Peptic ulcer risk factors
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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
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]
Risk Factors
Established Risk Factors
Helicobacter pylori Infection
- 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 and Aspirin Use
NSAID-associated ulcer risk is dose- and duration-dependent:[7]
| Exposure | Risk estimate |
|---|---|
| Single NSAID | OR 1.64 (95% CI 1.43–1.87)[7] |
| Multiple concurrent NSAIDs | OR 3.82 (95% CI 2.16–6.73)[7] |
| NSAID use under 3 months | OR 1.07 (95% CI 0.84–1.35)[7] |
| NSAID use for 3 or more years | OR 2.46 (95% CI 1.92–3.16)[7] |
| High-dose NSAID (e.g., ibuprofen ≥1200 mg/day, naproxen ≥500 mg/day) vs lower dose | GI complication rate 15% vs 4%[1] |
| Low-dose aspirin alone | Relative risk of GI bleeding 2–4. Pooled RCT meta-analysis (>57,000 patients): RR 2.07 for significant GI bleeding[3] |
| Dual antiplatelet therapy (aspirin plus clopidogrel) | OR 2.62 (95% CI 1.12–6.11), independent of aspirin dose or duration[7] |
Interaction Between H. pylori and NSAIDs
- 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]
Factors That Amplify Risk in NSAID and Aspirin Users
- 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:
Additional Independent Risk Factors
A large case-control study (20,622 patients) used multivariable logistic regression to identify the following independent predictors of PUD:[5]
| Factor | Adjusted OR | Modifiable |
|---|---|---|
| NSAID use | 2.58 | Yes |
| H. pylori positivity | 2.41 | Yes |
| Age ≥60 years | 1.65 | No |
| Corticosteroid co-administration | 1.48 | Yes |
| Cigarette smoking | 1.45 | Yes |
| Diabetes mellitus | 1.42 | Partially |
| Opium use | 1.37 | Yes |
| Male sex | 1.27 | No |
| Antiplatelet/anticoagulant use | 1.25 | Partially |
| Alcohol consumption | 1.24 | Yes |
| Cardiovascular disease | 1.19 | No |
| Gastroprotective agent use | 0.71 (protective) | — |
Probable and Socioeconomic Associations
- 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]
Controversial or Uncertain Risk Factors
- Psychological and physical stress:
- 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:
Rare Hypersecretory and Specific Causes
- 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]
Clinical Pearls and Pitfalls
- 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]
References
- ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 Vakil N (2024). "Peptic ulcer disease: a review". JAMA. 332 (21): 1832–42. doi:10.1001/jama.2024.19094. PMID 39466269 Check
|pmid=value (help). - ↑ 2.0 2.1 2.2 2.3 2.4 2.5 Almadi MA, Lu Y, Alali AA, Barkun AN (2024). "Peptic ulcer disease". Lancet. 404 (10447): 68–81. doi:10.1016/S0140-6736(24)00155-7.
- ↑ 3.0 3.1 3.2 3.3 3.4 3.5 Lanza FL, Chan FK, Quigley EM; Practice Parameters Committee of the American College of Gastroenterology (2009). "Guidelines for prevention of NSAID-related ulcer complications". Am J Gastroenterol. 104 (3): 728–38. doi:10.1038/ajg.2009.115. PMID 19240698.
- ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 Malfertheiner P, Chan FK, McColl KE (2009). "Peptic ulcer disease". Lancet. 374 (9699): 1449–61. doi:10.1016/S0140-6736(09)60938-7. PMID 19683340.
- ↑ 5.0 5.1 Tahery, et al. Case-control study of risk factors for peptic ulcer disease. BMC Gastroenterology. 2026.
- ↑ 6.0 6.1 6.2 6.3 Yim MH, Kim KH, Lee BJ (2021). "The number of household members as a risk factor for peptic ulcer disease". Sci Rep. 11 (1): 5274. doi:10.1038/s41598-021-84892-5.
- ↑ 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 McConaghy JR, Decker A, Nair S (2023). "Peptic ulcer disease and H. pylori infection: common questions and answers". Am Fam Physician. 107 (2): 165–72. PMID 36791443 Check
|pmid=value (help). - ↑ Voelker R (2025). "Peptic ulcer disease". JAMA. 333 (10): 917. doi:10.1001/jama.2024.27195.
- ↑ Rossi RE, Elvevi A, Citterio D, Coppa J, Invernizzi P, Mazzaferro V, Massironi S (2021). "Gastrinoma and Zollinger Ellison syndrome: a roadmap for the management between new and old therapies". World J Gastroenterol. 27 (35): 5890–907. doi:10.3748/wjg.v27.i35.5890.
- ↑ Chatzipanagiotou, et al. Gastrinoma/Zollinger-Ellison syndrome. J Neuroendocrinol. 2023.
- ↑ Jensen RT, Metz DC. Zollinger-Ellison syndrome. In: Yamada's Atlas of Gastroenterology. 2022.
- ↑ Schubert ML, Peura DA (2008). "Control of gastric acid secretion in health and disease". Gastroenterology. 134 (7): 1842–60. doi:10.1053/j.gastro.2008.05.021.
- ↑ Yaghoobi M, Armstrong D (2022). Wang TC, Camilleri M; et al., eds. Yamada's Textbook of Gastroenterology (7th ed.). John Wiley & Sons. ISBN 978-1-119-60016-9.