Journal of Gastroenterology

, Volume 46, Issue 5, pp 612–619

Gastric acid secretion level modulates the association between Helicobacter pylori infection and low-dose aspirin-induced gastropathy

  • Katsunori Iijima
  • Nobuyuki Ara
  • Yasuhiko Abe
  • Tomoyuki Koike
  • Wataru Iwai
  • Kaname Uno
  • Naoki Asano
  • Akira Imatani
  • Shuichi Ohara
  • Tooru Shimosegawa
Original Article—Alimentary Tract



The relative contribution of gastric acid secretion and Helicobacter pylori infection to low-dose aspirin-induced gastropathy remains to be clarified. This is partly because the capability of the infection to modify gastric acid secretion complicates the interaction. The aim of this study was to estimate the association of aspirin-induced mucosal injury, as well as H. pylori infection, with gastric acid output.


A total of 186 male outpatients, comprising 60 aspirin takers, on 100 mg of enteric-coated aspirin daily and 126 non-aspirin takers were prospectively enrolled in this study. Gastrin-stimulated acid output was estimated by the endoscopic gastrin test. The grade of gastric mucosal injury was assessed endoscopically according to the modified Lanza score. Multiple logistic regression analyses were used to adjust for potential confounders.


The gastric acid secretion level, with an odds ratio (OR) (95% confidence interval [CI]) of 10.5 (3.0–36.9) and aspirin administration, with an OR (95% CI) of 7.4 (3.0–18.3) were independently associated with gastric mucosal injury, and the co-existence of both factors greatly elevated the risk of mucosal injury, with an OR (95% CI) of 77.0 (13.5–440.0). H. pylori infection, itself, did not show any significant effect on the aspirin-induced mucosal injury after adjusting for gastric acid secretion.


This study has demonstrated that aspirin-induced gastropathy is directly associated with gastric acid secretion. In addition, it also suggested that the gastric acid secretion level modulates the association between H. pylori infection and aspirin-induced gastropathy.


Aspirin Gastric acid secretion Gastric mucosal injury H. pylori 



Confidence interval


Endoscopic gastrin test




Modified Lanza score


Non-steroidal anti-inflammatory drug


Odds ratio


Proton pump inhibitor

Supplementary material

535_2011_385_MOESM1_ESM.doc (44 kb)
Supplementary material 1 (DOC 43 kb)


  1. 1.
    Weil J, Colin-Jones D, Langman M, Lawson D, Logan R, Murphy M, et al. Prophylactic aspirin and risk of peptic ulcer bleeding. BMJ. 1995;310:827–30.PubMedGoogle Scholar
  2. 2.
    Derry S, Loke YK. Risk of gastrointestinal haemorrhage with long term use of aspirin: meta-analysis. BMJ. 2000;321:1183–7.PubMedCrossRefGoogle Scholar
  3. 3.
    Yeomans ND, Lanas AI, Talley NJ, Thomson AB, Daneshjoo R, Eriksson B, et al. Prevalence and incidence of gastroduodenal ulcers during treatment with vascular protective doses of aspirin. Aliment Pharmacol Ther. 2005;22:795–801.PubMedCrossRefGoogle Scholar
  4. 4.
    Serrano P, Lanas A, Arroyo MT, Ferreira IJ. Risk of upper gastrointestinal bleeding in patients taking low-dose aspirin for the prevention of cardiovascular diseases. Aliment Pharmacol Ther. 2002;16:1945–53.PubMedCrossRefGoogle Scholar
  5. 5.
    Musumba C, Pritchard DM, Pirmohamed M. Review article: cellular and molecular mechanisms of NSAID-induced peptic ulcers. Aliment Pharmacol Ther. 2009;30:517–31 (Review).Google Scholar
  6. 6.
    Bjarnason I, Scarpignato C, Takeuchi K, Rainsford KD. Determinants of the short-term gastric damage caused by NSAIDs in man. Aliment Pharmacol Ther. 2007;26:95–106.PubMedCrossRefGoogle Scholar
  7. 7.
    Rowe PH, Starlinger MJ, Kasdon E, Hollands MJ, Silen W. Parenteral aspirin and sodium salicylate are equally injurious to the rat gastric mucosa. Gastroenterology. 1987;93:863–71.PubMedGoogle Scholar
  8. 8.
    Elliott SL, Ferris RJ, Giraud AS, Cook GA, Skeljo MV, Yeomans ND. Indomethacin damage to rat gastric mucosa is markedly dependent on luminal pH. Clin Exp Pharmacol Physiol. 1996;23:432–4.PubMedCrossRefGoogle Scholar
  9. 9.
    Lai KC, Lam SK, Chu KM, Wong BC, Hui WM, Hu WH, et al. Lansoprazole for the prevention of recurrences of ulcer complications from long-term low-dose aspirin use. N Engl J Med. 2002;346:2033–8.PubMedCrossRefGoogle Scholar
  10. 10.
    Lanas A, Rodrigo L, Márquez JL, Bajador E, Pérez-Roldan F, Cabrol J, EMPHASYS Study Group, et al. Low frequency of upper gastrointestinal complications in a cohort of high-risk patients taking low-dose aspirin or NSAIDS and omeprazole. Scand J Gastroenterol. 2003;38:693–700.PubMedCrossRefGoogle Scholar
  11. 11.
    Yeomans N, Lanas A, Labenz J, van Zanten SV, van Rensburg C, Rácz I, et al. Efficacy of esomeprazole (20 mg once daily) for reducing the risk of gastroduodenal ulcers associated with continuous use of low-dose aspirin. Am J Gastroenterol. 2008;103:2465–73.PubMedCrossRefGoogle Scholar
  12. 12.
    Lanas A, Fuentes J, Benito R, Serrano P, Bajador E, Sáinz R. Helicobacter pylori increases the risk of upper gastrointestinal bleeding in patients taking low-dose aspirin. Aliment Pharmacol Ther. 2002;16:779–86.PubMedCrossRefGoogle Scholar
  13. 13.
    Feldman M, Cryer B, Mallat D, Go MF. Role of Helicobacter pylori infection in gastroduodenal injury and gastric prostaglandin synthesis during long term/low dose aspirin therapy: a prospective placebo-controlled, double-blind randomized trial. Am J Gastroenterol. 2001;96:1751–7.PubMedCrossRefGoogle Scholar
  14. 14.
    Aalykke C, Lauritsen JM, Hallas J, Reinholdt S, Krogfelt K, Lauritsen K. Helicobacter pylori and risk of ulcer bleeding among users of nonsteroidal anti-inflammatory drugs: a case-control study. Gastroenterology. 1999;116:1305–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Papatheodoridis GV, Papadelli D, Cholongitas E, Vassilopoulos D, Mentis A, Hadziyannis SJ. Effect of Helicobacter pylori infection on the risk of upper gastrointestinal bleeding in users of nonsteroidal anti-inflammatory drugs. Am J Med. 2004;116:601–5.PubMedCrossRefGoogle Scholar
  16. 16.
    Hart J, Hawkey CJ, Lanas A, Naesdal J, Talley NJ, Thomson AB, et al. Predictors of gastroduodenal erosions in patients taking low-dose aspirin. Aliment Pharmacol Ther. 2010;31:143–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Wu CY, Poon SK, Chen GH, et al. Interaction between Helicobacter pylori and non-steroidal anti-inflammatory drugs in peptic ulcer bleeding. Scand J Gastroenterol. 1999;34:234–7.PubMedCrossRefGoogle Scholar
  18. 18.
    Stack WA, Atherton JC, Hawkey GM, Chang CS, Yeh HZ. Interactions between Helicobacter pylori and other risk factors for peptic ulcer bleeding. Aliment Pharmacol Ther. 2002;16:497–506.PubMedCrossRefGoogle Scholar
  19. 19.
    Santolaria S, Lanas A, Benito R, Montoro M, Sainz R. Helicobacter pylori infection is a protective factor for bleeding gastric ulcers but not for bleeding duodenal ulcers in NSAID users. Aliment Pharmacol Ther. 1999;13:1511–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Hawkey CJ, Laine L, Harper SE, Quan HU, Bolognese JA, Mortensen E, Rofecoxib Osteoarthritis Endoscopy Multinational Study Group. Influence of risk factors on endoscopic and clinical ulcers in patients taking rofecoxib or ibuprofen in two randomized controlled trials. Aliment Pharmacol Ther. 2001;15:1593–601.PubMedCrossRefGoogle Scholar
  21. 21.
    Cullen DJ, Hawkey GM, Greenwood DC, Humphreys H, Shepherd V, Logan RF, et al. Peptic ulcer bleeding in the elderly: relative roles of Helicobacter pylori and non-steroidal anti-inflammatory drugs. Gut. 1997;41:459–62.PubMedCrossRefGoogle Scholar
  22. 22.
    Lanza FL, Evans DG, Graham DY. Effect of Helicobacter pylori infection on the severity of gastroduodenal mucosal injury after the acute administration of naproxen or aspirin to normal volunteers. Am J Gastroenterol. 1991;86:735–7.PubMedGoogle Scholar
  23. 23.
    Graham DY, Lidsky MD, Cox AM, Evans DJ Jr, Evans DG, Alpert L, et al. Long-term nonsteroidal antiinflammatory drug use and Helicobacter pylori infection. Gastroenterology. 1991;100:1653–7.PubMedGoogle Scholar
  24. 24.
    Fletcher EH, Johnston DE, Fisher CR, Koerner RJ, Newton JL, Gray CS. Systematic review: Helicobacter pylori and the risk of upper gastrointestinal bleeding risk in patients taking aspirin. Aliment Pharmacol Ther. 2010;32:831–9.PubMedCrossRefGoogle Scholar
  25. 25.
    McColl KE, el-Omar E, Gillen D. Helicobacter pylori gastritis and gastric physiology. Gastroenterol Clin North Am 2000;29:687–703 (viii. Review).Google Scholar
  26. 26.
    Iijima K, Ohara S, Sekine H, Koike T, Kato K, Asaki S, et al. Changes in gastric acid secretion assayed by endoscopic gastrin test before and after Helicobacter pylori eradication. Gut. 2000;46:20–6.PubMedCrossRefGoogle Scholar
  27. 27.
    Lanza FL, Graham DY, Davis RE, Rack MF. Endoscopic comparison of cimetidine and sucralfate for prevention of naproxen-induced acute gastroduodenal injury. Effect of scoring method. Dig Dis Sci. 1990;35:1494–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Naito Y, Iinuma S, Yagi N, Boku Y, Imamoto E, Takagi T, et al. Prevention of indomethacin-induced gastric mucosal injury in Helicobacter pylori-negative healthy volunteers: a comparison study rebamipide vs famotidine. J Clin Biochem Nutr. 2008;43:34–40.PubMedCrossRefGoogle Scholar
  29. 29.
    Iijima K, Ohara S, Sekine H, Koike T, Kubota Y, Kato K, et al. A new endoscopic method of gastric acid secretory testing. Am J Gastroenterol. 1998;93:2113–8.PubMedCrossRefGoogle Scholar
  30. 30.
    Iijima K, Sekine H, Koike T, Imatani A, Ohara S, Shimosegawa T. Long-term effect of Helicobacter pylori eradication on the reversibility of acid secretion in profound hypochlorhydria. Aliment Pharmacol Ther. 2004;19:1181–8.PubMedCrossRefGoogle Scholar
  31. 31.
    Sasazuki S, Inoue M, Iwasaki M, Otani T, Yamamoto S, Ikeda S, et al. Effect of Helicobacter pylori infection combined with CagA and pepsinogen status on gastric cancer development among Japanese men and women: a nested case-control study. Cancer Epidemiol Biomarkers Prev. 2006;15:1341–7.PubMedCrossRefGoogle Scholar
  32. 32.
    Kimura K, Takemoto T. An endoscopic recognition of the atrophic border and its significance in chronic gastritis. Endoscopy. 1969;3:87–97.CrossRefGoogle Scholar
  33. 33.
    Graham DY, Smith JL. Aspirin and the stomach. Ann Intern Med. 1986;104:390–8 (Review).Google Scholar
  34. 34.
    Cryer B, Feldman M. Effects of very low dose daily, long-term aspirin therapy on gastric, duodenal, and rectal prostaglandin levels and on mucosal injury in healthy humans. Gastroenterology. 1999;117:17–25.PubMedCrossRefGoogle Scholar
  35. 35.
    Laine L, Maller ES, Yu C, Quan H, Simon T. Ulcer formation with low-dose enteric-coated aspirin and the effect of COX-2 selective inhibition: a double-blind trial. Gastroenterology. 2004;127:395–402.PubMedCrossRefGoogle Scholar
  36. 36.
    Nema H, Kato M, Katsurada T, Nozaki Y, Yotsukura A, Yoshida I, et al. Investigation of gastric and duodenal mucosal defects caused by low-dose aspirin in patients with ischemic heart disease. J Clin Gastroenterol. 2009;43:130–2.PubMedCrossRefGoogle Scholar
  37. 37.
    Donnelly MT, Goddard AF, Filipowicz B, Morant SV, Shield MJ, Hawkey CJ. Low-dose misoprostol for the prevention of low-dose aspirin-induced gastroduodenal injury. Aliment Pharmacol Ther. 2000;14:529–34.PubMedCrossRefGoogle Scholar
  38. 38.
    Iijima K, Ichikawa T, Okada S, Ogawa M, Koike T, Ohara S, et al. Rebamipide, a cytoprotective drug, increases gastric mucus secretion in human: evaluations with endoscopic gastrin test. Dig Dis Sci. 2009;54:1500–7.PubMedCrossRefGoogle Scholar
  39. 39.
    Iijima K, Ohara S, Koike T, Sekine H, Shimosegawa T. Gastric acid secretion of normal Japanese subjects in relation to Helicobacter pylori infection, aging, and gender. Scand J Gastroenterol. 2004;39:709–16.PubMedCrossRefGoogle Scholar
  40. 40.
    Graham DY, Smith JL, Dobbs SM. Gastric adaptation occurs with aspirin administration in man. Dig Dis Sci. 1983;28:1–6.PubMedCrossRefGoogle Scholar
  41. 41.
    Brzozowski T, Konturek PC, Konturek SJ, Ernst H, Stachura J, Hahn EG. Gastric adaptation to injury by repeated doses of aspirin strengthens mucosal defence against subsequent exposure to various strong irritants in rats. Gut. 1995;37:749–57.PubMedCrossRefGoogle Scholar
  42. 42.
    Hawkey CJ, Wilson I, Naesdal J, Långström G, Swannell AJ, Yeomans ND. Influence of sex and Helicobacter pylori on development and healing of gastroduodenal lesions in non-steroidal anti-inflammatory drug users. Gut. 2002;51:344–50.PubMedCrossRefGoogle Scholar
  43. 43.
    Baron JH. Studies of basal and peak acid output with an augmented histamine test. Gut. 1963;4:136–44.PubMedCrossRefGoogle Scholar
  44. 44.
    Ono S, Fujishiro M, Hirano K, Niimi K, Goto O, Kodashima S, et al. Retrospective analysis on the management of anticoagulants and antiplatelet agents for scheduled endoscopy. J Gastroenterol. 2009;44(12):1185–9.PubMedCrossRefGoogle Scholar
  45. 45.
    Ogoshi K, Kaneko E, Tada M, et al. The management of anticoagulation and antiplatelet therapy for endoscopic procedures. Gastroenterol Endosc. 2005;47:2691–5.Google Scholar
  46. 46.
    Wilcox MH, Dent TH, Hunter JO, Gray JJ, Brown DF, Wight DG, et al. Accuracy of serology for the diagnosis of Helicobacter pylori infection–a comparison of eight kits. J Clin Pathol. 1996;49:373–6.PubMedCrossRefGoogle Scholar
  47. 47.
    Shiotani A, Sakakibara T, Yamanaka Y, Nishi R, Imamura H, Fujita M, et al. The preventive factors for aspirin-induced peptic ulcer: aspirin ulcer and corpus atrophy. J Gastroenterol. 2009;44:717–25.PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2011

Authors and Affiliations

  • Katsunori Iijima
    • 1
  • Nobuyuki Ara
    • 1
  • Yasuhiko Abe
    • 1
  • Tomoyuki Koike
    • 1
  • Wataru Iwai
    • 1
  • Kaname Uno
    • 1
  • Naoki Asano
    • 1
  • Akira Imatani
    • 1
  • Shuichi Ohara
    • 1
  • Tooru Shimosegawa
    • 1
  1. 1.Division of GastroenterologyTohoku University Graduate School of MedicineSendaiJapan

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