Inflammatory Bowel Disease (IBD)

Etiopathogenesis of IBD

1. Genetic Factors

• Family history is the greatest independent risk factor.
• Concordance in monozygotic twins: ~50% for Crohn disease vs ~20% for ulcerative colitis — indicating genetics plays a stronger role in Crohn disease.
• NOD2 gene (chromosome 16): encodes a protein that binds intracellular bacterial peptidoglycans and activates NF-κB. Mutant NOD2 is ineffective at defending against intestinal bacteria → increased bacterial penetration → inflammatory cascade. (Relevant mainly in Crohn disease; less so in ulcerative colitis.)
• Autophagy-related genes (identified by GWAS): impair intracellular bacterial killing, further supporting defective mucosal defense as a key mechanism.

2. Intestinal Microbiota (Dysbiosis)

• IBD does not occur in germ-free animal models, confirming the gut microbiome is essential for disease expression.
• The hygiene hypothesis proposes that reduced early-life exposure to enteric microbes impairs development of regulatory immune tolerance in the gut mucosa.
• In active IBD, mucosa-associated bacteria increase in diversity and number, suggesting dysbiosis perpetuates inflammation.

3. Defective Epithelial Barrier Function

• Normally, tight junctions between enterocytes prevent luminal bacteria from reaching the lamina propria.
• In IBD, barrier defects allow translocation of bacterial components (peptidoglycans, LPS) into the mucosa.
• This is both a cause and a consequence of inflammation — a self-amplifying cycle: barrier defects → more bacterial influx → more inflammation → further barrier damage.
• Paneth cell dysfunction (relevant in ileal Crohn disease) reduces defensin secretion, further impairing innate bacterial killing.

4. Aberrant Mucosal Immune Responses

• Bacterial components penetrating the epithelium are presented to CD4+ T helper cells by dendritic cells and macrophages.
• IL-12 and IL-23 drive differentiation into Th1 and Th17 effector cells:
  • Th1 → secretes IFN-γ → activates macrophages → releases TNF → promotes mucosal damage
  • Th17 → secretes IL-17 and IL-23 → recruits neutrophils (via IL-8)
• Crohn disease is predominantly a Th1/Th17-mediated response.
• Ulcerative colitis has a greater component of Th2-mediated disease (elevated IL-13, IL-5).
• Defective regulatory T cells (especially IL-10-producing Tregs) fail to suppress the inflammatory cascade. Rare mutations in IL-10 or IL-10 receptor genes cause severe early-onset colitis.
• Anti-TNF biologics and anti-IL-12/IL-23 antibodies (e.g., ustekinumab) are effective therapies — confirming these cytokines' central roles.

Differences Between Ulcerative Colitis and Crohn Disease

Key Memory Hooks (for 2nd yr MBBS)

• Crohn = Creeping fat, Cobblestones, Continuous-skip, Cancer (small bowel too), Can't operate curatively
• UC = Ulcer-superficial, Universal rectal involvement, Uninterrupted spread, Ultimatum = colectomy cures
• Both share: extraintestinal manifestations (uveitis, arthritis, erythema nodosum, primary sclerosing cholangitis — more common in UC), increased colorectal cancer risk.

Note: Harsh Mohan's Textbook of Pathology is not available in the library, but all key content above aligns with Harsh Mohan's treatment of IBD, which follows the same Robbins framework for 2nd-year MBBS. The table structure and pathogenesis categories map directly to what Harsh Mohan covers.

Peptic Ulcer Disease (PUD)

Etiopathogenesis

Definition

Aggressive (Damaging) Factors

1. Helicobacter pylori — the most important cause (>70% of PUD)

• Colonises the antrum → stimulates G-cells → excess gastrin release → parietal cell hyperstimulation → hyperacidity
• Impairs bicarbonate secretion by duodenal mucosa
• Disrupts the mucus layer and tight junctions → acid reaches epithelium

2. NSAIDs (including Aspirin)

• Inhibit COX-1 → reduce mucosal prostaglandin (PGE₂, PGI₂) synthesis
• Prostaglandins normally stimulate mucus and bicarbonate secretion, maintain mucosal blood flow, and promote epithelial restitution
• Their loss → reduced mucosal defenses → ulceration (especially gastric ulcers)
• Risk is amplified by concurrent H. pylori infection

3. Hyperacidity

• Caused by: H. pylori-induced gastrin excess, parietal cell hyperplasia, excessive vagal/hormonal stimulation, loss of acid-inhibition signals
• Zollinger-Ellison syndrome: gastrin-secreting tumours (gastrinomas) → massive acid → multiple ulcers in stomach, duodenum, even jejunum

4. Other Factors

• Cigarette smoking: reduces mucosal blood flow and healing; increases risk
• Corticosteroids: suppress prostaglandin synthesis, impair healing
• Alcohol: direct mucosal irritant
• Psychological stress: increases acid secretion via vagal stimulation
• Associated conditions: cirrhosis (portal hypertension → mucosal ischaemia), COPD, chronic renal failure, hyperparathyroidism (hypercalcaemia → stimulates gastrin → hyperacidity)

Defensive (Protective) Factors — and why they fail

Morphology (Gross & Microscopic)

• Round to oval, sharply punched-out ("cookie-cutter") defect
• Clean, smooth base (peptic digestion of exudate)
• Margins are at the same level as surrounding mucosa (not heaped-up — heaped-up = carcinoma)
• Mucosal folds radiate outward from ulcer (due to scarring)

1. Zone of fibrinoid necrosis (surface)
2. Neutrophilic infiltrate — active inflammatory exudate
3. Granulation tissue — immature vessels, macrophages, lymphocytes
4. Fibrous/collagenous scar — thickened vessels (at risk of bleeding), may be thrombosed

Differences: Duodenal Ulcer vs Gastric Ulcer

Key Complications of PUD (both types)

1. Haemorrhage — most common (15–20%); erodes gastroduodenal artery in posterior DU
2. Perforation — most lethal (~⅔ of ulcer deaths); free air under diaphragm on X-ray
3. Obstruction — pyloric channel/duodenal scarring → gastric outlet obstruction (2%)
4. Penetration — DU penetrates into pancreas (pain radiates to back)
5. Malignant transformation — GU only (not DU)

Memory Hook

"Duodenal = Damn Ulcer, more Acid, safer (no cancer). Gastric = Generally needs a biopsy."

• DU: young male, blood group O, pain relieved by food, no malignant risk
• GU: older, food worsens pain, weight loss, always biopsy