Inflammatory Bowel Disease — Crohn vs UC

Genetic (non-modifiable)

• Family history: the single strongest risk factor; risk is highest with an affected first-degree relative and highest of all in monozygotic twins, more so for Crohn than UC
• NOD2/CARD15 variants: impair intracellular sensing of bacterial muramyl dipeptide by Paneth cells and macrophages — associated with ileal, stricturing/fibrostenotic Crohn disease
• IL-23R and autophagy genes (ATG16L1, IRGM): defective bacterial handling and Th17 skewing
• Ethnicity: increased prevalence in Ashkenazi Jewish populations; higher incidence in North America and Northern Europe
• Age: bimodal onset, with the main peak in adolescence/young adulthood and a smaller later-life peak

Microbial/immune mechanisms

• Dysbiosis: reduced diversity and loss of short-chain-fatty-acid–producing anaerobes, favoring mucosal immune activation
• Enteric infection: gastroenteritis (including C. difficile) can precipitate onset or a flare — always exclude infection before attributing symptoms to IBD activity

Modifiable/environmental

• Cigarette smoking: the classic exam discriminator — smoking increases risk and worsens the course of Crohn disease, but is protective in UC, with UC often presenting in recent ex-smokers
• NSAIDs: prostaglandin-mediated mucosal barrier injury; a common precipitant of flares
• Antibiotic exposure, particularly in early childhood, and a Western/high–ultra-processed-food diet
• Appendectomy: associated with reduced UC risk (a non-modifiable exposure once performed)
• Perceived-but-weak associations examiners use as distractors: oral contraceptives and isotretinoin — the isotretinoin link is not established

• Genetic predisposition: NOD2/CARD15 mutations (especially in Crohn disease) impair bacterial sensing; STAT3, IL-23 pathway variants affect immune tolerance
• Dysbiosis and barrier dysfunction: Altered intestinal microbiota composition and impaired tight junctions (claudins, zonula occludens-1) allow increased bacterial translocation and antigen exposure
• Aberrant T-cell response: Loss of regulatory T cell (Treg) function and expansion of pathogenic Th1/Th17 cells producing IFN-γ, IL-17, TNF-α, and IL-6
• Innate immune activation: Enhanced pattern recognition receptor signaling, increased intestinal permeability, and exaggerated response to commensal flora
• Tissue remodeling: Chronic inflammation drives fibrosis, stricture formation (especially in Crohn disease), and dysplasia in longstanding disease
• Key anatomical difference: Crohn disease causes transmural inflammation (all layers) while UC causes mucosal/submucosal inflammation only (limited to colon/rectum)

Common Features (Both CD and UC)

• Chronic diarrhea (often bloody in UC, non-bloody in CD) with urgency and tenesmus
• Abdominal pain and cramping, worse with CD due to transmural involvement
• Constitutional symptoms: Fatigue, weight loss, fever, malaise from chronic inflammation and malabsorption
• Extraintestinal manifestations: Arthritis/arthralgia (≤20%), erythema nodosum, pyoderma gangrenosum, uveitis, primary sclerosing cholangitis (more common in UC—10-15%), aphthous ulcers

Crohn Disease-Specific Features

• Ileocolonic involvement (most common—40%), but any part of GI tract mouth to anus (skip lesions)
• Right lower quadrant pain mimicking appendicitis; may present with fistulas, abscesses, obstruction
• Perianal disease: Fistulas, skin tags, abscesses (suggests CD diagnosis)
• Increased malabsorption from small bowel disease; B12/folate deficiency common

Ulcerative Colitis-Specific Features

• Continuous inflammation starting at rectum and extending proximally (never skip lesions)
• Bloody diarrhea with mucus (cardinal finding)
• Left lower quadrant/rectal urgency symptoms predominate
• Toxic megacolon risk during severe flares

• Colonoscopy with ileoscopy and biopsy: Gold standard; CD shows patchy inflammation with cobblestone appearance and fissuring ulcers, while UC shows continuous mucosal friability and crypt distortion; biopsy reveals granulomas in ~40% of CD but never in UC
• Inflammatory markers: Elevated C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR); CRP more sensitive in CD
• Fecal calprotectin: Non-invasive marker of intestinal inflammation; elevated in both conditions but helps distinguish IBD from IBS
• Complete blood count: Anemia (iron deficiency in CD with small bowel bleeding; B12/folate deficiency in CD with terminal ileum involvement)
• Imaging studies: CT enterography or MR enterography preferred for CD to assess small bowel involvement, fistulas, and strictures; less useful in UC (confined to colon)
• pANCA/ASCA serology: pANCA positive in 70% of UC, ASCA positive in 60% of CD (helps distinguish when endoscopy inconclusive)
• Exclusion of infectious causes: Stool studies (C. difficile, bacterial pathogens, parasites), negative CBC findings before diagnosis

Mild-to-Moderate Disease

• 5-aminosalicylates (5-ASA agents): Mesalamine 2.4-4.8 g/day divided doses (superior in UC; less effective in CD); sulfasalazine 3-6 g/day (avoid in sulfa allergy)
• Corticosteroids (acute flares): Prednisone 40-60 mg/day tapered over 8-12 weeks (induction only; not for maintenance due to side effects)
• Topical agents: Mesalamine enemas/suppositories for distal disease; hydrocortisone enemas for UC rectitis

Moderate-to-Severe Disease

• Immunomodulators: Azathioprine 1-2.5 mg/kg/day or mercaptopurine 1-1.5 mg/kg/day (takes 8-12 weeks; use with allopurinol to inhibit TPMT metabolism); methotrexate 15-25 mg/week (subcutaneous preferred; contraindicated in pregnancy)
• Biologic agents (TNF-α inhibitors—first-line for moderate-severe): Infliximab 5 mg/kg IV at weeks 0, 2, 6 then every 8 weeks; adalimumab 160 mg SC week 0, 80 mg week 2, then 40 mg every 2 weeks; certolizumab pegol; etanercept (less effective in CD)
• Non-TNF biologics: Vedolizumab (α4β7 integrin inhibitor)—effective in refractory disease; ustekinumab (IL-12/IL-23 inhibitor)—increasingly used; natalizumab (α4 integrin inhibitor—risk of PML)

Maintenance Therapy

• UC: Mesalamine for remission maintenance; biologic agents continued if induced remission
• CD: Azathioprine/mercaptopurine or biologics; mesalamine minimal benefit
• Avoid: Antimotility agents (risk of toxic megacolon in UC; increase obstruction risk in CD)

Special Situations

• Pregnancy: Mesalamine, sulfasalazine, corticosteroids, azathioprine, and biologics generally safe; methotrexate and thalidomide contraindicated
• Fulminant colitis/toxic megacolon: ICU admission, IV corticosteroids, broad-spectrum antibiotics, consideration for emergency colectomy
• Refractory disease: Consider escalation to combination biologics, switch biologic class, or surgical intervention (total proctocolectomy for UC; limited resection for CD)

Intestinal Complications

• Strictures and obstruction: More common in CD due to transmural fibrosis and stricturing phenotype; may require endoscopic dilation or surgery
• Fistulas and abscesses: CD-specific (transmural involvement); perianal, enteroenteric, enterovaginal, or enterocutaneous fistulas; require imaging (CT/MRI) and often surgical or biologic intervention
• Toxic megacolon: Acute colonic dilation (>6 cm) with systemic toxicity; more common in UC severe flares; medical emergency requiring ICU monitoring and potential emergency colectomy

Extraintestinal Complications

• Primary sclerosing cholangitis (PSC): ~10-15% of UC patients; associated with HLA-DR3; can develop independently of IBD activity; increases colorectal cancer risk
• Arthropathic manifestations: Type 1 arthropathy correlates with disease activity (may improve with IBD control); type 2 arthropathy independent of activity
• Thromboembolic disease: Hypercoagulability from chronic inflammation increases VTE risk (DVT/PE)

Neoplastic Complications

• Colorectal cancer: Increased risk

• Buzzword pairing: Crohn = skip lesions, cobblestoning, creeping fat, string sign on small bowel imaging, transmural inflammation, and non-caseating granulomas. UC = continuous rectal-to-proximal involvement, lead-pipe colon (loss of haustra), pseudopolyps, backwash ileitis, and crypt abscesses with neutrophils.
• The distractor to avoid: crypt abscesses are not specific to UC and granulomas are absent in the majority of Crohn biopsies — their absence never excludes CD. Likewise, mild ileal inflammation in a pancolitis patient is more likely backwash ileitis than Crohn.
• Single best next step in a suspected flare: stool studies for C. difficile and enteric pathogens before escalating immunosuppression. Superimposed CDI is common and steroids alone will worsen it.
• Best next step before starting an anti-TNF: screen for latent tuberculosis (IGRA or PPD plus chest radiograph) and hepatitis B, since TNF-α is required for granuloma maintenance and blockade causes reactivation with miliary/extrapulmonary disease.
• The association examiners love: UC and primary sclerosing cholangitis — think PSC when alkaline phosphatase is disproportionately elevated; MRCP shows beaded intra- and extrahepatic ducts. PSC independently magnifies colorectal cancer risk, so ACG/AGA advise beginning colonoscopic dysplasia surveillance at PSC diagnosis and continuing annually, versus roughly 8 years after onset of extensive colitis otherwise.
• Terminal ileal Crohn physiology: bile salt and B12 malabsorption produce megaloblastic anemia, gallstones, and calcium oxalate kidney stones from enteric hyperoxaluria — a favorite second-order question.
• Toxic megacolon: colonoscopy and barium enema are contraindicated; diagnose with plain abdominal radiograph and stop opioids/antidiarrheals/anticholinergics.
• Surgery: total proctocolectomy is curative for UC; Crohn recurs at the anastomosis, so resection is reserved for complications.