Crohn's Disease

Definition

Epidemiology & Etiology

• Genetics: Over 200 IBD-associated risk alleles identified. The most important is NOD2 (encodes an intracellular sensor for muramyl dipeptide, a bacterial cell wall component) - present in ~30% of CD patients vs. 5% of healthy individuals in European populations. CD is polygenic - accumulated polymorphisms in immune signaling, bacterial response, and epithelial defense genes all contribute. - Robbins, Cotran & Kumar Pathologic Basis of Disease
• Environmental: Tobacco use is implicated in etiology and exacerbation. Oral contraceptive use and alcohol have also been linked. - Schwartz's Principles of Surgery
• Microbiome: Dysregulated host-microbe interactions are central to disease initiation

Pathophysiology

1. Genetic susceptibility (NOD2 and >200 other loci)
2. Epithelial barrier dysfunction - barrier defects allow influx of bacterial components into the lamina propria
3. Aberrant immune responses - dendritic cells present bacterial antigens to CD4+ T cells, driving Th1 and Th17 polarization with release of TNF, IFN-γ, IL-17, IL-23, and other cytokines that sustain chronic inflammation

Pathogenesis of IBD - Robbins, Cotran & Kumar Pathologic Basis of Disease, Fig. 17.36

• Fibrosis and stricture formation
• Fistula and abscess formation (penetrating disease)
• Adhesions to adjacent bowel or organs
• "Fat wrapping" - mesenteric fat encroachment onto the bowel serosa, virtually pathognomonic of CD - Schwartz's Principles of Surgery

Distribution

• Small bowel involved in 80% of cases; colon alone in 20%
• Majority of small bowel disease = ileocecal disease
• Isolated perianal/anorectal disease: 5-10%
• Uncommon sites: esophagus, stomach (usually with concurrent intestinal disease), duodenum
• Skip lesions: discontinuous inflamed segments separated by normal-appearing intestine - Schwartz's Principles of Surgery

Pathology - Key Features

Clinical Presentation

1. Fibrostenotic - obstructive symptoms from strictures
2. Fistulizing / penetrating - internal fistulas, abscesses
3. Aggressive inflammatory - active mucosal inflammation

• Arthritis / arthralgia
• Skin: erythema nodosum, pyoderma gangrenosum
• Eyes: iritis, uveitis
• Oral: aphthous stomatitis
• Perianal disease (fissures, fistulas, abscesses)

Diagnosis & Disease Activity

• Remission: CDAI < 150
• Response to therapy: decrease in CDAI ≥ 100 points

• CRP - useful for tracking activity; elevated CRP correlates with active disease and risk of infectious complications
• Fecal calprotectin - pooled sensitivity 88%, specificity 67% for active CD vs. endoscopy. Also correlates with relapse risk and biologic therapy response
• Fecal lactoferrin - sensitive marker of intestinal inflammation

Symptoms do not always correlate with objective disease activity - mucosal healing (endoscopic + biomarker-based) has emerged as the therapeutic target beyond symptom control. - Sleisenger and Fordtran's GI and Liver Disease

Complications

• Small bowel obstruction (SBO): CD is the primary cause in ~5% of SBO cases. May result from active inflammation or chronic fibrosis/strictures. Up to 75% of patients undergo at least one abdominal surgery in their lifetime.
• Intra-abdominal abscess and fistulas
• Colorectal cancer: Risk increased after >8-10 years of colonic IBD
• Short bowel syndrome (from repeated resections)

Management

Medical Therapy

• Anti-TNF therapies are effective by inhibiting the pro-inflammatory cascade, but up to 50% of patients ultimately become unresponsive to their first anti-TNF biologic. Some respond to a second anti-TNF agent. - Robbins, Cotran & Kumar
• For gastric/duodenal CD: PPIs are first-line; controlled trial data on immunosuppressants and biologics is lacking, though infliximab has been used successfully. - Sleisenger and Fordtran's
• Despite biologic availability, up to 40% of CD patients still require long-term corticosteroids, which significantly increase surgical morbidity (infection, anastomotic leak). - Fischer's Mastery of Surgery

Surgical Therapy

• Preserve intestinal length - wide margins do not reduce recurrence but increase short bowel syndrome risk
• Indications: intra-abdominal abscess, medically intractable fistula, fibrotic stricture with obstruction, toxic megacolon, malignancy, failure of optimal medical therapy, steroid dependence, growth failure in children
• Most common operation: ileocecal resection with primary anastomosis, increasingly done laparoscopically
• The LIR:C trial showed no QOL difference at 12 months between laparoscopic ileocecal resection and infliximab in limited ileal CD (<40 cm) - suggesting primary resection is an acceptable alternative to biologic therapy in select patients
• Strictureplasty is preferred over resection for isolated fibrotic/scattered strictures (bowel-sparing)
• IPAA (ileal pouch-anal anastomosis) is generally avoided in established CD due to high pouch failure rates
• Risk of second surgery: ~30% at 5 years; ~33% of those needing a second surgery will need a third. - Sleisenger and Fordtran's

Surveillance

• A 2025 meta-analysis in J Crohn's Colitis found partial enteral nutrition (PEN) has a role in CD management, particularly in pediatric populations (PMID 39565924)
• A 2025 Lancet Gastroenterology & Hepatology systematic review proposed novel diagnostic criteria and management advice specifically for isolated perianal Crohn's disease (PMID 40315877)
• A 2024 meta-analysis in United European Gastroenterol J reviewed probiotics in IBD - modest benefit but not yet standard of care (PMID 39106167)