IPR2017-01987
`
`AbbVie Exhibit 2002
`Sandoz v. AbbVie
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`Page | of 20
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`

`

`Library of Congress Cataloging·in-Public~ata is available.
`
`Inflammatory bowel disease: from bench to beside I edited by Stephan R. Targan,
`Fergus Shanahan, and Loren C. Karp-2nd ed.
`p. ;em.
`Includes bibliographical references and index.
`ISBN 1-40200-713-2 (HB : alk. paper)
`I. Inflammatory bowel diseases. I. Targan, Stephan R. II. Shanahan, Fergus. III. Karp, Loren C.
`[DNLM: I. Inflammatory Bowel Diseases. WI 420 14237 2002)
`
`ISBN 1-40200-713-2
`
`Published by Kluwer Academic Publishers BV,
`PO Box 17, 3300 AA Dordrecht, The Netherlands.
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`All Rights Reserved
`~ 2003 Kluwer Academic Publishers
`First edition published 1993 by Williams & Wilkins
`No part of this publication may be reproduced or
`utilized in any form or by any means, electronic, mechanical,
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`Printed and bound in Great Britain by MPG Books Limited, Bodmin, Cornwall.
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`;)oo do 30oCJ. 1
`
`

`

`I Table of Contents
`
`Preface
`Stephan R. Targan/ Fergus Shanahan! Loren C. Karp
`
`SECTION 1: The laboratory bench
`I . Introduction: Inflammatory bowel diseases: from bench to bedside
`Fergus Shanahan, Loren C. Karp, Stephan R. 'Illrgan
`
`2. The changing faces of Crohn's disease and ulcerative colitis
`Anders Ekbom
`
`3. Genetics of inflammatory bowel disease
`Kent D. Taylor. Jerome 1 Rotter. Huiying Yang
`
`4. Experimental mouse models of inflammatory bowel disease: new insights into pathogenic
`mechanisms
`Charles 0. Elson a11d Casey T. %aver
`
`5. The normal intestinal mucosa: a state of 'controlled inflammation'
`Claudio Fiocchi
`
`6. The lymphocyte- epithelial- bacterial interface
`Robert Hershbergand RichardS. Blumberg
`
`7. The mucosal inflammatory response. Cytokines and chemokines
`Fabio Cominel/i, Kristen 0. Arseneau and Theresa T. Pi=arro
`
`8. Role of the microcirculation in chronic gut inflammation
`Matthew B. Grisham. F. Stephen Laroux and D. Neil Granger
`
`9. Remission, relapse, intestinal healing and repair
`Michael N GokeandDaniel Podolsky
`
`10. Antibodies in the exploration of inflammatory bowel disease pathogenesis
`and disease stratification
`Jonathan Braun, Offer Cohavy and Mark Eggena
`
`I I . Pathophysiology of inflammatory bowel disease: the effect of inflammation on intestinal function
`Stephen M Collins and Kenneth Croitoru
`
`12. Systemic consequences of intestinal inflammation
`Konstantinos A. Papadakis and Maria T. Abreu
`
`SECTION II: The bedside
`13. Understanding symptoms and signs in inflammatory bowel disease
`Cornelius C. Cronin and Fergus Shanahan
`
`v
`
`3
`
`5
`
`21
`
`67
`
`101
`
`121
`
`147
`
`177
`
`197
`
`211
`
`223
`
`235
`
`253
`
`

`

`xiv
`
`Table of contents
`
`14. Clinical course and complications of ulcerative colitis and ulcerative proctitis
`Remo Panaccione and Lloyd R. Sutherland
`
`I 5. Clinical features and complications of Crohn's disease
`William 1 Ti·emaine
`
`16. Mechanisms of systemic inflammation associated with intestinal injury
`R Balfour Sartor and Steven N Lichtman
`
`17. Pathology of inflammatory bowel diseases: a critical appraisal in diagnosis and management
`Galen Cortina and Klaus Lewin
`
`18. An endoscopic and histologic perspective of diagnosis: when, where, and what to do
`Charles N Bernstein and Robert H Riddell
`
`19. Radiologic (radiographic) and imaging features of ulcerative colitis and Crohn's disease
`Edward Fitzgerald
`
`20. New diagnostic approaches in inflammatory bowel disease
`Lori Kam and Eric Vasiliauskas
`
`21. D ifferential diagnosis of colitis
`Sue C. Eng and Christina M Surawicz
`
`22. 'Disease management' in chronic medical conditions
`David H Alpers
`
`23. Pha rmacoeconomics and inflammatory bowel disease
`Brian G Feagan
`
`24. Measuring quality of life in inflammatory bowel disease
`E. Jan Irvine
`
`25. Clinical pharmacology in inflammatory bowel disease: optimizing current medical therapy
`Laurence 1 Egan and William 1 Sandborn
`
`26. Multi-site therapeutic modalities for inflammatory bowel diseases - mechanisms of action
`Gerhard Rogier
`
`27. Targeted therapies for inflammatory bowel disease
`Sanderl H van Deventer
`
`28. Role of antibiotics and probiotics in the management of inflammatory
`bowel disease
`Philippe Marteau and Fergus Shanahan
`
`29. Nutrition in inflammatory bowel disease
`Gregg W.l11n Cittersand Henry C. Lin
`
`30. Medical management of ulcerative colitis
`William 1 Sandborn
`
`31. Surgical management of ulcerative colitis
`Jan Lindsey and Neill M cC Mortensen
`
`32. Pouchitis: clinical characteristics and management
`Uma Mahadevan and William 1 Sandborn
`
`33. Medical therapy for Crohn's disease
`Stephen B. Hanauer and Themistocles Dassopoulos
`
`269
`
`291
`
`305
`
`337
`
`357
`
`371
`
`409
`
`431
`
`451
`
`471
`
`481
`
`495
`
`523
`
`553
`
`573
`
`587
`
`605
`
`631
`
`643
`
`659
`
`

`

`Table of contents
`
`34. Surgery for Crohn's disease
`Robin S. McLeod
`
`35. Postoperative prevention of recurrence of Crohn's disease
`Filip Baert, Geert D'Haens and Paul Rutgeerts
`36. The molecular pathology of inflammatory bowel disease-associated neoplasia and preneoplasia
`Stephen Meltzer
`37. Dysplasia in inflammatory bowel disease: clinical pathology and current surveillance methods
`Catherine] Streutke1; Roger C. Haggitt and Robert H Riddell
`
`38. Hepatobiliary disorders
`Sue Cullen and Roger Chapman
`
`39. Articular and ocular complications of inflammatory bowel disease
`Timothy R. Orchard and Derek P. Jewell
`
`40. Cutaneous manifestations of inflammatory bowel disease
`Scott W Binder
`
`41. Fertility and pregnancy in inflammatory bowel disease
`William Connell
`42. Special considerations in the diagnosis and management of inflammatory bowel disease in
`the pediatric age group
`Ernest G. Seidman and Arlene Caplan
`
`43. Microscopic colitis: collagenous and lymphocytic colitis
`Diarmuid O'Donoghue and Kieran Sheahan
`
`44. Colon ischemia
`Seth E. Persky and Lawrence 1 Brandt
`
`45. Diversion colitis
`Konrad H Soergel
`
`46. Pseudomembranous colitis and Clostridium difficile infection
`Richard 1 Farrell, Lorraine Kyne and Cia ran P. Kelly
`
`47. Infectious colitis
`Michael J G. Farthing
`48. Human immunodeficiency virus and inflammatory bowel disease
`Charles Mel Wilcox
`49. Bone metabolism and inflammatory bowel disease
`Maria T. Abreu
`
`SECTION Ill: Back to the laboratory bench
`50. Epilogue: Bench to bedside and back to bench
`Stephan R. Targan, Loren C. Karp and Fergus Shanahan
`
`Index
`
`xv
`
`681
`
`697
`
`711
`
`719
`
`731
`
`747
`
`757
`
`763
`
`773
`
`791
`
`799
`
`811
`
`823
`
`845
`
`863
`
`875
`
`887
`
`893
`
`

`

`13 Understanding symptoms and signs in
`inflammatory bowel disease
`
`CORNELIUS C. CRONIN AND FERGUS SHANAHAN
`
`Introduction
`The natural history of Crohn's disease (CD) and
`ulcerative colitis (UC) is highly variable, but most
`typically follows a course of relapses and remissions.
`Some patients have chronically active disease with
`no or few apparent remissions. In some, the condi(cid:173)
`tion appears to 'burn out', and they enter long term
`remission. Series from specialized centers may tend
`to over-estimate clinical severity [1]. Generally,
`symptoms of UC tend to be uniform; most patients
`complain of abrupt onset passage of blood, diarrhea
`and weight loss. Each acute relapse typically has
`similar clinical features. Because of its greater anato(cid:173)
`mical distribution potentially involving any part of
`the gastrointestinal tract, its transmural distribution
`and its propensity to give raise to complications such
`as strictures and fistulae, CD shows greater
`variability between patients in clinical features. Also,
`as the disease evolves involving different parts of the
`gastrointestinal tract, the clinical features in any one
`patient may also change through time.
`Symptoms and signs of inflammatory bowel
`disease (IBD) ultimately depend on the extent,
`distribution and severity of the gastrointestinal
`inflammation. Many of the clinical features of CD
`and UC are related to the anatomical location of
`disease. Abdominal colic is caused by intestinal
`strictures and diarrhea by intestinal inflammation.
`Other features such as anorexia, weight loss and
`malnutrition, anemia and constitutional features
`are largely due to the systemic consequences of
`intestinal inflammation. In recent years, the role of
`soluble mediators of intestinal inflammation in the
`pathogenesis of non·intestinal features of IBD has
`been appreciated. Cytokines are produced by many
`different tissues in response to immune stimulation
`and mediate a multiplicity of immunologic and non(cid:173)
`immunologic functions [2, 3]. As well as local (auto(cid:173)
`crine-paracrine) actions, cytokines have systemic
`
`(endocrine) effects, many mediated hy the central
`nervous system [4, 5]. While the short-term, local
`effects of cytokines may be beneficial to the organism
`in the acute phase of an immune reaction, prolonged
`systemic cytokine activity as in lBD is often deleter(cid:173)
`ious (Table I) [6, 7].
`
`Disease vs Illness
`There is an imperfect association between disease
`activity and patient disability. The objective assess(cid:173)
`ment of disease activity often provides a poor guide
`to the subjective impact of the condition on the
`
`Tabla 1. Adaptions associated with pro-inflammatory
`cytokines
`
`Behavioral
`Anorexia
`Fatigue
`Malaise
`Altered sleep pattern
`Altered level of consciousness
`
`Physiologic
`Elevated body temperture
`Increased resting energy expenditure
`Stress hormone response
`Skeletal muscle wasting
`Hepatic acute phase response
`Trace mineral sequestration
`Decreased gastric emptying, intestinal transit time
`Bone marrow suppression
`Diuresis
`
`Nutritional
`Weight loss
`Negative nitrogen balance
`Hypoalbuminemia
`Hyperinsullnemia
`Hypertriglyceridemia
`Hypocholesterolemia
`
`Adapted from ref. 7
`
`Sttphan R. Targa1~ Fergus ShaMIJall and I.Artn C. Karp (tds.). Inflammatory Bo•·tl DlseaM: From Be11cil 10 lkdsidt, lnd Editio11, 253- 267.
`r. 2003 Klu~'"' AtoJtmic Publuh~rs. PdtJtttJ in GrNI Britain
`
`

`

`254
`
`Understanding symptoms and signs in inflammatory bowel disease
`
`patient: disease does not equate with illness. The
`biomedical model - the notion that the disease
`activity determines the clinical outcome - had long
`been dominant in western medicine. The biopsycho(cid:173)
`social model, as described by Engel [8] and further
`expanded in relation to chronic gastrointestinal
`disease by Orossman [9], proposes that illness and
`disease result from simultaneously interacting sys(cid:173)
`tems at the cellular, tissue, organism, interpersonal
`and environmental levels. This approach integrates
`biological science with the uniqueness of the indivi(cid:173)
`dual, to determine the degree to which biological and
`psychosocial factors interact to explain the disease,
`illness and outcome. Patients with chronic gastro(cid:173)
`intestinal conditions may develop a variety of
`psychosociologic responses such as depression,
`decreased activities, increased illness behaviour,
`dependent relationships, and decreased responsibil(cid:173)
`ities. Patients often have difficulties in employment,
`recreation and marital relations. The problems con(cid:173)
`sequent on constitutional symptoms such as malaise
`and loss of energy may contribute more to patient
`disability than gastrointestinal symptoms. Illness,
`particularly that arising from chronic disease, is
`therefore best understood in terms of a multifactorial
`model, integrating biologic, psychologic and socio(cid:173)
`logic variables. Such a model facilitates and
`optimizes diagnosis, treatment and ultimately
`patient care. The aphorism 'treat the patient, not the
`disease' is particularly relevent in the long-term
`management of chronic lBO.
`The unknown primary cause (or causes) of lBO
`and multiple secondary variables produce the
`heterogenous pathological and clinical manifesta(cid:173)
`tions of the illness. A representative list of such
`factors is shown in Table 2. The clinical features of
`IBD are numerous and varied. No symptom or sign
`exists in isolation. A single mechanism or etiopatho(cid:173)
`genesis rarely explains any one symptom or sign;
`nearly all are multifactorial. This chapter reviews
`aspects of the mechanisms, etiopathogenesis and
`clinical features of the major clinical features of
`IBD: abdominal pain, malnutrition and diarrhea.
`
`Pain
`Pain is a subjective experience that cannot be
`accounted for solely by consideration of distur(cid:173)
`bances in structure and function. The perception of
`pain involves interaction between pathophysiologic
`and psychosocial events. The primary pathophysio-
`
`Table 2. A representative list of variables underlying clinical
`features in inflammatory bowel disease
`Demographic factors: age, gender and age of onset
`Distribution, extent and severky of Inflammation
`Disease 'activity' as evidenced by pain, diarrhea, anorexia etc
`Anatomical complications such as abscesses. fistulas and
`obstruction, either mechanical or inflammatory, perianal disease
`Nutritional status and related factors
`Extraintestinal manifestations affecting the liver, joints, skin, eye etc
`Presence of associated diseases
`Iatrogenic factors, medical aoo surgical
`Psychological, family and social factors
`
`logic factor is the nature, intensity and extent of the
`stimulus that causes pain, but the perception of the
`painful stimulus is also dependent on the type and
`number of the receptor involved, on the organisation
`of the anatomical pathways transmitting the stimuli,
`and also on the compleK role of modifying influences
`on the transmission, interpretation and reaction to
`the painful stimuli. Psychosocial factors are of parti(cid:173)
`cular importance in chronic conditions such as mo
`and include the setting in which the pain occurs,
`personality factors, and family, ethnic and cultural
`background. All of these factors by influencing the
`stoicism of the patient affect the reaction to, and
`description of, pain and discomfort.
`The goal of management in patients complaining
`of pain is to identify and treat the underlying cause.
`This however is often not possible in patients with
`chronic IBD. Although a multi-disciplinary
`approach is necessary to help the patient cope with
`the physical and psychologic manifestations of
`chronic pain, the central role in long-term manage(cid:173)
`ment should be taken by a supportive, caring
`clinician with an unhurried approach. The propen(cid:173)
`sity to addictive behaviour in IBO patients with
`chronic pain should not be underestimated.
`In IBD, pain may arise from non-obstructed
`inflamed bowel, from bowel distension due to
`obstruction or from extension of the inflammatory
`process beyond the bowel wall, from perforation,
`fistula, or abscess. Temporal aspects, such as its
`frequency, tempo of onset, duration and its progress
`over time, often provide a guide to the pathological
`process causing the pain. Because of the greater
`extent of inflammation, its transmural distribution,
`the tendency for stricture formation and obstruction,
`
`

`

`Cornelius C. Cronin and Fergus Shanahan
`
`and involvement of extraintestinal tissues, abdom(cid:173)
`inal pain is more a feature of CD than UC. However,
`persistent or severe abdominal pain in patients with
`UC should alert the clinician to the possibility of the
`presence of complications such as fulminant colitis.
`Intermittent, recurrent or chronic pain is a feature
`of most patients with CD. As a general rule, the
`degree of pain runs parallel to disease activity,
`although there are important exceptions. Pain may
`result from fibrous strictures in the absence of active
`inflammation. Frequently, irritable bowel syndrome(cid:173)
`like symptoms of bloating, gaseous distension and
`sensation of incomplete evacuation after defecation
`are present. CD involving the upper gastrointestinal
`tract may cause odynophagia from esophageal
`involvement, or when the antrum and duodenum
`are involved, peptic ulcer disease-like symptoms.
`Typically, patients with CD of the iliocecal region
`have steady, mild-to-moderate discomfort in the
`right iliac fossa. A mass may be palpable. Peritoneal
`signs are absent. Often, there is superimposed
`colicky pain, referred to the umbilicus, due to
`obstruction, or in the absence of obstruction, from
`hyperalgesia. With bacterial overgrowth, bacterial
`metabolism of carbohydrate to hydrogen and carbon
`dioxide may cause abdominal pain from gaseous
`distension. When obstruction supervenes from either
`a stricture or from intra-luminal material impacting
`on a narrowed segment, the classical symptoms of
`post-prandial colicky cramps, often severe, with
`nausea and vomiting are found.
`With colonic inflammation in either CD or UC,
`there may be crampy pain in the iliac fossae. Often,
`the patient has the sensation that bowel opening
`might provide relief; a similar sensation may be
`present with small bowel inflammation but is gen(cid:173)
`erally less urgent. Inflammation of the distal colon
`tends to cause tenesmus and pain in the lower back.
`Fulminant, diffuse abdominal pain with signs of
`peritoneal inflammation is suggestive of toxic mega(cid:173)
`colon. Pain and discomfort from perianal CD is
`mediated by somatic nerves and is sharply localized.
`Perianal pain usually implies the presence of sepsis.
`The extrinsic innervation of the gastrointestinal
`tract is through the sympathetic and parasympa(cid:173)
`~hetic nerves [I 0, 11]. Although sensory information
`ts carried by both spinal afferent (sympathetic) and
`vagal (parasympathetic) fibers, pain is mediated
`primarily by spinal afferents. Free nerve ending
`mediate both physiological and nociceptive inputs.
`In health, afferent activity in the gastrointestinal
`tract seldom reaches the level of consciousness.
`
`255
`
`In contrast to skin receptors which are highly
`specialized and complex structures, visceral recep(cid:173)
`tors do not show any morphologic specialization and
`consist mainly of relatively simple free nerve endings.
`The abdominal viscera are relatively insensitive to
`stimuli, such as cutting, tearing and crushing that
`when applied to, for example, the skin would evoke
`severe pain. While stimuli from the skin may give
`raise to a variety of sensations, the only consciously
`perceived noxious sensation from the viscera is of
`pain or discomfort. While a range of appropriate and
`protective reflexes are available to respond to
`somatic pain, the repetoire of response to visceral
`pain is limited and generally ineffectual.
`Among the stimuli that may give raise to pain in
`the abdominal viscera are irritation or ulceration of
`the mucosa or serosa, gross visceral distension,
`torsion or traction of the mesentery, and forceful
`contractions, especially when the lumen is
`obstructed. Receptors are located within the
`mucosa, submucosa and walls of hollow organs, on
`the serosal peritoneum and capsules of the solid
`organs, and in the mesentery. Free nerve endings
`respond to both mechanical and chemical stimuli.
`The principal mechanical signal to which visceral
`nocioceptors respond is stretch. Tension receptors
`are in series with the smooth muscle of hollow
`organs. Pain results when intestinal smooth muscle
`undergoes a sufficient change in tension.
`Pain receptors may be activated by chemical
`mediators generated or released during intestinal
`injury and inflammation, tissue hypoxia or necrosis.
`Mucosal receptors respond primarily to chemical
`stimuli. After local tissue injury, the release of
`inflammatory and chemical mediators such as
`prostaglandins and bradykinin can directly activate
`nerve endings, and also trigger the release from
`afferent nerves and other cells of algesic mediators
`such as histamine, 5-HT, nerve growth factor (NGF)
`and prostanoids [12, 13). This assembly of chemicals
`sensitizes endings of afferent nerve terminals, result(cid:173)
`ing in an increased response to painful stimuli, and
`furthermore to a secondary sensitization of nearby
`nociceptors, in which neuromediators in the extra(cid:173)
`cellular space, such as substance P, histamine, 5-HT
`and cytokines play a role. Substance P released from
`nerve endings in intimate contact with mast cells
`causes degranulation and further histamine release,
`in turn amplifying release of substance P and NGF.
`In chronic inflammation, nerve remodelling occurs,
`increasing nerve sensitivity and lowering the pain
`
`

`

`256
`
`Understanding symptoms and signs in inflammatory bowel disease
`
`Table 3. Embryologic origin of Intestinal innervation
`
`Intestinal structures
`
`Distal esophagus, gastric, proximal duodenum
`
`Small intestine. cecum, ascending and proximal transverse colon
`
`Distal transverse. descending and rectosigmoid colon
`
`Adapted from ref. 1 0.
`
`threshold. Pain may be mediated in part by smooth
`muscle contraction induced by these mediators.
`Somatic structures are densely innervated, and
`somatic pain is distinct and precisely localized. In
`contrast, visceral pain is ill-defined and poorly
`localized. The greater part of the extensive enteric
`nervous system is involved in local physiological
`control of secretion, absorption and motility, and
`does not have a role in the mediation of pain
`perception. There is no separate visceral sensory
`pathway. Furthermore, there is a relative paucity of
`visceral afferent nerves that project to the central
`nervous system. Also, splanchnic nerves from a
`single tissue or organ enter the spinal cord through
`several levels, further diluting the accuracy of locali(cid:173)
`sation. Most abdominal structures are embryo(cid:173)
`logically midline, and receive bilateral and symme(cid:173)
`trical innervation. Visceral pain generally localizes to
`the midline. Clearly lateralized pain arising from the
`abdominal viscera is usually from those few
`structures whose innervation is predominantly one(cid:173)
`sided; or from structures with somatic rather than
`visceral innervation. The parietal peritoneum is
`innervated by somatic nerves, and when involved in
`the inflammatory process, pain is more precisely
`localized. In addition, between individuals, there is
`considerable variability of innervation, and therefore
`the same stimulus may be differently localized.
`The tendency to perceive visceral abdominal pain
`at a different location from its origin further impairs
`accurate localisation of visceral pain. In this
`phenomenon of referred pain, pain is perceived in
`the skin dermatomes whose afferent nerve roots
`enter the same levels of the spinal cord as the
`involved abdominal structure. There are no separate
`pathways within the spinal cord for visceral and
`somatic pain. Because somatic afferents are more
`numerous, the brain tends to associate activation of
`the second order neurones with a somatic source,
`irrespective of its origin.
`
`Embryologic origin
`
`Spinal segments
`
`Foregut
`
`Midgut
`
`Hindgut
`
`T5-6 toTB-9
`
`TS-11 to L1
`
`T11 to L1
`
`Pain location
`
`Epigastric
`
`Periumbilical
`
`Suprapubic
`
`The embryologic origin of abdominal tissues and
`organs provides a general guide to the localization of
`gastrointestinal pain [I 0] (Table 3). Pain arising from
`foregut structures is generally perceived in the epi(cid:173)
`gastrium, from midgut structures in the periumbili(cid:173)
`cal region, and from the hindgut, suprapubically.
`
`Malnutrition
`Malnutrition is common in patients with IBD (Table
`4) (14, IS]. Nutritional deficiencies are related to the
`extent and the activity of disease. Because of small
`bowel involvement, malnutrition tends to be more
`common in patients with CD. Many of the studies
`assessing malnutrition have been in hospitalized
`patients or in those attending specialized clinics,
`which may tend to overstate its frequency and
`severity_ In addition, with improved medical and
`surgical treatment and with the appropriate empha(cid:173)
`sis on ensuring adequate nutrition in patients with
`IBD, the prevalence of serious malnutrition may
`have declined in recent years. Nonetheless, malnutri(cid:173)
`tion remains a major problem in those with IBD,
`particularly in pediatric patients, and is a major
`contributer to poor quality of life, morbidity and
`mortality.
`Malnutrition in patients with IBD is multifactorial
`(Table S). Several mechanisms may be involved in
`any one patit:nt, chief among which huwt:vt:r in must
`patients is curtailment of caloric intake due to any
`combination of anorexia, nausea, post-prandial
`abdominal pain and vomiting, and dietary restric(cid:173)
`tions [16]. The importance of poor caloric intake as a
`cause of weight loss is best illustrated by the some(cid:173)
`times dramatic effect supplemental enteral feeding
`has on reduced weight in children with IBD [17- 19].
`Maldigestion and malabsorption of ingested nutri(cid:173)
`ents is likely to be a factor only in those with extensive
`and chronically active CD or in those who have had
`major small bowel excisional surgery.
`
`

`

`Cornelius C. Cronin and Fergus Shanahan
`
`257
`
`Percentage
`
`Table 4. Incidence of malnutrition In patients with Grahn's
`disease
`Feature
`Weight loss
`Growth failure in children
`Muscle wasting
`Fat depletion
`Hypoalbuminemia
`Iron deficiency
`812 deficiency
`Folate defiCiency
`Hypokalemia
`Hyponatremia
`Hypomagnesemia
`Zinc deficiency
`Fat soluble vitamins:
`0
`K
`A
`Clinical osteomalacia
`
`4G-80
`15-88
`59
`15-30
`25-76
`25-50
`21}..37
`13-37
`33
`10
`14--66
`40
`
`75
`31}..50
`21
`36
`
`Adapted from ref. 15.
`
`Inadequate caloric Intake
`Postprandial symptoms may occasionally be a disin(cid:173)
`centive to the maintenance of adequate nutritional
`intake in patients with IBD, particularly the fear of
`diarrhea or, in patients with stricturing disease, of
`colicky abdominal pain. Many of the drugs used in
`the treatment ofiBD may themselves cause nausea
`or anorexia. The use of any nutritionally restrictive
`dietary therapy is now outmoded. However, the
`major cause of poor caloric intake is inflammation(cid:173)
`related anorexia and loss of appetite. Weight loss
`often predates the clinical onset of CD and in
`children, decreased growth velocity precedes diag(cid:173)
`nosis [20]. Not infrequently, anorexia and weight loss
`is the predominant initial feature in IBD. Anorexia,
`particularly in young patients, may occasionally be
`wrongly attributed to anorexia nervosa. Rapid
`weight loss is a feature of intra-abdominal sepsis,
`which may be occult or, less comonly, of intra(cid:173)
`abdominal neoplasia.
`
`Physiology of appetite and hunger
`Anorexia is the diminution or absence of hunger and
`appetite. Hunger and appetite both refer to the desire
`to eat, but whereas the determinants of hunger are
`related to physiological mechanisms present at a
`given time, appetite is in addition influenced by
`ongoing pathophysiological, psychological and
`
`Table II. Causes of malnutrition in patients wlth Crohn's
`disease
`Inadequate Intake
`
`Nausea
`Anorexia
`Fear of pain after food
`Fear of diarrhea after food
`Restrictive diets
`
`Malabsorption
`
`Loss of absorptive mucosa (disease/
`surgery)
`Stagnant loops/bacteria. overgrowth
`Bile salt deficiency after Ileal resection
`Rapid Gl transit - mucosal disease/
`fistulas
`Lymphangiectasia
`
`Increased requirements/
`decreased synthesis
`
`Active inflammation
`Increased cell turnover
`Sepsis
`
`Enteric loss of nutrients
`
`Protein-losing enteropathy
`Interrupted enterohepa!ic circulation
`Gastrointestinal blood loss
`Electrolyte, mineral loss In diarrhea
`
`Drugs
`
`Sutfasalazine
`Corticosteroids
`Cholestyramlne
`lnvnunosuppressives
`
`environmental processes. Satiety is the gratification
`of hunger and appetite.
`The drive to eat is basic and essential to survival.
`Its control is complex, multifactorial and ill-under(cid:173)
`stood. The generally accepted working model
`proposes that eating is regulated by a central feeding
`drive that is held in check during feeding by a
`peripheral satiety system. Various gastrointestinal,
`endocrine/ metabolic and neurological stimuli are
`perceived by peripheral and central receptors and,
`centrally integrated, ultimately produce the sensa(cid:173)
`tions of hunger and satiety, and determine eating
`behaviour. The hypothalamus plays a key role in
`interpreting and integrating these signals [21]. From
`animal experiments, the lateral nucleus of the
`hypothalamus has been proposed as a center for
`hunger, and the ventromedial nucleus a center for
`satiety. Whether such concepts of anatomical centers
`are applicable to humans is unclear; appetite regula(cid:173)
`tion may be more appropriately viewed as the
`hypothalmic integration of neurotransmitter(cid:173)
`mediated neuropharmacologic systems with oppos(cid:173)
`ing effects on hunger/appetite and on satiety.
`
`

`

`258
`
`Understanding symptoms and signs in inflammatory bowel disease
`
`Many peptides and neurotransmitters acting cen(cid:173)
`trally and peripherally have been proposed as candi(cid:173)
`dates for control of food intake (Table 6) [22- 24].
`Dopaminergic tracts appear to be vital in initiating
`feeding, and norepinephric systems and neuropep(cid:173)
`tide Y (NPY) and peptide YY also promote feeding.
`NPY, a 36 amino acid peptide is the most potent
`orexigenic peptide in the hypothalamus, and appears
`to be of fundamental importance in the regulation of
`energy homeostasis [25). Most anorectic peptides
`exert their effects through interruption of NPY
`release or action. Among the satiety factors acting
`on the hypothalamus, serotonin (5-hydroxytrypta(cid:173)
`mine [5-HT)) plays a central role [26]. Most of the
`clinically available drugs affecting appetite act on
`serotonin [27]. Injection of serotonin into specific
`areas of the hypothalamus inhibits feeding in a
`variety of species. Plasma free tryptophan is the
`precursor of serotonin, and tryptophan availability
`parallels synthesis and release of brain serotonin.
`Carbohydrate ingestion increases circulating trypto(cid:173)
`phan, mediated in part by insulin. The consequent
`increased post-prandial brain serotonin levels is a
`proposed mechanism by which the macronutrient
`content of a meal is sensed by the brain, promoting
`satiety. Other proposed appetite-inhibiting neuro(cid:173)
`peptides are cholecystokinin, corticotrophin-releas(cid:173)
`ing peptide (CRP), calcitonin gene-related peptide
`and neurotensin.
`Several peripheral factors influence appetite, hun(cid:173)
`ger and satiety [22], including the composition of
`food and not least taste and smell (palatability).
`Gastric distension is an obvious and important
`satiety signal, mediated by neural (vagal) and
`humoral (bombesin) signals, and explains why bulky
`meals give rise to greater satiety than meals of refined
`carbohydrates of equal caloric value. Intestinal
`cholecystokinin (CCK) by sensing intestinal nutrient
`concentration and the volume and rate of luminal
`emptying may be an important peripheral regulator
`of satiety [24]; CCK causes pyloric contraction with
`resultant gastric distension and binds to the gastric
`afferent vagus which ultimately courses to the ven(cid:173)
`tromedial hypothalamus. Peripherally released CCK
`may also exert a central satiety effect. Meal size is
`reduced by exogenously administered CCK at
`physiological concentrations, and is increased by
`specific CCK antagonists, implying that meal size
`may be physiologically limited by these factors (28,
`29]. Ingestion of food presents a large antigen load to
`the intestine. The substantial amounts of cytokines
`
`that are produced in response may also play a role in
`the control of feeding.
`Although these complex neuroendocrine signals
`may provide a basis for an understanding of how
`feeding is initiated and terminated, they do not
`explain how most individuals maintain a stable body
`weight over long periods of time. The lipostat model
`hypthesized that signals proportional to the size of
`body fat stores become integrated with other regula(cid:173)
`tors of food intake [30]. How the size of body fat
`stores might influence appetite and hunger has been
`at least in part recently elucidated. Leptin, the
`protein product of the obese (ob) gene, is secreted
`into the circulation by adipose cells [31]. A rising
`circulating leptin (from the Greek leptos, meaning
`thin) concentration with increasing adiposity is pro(cid:173)
`posed to serve