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Ulcerative Colitis

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Definition & Overview

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Epidemiology

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Pathogenesis

• Activation of cytokines → mucosal inflammation cascade
• Gut microbiota central to pathogenesis; Western diet, early antibiotic use, and reduced microbial exposure increase risk
• Cigarette smoking paradoxically protects against UC (opposite of Crohn disease)
• Genetic loci include IL23R, TKY2 (shared with Crohn), and others
• Approximately 10% of chronic colitis cannot be classified as UC or Crohn — termed indeterminate colitis

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Gross & Microscopic Pathology

• Mucosa is granular, hyperemic, edematous in mild disease
• As severity increases: mucosal ulceration extending into the lamina propria
• Starts in rectum, extends proximally, continuously, affects only the colon
• Pseudopolyps may form from epithelial regeneration after recurrent attacks
• Chronic disease: loss of normal fold pattern, colonic shortening and narrowing
• No fistulas, no strictures (distinguishes from Crohn)

• Early: epithelial necrosis, acute inflammatory infiltrate in lamina propria, cryptitis and crypt abscesses
• Chronic: lymphocytic infiltrate, distortion of crypt architecture (branching and shortening of crypts), goblet cell depletion, Paneth cell metaplasia
• Inflammation is mucosal only (except toxic megacolon, where transmural involvement occurs)
• No granulomas (granulomas favor Crohn)

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Clinical Manifestations

• Blood, mucus, and pus in the stool + diarrhea — the hallmark triad
• Tenesmus, urgency, cramping abdominal pain (especially with bowel movements), nocturnal bowel movements
• Constipation may occur with proctitis (paradoxically)
• Onset can be insidious or acute and fulminant

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Classification

Montreal Classification of Extent (E):

Montreal Severity (S):

Pediatric Ulcerative Colitis Activity Index (PUCAI):

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Diagnosis

• Score 0: Normal mucosa
• Score 1: Erythema, decreased vascular pattern, mild friability
• Score 2: Marked erythema, absent vascular pattern, friability, erosions
• Score 3: Spontaneous bleeding, ulceration

• Anemia (iron deficiency from blood loss, or chronic disease)
• Elevated WBC (only with severe disease), elevated ESR/CRP (may be normal even in fulminant colitis)
• Fecal calprotectin — elevated in active disease, more sensitive/specific than serum markers
• Hypoalbuminemia (active/severe disease)
• pANCA positive ~70%; ASCA-negative helps distinguish from Crohn

• Plain abdominal X-ray: loss of haustral markings; colon diameter >6 cm suggests toxic megacolon
• CT/MRI enterography: used when Crohn must be excluded; barium enema is CONTRAINDICATED in potential toxic megacolon
• Barium enema: historically showed small ulcerations uniformly distributed from rectum proximally; late changes show a featureless, shortened colon

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Extraintestinal Manifestations

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Differential Diagnosis

• Infectious colitis: Campylobacter, Shigella, Salmonella, E. coli O157:H7, C. difficile (especially if postantibiotic; can provoke a UC flare too), Entamoeba histolytica
• Crohn colitis — most difficult distinction, especially in young children; discrete ulcers, perianal disease, granulomas, small bowel involvement favor Crohn
• Hemolytic-uremic syndrome — colitis + schistocytes + thrombocytopenia + renal failure
• Allergic/dietary protein colitis (infants)
• Microscopic colitis, Behçet disease, ischemic colitis

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Treatment

Mild–Moderate UC: 5-Aminosalicylates (5-ASA)

Moderate–Severe UC: Corticosteroids

• Oral prednisone: 1–2 mg/kg/day (40–60 mg max), once or twice daily
• IV methylprednisolone: 40–60 mg/day for severe/hospitalized disease
• Effective for acute flares; not maintenance therapy (loss of effect, significant side effects: growth failure, adrenal suppression, cataracts, osteopenia, avascular necrosis, glucose intolerance)
• If no response to IV steroids in 3–5 days: escalate therapy or proceed to surgery

Immunomodulators

• Azathioprine: 2.0–2.5 mg/kg/day
• 6-Mercaptopurine (6-MP): 1–1.5 mg/kg/day
• Not appropriate for acute severe non-responders (slow onset ~3 months)
• Risk: lymphoproliferative disorders (thiopurines)

Biologics

JAK Inhibitors & Small Molecules

• Tofacitinib (oral JAK inhibitor): 10 mg BID × ≥8 weeks; risks: herpes zoster reactivation, abnormal lipids, thrombosis, lymphoma
• Upadacitinib (selective JAK inhibitor): 45 mg OD × 8 weeks induction → 15 mg OD maintenance (30 mg OD for refractory/extensive disease)
• Ozanimod: sphingosine-1-phosphate receptor modulator → peripheral lymphocyte sequestration
• Broad-spectrum oral antibiotics ×2–3 weeks: being studied in refractory severe pediatric UC

Probiotics

• Effective in adults for maintenance of remission (but do NOT induce remission during active flare)
• Best evidence: prevention of pouchitis following ileal pouch–anal anastomosis

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Surgical Management

1. Total colectomy — curative for UC
2. Optimal: endorectal pull-through with J-pouch ileal pouch–anal anastomosis (IPAA) — preserves continence
3. A temporary loop ileostomy is usually created; closed within months
4. After closure: stool frequency often increased; loperamide may help

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Prognosis & Cancer Surveillance

• Clinical course is marked by remissions and exacerbations
• Only ~5% of children have prolonged remission (>3 years) after initial treatment
• ~25% of children presenting with severe UC require colectomy within 5 years (vs. 5% with mild disease)
• Colon cancer risk begins to rise after 8–10 years of disease, then increases ~0.5–1% per year
• Surveillance colonoscopy every 1–2 years after 8–10 years of disease (earlier with pancolitis, PSC)
• Risk delayed ~10 years in left-sided colitis; proctitis alone confers essentially no increased risk

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Recent Evidence (2024–2026)

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Crohn Disease (Regional Enteritis)

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Definition & Overview

• Transmural (full-thickness bowel wall inflammation)
• Segmental/discontinuous (skip lesions — normal bowel between diseased segments)
• Capable of fistula, stricture, and abscess formation
• Not curable by medical or surgical therapy

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Epidemiology

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Pathogenesis

• Dysregulated immune response to environmental/microbial factors in a genetically susceptible host
• NOD2 gene (on chromosome 16): first identified IBD gene; involved in bacterial recognition, NF-κB activation, autophagy
• Other key genes: IL10, IL10RA, IL10RB, IRGM, ATG16L1, IL23R
• Cigarette smoking increases risk (opposite of UC)
• Gut microbiota play a central role; alterations linked to increasing IBD incidence
• Activated cytokines (especially TNF-α, IL-12, IL-23) drive the inflammatory cascade — these are therapeutic targets

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Gross & Microscopic Pathology

• Aphthous ulcers (earliest lesion) → progress to deep, discrete, serpiginous ulcers
• Cobblestone appearance: longitudinal ulcers crossed by transverse fissures create a "cobblestone" mucosa
• Skip lesions: diseased segments separated by normal bowel
• Transmural inflammation: extends through all wall layers — enables fistula and abscess formation
• Fat creeping/wrapping on the serosal surface (mesenteric fat encircles the bowel)
• Chronic disease: fibrotic strictures (~30% develop fistulas over their disease course)
• Can occur mouth to anus; most common site = ileocecal region

• Early: acute inflammatory infiltrate, cryptitis, crypt abscesses (similar to UC early on)
• Later: lymphocytic infiltrate, crypt architectural distortion (branching and shortening)
• Noncaseating granulomas — the hallmark; found in:
  • Up to 15% of endoscopic biopsy specimens
  • Up to 70% of surgical specimens
  • Not unique to Crohn but strongly supportive when present
• Transmural inflammation — identified only in surgical specimens (not endoscopic biopsies)

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Montreal Classification

Location (L):

Behavior (B):

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Clinical Manifestations

Presentation Patterns

• Diarrhea (often without blood — only 25% have GI bleeding)
• Abdominal pain (especially right lower quadrant — classic)
• Low-grade fever, malaise, fatigue
• Weight loss, anorexia
• Only 25% initially have the classic triad of diarrhea + weight loss + abdominal pain

• Cramping postprandial abdominal pain, borborygmus
• Intermittent abdominal distention
• Partial small bowel obstruction
• Gurgling sensation when intestinal contents pass through a narrowed segment

Systemic Features (more common than in UC)

• Growth failure in pediatric patients: height velocity decreased in ~88% of prepubertal patients — often precedes GI symptoms by 1–2 years
• Weight loss and malnutrition
• Delayed bone maturation and delayed sexual development/puberty
• Primary or secondary amenorrhea
• Digital clubbing
• Fever and malaise

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Extraintestinal Manifestations

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Diagnosis

Laboratory Findings

• CBC: anemia (iron deficiency most common), thrombocytosis (marker of active inflammation)
• ESR and CRP: often elevated but can be normal
• Fecal calprotectin and lactoferrin: more sensitive/specific than serum markers; reflect mucosal neutrophil activity
• Serum albumin: low with active disease or protein-losing enteropathy
• Vitamin B12: low with terminal ileal involvement
• ASCA (anti-Saccharomyces cerevisiae antibodies): positive in 40–70% of Crohn patients (IgA + IgG ASCA highly specific for Crohn: 89–100% specificity)
• pANCA: negative (positive in UC)

ASCA+/pANCA− combination: sensitivity 55%, specificity 93% for Crohn disease

Endoscopy

• Patchy erythema, friability, aphthous ulcers, linear ulcers, cobblestone pattern, nodularity, strictures
• Biopsies: noncaseating granulomas (pathognomonic if present), chronic inflammatory changes
• Transmural inflammation only visible in surgical specimens

• Evaluates small bowel mucosa not accessible by standard endoscopy
• CONTRAINDICATED in stricturing disease (risk of capsule retention)
• Patency capsule should be used first if stricture is suspected

Radiology

• Normal, or shows partial small bowel obstruction, thumbprinting of the colon wall (submucosal edema)

• Aphthous ulcers, thickened/nodular folds, luminal narrowing/strictures
• Linear ulcers → cobblestone appearance
• Separation of bowel loops (mesenteric thickening/fat)

• Mural hyperenhancement, mural thickening, "comb sign" (engorged peri-enteric vessels resembling comb teeth — from hypervascularity adjacent to inflamed loop)
• Detects extraluminal complications: intraabdominal abscess, fistulas, perianal involvement
• MRI is preferred (no ionizing radiation) especially in children; MR pelvis for perianal disease
• Bowel ultrasound: can show mural thickening and hyperemia; no radiation

Disease Activity Scoring

• Composite of subjective symptoms + objective findings
• Remission: CDAI < 150
• Response: decrease in CDAI ≥ 100 points
• Used primarily in clinical trials; symptoms alone do not always correlate with endoscopic activity

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Differential Diagnosis

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Treatment

Step-up vs. Top-down Approach

• Step-up (traditional): start with 5-ASA/steroids; escalate if needed
• Top-down (increasingly preferred, especially in pediatrics): start with biologic therapy early to achieve mucosal healing, improve remission rates, reduce cumulative steroid exposure and long-term complications

5-Aminosalicylates (5-ASA)

• Mesalamine: 50–100 mg/kg/day (max 3–4 g/day); pH-dependent release
• Less effective in Crohn than in UC; not useful for maintenance in moderate-severe disease

Antibiotics

• Metronidazole: 5 mg/kg/dose TID (up to 250 mg TID) — infectious complications and first-line for perianal disease
  • Perianal disease usually recurs when stopped
  • Low-dose may treat mild-moderate Crohn disease
• Ciprofloxacin: used for perianal and colonic disease
• Note: antibiotics effective for perianal fistulas; disease usually recurs on stopping

Corticosteroids

• Oral prednisone: 1–2 mg/kg/day (max 40–60 mg); once or twice daily for acute exacerbations
• Taper as soon as disease is quiescent (clinicians vary in schedules)
• No role for maintenance corticosteroids — tolerance develops; no mucosal healing; significant side effects (growth failure, adrenal suppression, cataracts, osteopenia, avascular necrosis, glucose intolerance)
• Enteric-release budesonide: 9 mg/day — for mild-moderate ileal/ileocecal Crohn; lower systemic bioavailability (10%); more effective than mesalamine but less effective than prednisone; fewer steroid side effects

Immunomodulators

Biologic Therapy

Anti-TNF-α Agents

Anti-Integrins

Anti-IL-12/23 and Anti-IL-23

Enteral Nutritional Therapy (Exclusive Enteral Nutrition / EEN)

• All calories delivered via formula (elemental, semi-elemental, or polymeric)
• Equivalent in onset/efficacy to prednisone for clinical symptoms
• Superior to steroids for mucosal healing
• Side-effect free; avoids corticosteroid complications; simultaneously addresses nutritional rehabilitation
• Often given via nasogastric tube overnight (formulas are unpalatable)
• Patients cannot eat a regular diet during treatment
• A partial EEN approach (80–90% formula + some food) has shown success and is better tolerated
• High-calorie oral supplements: less effective but useful for inadequate weight gain

Total Parenteral Nutrition (TPN)

• No primary therapeutic benefit for Crohn (unlike short bowel syndrome where it's necessary)
• Used pre-operatively to optimize nutritional status if oral/enteral intake is insufficient
• Consider octreotide adjunctively for high-output fistulas (reduces GI secretions, decreases fistula output)

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Complications & Their Management

Abscesses

• Occur in 15–20% of patients (especially terminal ileum)
• Intra-abdominal abscess: fever, abdominal pain, tenderness, leukocytosis; diagnose by CT scan
• Treatment: broad-spectrum antibiotics (include anaerobic coverage) + percutaneous CT/US-guided drainage
• Surgical resection of involved bowel usually required for definitive treatment (persistent communication between abscess and intestinal lumen)
• Hepatic/splenic abscess: may occur with or without local fistula
• Psoas abscess: hip pain, decreased hip extension (psoas sign), fever

Obstruction

• Common in small intestine; leading indication for surgery
• Causes: mucosal thickening (acute inflammation), muscular hyperplasia and scarring, food impaction in stricture, adhesions
• Treatment:
  • Acute inflammatory obstruction: corticosteroids (IV methylprednisolone 40–60 mg/day, or hydrocortisone 200–300 mg/day × 5–14 days) + nasogastric decompression
  • Fibrotic/fixed stricture: surgery (resection or strictureplasty)
  • ⚠️ Common error: treating fixed fibrotic obstruction with prolonged steroids (ineffective, delays surgery)

Perianal Disease

• Assessment: examination under anesthesia; cross-sectional CT or MRI for extent of perianal abscesses
• Perianal abscess: painful; requires drainage (often surgical); local redness, tenderness, fluctuation
• Perianal fistula: seton placement by surgeon (keeps tract open while medical therapy works) → fistulotomy only if sphincter not at risk
• Medical therapy: metronidazole, infliximab, adalimumab, certolizumab, ustekinumab, vedolizumab, azathioprine/6-MP; disease often recurs when stopped
• Diversion of fecal stream can reduce perianal disease activity

Fistulas

Short Bowel Syndrome

• Rare in children; risk increases with each intestinal resection
• Consequences of terminal ileal resection (>100 cm): vitamin B12 malabsorption, bile acid malabsorption (diarrhea), fat malabsorption → oxaluria → calcium oxalate renal stones
• Increased calcium intake paradoxically decreases oxalate stone risk (binds oxalate in gut)
• Increased cholelithiasis risk: bile acid depletion from terminal ileal disease/resection

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Surgical Management

Indications for Surgery

• Localized small bowel or colonic disease unresponsive to medical treatment
• Fibrosed stricture with symptomatic partial small bowel obstruction
• Bowel perforation
• Intractable bleeding
• Intraabdominal abscess refractory to drainage

Surgical Principles

• Remove as limited a length of bowel as possible — conservative resection (no benefit to removing histologically involved margins; reduces risk of short bowel syndrome)
• Laparoscopic approach preferred — reduced postoperative recovery
• Strictureplasty (rather than resection): for short strictures without active disease — longitudinal incision closed transversely; preserves bowel length; reoperation rate equivalent to resection
• Diversion of fecal stream: temporary for severe perianal disease (disease recurs on reconnection)
• Postoperative prophylaxis: mesalamine, metronidazole, azathioprine, or infliximab to reduce postoperative recurrence

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Prognosis

• Chronic, high-morbidity but low-mortality disease
• Symptoms recur despite treatment, often without apparent explanation
• Growth failure: up to 15% of patients with early growth retardation have permanent decrease in linear growth
• Osteopenia: especially with chronic malnutrition + frequent corticosteroid exposure; DEXA scan to identify at-risk patients; treat with vitamin D, calcium, weight-bearing exercise
• Region of bowel involved and complications tend to increase over time
• Most patients eventually require surgery; reoperation rate is high
• Colon cancer risk: long-standing Crohn colitis → risk approaches that of UC; surveillance colonoscopy every 1–2 years after 8–10 years of colonic disease
• Most children lead active, full lives with intermittent flare-ups

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Crohn vs. Ulcerative Colitis — Key Distinctions

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Recent Evidence (2024–2026)

• A 2024 network meta-analysis (PMID 38185396) compared advanced therapies for endoscopic outcomes in Crohn disease — ustekinumab and combination anti-TNF + immunomodulator therapy showed superior mucosal healing in network comparisons.
• A 2025 Lancet Gastroenterology consensus (PMID 40315877) proposed novel diagnostic criteria and management guidance specifically for isolated perianal Crohn disease — an historically underrecognized phenotype.

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