Peptic Ulcer Disease - Pathophysiology & Treatment

(Full-Marks MBBS Physiology Answer)

DEFINITION

• Most common sites: within a few cm of the pylorus, the duodenal cap (D1), and the lesser curvature of the gastric antrum
• A marginal ulcer can occur at a surgical gastrojejunostomy anastomosis

Fig. 67.1 - Guyton and Hall Textbook of Medical Physiology: Causes and sites of peptic ulcer

PATHOPHYSIOLOGY

Core Concept: Imbalance Between Aggressive and Defensive Factors

Aggressive Factors > Defensive Factors → PEPTIC ULCER

A. DEFENSIVE (MUCOSAL PROTECTIVE) FACTORS

B. AGGRESSIVE (DAMAGING) FACTORS

1. Helicobacter pylori (Most Important - >70% of PUD)

• Gram-negative, spiral, flagellated bacterium that colonizes gastric mucosa
• Survives in acidic pH by producing urease enzyme → converts urea to NH3 → alkalinizes the local microenvironment
• NH4+ (in equilibrium with NH3) is itself cytotoxic to mucosal cells
• Releases cytotoxins (CagA toxin, VacA) that break down the protective mucous barrier
• Burrows through mucus, adheres to gastric epithelial cells, and triggers inflammation

• Gastric ulcer: Direct mucosal damage - H. pylori colonizes antral mucosa, breaks down barrier → H+ and pepsin attack unprotected epithelium
• Duodenal ulcer (indirect): H. pylori inhibits somatostatin secretion from D cells → loss of somatostatin inhibition of G cells → ↑ gastrin → ↑ H+ secretion → excess acid load in duodenum. Additionally, H. pylori spreads to duodenum and inhibits duodenal HCO3- secretion → insufficient neutralization → duodenal erosion

2. NSAIDs and Aspirin

• Inhibit cyclo-oxygenase (COX-1) → reduced prostaglandin (PGE2) synthesis
• Loss of PGE2 → reduced mucus and HCO3- secretion, reduced mucosal blood flow → barrier breakdown
• NSAIDs also have a direct topical irritant effect on gastric epithelium

3. Acid Hypersecretion

• In duodenal ulcer: acid secretion can be up to twice normal
• In Zollinger-Ellison syndrome: gastrinoma (pancreatic islet cell tumor) secretes gastrin constitutively → massive acid hypersecretion → multiple peptic ulcers (stomach, duodenum, even jejunum)
• Parietal cell hyperplasia (increased parietal cell mass) in duodenal ulcer patients

4. Other Factors

C. FEEDBACK CONTROL MECHANISMS (NORMALLY PROTECTIVE - IMPAIRED IN PUD)

1. When excess acid enters the duodenum → inhibits gastric secretion and peristalsis via nervous reflexes and hormonal feedback → slows gastric emptying
2. Acid in the small intestine → releases secretin from S cells → stimulates pancreatic NaHCO3 secretion → neutralizes acid

COMPARISON: GASTRIC ULCER vs DUODENAL ULCER

ZOLLINGER-ELLISON SYNDROME (Special High-Yield Topic)

• Pancreatic islet cell adenoma (gastrinoma) secretes gastrin uncontrollably
• Massive H+ secretion → multiple, refractory peptic ulcers in stomach, duodenum, and jejunum
• Steatorrhoea: excess H+ inactivates pancreatic lipase → fat malabsorption
• Gastrin not feedback-inhibited by H+ (unlike normal G cells)
• Treatment: PPIs (high-dose), surgical removal of tumor

TREATMENT OF PEPTIC ULCER DISEASE

1. H. PYLORI ERADICATION THERAPY

Standard Triple Therapy (14 days - first line where clarithromycin resistance <15%):

• PPI (omeprazole 20 mg BD) + Clarithromycin 500 mg BD + Amoxicillin 1g BD
• Eradication rates: 70-85%
• If penicillin-allergic: replace amoxicillin with metronidazole

Bismuth Quadruple Therapy (first line where clarithromycin resistance >15%):

• PPI + Bismuth subcitrate + Tetracycline + Metronidazole × 14 days

Test of cure: Repeat 13C-urea breath test or stool antigen test 4 weeks after completing therapy (while OFF PPIs)

2. ACID SUPPRESSION DRUGS

A. Proton Pump Inhibitors (PPIs) - Drug of Choice

• Drugs: Omeprazole, Pantoprazole, Lansoprazole, Rabeprazole, Esomeprazole
• Mechanism: Irreversibly bind and block H+/K+-ATPase (proton pump) on the luminal surface of parietal cells → inhibit final step of acid secretion → suppress acid by ~90%
• Note: Are prodrugs - require acidic environment for activation
• Uses: PUD, GERD, Zollinger-Ellison, H. pylori eradication regimens
• Side effects (long-term): Hypomagnesaemia, C. difficile infection, osteoporosis, dementia risk, community-acquired pneumonia, renal injury
• Drug interaction: PPIs (especially omeprazole) inhibit CYP2C19 → reduce activation of clopidogrel (give PPI in morning, clopidogrel at night to minimize)

B. H2-Receptor Blockers (H2 Antagonists)

• Drugs: Ranitidine, Famotidine, Cimetidine, Nizatidine
• Mechanism: Competitively block H2 receptors on parietal cells → reduce histamine-stimulated acid secretion by 70-80%
• Cimetidine special points: weak anti-androgenic effect; potent CYP enzyme inhibitor (multiple drug interactions)
• Use: Milder PUD; maintenance therapy; OTC heartburn relief

C. Potassium-Competitive Acid Blockers (P-CABs) - Newer Class

• Drug: Vonoprazan (FDA-approved), Tegoprazan, Revaprazan
• Mechanism: Competitively bind to the potassium-binding site of H+/K+-ATPase → reversible inhibition
• Advantage: Faster onset than PPIs; effective in H. pylori eradication (may be superior to PPIs in combination therapy)

D. Antacids

• Drugs: Aluminium hydroxide [Al(OH)3], Magnesium hydroxide [Mg(OH)2], Sodium bicarbonate, Calcium carbonate
• Mechanism: Chemically neutralize secreted HCl → raise gastric pH → inactivate pepsin (inactive above pH 4)
• Use: Symptomatic relief only; not disease-modifying
• Side effects: Al(OH)3 → constipation; Mg(OH)2 → diarrhoea; combined to cancel out

E. Sucralfate (Cytoprotective)

• Mechanism: Sucrose sulfate-aluminum complex; polymerizes in the acidic ulcer bed forming a viscous paste that physically coats and protects the ulcer crater; binds growth factors (EGF), stimulates prostaglandin synthesis and mucus/HCO3- secretion
• Given: 4x daily (1g before meals and at bedtime) - very insoluble, no systemic effects
• Use: Adjunct in PUD; safe in pregnancy and renal failure (minimal absorption)

F. Misoprostol (Cytoprotective Prostaglandin Analogue)

• Mechanism: PGE1 analogue → replaces prostaglandins inhibited by NSAIDs → maintains mucosal barrier, stimulates mucus and HCO3- secretion
• Use: Prevention of NSAID-induced gastric ulcers (especially in high-risk patients)
• Side effects: Diarrhoea, abdominal cramps; contraindicated in pregnancy (uterotonic - used in obstetrics for this reason)

3. GENERAL MEASURES (Lifestyle)

• Avoid NSAIDs, aspirin (use paracetamol instead)
• Stop smoking (reduces mucosal blood flow, impairs healing)
• Avoid alcohol
• Avoid caffeine (stimulates acid secretion)
• Small, frequent meals
• Avoid eating 2-3h before bedtime

4. SURGICAL TREATMENT (Rarely needed now)

• Highly selective vagotomy (HSV) / Proximal gastric vagotomy: Cuts vagal branches to parietal cells only (preserves antral innervation) → reduces acid secretion
• Truncal vagotomy + pyloroplasty/drainage: Cuts both vagal trunks; needs drainage procedure because of gastric atony
• Partial gastrectomy (Billroth I or II): Removes acid-secreting mucosa; rarely done today
• Complications: Dumping syndrome, diarrhoea, afferent loop syndrome, pernicious anaemia (after total gastrectomy)

COMPLICATIONS OF PEPTIC ULCER (MBBS Must-Know)

QUICK SUMMARY DIAGRAM

H. pylori / NSAIDs / Acid Hypersecretion
              ↓
  Breakdown of Mucosal Barrier
  ↓                        ↓
  ↓ Mucus/HCO3-       ↑ H+ & Pepsin
              ↓
       PEPTIC ULCER
       
Treatment:
  Eradicate H. pylori (Triple/Quadruple therapy)
  + Suppress Acid (PPI > H2 blocker)
  + Protect Mucosa (Sucralfate, Misoprostol)