Can peptic ulcer disease develop without elevated gastric acidity (normal or low gastric pH)?

Can Peptic Ulcer Disease Develop Without Acidic pH?

Yes, peptic ulcer disease can absolutely develop in the setting of normal or even low gastric acidity, though acid remains a necessary cofactor in most cases.

The Evolving Understanding of PUD Pathophysiology

The traditional dictum "no acid, no ulcer" has been fundamentally challenged by modern research. While acid and pepsin remain necessary ingredients in the ulcerative process, they are not sufficient on their own to cause ulceration 1, 2.

Key Evidence Against Acid Hypersecretion as Primary Cause

• The majority of gastric ulcers and a substantial number of duodenal ulcers do not have increased gastric acid secretion 2
• Studies have failed to demonstrate a correlation between acid output and clinical outcomes of ulcer disease, or between ulcer recurrence rates after vagotomy and preoperative acid secretion 3
• Research has been unable to consistently demonstrate increased acidity in the duodenal bulb in patients with duodenal ulcer 3

The Shift to Mucosal Defense Mechanisms

Modern understanding emphasizes that peptic ulcers result from a disequilibrium between aggressive factors and defensive mechanisms, with failing mucosal defense being equally or more important than acid hypersecretion 1.

Dominant Mechanisms That Cause PUD Without Elevated Acidity

H. pylori Infection (Primary Cause)

• H. pylori is now recognized as the leading cause of PUD, present in most gastric ulcers and all duodenal ulcers in the absence of NSAIDs and gastrinoma 2
• The infection works by disrupting mucosal defense and regeneration processes, not by increasing acid 4
• H. pylori actually inhibits bicarbonate secretion, a key mucosal protective mechanism, independent of acid levels 3

NSAID-Induced Ulceration

• NSAIDs cause significant numbers of gastric and duodenal ulcers primarily through inhibition of prostaglandin production with loss of protective effects, not through acid hypersecretion 2
• This mechanism operates independently of gastric acidity levels 1, 5
• Multiple guidance statements recognize NSAID-induced ulcers as a major category requiring PPI gastroprotection regardless of baseline acid status 4

Impaired Mucosal Defense

• Gastric ulcers often occur with decreased acid-peptic activity, suggesting mucosal defensive impairments are the primary problem 2
• The combination of inflammation, protective deficiencies, and even moderate amounts of acid and pepsin may be sufficient to induce ulceration 2
• Disruption of the bicarbonate secretion, mucus layer, epithelial tight junctions, and mucosal blood flow can lead to ulceration even with normal acid 1, 3

Clinical Algorithm for Understanding PUD Without Elevated Acidity

Step 1: Identify the Underlying Mechanism

• Check for H. pylori infection - present in most cases without hypersecretion 4
• Review medication history - NSAIDs, aspirin, corticosteroids 4, 2
• Assess for vascular disorders - impaired mucosal perfusion 1
• Consider caustic injury or physicochemical damage 1

Step 2: Recognize That Acid is Necessary But Not Sufficient

• Even moderate amounts of acid (normal physiologic levels) combined with impaired defense mechanisms can cause ulceration 2
• The pH gradient from luminal acid to near-neutrality at epithelial cells is disrupted in PUD, even without acid hypersecretion 3

Step 3: Treatment Implications

• PPI therapy works by creating an environment where even normal defensive mechanisms can heal the ulcer, not necessarily by correcting acid hypersecretion 1
• Healing rates correlate with acid suppression in duodenal ulcer but not entirely in gastric ulcer, supporting the role of non-acid mechanisms 6
• H. pylori eradication prevents ulcer recurrence by restoring mucosal defense, independent of acid reduction 4

Important Clinical Caveats

• Hypersecretory states like Zollinger-Ellison syndrome are exceptions where acid hypersecretion is the primary mechanism and patients should never have PPIs de-prescribed 4
• During Ramadan fasting, increased gastric acid and pepsin secretion during daytime can activate peptic ulcers, but this occurs on a background of pre-existing mucosal vulnerability 4
• Rebound acid hypersecretion after PPI discontinuation can cause symptoms, but this is a physiologic phenomenon related to parietal cell proliferation during therapy, not the original ulcer mechanism 4

The Bottom Line

Peptic ulcers develop when mucosal defense mechanisms fail in the presence of any amount of acid and pepsin—even normal physiologic levels. The emphasis has shifted from viewing PUD as primarily an acid hypersecretion disease to understanding it as predominantly a mucosal defense failure disease, with H. pylori infection and NSAID use being the two dominant mechanisms that operate largely independent of baseline gastric acidity 1, 2, 3.