Description

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

Epidemiology

• 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

Prevalence
US adults: 100–200 cases/100,000

Risk Factors

• 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.

• 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

Pathophysiology

• 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

Etiology

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