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`PAO 003854
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`HARRISONS LPLHL
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`BRAUNWALD
`FAUCI
`KASPER
`HAUSER
`LONGO
`JAMESON
`
`Page 1 of9
`
`Sandoz V. Abeie
`
`IPR2017-01987
`
`Abeie Exhibit 2003
`
`

`

`McGraw-Hill
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`Harrison's
`PRINCIPLES OF INTERNAL MEDICINE
`Fifteenth Edition
`
`Copyright C 2001, 1998, 1994, 1991, 1987, 1983, 1980, 1977, 1974, 1970, 1966,
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`1234567890 DOWDOW 0987654321
`ISBN 0-07-007272-8 (Combo)
`0-07-007273-6 (Vol. I)
`0-07-007274-4 (Vol. 2)
`0-07-913686-9 (Set)
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`FOREIGN LANGUAGE EDITIONS
`Arabic (Thirteenth Edition)-McGraw-Hill Libri Italia sri (est. 1996)
`Chinese (Twelfth Edition)- McGraw-Hill Book Company-Singapore Cl 1994
`Croatian (Thirteenth Edition)-Placebo, Split, Croatia
`French (Fourteenth Edition)-McGraw-Hill Publishing Co., Maidenhead, UK 10 1999
`German (Fourteenth Edition)- McGraw-Hill Publishing Co., Maidenhead, UK 10 1999
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`Italian (Fourteenth Edition)- McGraw-Hill Libri ltalia sri, Milan C 1999
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`Spanish (Fourteenth Edition)-McGraw-Hill Interamericana de Espana, Madrid @ 1998
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`This book was set in Times Roman by Progressive Information Technologies. The
`editors were Martin Wonsiewicz. and Mariapaz. Ramos Englis. The production director
`was Robert Laffter. The index was prepared by Irving C. Tullar. The text and cover
`designer was Marsha Cohen/Parallelogram Graphics.
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`R. R. Donnelley and Sons, Inc. was the printer and binder.
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`Library of Congress Cataloging-in-Publication Data
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`Harrison's principles of internal medicine- 15th ed./editors, Eugene Braunwald ... [et al.).
`Includes bibliographical references and index.
`ISBN 0-07-913686-9 (set)-ISBN 0-07-007273-6 (v. I)-ISBN 0-07-0072744-4 (v. 2)
`I. Internal medicine. I. Braunwald, Eugene, date
`RC46.H333 2001
`616- dc21
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`p. em.
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`00-063809
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`

`

`Table 286-10 Pathophysiology of Clinical Manifestations
`or Malabsorption Disorders
`SJIDPiom or Sign
`
`Mechanism
`
`287 Inflammatory Bowel Disease
`
`Table 287-l Epidemiology of IBD
`
`1679
`
`Weight Joss/malnutrition
`Dianbea
`
`Aarus
`
`Glossitis, cheilosis, sto·
`m&Jitis
`Abdominal pain
`Bone pain
`
`Tetany. paresthesia
`Weakness
`Nocturia
`Azotemia, hypotension
`Amenorrhea, decreased
`libido
`Anemia
`
`Bleeding
`
`Night blindness/xeroph·
`thalmia
`Peripheral neuropathy
`Dermatitis
`
`Anorexia, malabsorption of nutrients
`Impaired absorption or secretion of water and
`electrolytes; unabsorbed dihydroxy bile acids
`and fany acids
`Bacterial fermentation of unabsorbed carbohy·
`drate
`Deficiency of iron, vitamin B12, folate, and vi·
`taminA
`Bowel distention or inflammation, pancreatitis
`Calcium, vitamin D malabsorption, protein de·
`ficiency, osteoporosis
`Calcium and magnesium malabsorption
`Anemia, electrolyte depletion (particularly K•)
`Delayed absorption of water, hypokalemia
`Fluid and electrolyte depletion
`Protein depletion, decreased calories, second·
`ary hypopituitarism
`Impaired absorption of iron, folate,
`vitamin 8 12
`Vitamin K malabsorption, hypoprolhrombin·
`emia
`Vitamin A malabsorption
`
`Vitamin B 12 and thiamine deficiency
`Deficiency of vitam.in A, zinc, and essential
`fatty acid
`
`I fat diet and the administration of MCfs (Table 286-3), which do not
`
`exit from the intestinal epithelial cells via lymphatics but are delivered
`lo the body via the ponal vein.
`
`SUMMARY
`A pathophysiologic classification of the many conditions that can pro·
`duce malabsorption is given in Table 286-9. A summary of the path(cid:173)
`ophysiology of the various clinical manifestations of malabsorption is
`given in Table 286-10.
`
`BmLIOGRAPHY
`AMIDuCA!< 0A5TIIOENr'EROLOGICAL ASSOCIATION: Technical review on the evaluation
`and management of chrome diarrhea. Gastroenterology 116:1464. 1999
`COOK Sl, SI!Ll.lN JH: Short chain fatty acids in health and disease. Aliment Phannacol
`Ther 12:499, 1998
`Clwo RM, I!H!u!NPREJS ED: o-Xylose testing. J Clin Gastroentero129:143, 1999
`<lREBNIII!llGI!ll NJ: Enzymatic therapy in patients with chronic pancreatitis. Gastroentero1
`Ctin North Am 28:687, 1999
`IIAAEwooo GC, MURRAy JA: Approaching the patient with chronic malabsorption syn(cid:173)
`drome. Semin Gastrointest Dis 14:138, 1999
`IIAMAwt C, BOYNT'ON RF: Whipple's disease. G85troenterol Clin North Am 27:683, 1998
`SHAw AD. DAVIES OJ: Lactose intolerance: Problems in diagnosis and tn:81ment.J Clin
`Ou<roenterol 28:208, 1999
`'i'lu!!R lS: Diagnosis of celiac sprue. Gastroenterology 115:211, 1998
`
`Sonia Friedman, RichardS. Blumberg
`
`INFLAMMATORY BOWEL
`DISEASE
`
`~ammatory bowel disease (IBD) is an idiopathic and chronic intes(cid:173)
`tinlll inflammation. Ulcerative colitis (UC) and Crohn's disease (CD)
`~the two major types of IBD.
`
`EPIDEMIOLOGY
`~e incidence of IBD varies within different geographic areas.
`onhem countries, such as the United States, United Kingdom, Nor-
`
`Incidence (U.S.)
`Age of onset
`Ethnicity
`
`Male:female ratio
`Smoking
`Oral contraceptives
`Appendectomy
`Monozygotic twins
`Dizygotic twins
`
`Ulcerati•e Colitis
`
`Crohn's Disease
`
`7/ 100,000
`11/100,000
`15- 30 & 60-80
`15- 30 & 60- 80
`Jewish > Non-Jewish Caucasian > African
`American > Hispanic > Asian
`1:1
`1.1 - 1.8:1
`May prevent disease
`May cause disease
`No increased risk
`Relative risk 1.9
`Protective
`Not protective
`8% concordance
`67% concordance
`0% concordance
`20% concordance
`
`way, and Sweden, have the highest rates. The incidence rates of UC
`and CD in the United States are about 11 per 100,000 and 7 per
`100,000, respectively (Table 287-1 ). Countries in southern Europe,
`South Africa, and Australia have lower incidence rates: 2 to 6.3 per
`100,000 for UC, and 0.9 to 3.1 per 100,000 for CD. In Asia and South
`America, IBD is rare; incidence rates of UC and CD are 0.5 and 0.08
`per 100,000, respectively. The highest monality in IBD patients is
`during the first years of disease and in long duration disease due to
`the risk of colon cancer. In a Swedish population study, the standard(cid:173)
`ized monality ratios for CD and UC were 1.51 and 1.37, respectively.
`The peak age of onset of UC and CD is between 15 and 30 years.
`A second peak occurs between the ages of 60 and 80. The male to
`female ratio for UC is 1:1 and for CD is 1.1 to 1.8:1. A two- to fourfold
`increased frequency of UC and CD in Jewish populations has been
`described in the United States, Europe, and South Africa. Funhermore,
`disease frequency differs within the Jewish populations. The preva(cid:173)
`lence of IBD in Ashkenazi Jews is about twice that of Israeli-born,
`Sephardic, or Oriental Jews. The prevalence decreases progressively
`in non-Jewish Caucasian, African-American, Hispanic, and Asian pop(cid:173)
`ulations. Urban areas have a higher prevalence of IBD than rural areas
`and high socioeconomic classes have a higher prevalence than lower
`socioeconomic classes.
`The effects of cigarette smoking are different in UC and CD. The
`risk of UC in smokers is 40% that of nonsmokers. Additionally, former
`smokers have a 1.7-fold increased risk for UC than people who have
`never smoked. In contrast, smoking is associated with a twofold in(cid:173)
`creased risk of CD. Oral contraceptives are also linked to CD; the
`relative risk of CD for oral contraceptive users is about 1.9. Appen(cid:173)
`dectomy appears to be protective against UC but funher studies are
`needed.
`IBD runs in families. If a patient has IBD, the lifetime risk that a
`first-degree relative will be affected is -10%. If two parents have IBD,
`each child has a 36% chance of being affected. In twin studies, 67%
`of monozygotic twins are concordant for CD and 20% are concordant
`for UC, whereas 8% of dizygotic twins are concordant for CD and
`none are concordant for UC. There is also concordance for anatomic
`site and clinical type of CD within families.
`Additional evidence for genetic predisposition to IBD comes from
`its association with cenain genetic syndromes. UC and CD are both
`associated with Turner's syndrome, and Hermansky-Pudlak syndrome
`is associated with a granulomatous colitis. Glycogen storage disease
`type lb can present with Crohn's-like lesions of the large and small
`bowel. Other immunodeficiency disorders, such as hypogammaglob(cid:173)
`ulinemia, selective lgA deficiency, and hereditary angioedema, also
`exhibit an increased association with IBD.
`
`ETIOLOGY AND PATHOGENESIS
`Although lBO has been described as a clinical entity for over 100
`years, its etiology and pathogenesis have not been definitively elabo(cid:173)
`rated. Various studies have led to a consensus hypothesis that in ge(cid:173)
`netically predisposed individuals, both exogenous factors (e.g., infec-
`
`

`

`1680
`
`XI Disorders or the Gastrointestinal System
`
`tious agents, normal lumenal flora) and host factors (e.g., intestinal
`epithelial cell barrier function, vascular supply, neuronal activity) to(cid:173)
`gether cause a chronic state of dysregulated mucosal immune function
`that is further modified by specific environmental factors (e.g., smok(cid:173)
`ing). Although it is possible that the chronic activation of the mucosal
`immune system may represent an appropriate response to a chronic
`unidentified infectious agent, a search for such an agent has thus far
`been unrewarding. As such, IBD must currently be considered an in(cid:173)
`appropriate response to either the endogenous microbial flora within
`the intestine, with or without some component of autoimmunity. Im(cid:173)
`portantly, the normal intestine contains a significant concentration of
`immune cells in a chronic state of so-called physiologic inflammation,
`in which the gut is poised for, but actively restrained from, full im(cid:173)
`munologic responses. During the course of infections in the normal
`host, full activation of the gut-associated lymphoid tissue occurs but
`is rapidly superceded by downregulation of the immune response and
`tissue repair. In IBD this process is not regulated nonnally.
`
`illD is a polygenic disorder
`~ GENETIC CONSIDERATIONS
`(2 that gives rise to multiple clinical subgroups within UC and CD.
`Genome-wide searches have shown that potential disease-associated
`loci are present on chromosomes 16, 12, 7, 3, and I, although the
`specific gene associations are undefined. HLA alleles may play a role.
`UC patients disproportionately express DR2-related alleles, whereas
`in CD an increased use of the DR5 DQ I haplotype or the DRB*030 I
`allele has been described. In UC patients with pancolitis undergoing
`total proctocolectomy, 14.3% versus 3.2% of non-IBD controls ex(cid:173)
`press the HLA DRB1*0103 allele. This allele is associated with ex(cid:173)
`tensive disease and extraintestinal manifestations such as mouth ul(cid:173)
`cers, arthritis, and uveitis. Other associations with immunoregulatory
`genes include the intercellular adhesion molecule R241 allele in UC
`and CD and the interleuk.in (IL) 1 receptor antagonist allele 2 in UC
`patients that is associated with total colonic inflammation. Although
`not proven at the genetic level, patients with lBO and their first-degree
`relatives may exhibit diminished intestinal epithelial cell barrier func(cid:173)
`tion.
`•
`DEFECTIVE IMMUNE REGULATION IN mo The nor(cid:173)
`mal state of the mucosal immune system is one of inhibited immune
`responses to lumenal contents due to oral tolerance that occurs in the
`normal individual. When soluble antigens are administered orally
`rather than subcutaneously or intramuscularly, antigen-specific non(cid:173)
`responsiveness is induced. Multiple mechanisms are involved in the
`induction of oral tolerance and include deletion or anergy of antigen(cid:173)
`reactive T cells or activation of CD4+ T cells that suppress gut in(cid:173)
`flammation through secretion of inhibitory cytok.ines (IL-10, TGF-,8).
`Oral tolerance may be responsible for the lack of immune responsive(cid:173)
`ness to dietary antigens and the com£ensa1 flora in the intestinal lu(cid:173)
`men. In IBD this tightly regulated state of suppression of inflammation
`is altered, leading to uncontrolled inflammation. The mechanisms that
`maintain this regulated state of immune suppression are unknown.
`Gene knockout ( -1-) or transgenic (Tg) mouse models of colitis
`have revealed that deleting specific cytok.ines (e.g., IL-2, IL-10, TGF(cid:173)
`,8) or their receptors, deleting molecules associated with T-cell antigen
`recognition (e.g., T-cell antigen receptors, MHC class II), or interfer(cid:173)
`ing with intestinal epithelial cell barrier function (e.g., blocking N(cid:173)
`cadherin, deleting multidrug resistance gene Ia or trefoil factor) leads
`to colitis. Thus, a variety of specific alterations can lead to unregulated
`autoimmunity directed at the colon in mice.
`In both UC and CD, activated CD4+ T cells present in the lamina
`propria and peripheral blood secrete inflammatory cytok.ines. Some
`directly activate other inflammatory cells (macrophages and B cells)
`and others act indirectly to recruit other lymphocytes, inflammatory
`leukocytes, and mononuclear cells from the peripheral vasculature into
`the gut through interactions between homing receptors on leukocytes
`(e.g., a4,87 integrin) and addressins on vascular endothelium (e.g.,
`MadCAM1). CD4+ T cells can be subdivided into two major care-
`
`gories both of which may be associated with colitis in animal models
`and humans: THl cells (IFN-y, TNF) and TH2 cells (IIA, IL-5, IL-
`13). TH1 cells appear to induce transmural granulomatous inflamma(cid:173)
`tion that resembles CD, and T H2 cells appear to induce superficial
`mucosal inflammation more characteristic of UC. The THl cytok.ine
`pathway is initiated by IL-12, a key cytokine in the pathogenesis of
`experimental models of mucosal inflammation. Thus, use of antibodies
`to block proinflammatory cytokines (e.g., anti-TNF-a, anti-IL-12) or
`molecules associated with leukocyte recruitment (e.g., anti-a4,87) or
`use. of cytokines that inhibit inflammation (e.g., IL-10) or promote
`intestinal barrier function (e.g., IL-11) may be beneficial to humans
`with colitis.
`THE INFLAMMATORY CASCADE IN lBD Once initi(cid:173)
`ated in IBD, the immune inflammatory response is perpetuated as a
`consequence ofT-cell activation. A sequential cascade of inflamma(cid:173)
`tory mediators acts to extend the response; each step is a potential
`target for therapy. Inflammatory cytokines, such as IL-l, IL-6, and
`tumor necrosis factor (TNF) have diverse effects on tissue. They pro(cid:173)
`mote fibrogenesis, collagen production, activation of tissue metallo(cid:173)
`proteinases, and the production of other inflammatory mediators; they
`also activate the coagulation cascade in local blood vessels (e.g., in(cid:173)
`creased production of von Willebrand's factor). These cytokines are
`normally produced in response to infection, but are usually turned off
`or inhibited at the appropriate time to limit tissue damage. In mo their
`activity is not regulated, resulting in an imbalance between the proin(cid:173)
`flammatory and anti-inflammatory mediators. Therapies such as the 5-
`ASA compounds are potent inhibitors of these inflammatory mediators
`through inhibition of transcription factors such as NF-KB that regulate
`their expression.
`EXOGENOUS FACTORS TBD may have an as yet undefined
`infectious etiology. Three specific agents have received the greatest
`attention, Mycobacterium paratuberculosis, Paramyxovirus, and Hel(cid:173)
`icobacter species. The immune response to a specific organism could
`be expressed differently, depending upon the individual's genetic
`background. Although M. paratuberculosis had initially been identi(cid:173)
`fied in CD patients, further studies have not confirmed a disease as(cid:173)
`sociation. In addition, antimycobacterial agents have not been effective
`in treating CD. A role for the measles virus or paramyxoviruses in the
`development of CD has been suggested based on an increase in the
`incidence of CD in England that paralleled use of the measles vaccine.
`However, studies in the United States have not substantiated this find(cid:173)
`ing. In an animal model of ffiD, Helicobacter hepaticus has been
`implicated as a trigger for the inflammatory response; evidence in peo(cid:173)
`ple is Jacking.
`Multiple pathogens (e.g., Salmonella, Shigella sp., Campylobacter
`sp.) may initiate IDD by triggering an inflammatory response that the
`mucosal immune system may fail to control. However, in an ffiD
`patient the normal flora is likely perceived as if it were a pathogen.
`Anaerobic organisms, particularly Bacteroides species, may be re(cid:173)
`sponsible for the induction of inflammation. Such a notion is supported
`by the response in patients with CD to agents that alter the intestinal
`flora, such as metronidazole, ciprofloxacin, and elemental diets. CD
`also responds to fecal diversion, demonstrating the ability of lumenal
`contents to exacerbate disease. On the other hand, other bacterial or(cid:173)
`ganisms, so-called probiotics such as Lactobacillus sp., downregulate
`inflammation in animal models and humans.
`Psychosocial factors can contribute to clinical exacerbation of
`symptoms. Major life events such as illness or death in the family,
`divorce or separation, interpersonal conflict, or other major loss, are
`associated with an increase in IBD symptoms such as pain, bowel
`dysfunction, and bleeding. Acute daily stress can exacerbate bowel
`symptoms even after controlling for major life events. When the sick(cid:173)
`ness impact profile, a measurement of overall psychological and phys·
`ical functioning is used, mo patients have functional impainnent
`greater than that of a health maintenance organization population but
`less than that of patients with chronic back pain or amyotrophic lateral
`sclerosis. IBD patients have been hypothesized to have a characteristic
`personality that renders them susceptible to emotional stresses. How-
`
`

`

`PATHOLOGY
`ULCERATIVE COLITIS: MACROSCOPIC FEATURES
`UC is a mucosal disease that usually involves the rectum and extends
`proximally to involve all or part of the colon. Approximately 40 to
`50% of patients have disease limited to the rectum and rectosigmoid,
`30 to 40% have disease extending beyond the sigmoid but not involv(cid:173)
`ing !he whole colon, and 20% have a total colitis. Proximal spread
`occurs in continuity without areas of uninvolved mucosa. When the
`whole colon is involved, !he inflammation extends I to 2 em into the
`terminal ileum in 10 to 20% of patients. This is called backwash ileitis
`and has little clinical significance. Although variations in macroscopic
`activity may suggest skip areas, biopsies from normal-appearing mu(cid:173)
`cosa are usually abnormal. Thus, it is important to obtain multiple
`biopsies from apparently uninvolved mucosa, whether proximal or dis(cid:173)
`tal, during endoscopy.
`With mild inflammation, the mucosa is erythematous and has a
`fine granular surface that looks like sandpaper. In more severe disease,
`!he mucosa is hemorrhagic, edematous, and ulcerated (Fig. 287-1). In
`long-standing disease, inflammatory polyps (pseudopolyps) may be
`present as a result of epithelial regeneration. The mucosa may appear
`normal in remission but in patients with many years of disease it ap(cid:173)
`pears atrophic and featureless and the entire colon becomes narrowed
`and foreshortened. Patients with fulminant disease can develop a toxic
`colitis or a toxic megacolon where the bowel wall becomes very thin
`and the mucosa is severely ulcerated, which may lead to perforation.
`ULCERATIVE COLITIS: MICROSCOPIC FEATURES
`Histologic findings correlate well with the endoscopic appearance and
`clinical course of UC. The process is limited to the mucosa and su(cid:173)
`perficial submucosa with deeper layers unaffected except in fulminant
`disease. In UC, two major histologic features are indicative of chro(cid:173)
`nicity and help distinguish it from infectious or acute self-limited co(cid:173)
`litis. First, the crypt architecture of the colon is distorted; crypts may
`be bifid and reduced in number, often with a gap between the crypt
`bases and !he muscularis mucosae. Second, some patients have basal
`plasma cells and multiple basal lymphoid aggregates. Mucosal vas(cid:173)
`oular congestion with edema and focal hemorrhage, and an inflam(cid:173)
`matory cell infiltrate of neutrophils, lymphocytes, plasma cells, and
`macrophages may be present. The neutrophils invade the epithelium,
`usually in the crypts, and give rise to cryptitis and, ultimately, to crypt
`abscesses (Fig. 287-2). The cryptitis is associated with mucus dis(cid:173)
`charge from goblet cells and increased epithelial cell turnover. His-
`
`FIGURE 287-2 Characteristic findings of ffiD in a case of ulcerative colitis:
`crypt distonion. cryptitis, and crypt abscess. (Courtesy of Dr. EK Rosado and
`Dr. CA Perkos. Division of Gastroilll~stinal Pathology. Deparrmmt of Pa·
`thology. Emory University, At/all/a, Georgia.)
`
`tologically, this results in goblet cell depletion. Other chronic changes
`that are sometimes seen are neuronal hypertrophy and fibromuscular
`hyperplasia of the muscularis mucosae.
`CROHN'S DISEASE: MACROSCOPIC FEATURES CD
`can affect any part of the gastrointestinal tract from the mouth to the
`anus. Some 30 to 40% of patients have small bowel disease alone, 40
`to 55% have disease involving both the small and large intestines, and
`15 to 25% have colitis alone. In the 75% of patients with small intes(cid:173)
`tinal disease, the terminal ileum is involved in 90%. Unlike UC, which
`almost always involves the rectum, the rectum is often spared in CD.
`CD is segmental, with skip areas in the midst of diseased intestine
`(Fig. 287-3). Perirectal fistulas, fissures, abscesses, and anal stenosis
`are present in one-third of patients with CD, particularly those with
`colonic involvemem. CD may also involve the liver and the pancreas.
`Unlike UC, CD is a transmural process. Endoscopically, aphthous
`or small superficial ulcerations characterize mild disease; in more ac-
`
`PIGUJtE 287-1 Pan-ulcerative colitis. Mucosa has a lumpy. b~thpy appear(cid:173)
`lllce because of areas of inflamed but intact mucosa separated by ulcerated
`~·(Courtesy of Dr. EK Rosado and Dr. CA Perkos. Division of Gasrroin(cid:173)
`eumo/ Pathology. Department ofPatlrology. Emory University. Atlanta, Geor(cid:173)
`lla.J
`
`FIGURE 287-3 Portion of colon with stricture in patient with CD. (Courtesy
`of Dr. EK Rpsado and Dr. CA Perkos. Division ofGastroinrestinol Patlrology.
`Departmelll of Pathology, Emory University, Atlama, Georgia.)
`
`

`

`1682
`
`XI Disorders of the Gastrointestinal Systom
`
`FIGURE 287-4 Granulomas (arrow) in bowel wall and serosa of colon, CD.
`(Courtesy of Dr. EK Rosado and Dr. CA Perkos, Division of Gastrointestinal
`Pathology, Department of Pathology, Emory University, Atlanta, Georgia.)
`
`live disease, stellate ulcerations fuse longitudinally and transversely
`to demarcate islands of mucosa that frequently are histologically nor(cid:173)
`mal. This "cobblestone" appearance is characteristic of CD, both en(cid:173)
`doscopically and by barium radiography. As in UC, pseudopolyps can
`form in CD.
`Active CD is characterized by focal inflammation and fonnation
`of fistula tracts, which resolve by fibrosis and st.ricturing of the bowel.
`The bowel wall thickens and becomes narrowed and fibrotic, leading
`to chronic, recurrent bowel obstructions. Projections of thickened mes(cid:173)
`entery encase the bowel ("creeping fat") and serosal and mesenteric
`inflammation promote adhesions and fistula fonnation.
`CROHN'S DISEASE: MICROSCOPIC FEATURES The
`earliest lesions are aphthoid ulcerations and focal crypt abscesses with
`loose aggregations of macrophages, which fonn noncaseating granu(cid:173)
`lomas in all layers of the bowel wall from mucosa to serosa
`(Fig. 287-4). Granulomas can be seen in lymph nodes, mesentery,
`peritoneum, liver, and pancreas. Although granulomas are a pathog(cid:173)
`nomonic feature of CD, only half of cases reveal granulomas on sur(cid:173)
`gical or endoscopic biopsy specimens. Other histologic features of CD
`include submucosal or subserosa) lymphoid aggregates, particularly
`away from areas of ulceration, gross and microscopic skip areas, and
`transmural inflammation that is accompanied by fissures that penetrate
`deeply into the bowel wall and sometimes fonn fistulous tracts or local
`abscesses.
`
`CLINICAL PRESENTATION
`ULCERATIVE COLITIS Signs and Symptoms The major
`symptoms of UC are diarrhea, rectal bleeding, terlesmus, passage of
`mucus, and crampy abdominal pain. The severity of symptoms cor-
`
`Table 287-2 Ulcerative Colitis: Disease Presentation
`
`Mild
`
`Moderate
`
`Bowel movements
`Blood in stool
`Fever
`Tachycardia
`Anemia
`Sedimentation rate
`Endoscopic appear-
`ance
`
`< 4 per day
`Small
`None
`None
`Mild
`< 30mm
`Erythema, decreased
`vascular panem, fine
`granularity
`
`4 - 6 per day
`Moderate
`< 37.S0Cmean
`< 90 mean pulse
`> 75%
`
`Marked erythema,
`coarse granularity,
`absent vascular
`markings, contact
`bleeding. no ulcera-
`tions
`
`relates with the extent of disease. Although UC can present acutely,
`symptoms usually have been present for weeks to months. Occasion(cid:173)
`ally, diarrhea and bleeding are so intennittent and mild that the patient
`does not seek medical attention.
`Patients with proctitis usually pass fresh blood or blood-stained
`mucus, either mixed with stool or streaked onto the surface of a nonnal
`or hard stool. They also have tenesmus, or urgency with a feeling of
`incomplete evacuation. They rarely have abdominal pain. With proc(cid:173)
`titis or proctosigmoiditis, proximal transit slows, which may account
`for the constipation that is commonly seen in patients with distal dis(cid:173)
`ease.
`When the disease extends beyond the rectum, blood is usually
`mixed with stool, or grossly bloody diarrhea may be noted. Colome
`motility is altered by inflammation with rapid transit through the in(cid:173)
`flamed intestine. When the disease is severe, patients pass a liquid
`stool containing blood, pus, and fecal matter. Diarrhea is often noc(cid:173)
`turnal and/or postprandial. Although severe pain is not a prominent
`symptom, some patients with active disease may experience vague
`lower abdominal discomfort or mild central abdominal cramping. Se(cid:173)
`vere cramping and abdominal pain can occur in association with severe
`attacks of the disease. Other symptoms in moderate to severe disease
`include anorexia, nausea, vomiting, fever, and weight loss.
`Physical signs of proctitis include a tender anal canal and blood
`on rectal exam. With more extensive disease, patients have tenderness
`to palpation directly over the colon. Patients with a toxic colitjs have
`severe pain and bleeding, and those with megacolon have hepatic tym(cid:173)
`pany. Both may have signs of peritonitis if a perforation has occurred.
`The classification of disease activity is shown in Table 287-2.
`Laboratory, Endoscopic, and Radiographic Features Active
`disease can be associated with a rise in acute phase reactants (C-re(cid:173)
`active protein, orosomucoid levels), platelet count, erythrocyte sedi(cid:173)
`mentation rate (ESR) and a decrease in hemoglobin. In severely ill
`patients, the serum albumin level will fall rather quickly. Leukocytosis
`may be present but is not a specific indicator of disease activity. Proc(cid:173)
`titis or proctosigmoiditis rarely causes a rise in C-reactive protein.
`Diagnosis relies upon the patient's history; clirllcal symptoms, nega(cid:173)
`tive stool examination for bacteria, Clostridium difficile toxin, and ova
`and parasites; sigmoidoscopic appearance; and histology of rectal or
`colonic biopsy specimens.
`Sigmoidoscopy is used to assess disease activity and is often per(cid:173)
`fonned before treatment. Histologic features change more slowly than
`clinical features but can also be used to grade disease activity.
`Patients with a severe: attack of UC should have a plain, supine
`film of the abdomen. In the presence of severe disease, .the margin of
`the colon becomes edematous and irregular (Fig. 287-5). Colome
`thickening and toxic dilation can both be seen on a plain radiograph.
`The. earliest radiologic change of UC seen on single-contrast bar(cid:173)
`ium enema is a fine mucosal granularity. With increasing severity, the
`mucosa becomes thickened and superficial ulcers are seen. Deep ul(cid:173)
`cerations can appear as "collar-button" ulcers, which indicate that the
`ulceration has penetrated the mucosa. Haustral folds may be nonnal
`in rrllld disease, but as activity progresses they become edematous and
`thickened. Loss of haustration can occur, especially in patients with
`long-standing disease. In addition, the colon be"
`comes shortened and narrowed. Polyps in the
`colon may be postinflarnmatory polyps or pseudo(cid:173)
`polyps, adenornatous polyps, or carcinoma.
`Computed tomography (CT) scanning is
`not as helpful as endoscopy and barium enema
`in making the diagnosis of UC, but typical
`findings include mild mural thickening ( <1.5
`em), inhomogeneous wall density, absence of
`small bowel thickening, increased perirectal
`and presacral fat, target appearance of file rec(cid:173)
`tum, and adenopathy.
`Complications Only 15% of patients
`with UC present initially with catastrophic ill(cid:173)
`ness. Massive hemorrhage occurs with severe
`
`> 6 per day
`Severe
`> 37.5°C mean
`> 90 mean pulse
`:S75%
`> 30mm
`Spontaneous bleed-
`ing, ulcerations
`
`Severe
`
`

`

`287
`
`Inflammatory Bowel Disease
`
`1683
`
`and is relieved by defecation. A low-grade fever is usually noted.
`High-spiking fever suggests
`intraabdorninal abscess formation.
`Weight loss is common-typically 10 to 20% of body weight-
`and
`develops as a consequence of diarrhea, anorexia, and fear of eating.
`An inflammatory mass may be palpated in the right lower quadrant
`of the abdomen. The mass is composed of inflamed bowel, adherent
`and indurated mesentery, and enlarged abdominal lymph nodes. Ex(cid:173)
`tension of the mass can cause obstruction of the right ureter or bladder
`inflammation, manifested by dysuria and fever. Edema, bowel wall
`thickening, and fibrosis of the bowel wall within the mass account for
`the radiographic "string sign" of a narrowed intestinal lumen.
`Bowel obstruction may take several forms. In the early stages of
`the disease, bowel wall edema and spasm produce intermittent obstruc(cid:173)
`tive manifestations and increasing symptoms of postprandial pain.
`Over several years, this persistent inflammation gradually progresses
`to fibrostenotic narrowing and stricture. Diarrhea will decrease and
`eventually lead to chronic bowel obstruction and obstipation. Acute
`episodes of obstruction occur as well, precipitated by bowel inflam(cid:173)
`mation and spasm or sometimes by impaction of undigested food.
`These episodes usually resolve with intravenous fluids and gastric de(cid:173)
`compression.
`Severe inflammation of the ileocecal region may lead to localized
`wall thinning, with microperforation and fistula formation to the ad(cid:173)
`jacent bowel, the skin, the urinary bladder, or to an abscess cavity in
`the mesentery. Enterovesical fistulas typically present as dysuria or
`recurrent bladder infections or less commonly as pneumaturia or fe(cid:173)
`caluria. Enterocutaneous fistulas follow tissue planes of least resis(cid:173)
`tance, usually draining through abdominal surgical scars. Enterova(cid:173)
`ginal fistulas are rare and present as dyspareunia or as a feculent or
`foul-smelling, often painful vaginal discharge. They are unlikely to
`develop without a prior hysterectomy.
`Jejunoileitis Extensive inf