A 52-year-old man from Delhi presents with a 6-month history of epigastric pain and heartburn. Upper endoscopy reveals a large duodenal ulcer with active bleeding. On further questioning, he reports taking NSAIDs daily for chronic knee pain. Laboratory investigations show serum gastrin level of 85 pg/mL (normal <100 pg/mL) and gastric pH of 1.8. Which of the following best explains the mechanism of ulcer formation in this patient?

Explanation

## Mechanism of NSAID-Induced Gastric Ulceration **Key Point:** NSAIDs cause ulcers primarily through inhibition of cyclooxygenase (COX) enzymes, which reduces prostaglandin E₂ (PGE₂) synthesis. PGE₂ is essential for maintaining mucosal integrity. ### Pathophysiology of NSAID Ulcers Prostaglandins, particularly PGE₂, exert cytoprotective effects on the gastric mucosa through multiple mechanisms: 1. **Stimulation of mucus secretion** — PGE₂ acts on EP3 receptors on mucus-secreting cells 2. **Stimulation of bicarbonate secretion** — PGE₂ enhances HCO₃⁻ output from surface epithelial cells 3. **Maintenance of mucosal blood flow** — PGE₂-mediated vasodilation ensures nutrient delivery 4. **Epithelial cell proliferation and migration** — promotes healing and restitution When NSAIDs block COX-1 and COX-2, PGE₂ levels drop sharply, and all four protective mechanisms fail simultaneously. This leaves the mucosa vulnerable to acid-peptic injury despite normal or even low gastric acid secretion. **High-Yield:** In NSAID-induced ulcers, gastric acid secretion is typically **normal or reduced**, not elevated. The problem is not excess acid but loss of mucosal defense. ### Why This Patient's Findings Support This Mechanism - **Serum gastrin 85 pg/mL (normal)** — rules out Zollinger-Ellison syndrome - **Gastric pH 1.8 (acidic)** — confirms acid is present, but the ulcer is due to impaired defense, not acid overproduction - **Daily NSAID use** — the clear culprit - **Large, bleeding ulcer** — typical of NSAID pathology (often in antrum and duodenum) ### Comparison: NSAID vs. H. pylori vs. ZES Ulcers | Feature | NSAID Ulcer | H. pylori Ulcer | Zollinger-Ellison | |---------|-------------|-----------------|-------------------| | **Gastrin level** | Normal | Normal | Markedly elevated (>1000) | | **Gastric pH** | Normal to low | Normal to low | Very acidic (<2) | | **Mechanism** | Loss of PGE₂-mediated defense | Chronic inflammation + acid | Acid hypersecretion | | **Location** | Antrum, duodenum | Antrum, lesser curve | Duodenum (often distal) | | **Treatment** | Stop NSAID + PPI | Eradicate H. pylori | PPI + surgery | **Clinical Pearl:** The presence of a normal serum gastrin level in a patient with an active duodenal ulcer effectively excludes Zollinger-Ellison syndrome and points to either NSAID use or H. pylori infection. The NSAID history is the decisive clue here.