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Crohn disease (CD), a chronic, relapsing inflammatory GI tract disorder, most often terminal ileum (80%):
- Hallmark features:
- Transmural inflammation, which can result in fibrosis and stricture formation, as well as fissures leading to sinus tracts, abscesses, or fistulas
- Noncaseating granulomas (50%), crypt abscesses
- Skip lesions: Patchy, segmental distribution of disease; lesions may affect multiple bowel segments, interspersed with areas of normal mucosa; however, disease can also be continuous, potentially mimicking ulcerative colitis (UC).
- Diverse presentations: Ileocolitis (50%); isolated colitis (20%); of the latter, 10% involve the rectum; anorectal (1/3); adult upper GI disease(<5%).
- Early disease:
- Ulcerations: Initially focal with surrounding edema, resembling aphthous ulcers
- Perianal disease (pain, anal fissures, perirectal abscess) may precede intestinal disease.
- May present as wasting illness or anorexia
- Developed disease:
- Cobblestoning of mucosa; stenotic lumen; creeping fat; fissures develop between mucosal folds, resulting in strictures/adhesions and/or fistulae
- In the US, 8–10 cases/100,000 adult; incidence is rising in the US and Western Europe
- Bimodal age distribution: Predominant age is 15–25 years, with a second smaller peak at 50–70 years
- Females slightly > males; increased incidence among patients in northern climates
- Increased risk in whites vs. nonwhites: 2–5 times
- Increased risk in Ashkenazi Jews: 3–5 times
US adults: 100–200 cases/100,000
- Environmental factors:
- Cigarette smoking doubles the risk of developing CD; cessation may reduce frequency of flares, relapse after surgery
- Dietary factors: Higher incidence in diets high in refined sugars, protein (meat, fish)
- Salmonella or Campylobacter confer increased risk of developing inflammatory bowel disease (IBD) (highest in 1 year).
- Clostridium difficile infection may trigger a flare of IBD and make treatment more difficult.
- Immunological abnormalities: Not established whether immune responses in IBD are directed against self-antigens of intestinal epithelium or foreign, bacterial antigens:
- Tumor necrosis factor (TNF): Up-regulation of inflammatory Th1 cytokines
- Recent studies indicate that tissue inflammation may result from increased secretion of cytokine IL-17, by Th17 subset of CD4+ T cells.
Of CD patients, 15% have a 1st-degree relative with IBD; 1st-degree relative of an IBD patient has 3–30 times the increased risk of developing IBD by age 28. As of May, 2012, 163 genes associated with IBD.
- Mutations in susceptibility loci:
- Ileal CD: IBD1 gene (chrom 16) encodes protein NOD2 (CARD15), which is expressed in Paneth cells; aberrant forms of NOD2 may have a dysfunctional response to bacterial pathogens.
- Early-onset CD (age <15): Mutations in 5q31-33 (IBD5), 21q22, and 20q13
- North American white males with CD: 30% have HLA-DR7 and DQ4
- Extra-intestinal manifestations of CD: Mutations in HLA-A2, HLA-DR1, HLA-DQw5
- Others: IL-10, IL-23 receptors; ATG16L1; IRGM
- Genetic syndromes associated with IBD: Turner and Hermansky-Pudlak syndromes, glycogen storage disease, type 1b
- General: Clinical manifestations result from activation of inflammatory cells, whose by-products produce nonspecific tissue injury.
- Mechanism of diarrhea: Excess fluid secretion and impaired fluid absorption; bile salt malabsorption in inflamed ileum, with subsequent steatorrhea; bacterial overgrowth
Multifactorial: Genetic, environmental triggers and immunological abnormalities result in inflammation and tissue injury, in the genetically predisposed.
Commonly Associated Conditions
- Extraintestinal manifestations:
- Arthritis (20% of patients): Seronegative, primarily involving large joints; axial arthritis or ankylosing spondylitis (AS) and sacroiliitis (SI).
- Skin disorders (10%): Erythema nodosum, pyoderma gangrenosum, psoriasis
- Ocular disease (5%): Uveitis, iritis, episcleritis
- Kidney stones: Calcium oxalate stones (from steatorrhea and diarrhea) or uric acid stones (from dehydration and metabolic acidosis)
- Fat-soluble vitamin deficiency (A, D, E, K), B12
- Osteopenia and osteoporosis; hypocalcemia
- Hypercoagulability: Venous thromboembolism prophylaxis critical in hospitalized patients
- Gallstones: Cholesterol stones, resulting from impaired bile acid reabsorption
- Primary sclerosing cholangitis (5%): More common with UC; asymptomatic, elevated alkaline phosphatase
- Autoimmune hemolytic anemia
- Conditions that correlate with increased disease activity in the bowel:
- Peripheral arthropathy (but not SI and AS)
- Episcleritis (but not uveitis)
- Oral aphthous ulcers and erythema nodosum
- SI, AS, and uveitis are associated with HLA-B27.
- Potentially devastating complications: GI bleed, toxic megacolon, bowel perforation/peritonitis, malignancy, sclerosing cholangitis