Crohn's Disease

Overview

Epidemiology

• Bimodal age of onset: peak in the 2nd–3rd decade, with a smaller peak in the 5th–6th decade
• Most common in North America, northern Europe, and Australia; incidence rising in Africa, South America, and Asia
• Higher prevalence among Ashkenazi Jewish populations (3–5× general population)
• Equal sex distribution; slight female predominance in some series
• The hygiene hypothesis links rising incidence to improved food storage, decreased microbial exposure, and altered gut microbiome composition, predisposing to dysregulated mucosal immunity

Etiology and Pathogenesis

Fig. Distribution of lesions in IBD — Crohn disease (top) vs. ulcerative colitis (bottom). Note transmural inflammation, skip lesions, strictures, creeping fat, deep fissures (Robbins, Cotran & Kumar)

Genetics

• 200 IBD-associated risk alleles identified, but account for <20% of CD risk

• NOD2 (intracellular sensor of muramyl dipeptide — a bacterial cell wall component) is the strongest genetic risk factor; 3 major NOD2 risk alleles are found in ~30% of CD patients vs. 5% of healthy individuals
• CD is polygenic; accumulated polymorphisms impact susceptibility (disease location, stricturing vs. penetrating behavior)
• PTPN22 and NOD2 variants increase CD risk but are protective in UC
• Rare monogenic early-onset IBD involves mutations in IL-10 and IL-10 receptor subunits

Environmental Factors

• Smoking doubles the risk of CD (opposite effect in UC)
• NSAIDs, appendectomy, dietary factors (processed foods, emulsifiers), and alterations in gut microbiome (dysbiosis) are implicated
• Stress, enteric infections can trigger relapses

Immunobiology

• CD4+ Th1 and Th17 cells drive inflammation; key cytokines: TNF-α, IL-12, IL-23, IFN-γ, IL-17
• Defective mucosal barrier and impaired clearance of bacteria allow luminal antigens to perpetuate immune activation
• Dysfunctional regulatory T-cell responses fail to suppress the inflammatory cascade

Pathology (Gross and Microscopic)

Common Sites

• Terminal ileum ± cecum: most common (~40% small intestine only)
• Small intestine + colon: ~30%
• Colon only: ~30%
• Rarely: esophagus, stomach, duodenum

Gross Features

Microscopic Features

Fig. Microscopic pathology of Crohn disease: (A) haphazard crypt organization from repeated injury/regeneration; (B) noncaseating granuloma; (C) transmural disease with markedly thickened wall, submucosal and serosal granulomas (arrows) — Robbins & Kumar Basic Pathology

• Transmural inflammation (entire bowel wall) — key distinction from UC
• Neutrophil infiltration of crypts → crypt abscesses
• Crypt architectural distortion (branching, irregular)
• Noncaseating granulomas (~35% of cases) — hallmark, though absence does not exclude diagnosis
• Pyloric gland metaplasia and Paneth cell metaplasia
• Ulcers: deep, knife-like (vs. UC's broad-based, superficial ulcers)

CD vs. UC: Key Distinctions

Clinical Features

Intestinal Manifestations

• Symptoms: intermittent diarrhea (may be non-bloody), crampy abdominal pain (especially RLQ), fever, weight loss, anorexia, malaise
• ~20% present acutely with RLQ pain/fever mimicking appendicitis
• Disease behavior (Montreal classification):
  • B1 (Inflammatory/non-stricturing, non-penetrating): most common early
  • B2 (Stricturing): fibrosis → partial or complete bowel obstruction
  • B3 (Penetrating/Fistulizing): fistulae (enterocutaneous, enterovesical, rectovaginal), abscesses, free perforation

Perianal Disease

• Perianal fistulae, skin tags, anal fissures, abscesses
• Especially prominent in colonic CD

Extraintestinal Manifestations (~30% of patients)

• Joints: migratory peripheral arthritis, sacroiliitis, ankylosing spondylitis
• Skin: erythema nodosum, pyoderma gangrenosum
• Eyes: uveitis, episcleritis
• Liver/biliary: primary sclerosing cholangitis (more common in UC but occurs in CD)
• Thromboembolic: DVT/PE due to hypercoagulable state
• Nutrition: malabsorption → B12 deficiency (terminal ileal disease), fat-soluble vitamin deficiency, iron-deficiency anemia

Diagnosis

Endoscopy

• Ileocolonoscopy with biopsies is the gold standard
• Findings: aphthous ulcers, cobblestoning, skip lesions, deep fissuring ulcers
• Upper GI endoscopy if upper GI symptoms

Radiology

• MR enterography (MRE): modality of choice for small bowel evaluation; shows mural thickening, hyperenhancement, the "comb sign" (engorged peri-enteric vasculature), fistulae, abscesses
• CT enterography: faster, accessible, good for complications
• Capsule endoscopy: mucosal evaluation of small bowel (avoid if strictures suspected)

Biomarkers

• C-reactive protein (CRP): correlates with disease activity; elevated in active disease
• Fecal calprotectin: pooled sensitivity 88%, specificity 67% for active CD endoscopy; useful for monitoring
• Fecal lactoferrin: another neutrophil marker of intestinal inflammation
• Complete blood count: anemia, leukocytosis
• Serology: ASCA (anti-Saccharomyces cerevisiae antibody) positive in ~50–60% CD; pANCA typically negative

Disease Activity

• Crohn Disease Activity Index (CDAI): Remission = CDAI <150; clinical response = decrease ≥100 points
• Mucosal healing is now a therapeutic target beyond symptom control

Treatment

Mild to Moderate CD

Moderate to Severe CD

• Combination therapy: Infliximab + azathioprine > either alone (SONIC trial); early combined immunosuppression preferred in high-risk disease
• ~50% of patients relapse within 1 year of discontinuing infliximab + azathioprine
• Avoid long-term corticosteroids (lymphoma risk with thiopurines + anti-TNF combination must be weighed)

Perianal/Fistulizing Disease

• Antibiotics (metronidazole/ciprofloxacin) for acute management
• Infliximab: fistula healing rates up to 60% in RCTs
• Azathioprine/cyclosporine: ~30% success
• Surgical drainage of abscesses prior to biologic therapy

Surgery

• ~75% of CD patients require surgery within 20 years of symptom onset
• Surgery rates at 1, 5, 10 years: 16%, 33%, 47% (population-based meta-analysis)
• Guiding principle: preservation of intestinal length (wide margins do not reduce recurrence)
• Most common procedure: ileocecal resection with primary anastomosis (often laparoscopic)
• Bowel-sparing: strictureplasty for scattered strictures
• Indications: intra-abdominal abscess, medically intractable fistula, fibrotic stricture with obstruction, cancer, growth failure in children, glucocorticoid-refractory disease
• Surgery rates have declined significantly over 6 decades with better medical therapy

Complications

Monitoring & Targets

• Treat-to-target: goal is mucosal healing (endoscopic remission) + symptom resolution
• Monitor CRP, fecal calprotectin, and periodic ileocolonoscopy
• Screen for lymphoma, skin cancers with long-term immunosuppressant use
• Colorectal cancer surveillance colonoscopy for long-standing colonic disease

Recent Evidence