, 121, 129, 132, 137 correlations, 133, 134, 141 corticosteroid therapy, 39, 50 cost-effective, 64 costs, viii counseling, 45 C-reactive protein, 114 cross-sectional, 32, 95, 102, 112, 115, 118, 123, 124 CRP, 39, 48 CSF, 14 CT, viii, 105, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 129, 131 CT scan, 124 C-terminal, 4, 10 culture, 8, 54, 58 cyclooxygenase, 32 cyclooxygenase-2, 32 cytokine, viii, 4, 6, 9, 17, 18, 31 cytokine response, 4 cytokines, 10, 11, 12, 18, 40 cytoplasm, 11 cytosine, 11 cytosolic, 40

D dairy products, 13 database, 30 death, 24, 30, 31 death rate, 24 decision making, viii defects, 8 deficiency, 48, 64 definition, 72 deflation, 85 degradation, 6 dehydration, 46, 55 delirium, 43 delivery, 14

dendritic cell, 4, 9 Denmark, 23, 29, 30 density, 144 deposition, 113 depression, 19 desert, 6, 17 detection, 10, 13, 19, 28, 40, 53, 59, 63, 65, 68, 71, 76, 87, 116, 130, 131, 132, 133, 134, 137, 139, 140, 142, 143, 144 developed countries, 27 diagnostic criteria, 21, 54 diapedesis, 11 diarrhea, 18, 37, 47, 48, 54, 55, 73 diet, 14, 22, 26, 28, 31, 32, 55 dietary, 19, 26, 32 differential diagnosis, vii, viii, 35, 37, 47, 57, 58, 66, 99, 139, 142, 143 differentiation, 6, 8, 107, 108, 128, 145 diffusion, 84, 87, 128, 130, 133 diffusivity, 97 digestion, 7 dilation, 63 diodes, 70, 71 discomfort, viii, 55, 102 discrimination, 137 disease activity, 39, 42, 45, 46, 76, 119, 121, 129, 130, 135, 136, 141, 143, 144 disease rate, 25 diseases, 47, 123, 133 disorder, 3, 17 disposition, 100 distribution, 8, 18, 21, 25, 57 diverticulitis, 133 dizygotic, 15 dizygotic twins, 15 DNA, 9, 11, 13, 19 doppler, 136, 137, 139, 142, 144, 145 drainage, 98, 118, 122, 139 drug therapy, 35 drug-induced, 25, 75, 124 drugs, vii, 7, 32, 44, 46, 47, 58, 97, 110 duodenum, 37, 72, 76, 82, 83 duration, 22, 64

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Index dyspepsia, 37 dysphagia, 37 dysplasia, 43, 54, 64, 68

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E E. coli, 47 edema, 62, 76, 77, 113, 117, 128, 130 effusion, 135, 138 elbows, 39 elderly, 28 electrolyte, 55 electrolyte imbalance, 55 EMF, 73 endoscope, 54, 65, 69, 70, 81, 82, 85, 87, 89 endoscopy, viii, 26, 36, 53, 54, 55, 57, 65, 68, 69, 70, 72, 73, 75, 76, 78, 79, 80, 81, 83, 85, 86, 87, 88, 89, 90, 95, 103, 105, 110, 118, 119, 120, 122, 123, 129, 130, 131, 140, 141, 144 endothelium, 11 enemas, 55, 57 England, 24, 30, 31 enlargement, 43, 135, 138 enteritis, 47, 112, 114 environment, 7, 14, 17 environmental factors, 13, 25, 28 epidemiologic studies, 23 epidemiology, viii, 29, 30 episcleritis, 39 epithelial cells, 8, 16 erosion, 77 erythema nodosum, 39, 44 erythrocyte sedimentation rate, 48 erythrocytes, 40 esophagus, 37 ESR, 40, 48 ethanol, 8 ethnic groups, 25, 28 etiologic agent, 21 etiology, 3, 15, 25, 27 etiopathogenesis, viii, 13, 17, 25, 28 eukaryotic cell, 6

153

Europe, 22, 27, 29, 31 evolution, 45, 66, 142 examinations, 55, 95, 101, 102, 103, 104, 108, 125 excitation, 65 excretion, 41, 50, 72 exposure, 27, 28, 58, 109, 118, 124, 131 extravasation, 11 exudate, 77

F factorial, 37, 39 faecal, 50 failure, 13, 14, 37, 43, 48, 69, 77 failure to thrive, 37 false negative, 140 false positive, 140 familial, 4 familial aggregation, 4 family, 4, 7, 9, 40 family members, 4 fasting, 110 fat, 7, 26, 36, 113, 114, 119, 121, 127, 129, 130, 132, 140 fatty acids, 26, 32 feces, 40, 43 females, 25, 39 fever, 43, 44, 46, 48, 73 fibrosis, 35, 39, 130, 135, 137 fibrous tissue, 131 film, 71, 79 fistulas, 100, 101, 102, 108, 115, 116, 129, 131, 133, 145 flare, 26, 38 flexibility, 137 flora, 7, 14, 17 flow, 97, 123, 142 flow rate, 97 fluid, 43, 116, 117, 126, 128, 138, 139 fluoroscopy, 96 focusing, 70, 125 food, 26, 43, 110

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Index

154 food additives, 26 forceps, 81 Fourier, 128 fractures, 43 fragility, 55 frameshift mutation, 15 France, 29, 67 friction, 83 fruits, 26, 32

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G gadolinium, 120, 127, 128, 129, 132 gas, 77, 117, 137 gastric, 36 gastroenterologist, 47, 87 gastrointestinal, vii, viii, 14, 19, 26, 33, 36, 40, 42, 48, 64, 67, 70, 73, 83, 88, 102, 104, 121, 125, 133 gastrointestinal bleeding, 42, 64, 67, 70, 73, 88 gastrointestinal tract, vii, viii, 26, 36, 40, 83, 102, 121, 125, 133 gender, 25 gene, 4, 5, 6, 10, 16, 17 generation, 79, 137 genes, 5, 6, 7 genetics, vii, 4, 8 genome, vii, 5, 7, 16, 17 genomic, 5 genotype, viii, 14 Germany, 137 glaucoma, 43 globalization, 25 glomerulonephritis, 49 glucocorticoids, 40 glucocorticosteroids, 59, 64 glycol, 108, 120 GM-CSF, 14 gold, 74, 75, 118 gold standard, 74, 75, 118 Gore, 102, 103, 104, 119 grading, 128

Gram-negative, 10 Gram-positive, 10 granulocyte, 14, 50 granulomas, 19, 36, 57 gravity, 40 groups, 4, 25, 28, 48, 84 growth, 6, 13 guanine, 11 guidance, 82 guidelines, 21, 64 gut, 13, 17, 18, 40, 47, 68

H hands, 53, 64, 140 harm, viii, 54 healing, 31, 36, 46, 54 health, 18, 21, 22, 28, 46 health care, 22, 46 health care professionals, 46 heat, 19 Helicobacter pylori, 27, 33 helper cells, 6 hematocrit, 44 hemoglobin, 65 hemorrhage, 113, 117, 121 hemorrhages, 101 hemostasis, 64 heritability, 15 heterogeneity, viii, 14, 40 heterogeneous, vii, 4, 42, 56, 74 high resolution, 65, 68 high risk, 39, 61, 83 Hispanics, 25 histological, 35, 53, 54, 65, 75, 77, 81, 85, 87, 140, 144 histopathology, 56 HIV, 60 homeostasis, 3, 9 homogeneity, 97 homogenous, 112 hospitalization, 114 host, 5, 14, 17

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Index human, vii, 7, 10, 17, 58 human immunodeficiency virus, 58 humans, 4, 32, 40 hydro, 132 hygiene, 27 hygienic, 27 hypercoagulable, 39 hyperemia, 77, 136 hyperplasia, 35, 57, 58 hypertrophy, 138 hypothesis, 10, 13, 19, 27 hypotonia, 97, 102

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I IBD, 17, 21, 24, 26, 27, 29, 40, 67, 124, 147 ICAM, 11 ICD, 24 identification, 6, 78 idiopathic, vii, 49 IFN, 12 IFNγ, 8, 10 IL-1, 10, 11, 12, 15, 18 IL-13, 12 IL-17, 10, 12, 18 IL-2, 6, 7, 10, 12 IL-21, 12 IL-6, 10, 12 IL-8, 12, 15 ileum, 8, 36, 53, 56, 57, 58, 59, 61, 62, 83, 84, 95, 96, 98, 100, 126, 130, 135, 136, 140 illumination, 70 images, 65, 70, 73, 100, 110, 111, 128 imaging, viii, 26, 48, 55, 63, 65, 68, 69, 70, 74, 95, 102, 105, 112, 115, 116, 118, 119, 120, 123, 124, 125, 127, 131, 132, 133, 140, 144, 145 immune cells, 4, 8, 9, 18 immune response, 8, 9, 13, 14 immune system, 3, 4, 7, 10, 14 immunity, 7, 9, 16, 18 immunodeficiency, 6, 14 immunological, 8

155

immunosuppressive, 14 immunosuppressive drugs, 14 in vitro, 145 in vivo, 18, 135, 145 incidence, 22, 24, 25, 27, 28, 29, 30, 31, 33, 42, 59, 61, 89 inclusion, 85 India, 30 Indian, 30, 31 indication, 54, 65, 88, 95, 139 indices, 50 indigenous, 31 indium, 50 indomethacin, 32 induction, 8 industrialized countries, 59 industry, 124 inert, 78 infancy, 84, 87 infarction, 33 infection, 13, 14, 33, 40 infections, 40, 112, 124 infectious, vii, 6, 12, 13, 27, 36, 58, 75, 140 infectious disease, 6 inflammation, vii, 5, 8, 10, 12, 14, 17, 18, 19, 26, 32, 36, 37, 39, 40, 49, 50, 56, 63, 76, 95, 100, 113, 114, 117, 123, 127, 129, 134, 135, 137, 138 inflammatory bowel disease, vii, 4, 5, 8, 12, 15, 16, 17, 19, 21, 25, 26, 28, 29, 30, 31, 32, 33, 35, 38, 39, 40, 41, 47, 49, 50, 53, 54, 55, 58, 64, 66, 68, 73, 88, 103, 104, 121, 123, 124, 131, 133, 141, 142, 143, 145 inflammatory cells, 8 inflammatory disease, 39, 40, 113, 142 inflammatory response, 14, 136 inflation, 82, 85 infliximab, 43, 64, 66, 67 ingestion, 78, 87 inhibition, 18 injection, 64, 67, 81, 97, 110, 112, 120, 125, 129

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156 injuries, 58 injury, 3, 14, 47, 86, 89 innate immunity, viii, 6, 9, 15 insertion, 13, 69, 81, 82, 84, 85, 86 insertion sequence, 13 insight, vii, 22, 25 institutions, 102, 118, 124 instruments, 123 integration, 54, 55 integrin, 12 integrity, 4, 26 intensity, 65, 128, 129, 130, 137 interaction, 6, 10, 11, 14, 46 interactions, 16, 17 intercellular adhesion molecule, 11 interface, 134 interferon, 10, 12 interferon-γ, 10 interleukin, 7, 8, 10, 11, 12, 19, 40 interleukin-1, 10 Interleukin-1, 18 interleukin-17, 10 interleukin-17 (IL-17), 10 interleukin-2, 10 interpretation, 57, 79, 120 interval, 22, 64, 65 intervention, 46, 63, 75, 80, 117 intestinal flora, 7 intestinal obstruction, 145 intestinal perforation, 117 intestinal tract, 16, 95, 113, 133 intestine, 8, 11, 17, 62, 69, 82, 86, 110, 117 intra-abdominal abscess, 134, 145 intraoperative, 143 intraperitoneal, 116 intravascular, 129 intravenous, 108, 110, 120, 125, 137, 142 intrinsic, 9, 123 invasive, 48, 70, 75, 87, 140, 141 iodinated contrast, 113 iodine, 108, 112 ionizing radiation, viii, 75, 119, 123, 124 iritis, 39, 44

Index iron, 64 iron deficiency, 64 irritable bowel syndrome, 31, 41, 47, 50, 86 ischemia, 112, 121 ischemic, vii, 13, 22, 25, 47, 58, 75 isotonic solution, 119 isotropic, 107, 110, 111 Israel, 23, 29, 70, 73, 78 Italy, 3, 21, 23, 29, 35, 53, 66, 69, 95, 107, 123, 133, 137, 147

J Japan, 23, 29, 65, 72, 73, 81, 85 Japanese, 81 jejunum, 19, 83, 95 Jews, 25, 31 joints, 39

K kinase, 8 kinases, 18 knees, 39 Korea, 72, 73

L L1, 41, 45 L2, 41, 45 lactoferrin, 40, 48 lactose, 78 lamina, 8, 11, 100 large intestine, 32 laser, 19 latex, 81, 82 laxatives, 55 layering, 135 learning, 85, 90 Lebanon, 23, 30 lesions, viii, 35, 37, 39, 55, 56, 57, 59, 62, 63, 65, 68, 69, 73, 75, 79, 84, 86, 97, 102, 107, 108, 110, 112, 118, 123, 130, 139, 140, 141, 142 leucine, 4, 10, 15

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Index leukocyte, 41 leukocytosis, 48 life expectancy, 24 lifestyle, 22, 28 life-threatening, 42, 46 ligament, 82 ligand, 9, 19 ligands, 12, 15 light emitting diode, 71 light-emitting diodes, 70 likelihood, 74 limitations, 22, 24, 45, 46, 72, 90, 107, 109 linear, 56, 100 lipoproteins, 4 liver, 38, 40, 116, 129 liver disease, 38 livestock, 13 localization, vii, 72, 117 location, 4, 22, 35, 36, 37, 38, 43, 45, 59, 72, 82, 86, 112, 116, 118, 130, 135, 144 locus, 6, 9, 17 long period, 23, 71, 74 low risk, 25 LPS, 9 lumen, viii, 63, 101, 107, 108, 116, 125, 134, 138, 139 luminal, 3, 7, 76, 108, 117, 123, 124, 125, 128, 129, 133, 134, 139 lupus erythematosus, 121 lymph, 108, 114, 125, 131, 134, 135, 138, 139 lymph node, 108, 114, 131, 134, 135, 138, 139 lymphadenitis, 36 lymphadenopathy, 125 lymphocyte, 19 lymphoid, 35, 57 lymphoid hyperplasia, 35 lymphoma, 124 lysosomes, 6 lysozyme, 40

157

M macrophages, 4, 9 magnetic, , viii, 73, 74, 119, 131, 132 magnetic field, 73 magnetic resonance, vi, viii, 74, 119, 131, 132 magnetic resonance imaging, 74, 119, 123, 131 magnetic resonance spectroscopy, 131 maintenance, 4, 8, 28 malabsorption, 37, 39, 43 males, 39 malignancy, 117 malignant, 65 malnutrition, 37, 40 management, vii, viii, 13, 28, 29, 39, 42, 45, 53, 55, 61, 63, 70, 87, 88, 90, 115, 118, 122, 133, 141 manipulation, 7 mannitol, 108, 125 manufacturer, 128 margarine, 26 maternal, 8 maturation, 9 measurement, 42, 112, 128, 130 media, 97 median, 25, 74 medicine, 21 membranous nephropathy, 39 mesentery, viii, 101, 104, 114, 116, 134, 139 meta-analysis, 13, 19, 24, 74, 88, 133, 134, 142 metabolism, 26 metal oxide, 70 metastatic, 39 methylcellulose, 97, 103, 104, 108, 110 microbial, 4, 7, 9, 11, 17 microbiota, 7 micro-organisms, 8, 9, 14, 58 microparticles, 137 microvascular, 27 migrants, 25, 28, 31

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158

Index

migration, 11, 25, 40 milk, 13, 19 mimicking, 37, 55 Minnesota, 28 minorities, 25 misinterpretation, 110 mitogen, 10, 11 mitogen activated protein kinase (MAPK), 10, 11 modalities, iv, 22, 74, 75, 88, 95, 96, 102, 103, 115, 119, 123 modality, 96, 98, 102, 108, 118, 124 models, 6, 8, 10, 26 molecules, 8, 10, 11, 19 monoclonal, 12 monoclonal antibody, 12 monocytes, 12, 14 monogenic, 5 monolayer, 137 mononuclear cells, 11 monozygotic twins, 4 morbidity, 80 morphogenesis, 6 morphological, 27 mortality, 24, 30, 31, 80 mortality rate, 24 mortality risk, 24 motion, 110, 128, 130 mouse, 8, 18 mouth, 36, 81 movement, 109, 125, 128 MRI, 123, 124, 125, 128, 130, 131, 132 mRNA, 31 mucin, 36 mucosa, viii, 9, 14, 35, 53, 56, 57, 59, 60, 63, 65, 73, 75, 81, 83, 87, 101, 102, 110, 113, 134 mucosal barrier, 3, 8, 13 mucus, 26 multiplier, 44 murine model, 17, 18 muscle, 116 muscles, 116, 130

mutation, 5, 6, 15, 16 mutations, 4, 5, 6, 9, 15, 16 Mycobacterium, 13, 19, 59 myeloperoxidase, 40 myosin, 8

N natural, 10, 30, 46, 50, 69, 72, 130 natural killer, 10 nausea, 46 necrosis, 11, 12, 40, 43 neoplasia, 40, 65, 67, 68 neoplasms, 121 neoplastic, 47, 65, 101, 113, 114, 124, 140 neoplastic degeneration, 101 nephritis, 49 nephropathy, 39, 43 neuroendocrine, 8 neutrophil, 40, 41 neutrophils, 4, 9, 12, 41 NFkB, 7 NF-kB, 4 NF-kB, 10 NF-kB, 11 Nielsen, 28, 49 nodes, 114 nodules, 63, 99, 100, 138 non invasive, 41, 50, 118 non-invasive, viii, 70, 123, 133, 141 normal, 3, 4, 12, 40, 55, 56, 65, 75, 87, 88, 104, 108, 110, 112, 113, 114, 127, 130, 133, 134, 135, 136 North America, 22, 23, 24, 27, 30, 105 Norway, 66 NSAIDs, 13, 14, 26, 28, 58 N-terminal, 10 nuclear, 4, 7, 11 nutrient, 17

O OAS, 96 observations, 8, 26, 101, 105, 119, 120

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Index obstruction, 42, 46, 76, 77, 117 occluding, 8 occlusion, 78, 89 occult blood, 48 OCT, 7 oligomerization, 4, 7 omeprazole, 89 oncogenesis, 124 operator, 71, 75, 87, 140 optical, 72 optimal health, 21 optimization, 119 oral, viii, 13, 27, 28, 31, 32, 38, 46, 84, 103, 108, 109, 110, 111, 118, 119, 120 oral cavity, 84 oral contraceptives, 13, 27, 28, 32 organ, 38, 42, 43, 47 organic, 6, 7 organism, 12 organization, 28 osmotic, 55, 109 outpatients, 46 overweight, 140 oxalate, 39

P pain, 37, 43, 44, 46, 47, 48, 54, 55, 73, 77, 78, 144 pallor, 43 palmoplantar pustulosis, 39 palpation, 96 pancreatic, 83 pancreatitis, 37, 83 paradox, 6 parameter, 130 parenchyma, 129 Paris, 50 pasteurization, 13 pathogenesis, 3, 4, 7, 9, 13, 15, 17 pathogenic, 14, 27 pathologist, 35 pathology, 73, 76, 95, 145

pathophysiology, 6 pathways, 6, 9, 16, 18 patient care, 107 patient management, 45, 122 pattern recognition, 4, 9, 11 PCR, 19, 59 PDG, 11 pediatric, 22, 26, 45 peer, 73 pelvic, viii, 42 pelvis, 118, 128, 129 peptides, 4, 5 perforation, 26, 53, 54, 64, 83 performance, 110, 124, 125, 128 perfusion, 128 periodic, 96 peripheral, 38, 39 peristalsis, 72, 97, 124, 131, 138 peritoneal, 123 permeability, 8, 16, 17, 18, 41 pharmacological, 98 phenotype, viii, 14 phenotypes, 45 phenotypic, 14, 50 Philadelphia, 17, 18, 103, 104 phosphate, 55 phosphorylation, 9 physical activity, 39 physiological, 6 pilot study, 64, 67 placebo, 46, 67, 89 plantar, 38 plasma, 40 plastic, 70 Platelet, 40 play, 6, 9, 28, 118 policy makers, 22 polycythemia, 40 polyethylene, 108, 120 polymerase, 59 polymerase chain reaction, 59 polymorphism, 4, 6, 7 polymorphisms, 17

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159

Index

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160

polyps, 40, 101 polyuria, 43 poor, 44, 45, 108 population, 4, 6, 10, 15, 16, 18, 22, 23, 24, 25, 26, 28, 29, 30, 31, 50, 66, 67, 84, 90, 124 pore, 8 postoperative, 61, 63, 67, 75, 88, 142, 145 power, 136, 142, 145 prediction, 39 pressure, 82, 83, 137 prevention, 8, 67 probability, 41 proctitis, 60 production, 4, 7, 8, 9, 13, 40 prognosis, 39, 45, 54 program, 67 pro-inflammatory, 4, 10, 11, 31 proliferation, 104, 114, 115, 130 propagation, 87 property, 110 prostaglandin, 17 protein, 6, 8, 10, 37, 39, 40, 42, 48, 50 proteins, 8, 18, 39, 40 protocol, 112, 119, 127, 130 prototype, 65 proximal, 69, 76, 83, 84, 102, 117, 138, 139 pseudo, 65 Pseudomonas, 42 psychological stress, 13 public health, 21 pulmonary circulation, 137 pulmonary embolism, 43 pulse, 127 pumps, 104 pylorus, 97 pyoderma gangrenosum, 39, 44

Q quality of life, 39, 45

R radiation, vii, 47, 58, 102, 109, 110, 112, 118, 123, 124 radio, 70, 73, 78, 100 radiofrequency, 73 radiography, 74, 104, 117 radiological, vii, 75, 96, 100, 101, 102, 103, 107 radiologists, 102, 124, 130, 142 random, 65 randomized controlled clinical trials, 65 range, 26, 81, 110, 137 ratings, 44 reactant, 40 reactive oxygen, 4, 7 reactive oxygen species (ROS), 4, 7 reactivity, 3 reading, 71, 72 rebound tenderness, 46 receptors, 4, 9, 11, 15, 16 recognition, 4, 9, 11, 15, 16, 22, 64 reconstruction, 26, 111 recovery, 40 rectum, 56, 61, 62, 102, 127 recurrence, 26, 32, 53, 54, 61, 63, 67, 88, 117, 131, 133, 141, 142, 144, 145 reduction, 46, 138 reflection, 65 refractoriness, 10, 53 refractory, vii, 20 regional, 30 registries, 22, 23 regular, 135, 138 regulation, 4, 7, 16 reinforcement, 50 reinforcement contingencies, 50 relapse, 8, 17, 26, 39, 46, 61, 75 relapses, 64 relationship, 26, 141 relatives, 4, 8, 18 relevance, 104, 118

Girelli, Carlo M., and Luca G. Crespit. Diagnostic Modalities in Crohn's Disease, Nova Science Publishers, Incorporated,

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Index reliability, 130 remission, 8, 23, 44, 46, 47, 114 remodeling, 3 renal, 117 replication, 6, 7 research, 5, 9, 13, 14, 21, 30, 81, 124, 142 researchers, 85 resection, 26, 42, 46, 61, 63, 65, 67, 75, 133, 141 residual disease, 46 resistance, 19 resolution, 65, 68, 107, 111, 130 resource allocation, 21 restitution, 18 retention, 76, 78, 89 RFID, 78 rigidity, 101, 128 risk, 4, 21, 25, 26, 27, 31, 32, 39, 42, 50, 53, 54, 55, 61, 71, 78, 83, 89, 124, 141, 144, 145 risk factors, 21, 25 risks, 26, 75 robustness, 96 Rome, 45 rural areas, 29

S Saccharomyces cerevisiae, 41 sacrum, 116 safety, 75, 86, 90, 137 salmonella, 47, 58 sample, 74, 87 sampling, viii, 59, 65, 81 sanitation, 30 saturation, 119 Scandinavia, 27 scores, 44, 45, 62, 76 second generation, 78, 137 sedation, 53, 82, 97, 102 sedimentation, 40 self limiting, 22 semiconductor, 70

161

sensing, 7 sensitivity, 18, 41, 75, 79, 118, 130, 134, 137, 140 sensors, 9 separation, 101 series, 22, 57, 59, 64, 67, 73, 81, 84, 90, 102, 104, 141 serological marker, 50 serology, 48, 58 serum, 40, 42 services, iv SES, 61, 63, 67 severity, 21, 44, 45, 54, 55, 61, 66, 67, 99, 101, 107, 108, 135 shape, 17, 82, 86, 101 Shigella, 47, 58 shortage, 22 side effects, 110 sigmoid, 43, 61, 62, 129 sigmoid colon, 43 sign, 44, 100, 112, 113, 114, 127, 128, 129, 138, 140, 142 signal transduction, 9 signaling, 4, 9 signaling pathway, 4, 9 signalling, 18 signals, 15, 137 signs, 48, 54, 99, 100, 101, 124 single nucleotide polymorphism, 4, 7 sinus, 101, 102, 108, 115, 116, 139 skills, viii, 102 skin, 39, 134 small intestine, 69, 70, 91, 97, 103, 104, 142, 144 smoke, 26 smokers, 26 smoking, 13, 15, 26, 32, 33, 46 SNP, 7 SNPs, 16 sodium, 18 software, 71, 72, 129 solubility, 137 somatic cell, 7

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162

Index

somatic cells, 7 SonoVue, 145 South America, 27 Spain, 23, 29 spasmolytic, 110 spatial, 107 species, 4, 7, 13 specificity, 40, 75, 79, 130, 134 spectroscopy, viii, 124 spectrum, 21, 26, 44, 46, 121 speed, 71, 112 spin, 128, 132 spleen, 129 stages, 113 standardization, 13 statistics, 24 stem cell transplantation, 20 stem cells, 14 stenosis, 42, 76, 123, 138, 144 steroid, 46, 47, 67 stimulus, 40 stochastic, 124 stomach, 37, 71, 72, 82 stomatitis, 38, 39, 44, 48 strain, 83 stratification, 112, 113, 135, 137, 138 stress, 14, 18 stretching, 69, 86 strictures, 35, 55, 63, 65, 67, 76, 78, 79, 87, 89, 101, 115, 142, 143 stroke, 39 subjective, 45, 137, 138 submucosa, 134 substances, 108, 109, 110 sugar, 26, 31 sulfate, 18 sulphate, 78 sulphur, 137 superiority, 73, 102, 116, 131 suppressor, 10 suppressor cells, 10 surgery, 30, 42, 46, 47, 61, 64, 67, 75, 77, 79, 118, 130, 139, 141, 142, 144, 145

surgical, 8, 26, 42, 45, 46, 53, 54, 63, 75, 76, 79, 115, 117, 118, 121, 131, 133, 139, 141 surgical intervention, 63, 117 surgical resection, 26, 42, 46, 63, 75, 133 surveillance, 53, 54, 64, 67, 68, 98 survival, 28 susceptibility, 5, 6, 9, 10, 15, 16, 17 susceptibility genes, 6 suspensions, 97, 108 swallowing, 72 Sweden, 29, 90 symmetry, 112 symptom, 37, 64 symptoms, 37, 43, 46, 48, 73, 77, 87, 117, 118 syndrome, 5, 16, 39, 47, 49, 63 synergistic, 4 synovitis, 38, 39, 49 systemic circulation, 137 systemic lupus erythematosus, 121 systems, 47, 73

T T cells, 6, 8, 10, 11, 12, 14, 18, 19 tachycardia, 43 targets, 12 taste, 110 technology, vii, 87, 107 temperature, 97 temporal, 22, 46, 107 therapy, 7, 10, 33, 36, 38, 39, 45, 46, 50, 53, 54, 57, 59, 61, 63, 64, 70, 81, 114, 119, 133 threatening, 117 threonine, 6 threshold, 112 thromboembolism, 39 thrombosis, 43 tight junction, 8, 17, 18 time, viii, 8, 22, 24, 28, 36, 42, 49, 65, 69, 71, 72, 74, 76, 78, 79, 85, 87, 97, 110, 118, 137 timing, 110

Girelli, Carlo M., and Luca G. Crespit. Diagnostic Modalities in Crohn's Disease, Nova Science Publishers, Incorporated,

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Index tissue, viii, 3, 8, 10, 12, 13, 54, 121, 128, 131 TLR, 4, 9, 11, 18 TLR2, 9, 15 TLR3, 9 TLR4, 9 TLR9, 9 tobacco smoke, 28 Tokyo, 72, 81, 85 tolerance, 8, 14 toll-like, 9, 15, 16, 18 toxic, 36, 42, 43 toxic megacolon, 36, 42 toxicity, 42, 46, 110 toxins, 6 training, 82 transcription, 11 transducer, 16 transmission, 72, 73, 87 transparent, 119 transplantation, 20 transverse colon, 61, 62 transverse section, 134 trend, 22, 124 trial, 67, 87 triggers, 9 tuberculosis, 13, 36, 47, 58, 66 tumor, 11, 12, 40 tumor necrosis factor (TNF), 10, 11, 12, 18, 40, 43, 59 tumors, 142 twin studies, 4 two-dimensional, 72 type II error, 74

U ulcer, 36, 47, 56, 64, 76, 77, 131 ulceration, 35, 61, 62, 64, 76, 100, 101, 128 ulcerative colitis, vii, viii, 13, 15, 18, 26, 28, 29, 30, 31, 32, 33, 35, 40, 41, 42, 49, 54, 57, 59, 60, 64, 66, 67, 68, 74, 88, 102, 119, 131, 143

163

ultrasonography, viii, 133, 140, 141, 142, 143, 144, 145 ultrasound, viii, 119, 123, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145 uncertainty, 27 unclassified, vii, 22, 41, 75, 79, 88 underreported, 21 uniform, 26 United Kingdom, 25 United States, 24 urban areas, 27 urinary, 42 urinary bladder, 42 uveitis, 38, 39, 44

V vagina, 42 validation, 67, 144 values, 128, 130, 134 variability, 22 variable, 23, 25, 64, 135 variables, 59, 62, 76 variation, 25, 130 vascular cell adhesion molecule, 12 vascular disease, 38, 39 vascularization, 136 vasculature, 121 vasculitides, 36 vasculitis, 47, 121 vegetables, 26, 32 vein, 43 venules, 12 vessels, 114, 137 veterans, 31 virus, 58 viscera, viii visible, 60, 135 vision, 43, 75, 130 visualization, viii, 53, 69, 80, 95, 98, 99, 107, 108, 110, 116, 117, 118, 123, 128 vitamin D, 39

Girelli, Carlo M., and Luca G. Crespit. Diagnostic Modalities in Crohn's Disease, Nova Science Publishers, Incorporated,

Index

164 vitamins, 7 vomiting, 43, 46, 55, 77, 110

W Wales, 31 war, 22, 24, 28 water, 37, 108, 109, 110, 113, 137 water absorption, 110 wavelengths, 65 weight loss, 37, 43, 46, 73 wellbeing, 44 western countries, vii western diet, 28 wireless, 70, 88 Wisconsin, 30 withdrawal, 82, 85 women, 26, 27, 32 workers, 23, 26, 57, 59, 74, 85, 134, 137 wrists, 39

X

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x-rays, 43

Y yield, viii, 56, 74, 75, 85, 86, 88, 90

Girelli, Carlo M., and Luca G. Crespit. Diagnostic Modalities in Crohn's Disease, Nova Science Publishers, Incorporated,