08 inflammatory bowel disease copy

Inflammatory bowel disease (IBD)

• Chronic condition resulting from inappropriate mucosal immune activation.

• Two types: • Ulcerative colitis • Crohn disease

• Ulcerative colitis  limited to colon and rectum and extends only into mucosa and submucosa • Crohn disease  involve any area of GI tract and is transmural • Both present in teens and early 20s • UC  slightly more common in females

Ulcerative colitis

Crohn disease

Pathogenesis • Results from combined effects of: • Alterations in host interactions with intestinal microbiota • Intestinal epithelial dysfunction • Aberrant mucosal immune responses • Altered composition of gut microbiome

Genetics • Genetic factors also contribute • Increased risk of disease in family member • Gene most strongly associated with Crohn disease  NOD2 (nucleotide oligomerization binding domain 2)

• ATG16L1 (autophagyrelated 16-like), and IRGM (immunity-related GTPase M) • All three  involved in recognition and response to intracellular pathogens • Supports hypothesisinappropriate immune reactions to luminal bacteria are important component

Mucosal immune responses • T helper cellsactivated in Crohn disease and response is TH1 type • Certain polymorphisms of IL-23 receptor (involved in development and maintenance of TH17 cells ) confer marked reductions in risk of both Crohn disease and UC

• Pro-inflammatory cytokines TNF, interferon-γ and IL-13, immunoregulatory molecules  IL10 and TGF-β, may play role in pathogenesis of IBD.

Epithelial defects • Defects in intestinal epithelial tight junction barrier function  Crohn disease • Barrier dysfunction associated with NOD2 polymorphisms

Microbiota • Linkage to NOD2involvement of microbes in Crohn disease • Presence of antibodies against bacterial protein flagellin  common in Crohn disease and associated with stricture formation, perforation, and small-bowel involvement • Anti-flagellin antibodies  uncommon in ulcerative colitis

Morphology Crohn disease • Occur in any area of GI tract • Most common sites are  terminal ileum, ileocecal valve, and cecum • Limited to small intestine (40% of cases), small intestine and colon are both involved in 30%

• Multiple, separate, sharply delineated areas of disease, resulting in skip lesions • Strictures  common in Crohn disease • Earliest lesion aphthous ulcer, may progress, and multiple lesions coalesce into serpentine ulcers oriented along axis of bowel

• Patchy distribution results in cobblestone appearance • Fissures may develop between mucosal folds and may extend deeply to become fistula or may perforation

• Intestinal wall  thickened and rubbery due to transmural edema, inflammation, submucosal fibrosis, and hypertrophy of muscularis propria  stricture formation • Mesenteric fat may extends around serosal surface  creeping fat

Microscopic • Clusters of neutrophils within crypt  crypt abscesses, crypt destruction • Abrupt transition between ulcerated and adjacent normal mucosa • Repeated cycles of crypt destruction and regeneration lead to distortion of mucosal architecture

• Epithelial metaplasia  pseudopyloric or paneth cell metaplasia • Later  mucosal atrophy,loss of crypts • Noncaseating granulomas  in Crohn disease • Granulomas may also be present in mesenteric lymph nodes

Clinical presentation • Intermittent attacks of mild diarrhea, fever, and abdominal pain. • May present acutely with right lower quadrant pain, fever, and bloody diarrhea mimicing acute appendicitis or bowel perforation

• Asymptomatic periods that last for weeks to months • Re-activation by external triggers  physical or emotional stress, specific dietary items, and cigarette smoking

Complications • • • • •

Iron-deficiency anemia Hypoalbuminemia, malabsorption Fibrosing strictures of terminal ileum Fistulae between loops of bowel Perforations and peritoneal abscesses

Extraintestinal manifestations • Uveitis, migratory polyarthritis, sacroiliitis, ankylosing spondylitis, erythema nodosum, and clubbing of fingertips • Pericholangitis and primary sclerosing cholangitis

Ulcerative Colitis • Limited to colon and rectum • Extraintestinal manifestations overlap with those of Crohn disease

Morphology Grossly • Always involves rectum, extends proximally in continuous fashion to involve part or all of colon (pancolitis) • Small intestine  normal, mild mucosal inflammation of distal ileum (backwash ileitis) in severe cases of pancolitis

• Involved mucosa  slightly red and granular or have extensive broadbased ulcers • regenerating mucosa bulge into lumen  pseudopolyps • Fusion of tips of polyps create mucosal bridges

• Chronic disease mucosal atrophy • Mural thickening is not present • Inflammatory mediators can damage muscularis propria  disturb neuromuscular function leading to colonic dilation and toxic megacolon  risk of perforation

• Histologic features  similar to Crohn disease but diffuse and limited to mucosa and superficial submucosa • No granulomas

Clinical Features • Attacks of bloody diarrhea with stringy, mucoid material, lower abdominal pain, and cramps • Temporarily relieved by defecation • Symptoms persist for days, weeks, or months • Smoking may partially relieve symptoms

Differences between CD & UC Features Macroscopic Bowel region Distribution Stricture Wall appearance

CD Ileum +/_colon Skip lesions Yes Thick

UC Colon only Diffuse Rare Thin

Features Microscopic Inflammation Pseudopolyps Ulcers

CD Transmural

Moderate Deep, knifelike Lymphoid rxn Marked Fibrosis Marked Serositis Marked Granulomas Yes (~35%) Fistula/sinuses Yes

UC Limited to mucosa Marked Superficial Moderate Mild to none Mild to none No No

Features Clinical Perianal fistula Fat/vitamin malabsorption Malignant potential Recurrence after surgery Toxic megacolon

CD

UC

Yes (in colonic No disease) Yes No With colonic involvement Common

Yes

No

Yes

No