Peptic ulcer pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ;Associate Editor(s)-in-Chief: Fahad Hasan, M.D.[2] Manpreet Kaur, MD [3]
Overview
Peptic ulcer disease develops when aggressive luminal factors (acid, pepsin, bile) overwhelm the gastroduodenal mucosal barrier. That barrier depends on tight epithelial junctions, an adherent mucus layer, bicarbonate secretion, and prostaglandin-maintained mucosal blood flow.[1][2] Helicobacter pylori causes chronic active gastritis, and the anatomic pattern of that gastritis determines the ulcer type. Antral-predominant gastritis produces hypergastrinemia and acid hypersecretion, which leads to duodenal ulcer. Pangastritis produces hypochlorhydria and gastric ulcer, along with a risk of atrophy and gastric cancer.[3] NSAIDs and aspirin injure the mucosa through COX-1-mediated prostaglandin depletion and through direct topical toxicity. NSAID-associated ulcers are often painless until bleeding or perforation occurs.[4][5] In critical illness, stress-related mucosal injury results from mucosal hypoperfusion, independent of H. pylori or NSAID exposure.[6] H. pylori and NSAIDs act synergistically, so the combination carries greater risk of ulceration and bleeding than either factor alone.[1]
Pathophysiology
Normal Mucosal Defense
The gastroduodenal mucosal barrier has three interdependent components:[1]
- Tight epithelial junctions that resist back-diffusion of acid and pepsin into the submucosa
- Adherent mucus layer (glycoprotein gel) that resists proteolysis and slows acid diffusion
- Bicarbonate secretion by surface epithelial cells, which neutralizes acid at the mucus-epithelial interface
Endogenous prostaglandins maintain this barrier. These are largely derived from COX-1. They sustain mucosal blood flow, stimulate mucus and bicarbonate secretion, and promote epithelial proliferation and restitution.[5] Disruption of any of these components predisposes to ulceration, whether the cause is pharmacologic, infectious, or ischemic.
Helicobacter pylori
H. pylori colonizes the gastric epithelial surface, where it is shielded from luminal acid. Its spiral morphology and flagella allow it to penetrate the mucus layer.[3] Bacterial urease hydrolyzes urea to ammonia and bicarbonate. This buffers local acid and reduces mucus viscosity, which aids bacterial motility.[3]
Several factors mediate epithelial injury and the host immune response:[3]
- Virulence factors, including CagA, VacA, and OipA
- Bacterial phospholipases
- The neutrophil-predominant cytokine response (IL-8, TNF-α, IL-1)
Together these produce chronic active gastritis and impair tight junctions and the mucus-bicarbonate barrier.
The anatomic distribution of gastritis largely determines the ulcer phenotype:[3][1]
| Feature | Antral-predominant gastritis | Corpus-predominant gastritis / pangastritis |
|---|---|---|
| Key mechanism | Antral inflammation suppresses D-cell somatostatin. This disinhibits G-cell gastrin release. | Inflammation extends into the acid-secreting corpus and causes gland atrophy. |
| Acid secretion | Increased. Hypergastrinemia drives histamine release from enterochromaffin-like cells, which increases parietal cell acid output. | Decreased (hypochlorhydria). |
| Duodenal consequence | Excess acid delivered to the duodenum causes gastric metaplasia of the duodenal bulb. This metaplastic tissue can be colonized by H. pylori and ulcerate. | None specific. |
| Ulcer phenotype | Duodenal ulcer | Gastric ulcer |
| Long-term implication | Eradication corrects the mechanism and markedly reduces recurrence. | Precursor to atrophic gastritis, intestinal metaplasia, and gastric cancer. |
NSAIDs and Aspirin
NSAIDs and aspirin injure the mucosa through both systemic and local mechanisms:[4][5]
- COX-1 inhibition is the dominant systemic mechanism. It depletes protective prostaglandins, which reduces mucosal blood flow, mucus and bicarbonate secretion, and epithelial repair.
- COX-2 inhibition impairs healing and leukocyte-endothelial interactions. COX-2 is mainly inducible rather than constitutive in normal mucosa.
- Direct topical toxicity acts independently of COX inhibition. Acidic, lipophilic NSAIDs disrupt the mucus phospholipid layer and uncouple mitochondrial oxidative phosphorylation, which injures epithelial cells directly.
Prostaglandins sensitize submucosal pain fibers. As a result, NSAID-associated ulcers are more often clinically silent and are more likely to present first with bleeding or perforation.[5]
Selective COX-2 inhibitors (e.g., celecoxib) spare COX-1 and cause less gastroduodenal toxicity than nonselective NSAIDs. The risk is reduced but not eliminated.[4][5]
Ulcer risk increases with NSAID dose and duration, with concurrent use of multiple NSAIDs, and with combined antiplatelet therapy.[1]
Stress-Related Mucosal Disease
In critical illness, several factors impair mucosal perfusion and defense:[6]
- Hypovolemia
- Reduced cardiac output
- Catecholamine-mediated splanchnic vasoconstriction
- Release of proinflammatory cytokines
These produce stress-related mucosal injury independent of H. pylori or NSAID exposure.
Interaction Between H. pylori and NSAIDs
H. pylori infection and NSAID use each independently impair mucosal defense. Together they act synergistically, raising the risk of ulceration and ulcer bleeding above that of either factor alone.[1]
Clinical Correlates
- Testing: The H. pylori-related mechanism persists until the organism is eradicated. For this reason, H. pylori testing is recommended for all patients with active or prior peptic ulcer disease.[7]
- Recurrence: The antral-predominant mechanism (hypergastrinemia followed by acid hypersecretion) explains why eradication is particularly effective at preventing duodenal ulcer recurrence.[3]
- Silent presentation: NSAID ulcers are frequently painless. Consider NSAID or aspirin use in any patient whose first presentation is a bleeding or perforated ulcer without preceding dyspepsia.[5]
- Combined risk: Ask about NSAID and aspirin use in H. pylori-positive patients, and test NSAID users for H. pylori, because the two mechanisms commonly coexist and compound each other's risk.[1]
- Critical illness: Stress-related mucosal disease is a distinct entity. Consider it in critically ill patients without H. pylori infection or NSAID exposure.
Areas of Uncertainty
- The clinical contribution of COX-independent injury, such as mitochondrial toxicity and membrane damage, relative to COX-1-mediated prostaglandin depletion is not fully resolved.[4]
- The mechanisms of ulcers that are both H. pylori-negative and NSAID-negative ("idiopathic" ulcers) are poorly defined, even though their proportion appears to be rising.[2]
- It is incompletely characterized how strain-level virulence, such as cagA/vacA variation, interacts with host factors to determine gastric versus duodenal phenotype.[3]
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Lanas A, Chan FKL (2017). "Peptic ulcer disease". Lancet.
- ↑ 2.0 2.1 Almadi MA, Lu Y, Alali AA, Barkun AN (2024). "Peptic ulcer disease". Lancet.
- ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 Crowe SE (2019). "Helicobacter pylori infection". N Engl J Med.
- ↑ 4.0 4.1 4.2 4.3 Bjarnason I, Scarpignato C, Holmgren E; et al. (2018). "Mechanisms of damage to the gastrointestinal tract from nonsteroidal anti-inflammatory drugs". Gastroenterology.
- ↑ 5.0 5.1 5.2 5.3 5.4 5.5 Wolfe MM, Lichtenstein DR, Singh G (1999). "Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs". N Engl J Med.
- ↑ 6.0 6.1 Vakil N (2024). "Peptic ulcer disease: a review". JAMA.
- ↑ Chey WD, Howden CW, Moss SF, et al. ACG Clinical Guideline: Treatment of Helicobacter pylori Infection. 2024.