The two dominant, largely modifiable risk factors for peptic ulcer disease (PUD) are Helicobacter pylori infection and use of aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs). Together they account for roughly 70% to 78% of cases.^[1][2] These two exposures interact synergistically, so combined exposure raises ulcer bleeding risk more than either alone.^[3][4] In NSAID users, the strongest predictor of a future ulcer complication is a prior ulcer complication. Concomitant corticosteroids, anticoagulants, antiplatelet agents, or SSRIs and older age further amplify risk.^[4][2] Additional independent associations include cigarette smoking, alcohol use, male sex, diabetes mellitus, and cardiovascular disease.^[5] The proportion of idiopathic ulcers (negative for both H. pylori and NSAIDs) is rising as H. pylori prevalence declines.^[1][2]

• H. pylori is identified in approximately 42% of patients with PUD.^[1]
• Only about 10% of infected individuals develop an ulcer, compared with about 1% of uninfected individuals. This gap reflects the contribution of bacterial virulence factors, host genetics, and environmental cofactors.^[1]
• Infection is usually acquired in childhood through person-to-person transmission. It is associated with crowded living conditions and poor water quality.^[1]
• Household size is associated with PUD, but the association differs by sex.^[6]
  • In men, risk was higher with larger households.
  • In women, risk was lower in the largest households.
• Global seroprevalence has fallen from approximately 58% (1980–1990) to approximately 43% (2011–2022). United States rates are lower: about 20% by serology and about 9% by endoscopic testing in a large outpatient cohort.^[1]

NSAID-associated ulcer risk is dose- and duration-dependent:^[7]

• The interaction is synergistic rather than additive. Ulcer bleeding risk is increased 1.79-fold with H. pylori alone, 4.85-fold with NSAIDs alone, and 6.13-fold with both.^[3][4]
• Among NSAID users, uncomplicated PUD is more common in H. pylori-positive than H. pylori-negative patients (41.7% vs 25.9%; OR 2.12, 95% CI 1.68–2.67).^[1]
• Eradicating H. pylori before starting long-term NSAID therapy lowers subsequent ulcer risk (RR 0.35, 95% CI 0.20–0.61, vs placebo).^[3]
• Eradication alone does not remove risk in patients at high GI risk, such as those with prior ulcer bleeding. These patients need concomitant acid suppression; see primary prevention.^[3][4]

• Prior ulcer complication: this is the single strongest predictor of a future NSAID-related ulcer complication.^[4]
• Age: age over 65–70 years identifies NSAID users who warrant prophylaxis.^[2]
• Prior PUD, whether complicated or uncomplicated.^[2]
• Concomitant drugs: antiplatelet agents, anticoagulants, corticosteroids, and SSRIs.^[2]
• Corticosteroids:
  • Corticosteroids alone are not independently ulcerogenic at doses up to prednisone-equivalent 35 mg/day for 2 months.
  • They substantially increase ulcer bleeding risk when combined with NSAIDs.^[1][4]

A large case-control study (20,622 patients) used multivariable logistic regression to identify the following independent predictors of PUD:^[5]

• Lower income and lower educational attainment are associated with PUD.^[6]
• Adverse childhood circumstances, such as crowding and poor water quality, are also associated with PUD.^[1]
• These associations likely act partly through H. pylori acquisition. Behavioral confounders such as smoking and alcohol use also contribute.^[6]

• Psychological and physical stress:
  • Some population studies show an association with PUD, while others show none.
  • The discrepancy likely reflects confounding by smoking, alcohol use, and socioeconomic status.
  • Proposed mechanisms are altered gastroduodenal blood flow and impaired mucosal defense.^[8][6]
• Dyspepsia in NSAID users: it is unsettled whether dyspepsia is an independent risk factor for ulcer development or simply a presenting symptom.^[4]
• Idiopathic ulcers:
  • Ulcers negative for both H. pylori and NSAIDs now represent about 22% of cases.
  • Their underlying risk factors are incompletely defined.^[1][7]

• Rare acid-hypersecretory states should be considered in patients with multiple, refractory, distal duodenal/jejunal, or recurrent ulcers, particularly when H. pylori and NSAID exposure are absent. These states include:
  • Zollinger-Ellison syndrome^[9][10][11]
  • Systemic mastocytosis
  • Retained gastric antrum after Billroth II gastrectomy
  • Chronic hypercalcemia
  • Basophilic/myeloproliferative disorders
• These conditions are causes rather than risk factors. They are covered in the causes microchapter.^[12][13]

• H. pylori infection is far from sufficient for ulcer formation: only about 10% of infected individuals develop PUD.^[1]
• Ask specifically about over-the-counter NSAID and low-dose aspirin use, because patients often do not volunteer it.^[3]
• Do not attribute an ulcer to corticosteroids alone without looking for concomitant NSAID or antiplatelet use.^[1][4]
• Risk rises sharply with NSAID use of 3 years or longer and with combined NSAIDs, anticoagulants, or corticosteroids. Reassess GI risk whenever these agents are added.^[7][4]