Crohn's Disease

Definition and Overview

Epidemiology

• Bimodal age of onset: peak in young adults (15-25 years) with a second smaller peak in the 50s-60s
• Affects approximately 1 million people in the United States
• Incidence is rising globally, particularly in industrializing countries and those adopting Westernized diets
• Previously concentrated in Western Europe and North America; now increasingly seen in Asia and Latin America

Etiology and Pathogenesis

1. Genetic susceptibility - Hundreds of loci are associated with IBD. Key genes include NOD2 (innate immunity), IL-23R (interleukin receptor), and ATG16L1 (autophagy). No single gene variant is diagnostically useful on its own.
2. Dysregulated immune response - Abnormal immune activation in response to luminal antigens or gut microbiota
3. Microbiome dysbiosis - Altered gut bacterial composition
4. Environmental factors - Westernized diet, air pollution, industrialization, smoking (smoking increases risk of CD, in contrast to UC where it is protective)

Pathology

Gross Features

• Transmural inflammation - penetrates the full thickness of the bowel wall
• Skip lesions - diseased segments alternating with normal mucosa (distinguishes CD from UC)
• Cobblestone appearance - mucosal islands separated by deep linear fissuring ulcers
• Strictures - from fibrotic healing of transmural inflammation
• Fistulas - abnormal tracts between bowel loops, bladder, skin, or vagina due to fistulizing penetration
• Mesenteric fat wrapping ("creeping fat") - fat extends over the serosal surface of the bowel

Microscopic Features

• Transmural chronic inflammation
• Non-caseating granulomas - present in ~50% of cases; highly specific when found
• Crypt architectural distortion
• Submucosal fibrosis
• In the stomach: focally enhanced gastritis; serpiginous or longitudinal ulcers

Distribution and Classification

• Location: L1 (ileal), L2 (colonic), L3 (ileocolonic), L4 (upper GI modifier)
• Behavior: B1 (inflammatory), B2 (stricturing), B3 (penetrating)
• Perianal modifier: "p" added if perianal disease is present

Clinical Features

Intestinal Symptoms

• Chronic or intermittent abdominal pain (often right lower quadrant)
• Non-bloody diarrhea (blood may occur if colonic involvement)
• Weight loss and malnutrition
• Fever during flares
• Perianal disease: skin tags, fissures, abscesses, fistulas (highly characteristic of CD)

Complications

• Obstruction - from fibrotic strictures (chronic) or active inflammation (acute)
• Abscesses - intra-abdominal or perianal
• Fistulas - enteroenteric, enterovesical, enterocutaneous, rectovaginal
• Malabsorption - from reduced absorptive surface area, terminal ileal disease (B12 deficiency, bile salt malabsorption), small intestinal bacterial overgrowth (SIBO)
• Short bowel syndrome - after repeated resections
• Colorectal cancer - increased risk with longstanding colonic involvement

Extraintestinal Manifestations (EIMs)

• Joints: peripheral arthritis, ankylosing spondylitis, sacroiliitis
• Skin: erythema nodosum, pyoderma gangrenosum
• Eyes: episcleritis, uveitis
• Liver/biliary: primary sclerosing cholangitis (more common in UC but occurs in CD)
• Other: aphthous mouth ulcers, thromboembolic disease

Diagnosis

Laboratory

• Elevated CRP and ESR - correlate with disease activity; high CRP suggests active disease or infectious complication
• Fecal calprotectin and lactoferrin - sensitive markers of intestinal inflammation; useful for monitoring relapse and response to biologics
• Anemia (iron deficiency, B12 deficiency, anemia of chronic disease)
• Hypoalbuminemia

Endoscopy

• Colonoscopy with ileoscopy: aphthous ulcers, deep linear/serpiginous ulcers, cobblestoning, skip lesions
• Mucosal biopsies showing granulomas are highly supportive

Imaging

• MR enterography (MRE): modality of choice for small bowel assessment; shows mural thickening, mural hyperenhancement, and the "comb sign" (engorged peri-enteric vasculature resembling comb teeth - see image below)
• CT enterography: alternative when MRI is unavailable
• Ultrasound: useful bedside tool for bowel wall thickening

MR enterography with gadolinium contrast: coronal view showing mural hyperenhancement, mural thickening, and the comb sign (engorged peri-enteric vasculature) in the terminal ileum. - Sleisenger & Fordtran, Fig. 115.16

Disease Activity Scoring

• Crohn's Disease Activity Index (CDAI): remission = CDAI <150; clinical response = decrease ≥100 points. Used in clinical trials.
• Symptoms alone should not guide therapy - objective assessment (endoscopy, CRP, fecal calprotectin, imaging) is required, as symptom scores don't always correlate with objective inflammation.

Treatment

2025 Paradigm Shift: Treat-to-Target / Early Advanced Therapy

Drug Classes

• Aminosalicylates (mesalazine) have minimal evidence in CD and are not generally recommended
• Antibiotics (metronidazole, ciprofloxacin) are used for perianal fistulas and abscesses, not as primary CD therapy

Perianal Fistulizing Disease

• Combined surgical drainage + anti-TNF (infliximab) is standard
• Emerging evidence: stem cell therapy (darvadstrocel/Alofisel) for complex perianal fistulas - a recent 2025 meta-analysis (PMID 40205247) confirms efficacy and safety

Surgery

• ~47% of patients require surgery within 10 years of diagnosis; rates have been declining with improved medical therapy
• ~30% require a second operation within 5 years of the first
• Guiding principle: preserve intestinal length - wide margins do not reduce recurrence
• Most common procedure: ileocecal resection (often laparoscopic)
• Strictureplasty: preferred over resection for scattered fibrotic strictures to preserve length
• Indications: intra-abdominal abscess, medically intractable fistula, fibrotic stricture with obstruction, growth failure in children, steroid-refractory/dependent disease, patient preference over immunosuppression
• The LIR:C trial showed that in limited (<40 cm) ileal CD failing steroids/immunomodulators, laparoscopic ileocecal resection vs. infliximab yielded equivalent quality of life at 12 months - surgery is a valid alternative for select patients

CD vs. Ulcerative Colitis: Key Distinctions

Monitoring and Prognosis

• Mucosal healing (endoscopic remission) is the primary therapeutic target - biomarker and endoscopic monitoring is required even in asymptomatic patients
• Fecal calprotectin and CRP are useful non-invasive monitoring tools
• Patients on immunosuppressants/biologics require monitoring for infections (TB reactivation, hepatitis B reactivation), and regular skin/lymphoma surveillance

• Sleisenger and Fordtran's Gastrointestinal and Liver Disease, Chapters 115, 116, 123
• Rheumatology (Elsevier, 2022), Chapter 38
• 2025 ACG Clinical Guideline: Management of Crohn's Disease in Adults
• AGA 2025 Living Guideline: Pharmacologic Management of Moderate-to-Severe CD
• PMID 40205247 - Stem cell therapy for anal fistulas (2025 meta-analysis)