Medicine Marrow Pg 31-40 (GIT)

Management of Inflammatory Bowel Disease

• Supportive care and replacement therapy
• Gene therapy

Investigations

• Genetic testing

Markers of T-reg cells

• CD3: Pan T-cell marker
• CD25: T-reg cell
• CD4: Helper T-cell

Early Onset Childhood IBD

• Defect in IL-10 or IL-10 receptor function
• Severe refractory IBD in early life

Pathogenesis of IBD

• Exogenous and endogenous factors → Dysregulated mucosal immune response in a genetically susceptible individual.
• Most potent anti-inflammatory cytokine in the body: IL-10

Ulcerative Colitis

• Pathogenesis is unclear.
• Overactive adaptive immune system: Th lineage.

Crohn's Disease

• Genetically susceptible individuals:
  • NOD2 (CARD15) gene polymorphism on chromosome 16.
• Dysregulated mucosal immune response:
  • Defective innate immunity:
    • Decreased clearance of intracellular organisms (mycobacterium paratuberculosis, m.avium complex)
    • Decreased defensin production from Paneth cells
    • Defective autophagy
• Overactive adaptive immune system (Th lineage: Crohn's disease).
• Decrease in gut bacteria like Faecalibacterium (Gut protective).

Epidemiology

• Overall:
  • CD > UC
  • Males > Females

Comparison of UC and CD

• Female : Male Ratio:
  • UC: No information available
  • CD: No information available
• Age:
  • UC: 2 peaks: 15-30 years & 70-90 years
  • CD: No information available
• Ethnicity:
  • UC: Jews > Non-Jewish white > African American > Hispanic > Asian
  • CD: No information available
• Smoking:
  • UC: Protective
  • CD: Causative
• Appendicectomy:
  • UC: Protective
  • CD: No association
• OCP:
  • UC: No increased risk
  • CD: Increased risk
• Familial Inheritance (Concordance):
  • UC: No information available
  • CD: Significant CD > UC
• Antibiotics in 1st year of life:
  • UC: No information available
  • CD: Increases risk of IBD by 3 times

Behçet's disease

• GI manifestations like Crohn's disease.
• Share a common antibody: ASCA (Anti-Saccharomyces cerevisiae antibody).

Prolonged use of α-methyl dopa

• Causes features similar to ulcerative colitis.

Campylobacter jejuni

• Risk factor for IBD
• Also causes large bowel diarrhea, Guillain Barre syndrome.

Mucosa

• Villi are absent.
• Crypts: Contain microvilli - water absorption.
• Goblet cells: Secrete mucus.
• Diarrhea > 200 ml of stool volume.

Genetic Syndromes Associated With IBD

• Present as IBD in childhood:

Genetic Syndromes - UC (Non-granulomatous)

• Turner's syndrome: m/c

Genetic Syndromes - CD (Granulomatous)

• Wiskott-Aldrich Syndrome
• von Gierke's disease
• Hermansky-Pudlak syndrome

Clinical Features of Genetic Syndromes

IMMUNE POLYENDOCRINOPATHY X-LINKED SYNDROME (IPEX)

• Physiology: FOXP3: Transcription factor → Normal T-reg cell function (Cell tolerance)
• Pathology: Loss of FOXP3 function → Reduced cell tolerance → IPEX syndrome.
• Triad of:
  • Endocrinopathy (Type 1 Dm / Thyroiditis)
  • Dermatitis
  • uc-like enteropathy

Microscopy

• Transmural involvement: Involvement extends up to the muscularis propria, potentially leading to fissures and fistulas.
• Serosa involvement: This is a specific type of transmural involvement affecting the serosa layer.
• Non-caseating granulomas: Granulomas are present at various levels and can even form outside the intestine.
• Changes in crypts:
  • Cryptitis: Inflammation of the crypts
  • Crypt abscesses: Abscesses (pus-filled pockets) within the crypts.
• Crypt architecture: The structure of the crypts appears normal.
• Pyloric metaplasia: A change in the pyloric region of the intestine.
• Lymphoid aggregates: Clusters of lymphoid tissue.
• Possible causes of non-caseating granulomas:
  • Sarcoidosis
  • Tuberculosis
  • Cat Scratch disease
  • Berylliosis
  • Hypersensitivity pneumonitis
  • Crohn's disease

Crohn's Disease vs Intestinal Tuberculosis

• Involvement of ICV:
  • Crohn's disease: Common
  • Intestinal Tuberculosis: Usually strictured and patulous ICV
• Involvement of colon:
  • Crohn's disease: ≥4 segments, especially terminal ileum and ICV
  • Intestinal Tuberculosis: No information available.

Microscopy - Ulcerative Colitis

• Superficial Involvement: mucosa & superficial part of submucosa
• Cryptitis with loss of crypt architecture
• Paneth cell metaplasia (Seen distal to hepatic flexure)
• Basal plasma cell and lymphoid aggregates
  • Earliest finding
  • Can help in diagnosing relapse in remission patients

Factors against the diagnosis of ulcerative colitis

• Transmural involvement
• Skip lesions
• Deep ulcers

Pathology: Crohn's Disease

• Site of Involvement:
  • Ileocolitis: 40-50%
  • Ileitis: 30-40%
  • Colitis: 15-20%

Macroscopy - Crohn's Disease

• Deep, transmural, asymmetric skip lesions
• Earliest finding: Aphthous ulcers → Small, translucent ulcers
• Most visible finding: Linear, Serpenginous ulcers
• Cobblestone appearance: The ulcers fuse longitudinally and transversely with areas of uninvolved mucosa in between
• Peri rectal fissures, fistulas and abscesses
  • Fistula tracts resolve by fibrosis
    • a.Thickening of the wall
    • b.Strictures

Garden Hose Appearance

• Tubular lumen with extensive transmural fibrosis and stenosis seen in terminal ileum
• Creeping fat: Thickened mesentery encasing the bowel wall
• Note: Garden hose appearance in esophagus → well developed progressive systemic sclerosis

Pathology: Ulcerative Colitis

• Site of Involvement:
  • Rectum alone: 50%
  • Extension to sigmoid colon: 30-40%
  • Pancolitis (Rectum, sigmoid, colon involved): 10-20%
  • 10-20% of pancolitis patients: Ileum involvement → Backwash ileitis

Macroscopy - Ulcerative Colitis

• Superficial, continuous, symmetrical lesions
• Continuous involvement: Rectum → Sigmoid → Colon → Ileum (No skip lesions)
• 1st Change: Erythematous mucosa with fine, granular surface
• Hemorrhagic, edematous, ulcerated mucosa
• Pseudopolyps: Inflammatory polyp d/t epithelial regeneration

Chronic Long-Standing UC (rare)

• Lead pipe appearance (Atrophic, featureless colon):
  • a.Loss of haustrations
  • b.Shortening and narrowing of colon
• Fulminant colitis (very rare): Toxic megacolon (Colon diameter >6mm).

Additional Information

• Haustrations:
  • Present (uninvolved colon)
  • Absent
• Lead pipe appearance: Seen on barium study

Barium Enema Radiology

• Normal mucosa: A healthy lining of the colon.
• Fine mucosal granularities: Tiny, granular bumps on the mucosal layer.
• Superficial ulcerations: Shallow sores affecting the surface of the lining.
• Extensive ulcerations: Deeper sores affecting more of the lining.
• Inflammatory pseudopolyps: Small growths caused by inflammation.
• Deep ulcers extending to submucosa: Deep sores that penetrate into the submucosal layer.
• Collar stud ulcers: Ulcers with a characteristic collar-like appearance.
• Lead pipe appearance: Abnormally uniform, straight appearance of the colon (often associated with inflammation/strictures).
• Toxic megacolon: Extreme dilation of the colon.

Crohn's Disease

• Clinical Features:
  • Ileocolitis (most common):
    • Episodic right lower quadrant pain.
    • Relieved with diarrhea (Large bowel diarrhea d/t colitis).
  • D/t Th, profile (IL-2, IFN Y):
    • Fever.
    • Weight loss.
    • Systemic symptoms.
  • Jejunoileitis: Malabsorption due to inflammation of the jejunum and ileum.
  • Palpable inflammatory mass: Thickening of the bowel wall due to inflammation.
  • Bowel obstruction: Blockage of the bowel.
  • Fistulas: Abnormal connections between the bowel and other structures (Enterovesical > Perianal).
  • Fissures: Cracks in the bowel lining.
  • Fibroses & strictures: Scar tissue and narrowings in the bowel.

Additional Notes - Crohn's Disease

• Earliest change: Fine mucosal granularities.
• Serrations producing hazy margin.
• Mild narrowing of lumen.
• Loss of rectal valves.
• Backwash ileitis (Inflammation of terminal ileum).

Ulcerative Colitis - Clinical Features

• Based on the level of involvement:

Proctitis

• Painless bleeding PR (most common)
  • Differential Diagnosis (D/d):
    • Hemorrhoids
    • Malignancies
• Slow proximal transit → Constipation
• Normal physical examination.
• Systemic symptoms: very rare (Th2 lineage → Involves IL-4, 5, 13).
• 90% have relapsing course.

Proctosigmoiditis

• Streaks of blood onto formed stool.

Proctocolitis

• Large bowel diarrhea:
  • 1.Small, frequent stools with blood, pus, and mucus.
  • 2.Tenesmus

Fecal calprotectin

• most sensitive biomarker.
• used to assess disease severity, response to Rx & to diagnose relapse.

Endoscopy - Ulcerative Colitis

• Symmetrical, superficial, and continuous involvement.
• Findings:
  • Erythematous, red, velvety mucosa (earliest).
  • ↓sed vascularity → mucosal ulcerations with fine granulations and friability (Mayo score)
• Lead pipe/pipestem colon (very rare in endoscopy).

Radiology - Barium Enema - Ulcerative Colitis

• Target Sign: Characterized by mucosal ulcers with surrounding translucent edema.
• Significance: Earliest radiologic and endoscopic finding for IBD.

CT Scan - IBD

• Limited Role: CT scanning plays a limited role in diagnosing IBD, with MR enterography being preferred.
• Possible findings:
  • String sign: Indicates a fibrosed bowel.
  • Sinus tracts: Visible on the image as a tract or channel.
  • Fissures and string sign: Indicate specific pathologies.
  • Target appearance: Presence of thickened colonic walls.
  • Comb sign: A sign typically associated with Crohn's disease, implying hypervascular mesentery.
  • Fat halo sign: Describes a particular appearance.
  • Tissue Attenuation: The inner and outer layers of tissues show soft tissue attenuation, while the middle layer displays fatty attenuation.

Other Appearances - CT Scan - IBD

• Longitudinal ulceration
• Cobblestone appearance
• Rose thorn (Transmural ulcers)