Peptic Ulcer Disease II: Pathophysiology

H. pylori produces the enzyme urease, which hydrolyzes urea into ammonia and carbon dioxide. This creates a localized alkaline microenvironment around the bacterium, neutralizing gastric acid and allowing it to survive. The ammonia also reduces mucus viscosity, enhancing the bacterium's motility toward the epithelial surface.

H. pylori injects cytotoxin gene-associated protein A (CagA) through a type IV secretion system, disrupting cellular signaling and cell junctions. Vacuolating toxin A (VacA) forms membrane pores, damages mitochondria, induces apoptosis, and suppresses T-cell responses. These virulence factors collectively damage the gastric epithelium and promote immune evasion.

NSAIDs inhibit cyclooxygenase-1 (COX-1) enzymes, reducing prostaglandin synthesis. Prostaglandins are essential for mucus secretion, bicarbonate secretion, blood flow, and mucosal repair. Without adequate prostaglandins, gastric defenses weaken, exposing the mucosa to acid and pepsin, which erode the tissue and cause ulcer formation.

H. pylori alters its surface proteins to avoid recognition by toll-like receptors and induces regulatory T cells, which suppress inflammatory T-helper cell responses. This immune evasion allows persistent infection and chronic inflammation, gradually damaging the stomach lining and leading to ulcer development.

Both H. pylori infection and NSAID use impair mucosal defense, leading to chronic inflammation, epithelial damage, and necrosis. Ulcers appear as well-defined lesions extending into the submucosa. In severe cases, ulcers penetrate deeper layers, potentially causing perforation and peritonitis, which can lead to clinical manifestations and complications.

H. pylori uses its spiral, corkscrew shape and flagella to penetrate the gastric mucus layer. Once through the mucus, it employs mucolytic enzymes to further break down the protective barrier. The bacterium then adheres to gastric epithelial cells using outer membrane proteins, establishing infection.

Prostaglandins are critical for maintaining gastric mucosal defense by promoting mucus secretion, bicarbonate secretion, and blood flow to the mucosa. They also support cellular repair mechanisms. When prostaglandin synthesis is inhibited by NSAIDs, these protective functions fail, leaving the mucosa vulnerable to acid and pepsin damage.