Inflammatory Bowel Disease Pathology — Crohn and UC

Genetic Susceptibility

• NOD2/CARD15 mutations (most strongly associated with CD, particularly ileal disease) result in impaired bacterial sensing and dysregulated nuclear factor-kappa B (NF-κB) signaling
• IL23R polymorphisms increase susceptibility to both CD and UC through altered T-helper 17 (Th17) cell differentiation
• Over 200 genome-wide association study (GWAS) loci identified; many involved in innate immunity (pattern recognition receptors), autophagy, and IL-23 signaling
• Monozygotic twin concordance ~40-50% in CD, ~15% in UC, indicating multifactorial inheritance

Innate Immune Dysfunction

• Defective antimicrobial peptide production (reduced defensins and lysozyme in CD)
• Impaired intestinal barrier function: decreased tight junction proteins (claudins, occludin, zonula occludens-1), increased epithelial permeability, and loss of mucus layer integrity
• Dysregulated pattern recognition receptor signaling (TLR2, TLR4, NOD2) leading to abnormal bacterial sensing
• Aberrant neutrophil recruitment and activation, particularly in UC with formation of crypt abscesses

Adaptive Immune Response

• Th1/Th17-mediated predominance in CD: elevated IL-12, IFN-γ, IL-17 production driving interleukin-2 (IL-2) and tumor necrosis factor-alpha (TNF-α) secretion
• Th2-mediated response in UC: elevated IL-5 and IL-13; increased eosinophilic infiltration
• Loss of regulatory T cell (Treg) function: reduced IL-10 and TGF-β production, diminished Foxp3+ CD4+ T cells
• Dysbiosis: altered microbiota composition with decreased microbial diversity and loss of short-chain fatty acid (SCFA)-producing bacteria (Faecalibacterium prausnitzii, Roseburia spp.)

Epithelial and Mucosal Pathology

• Crypt architecture distortion: loss of normal straight parallel crypts in both conditions
• Increased intraepithelial lymphocytes (IELs): predominantly CD8+ T cells; >5-7 IELs/100 epithelial cells considered abnormal
• Goblet cell depletion: reduced mucin-secreting cells and decreased mucus layer thickness
• Epithelial regeneration abnormalities: impaired barrier repair due to increased apoptosis and cytokine-induced epithelial damage

Microbial and Environmental Factors

• Dysbiosis with expansion of pathobionts and reduction in protective commensals
• Molecular mimicry: bacterial antigens cross-reactive with intestinal epithelial antigens
• Loss of tolerance to self-antigens through defective immune regulation
• Environmental triggers (smoking worsens CD, protective in UC; diet; infections; antibiotics; NSAIDs)

Genetic Factors

• NOD2/CARD15 mutations: present in 40-50% of CD patients, 10% of UC patients; homozygous mutations confer 40-fold increased risk for ileal CD
• IL23R, STAT3, JAK2, ATG16L1 polymorphisms
• FUT2 gene variants affecting carbohydrate metabolism and glycosylation patterns

Environmental Risk Factors

• Smoking: increases CD risk and severity; protective effect in UC (paradoxically)
• Antibiotic use: early life exposure increases IBD risk through dysbiosis
• NSAIDs and oral contraceptives: modest increased risk
• High-fat, high-refined carbohydrate diet: reduced fiber and SCFA production
• Infections: Measles, enteroviruses, and atypical mycobacteria (Mycobacterium avium subspecies paratuberculosis) hypothesized but not definitively causative
• Appendectomy: protective against UC (possibly through altered immune development)

Immune System Dysregulation

• Loss of immune homeostasis with excessive pro-inflammatory Th1/Th17 responses
• Decreased Foxp3+ regulatory T cells and IL-10-producing cells
• Impaired innate lymphoid cell (ILC) function

Host-Microbiota Interactions

• Dysbiosis with reduced Faecalibacterium prausnitzii (butyrate producer)
• Expansion of pathobionts including adherent-invasive E. coli (AIEC)
• Loss of microbial metabolite production (short-chain fatty acids, secondary bile acids)

Crohn's Disease—Distribution-Specific Features

• Chronic diarrhea (often non-bloody, 3-4+ stools/day)
• Right lower quadrant pain simulating appendicitis; often postprandial and colicky
• Weight loss and malnutrition: due to malabsorption (terminal ileum involvement) and reduced oral intake
• Perianal disease (20-30% of patients): fistulas, skin tags, abscesses (pathognomonic)
• Palpable right lower quadrant mass (inflamed bowel loops or abscess)

• Chronic intermittent diarrhea
• Malabsorption syndrome: steatorrhea, deficiencies in B12, iron, fat-soluble vitamins
• Often missed on colonoscopy; requires small bowel imaging (capsule endoscopy, MR enterography)

• Bloody diarrhea, tenesmus, urgency (more prominent than ileal disease)
• Universal involvement of rectum (but non-continuous disease with "skip lesions")
• Toxic megacolon possible (though more common in UC)

• Fever (indicates active inflammation or complications like abscess)
• Abdominal distension and pain
• Growth retardation in pediatric CD (delayed puberty, linear growth failure)
• Extraintestinal manifestations (25-35% of patients):
• Arthritis/arthralgia (sacroiliitis, peripheral arthritis): HLA-B27 associated
• Erythema nodosum: appears on lower extremities, correlates with IBD activity
• Pyoderma gangrenosum: painful necrotic ulcers, independent of gut activity
• Uveitis, episcleritis: can precede GI symptoms
• Primary sclerosing cholangitis (PSC): more common in UC (1-4%), leads to cirrhosis
• Aphthous ulcers, oral ulcerations

Ulcerative Colitis—Continuous Mucosal Disease

• Rectal bleeding and mucus per rectum: bright red blood on toilet paper
• Tenesmus and urgency: frequent small stools
• Lower abdominal/rectal pain, especially with defecation
• No systemic symptoms if disease limited to rectum

• Bloody diarrhea (3-6+ stools/day)
• Left lower abdominal cramping
• Tenesmus, urgency, nocturnal diarrhea
• May progress to pancolitis

• Severe bloody diarrhea (10-20+ stools/day, often overnight)
• Systemic toxicity: fever, tachycardia, hypotension
• Severe abdominal pain and distension
• Risk of acute severe ulcerative colitis (ASUC) and toxic megacolon (colonic dilation >5.5 cm with perforation risk)
• Fulminant colitis: sepsis, hypotension, altered mental status; mortality 5-10% even with treatment

• PSC (3-7% of UC patients, rare in CD): associated with worse prognosis and increased colorectal cancer risk
• Arthritis, erythema nodosum, pyoderma gangrenosum
• Uveitis more common in UC than CD

Physical Examination Findings

• Abdominal distension, tenderness (periumbilical in UC; RLQ in CD)
• Rebound tenderness and guarding (suggests perforation or severe inflammation)
• Visible fistulous tracts, perianal erythema/skin tags (CD only)
• Pallor (from anemia of chronic disease or acute bleeding)
• Clubbing (long-standing disease)
• Hepatomegaly (from PSC or fatty infiltration)
• Dermatologic findings: erythema nodosum, pyoderma gangrenosum

Laboratory and Imaging Correlates

• Anemia: microcytic (iron deficiency) or macrocytic (B12/folate deficiency); hemoglobin often correlates with disease activity
• Elevated inflammatory markers: C-reactive protein (CRP) >10 mg/L and erythrocyte sedimentation rate (ESR) in active disease; fecal calprotectin >200 μg/g indicates intestinal inflammation
• Hypoalbuminemia (<3.5 g/dL): reflects chronic inflammation and malnutrition
• Elevated transaminases, alkaline phosphatase: suggests PSC
• Abdominal imaging (CT or MR enterography): shows bowel wall thickening, mesenteric fat stranding, fistulas (CD), or continuous superficial ulceration (UC)

Endoscopic Findings

• "Skip lesions": alternating areas of normal and inflamed mucosa (diagnostic hallmark)
• Cobblestone appearance: due to intersecting longitudinal and transverse ulcers with intervening raised nodular mucosa
• Aphthous ulcers: small shallow ulcers with halos on normal-appearing mucosa; earliest visible lesion
• Linear or stellate ulcers: deep, longitudinally oriented ulcerations
• Strictures: narrowing of lumen (fibrostenosing disease)
• Fistulas and sinus tracts: visible in rectum/colon
• Erythema, edema, loss of vascular pattern: signs of inflammation
• Rectal sparing common (unlike UC)

• Continuous inflammation starting at rectum, extending proximally without skip lesions
• Loss of vascular pattern: earliest change (normal mucosa shows vessel arborization)
• Granular, friable mucosa: appears rough and bleeds easily
• Mucosal ulceration: shallow ulcers with surrounding mucosa hyperemia
• Crypt distortion and crypt abscesses: visible as punctate exudates
• Pseudopolyps: regenerative islands of residual mucosa between ulcerated areas
• Backwash ileitis: inflammation of terminal ileum in continuity with colonic disease (indicates severe disease)
• Leadpipe appearance: loss of haustral markings on barium imaging due to fibrosis

Histopathology—The Gold Standard for Diagnosis

• Non-caseating granulomas: present in 30-50% of biopsies, 60% of resection specimens; found in any layer including submucosa and muscularis propria; absence does NOT exclude CD
• Full-thickness inflammation: extends from mucosa through muscularis propria and into serosa; patchy distribution
• Crypt distortion: irregular crypt architecture with loss of parallel orientation
• Increased intraepithelial lymphocytes (IELs): >5-7/100 epithelial cells; predominantly CD8+
• Subepithelial lymphocytic aggregates
• Preserved submucosal fat: characteristic finding distinguishing CD from UC
• Fissuring ulcers: deep ulcerations penetrating through submucosa
• Relatively preserved goblet cells (compared to UC)
• Skip lesions: histologically normal mucosa between inflamed areas
• Fibrosis and stricture formation: from repeated cycles of inflammation and healing

• Continuous inflammation limited to mucosa and superficial submucosa (NOT transmural)
• Crypt distortion and architectural disarray: loss of parallel crypts; irregular branching
• Crypt abscesses: collections of neutrophils within crypts, often with crypt rupture
• Marked goblet cell depletion: loss of mucin-secreting cells, decreased mucus
• Increased intraepithelial lymphocytes: predominantly CD8+ T cells
• Increased plasma cells in lamina propria: polyclonal, non-granulomatous inflammation
• Granulomas absent in UC (if present, raises suspicion for CD)
• Regenerative changes: hyperplastic mucosa with mucin depletion
• Flattened mucosa: complete loss of crypt architecture in severe disease
• Pseudopolyps: regenerating mucosa between areas of ulceration; histologically normal
• Increased intraepithelial eosinophils and neutrophils

Key Histological Distinction

Gross Pathology

• Bowel wall thickening: due to transmural fibrosis and inflammation
• "String sign" on barium imaging: narrow segment from spasm and wall fibrosis
• "Cobblestone" mucosa: intersecting linear ulcers creating nodular appearance
• Mesenteric fat wrapping: encroachment of fat onto serosal surface ("comb sign" on imaging)
• Skip lesions: alternating involved and normal segments
• Fistulas and sinus tracts: penetrating through wall

• Continuous mucosal ulceration starting at rectum
• Shallow ulcers with remnants of hyperplastic mucosa between (pseudopolyps)
• Loss of haustral markings: featureless "leadpipe" appearance
• Minimal wall thickening unless severe fibrosis develops
• Mucosa friable and hemorrhagic in active disease

Laboratory Investigations

• Fecal calprotectin/lactoferrin: markers of intestinal neutrophil infiltration; >200 μg/g highly sensitive for active IBD, useful for noninvasive monitoring
• Complete blood count: anemia (Hgb often

Immediate stabilisation (acute severe colitis)

• Hospitalise and resuscitate: IV fluids, transfuse for symptomatic anemia, correct potassium and magnesium (hypokalemia predisposes to colonic dilation). ACG guidance for acute severe ulcerative colitis directs stool testing for Clostridioides difficile and CMV assessment on biopsy in steroid-refractory cases, plus pharmacologic VTE prophylaxis despite bloody stools — IBD is a hypercoagulable state.
• IV corticosteroids (e.g., methylprednisolone) are first-line induction. Unresponsiveness by day 3–5 triggers rescue therapy with infliximab or cyclosporine, with early surgical consultation.

First-line maintenance/induction by disease

• Aminosalicylates (mesalamine): first-line induction and maintenance for mild-to-moderate UC per the ACG UC guideline; rectal mesalamine for proctitis, oral plus rectal for left-sided disease. Not effective in Crohn disease — a favourite distractor.
• Corticosteroids: induction only, never maintenance. Budesonide (high first-pass metabolism, ileal-release) is preferred for mild ileocecal Crohn disease per the ACG Crohn guideline.
• Immunomodulators: thiopurines (azathioprine) for steroid-sparing maintenance; methotrexate as an alternative in Crohn disease.

Escalation / second-line

• Anti-TNF agents (infliximab, adalimumab): mainstay for moderate-to-severe and fistulizing Crohn disease; combination with a thiopurine reduces immunogenicity.
• Anti-integrin vedolizumab (gut-selective α4β7) and anti-IL-12/23 or anti-IL-23 ustekinumab/risankizumab.
• JAK inhibitors (tofacitinib, upadacitinib) for UC after anti-TNF failure; FDA boxed warnings for zoster, thrombosis, and major cardiovascular events.

Definitive/surgical

• Total proctocolectomy with ileal pouch–anal anastomosis is curative in UC; Crohn disease recurs at anastomoses, so surgery is bowel-sparing (limited resection, strictureplasty) for obstruction, abscess, or fistula.

Contraindicated/avoid

• Opioids and antimotility agents (loperamide) in severe colitis — precipitate toxic megacolon.
• NSAIDs (flares), and anti-TNF without prior latent TB and hepatitis B screening.

Emergencies

• Toxic megacolon (EMERGENCY): transmural inflammation paralyses colonic smooth muscle with nitric oxide–mediated dilation; signalled by colonic diameter >6 cm on plain film with fever, tachycardia, and a paradoxically decreasing stool frequency. Colonoscopy and barium enema are contraindicated — they risk perforation.
• Free perforation and peritonitis (EMERGENCY): rebound, guarding, free air; more common in UC pancolitis and in steroid-masked patients.
• Massive lower GI hemorrhage (EMERGENCY): ulceration into submucosal vessels.
• Intra-abdominal or perianal abscess (EMERGENCY in Crohn): transmural fissuring ulcers penetrate the serosa; fever with a tender mass — drain before immunosuppression, since anti-TNF into an undrained abscess causes sepsis.

Disease-related (chronic)

• Fibrostenotic stricture and obstruction: Crohn > UC; postprandial cramping, string sign.
• Fistulas (enteroenteric, enterovesical, enterocutaneous): pneumaturia/fecaluria signals enterovesical.
• Colorectal adenocarcinoma: chronic inflammation drives an inflammation–dysplasia–carcinoma sequence (unlike sporadic adenoma–carcinoma); risk rises with disease duration, extent, and coexisting PSC. ACG recommends surveillance colonoscopy beginning about 8 years after diagnosis, and at PSC diagnosis.
• Terminal ileal disease/resection: B12 deficiency, bile-salt malabsorption diarrhea, cholesterol gallstones, and calcium oxalate nephrolithiasis (unabsorbed fat binds calcium, freeing oxalate for absorption).
• Venous thromboembolism, AA amyloidosis, growth failure in children, and PSC with cholangiocarcinoma risk (UC).

Treatment-related

• Corticosteroids: hyperglycemia, osteoporosis, adrenal suppression, masked perforation.
• Thiopurines: myelosuppression with low TPMT/NUDT15 activity, pancreatitis, non-melanoma skin cancer, and hepatosplenic T-cell lymphoma in young males on thiopurine plus anti-TNF.
• Anti-TNF: latent TB and hepatitis B reactivation, demyelination, heart-failure exacerbation.
• Mesalamine: interstitial nephritis. Pouchitis after ileal pouch–anal anastomosis.

• Non-caseating granuloma = Crohn; crypt abscess = UC: the single most tested histologic pair. Granulomas appear in a minority of Crohn biopsies, so their absence never excludes Crohn — the classic distractor.
• Depth decides the complication: transmural Crohn inflammation explains fistulas, abscesses, strictures, and creeping fat; mucosa-limited UC explains bloody diarrhea, pseudopolyps, and lead-pipe colon.
• Smoking: worsens Crohn, protective in UC. Examiners reverse this deliberately. Appendectomy is likewise protective against UC.
• PSC is the UC association: a young man with UC and a cholestatic pattern (elevated alkaline phosphatase) plus beading on MRCP — next step is MRCP, and he needs colonoscopic surveillance from the time of PSC diagnosis because his colorectal cancer risk is the highest of any IBD subgroup.
• Best next step in suspected toxic megacolon: abdominal plain film, not colonoscopy or barium enema — instrumentation perforates the atonic colon. Stop opioids and loperamide, and send stool for C. difficile.
• Terminal ileum is the Crohn organ: B12 deficiency, bile-acid diarrhea, cholesterol gallstones, and calcium oxalate kidney stones all trace back to it. A Crohn patient with a radiopaque stone is enteric hyperoxaluria until proven otherwise.
• Colectomy cures UC, not Crohn: total proctocolectomy with ileal pouch–anal anastomosis is definitive in UC (watch for later pouchitis); Crohn recurs at the anastomosis, so surgery is bowel-sparing.
• Serology is supportive, never diagnostic: p-ANCA leans UC, ASCA leans Crohn — biopsy plus endoscopic distribution remains the standard. Mesalamine works in UC and disappoints in Crohn.