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Potential adverse effects of proton pump inhibitors

Current Gastroenterology Reports volume 10, pages 208–214 (2008)Cite this article

Abstract

Proton pump inhibitors (PPIs) have revolutionized the management of gastroesophageal reflux disease and peptic ulcer disease over the past two decades. Among the most commonly prescribed agents worldwide, PPIs’ overall safety profile is unquestionable. However, emerging evidence indicates that PPI therapy, particularly with long-term and/or high-dose administration, is associated with several potential adverse effects, including enteric infections (eg, Clostridium difficile), community-acquired pneumonia, and hip fracture, all of which have received much attention recently. We review the current data on these and other potential consequences of PPI therapy. More judicious use of PPIs (eg, administering them in no more than the minimum effective dose to older adult patients) may help to further limit the impact of some of these possible adverse effects.

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References and Recommended Reading

  1. Shaheen NJ, Hansen RA, Morgan DR, et al.: The burden of gastrointestinal and liver diseases, 2006. Am J Gastroenterol 2006, 101:2128–2138.

    PubMed  Article  Google Scholar 

  2. Laine L, Ahnen D, McClain C, et al.: Review article: potential gastrointestinal effects of long-term acid suppression with proton pump inhibitors. Aliment Pharmacol Ther 2000, 14:651–668.

    PubMed  Article  CAS  Google Scholar 

  3. Hill AB: The environment and disease: association or causation? Proc R Soc Med 1965, 58:295–300.

    PubMed  CAS  Google Scholar 

  4. Thorens J, Froehlich F, Schwizer W, et al.: Bacterial over-growth during treatment with omeprazole compared with cimetidine: a prospective randomised double blind study. Gut 1996, 39:54–59.

    PubMed  Article  CAS  Google Scholar 

  5. Dial S, Alrasadi K, Manoukian C, et al.: Risk of Clostridium difficile diarrhea among hospital impatients prescribed proton pump inhibitors: cohort and case-control studies. CMAJ 2004, 171:33–38.

    PubMed  Google Scholar 

  6. Leonard J, Marshall JK, Moayyedi P: Systematic review of the risk of enteric infection in patients taking acid suppression. Am J Gastroenterol 2007, 102:2047–2056; quiz 2057.

    PubMed  Article  Google Scholar 

  7. Shah S, Lewis A, Leopold D, et al.: Gastric acid suppression does not promote clostridial diarrhoea in the elderly. QJM 2000, 93:175–181.

    PubMed  Article  CAS  Google Scholar 

  8. Loo VG, Poirier L, Miller MA, et al.: A predominantly clonal multi-institutional outbreak of Clostridium difficile-associated diarrhea with high morbidity and mortality. N Engl J Med 2005, 353:2442–2449.

    PubMed  Article  CAS  Google Scholar 

  9. Laheij RJ, Sturkenboom MC, Hassing RJ, et al.: Risk of community-acquired pneumonia and use of gastric acid-suppressive drugs. JAMA 2004, 292:1955–1960.

    PubMed  Article  CAS  Google Scholar 

  10. Gulmez SE, Holm A, Frederiksen H, et al.: Use of proton pump inhibitors and the risk of community-acquired pneumonia: a population-based case-control study. Arch Intern Med 2007, 167:950–955.

    PubMed  Article  CAS  Google Scholar 

  11. Laheij RJ, Van Ijzendoorn MC, Janssen MJ, Jansen JB: Gastric acid-suppressive therapy and community-acquired respiratory infections. Aliment Pharmacol Ther 2003, 18:847–851.

    PubMed  Article  CAS  Google Scholar 

  12. Canani RB, Cirillo P, Roggero P, et al.: Therapy with gastric acidity inhibitors increases the risk of acute gastroenteritis and community-acquired pneumonia in children. Pediatrics 2006, 117:e817–e820.

    PubMed  Article  Google Scholar 

  13. Sarkar MA, Yang YX: Are proton pump inhibitors (PPIs) associated with an increased risk of community-acquired pneumonia (CAP)? A nested case control study investigating recent PPI exposure and CAP [abstract]. Am J Gastroenterol 2007, 102:S446.

    Google Scholar 

  14. Chonan O, Takahashi R, Yasui H, Watanuki M: Effect of L-lactic acid on calcium absorption in rats fed omeprazole. J Nutr Sci Vitaminol (Tokyo) 1998, 44:473–481.

    CAS  Google Scholar 

  15. Bo-Linn GW, Davis GR, Buddrus DJ, et al.: An evaluation of the importance of gastric acid secretion in the absorption of dietary calcium. J Clin Invest 1984, 73:640–647.

    PubMed  Article  CAS  Google Scholar 

  16. Recker RR: Calcium absorption and achlorhydria. N Engl J Med 1985, 313:70–73.

    PubMed  CAS  Google Scholar 

  17. O’Connell MB, Madden DM, Murray AM, et al.: Effects of proton pump inhibitors on calcium carbonate absorption in women: a randomized crossover trial. Am J Med 2005, 118:778–781.

    PubMed  Article  CAS  Google Scholar 

  18. Mattsson JP, Vaananen K, Wallmark B, Lorentzon P: Omeprazole and bafilomycin, two proton pump inhibitors: differentiation of their effects on gastric, kidney and bone H(+)-translocating ATPases. Biochim Biophys Acta 1991, 1065:261–268.

    PubMed  Article  CAS  Google Scholar 

  19. Kocsis I, Arato A, Bodanszky H, et al.: Short-term omeprazole treatment does not influence biochemical parameters of bone turnover in children. Calcif Tissue Int 2002, 71:129–132.

    PubMed  Article  CAS  Google Scholar 

  20. Mizunashi K, Furukawa Y, Katano K, Abe K: Effect of omeprazole, an inhibitor of H+,K(+)-ATPase, on bone resorption in humans. Calcif Tissue Int 1993, 53:21–25.

    PubMed  Article  CAS  Google Scholar 

  21. Hollowell J: The General Practice Research Database: quality of morbidity data. Popul Trends 1997, Spring:36–40.

  22. Yang YX, Lewis JD, Epstein S, Metz DC: Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA 2006, 296:2947–2953.

    PubMed  Article  CAS  Google Scholar 

  23. Geller JL, Adams JS: Proton pump inhibitor therapy and hip fracture risk. JAMA 2007, 297:1429; author reply 1429–1430.

    PubMed  Article  CAS  Google Scholar 

  24. Vestergaard P, Rejnmark L, Mosekilde L: Proton pump inhibitors, histamine H2 receptor antagonists, and other antacid medications and the risk of fracture. Calcif Tissue Int 2006, 79:76–83.

    PubMed  Article  CAS  Google Scholar 

  25. Howden CW: Vitamin B12 levels during prolonged treatment with proton pump inhibitors. J Clin Gastroenterol 2000, 30:29–33.

    PubMed  Article  CAS  Google Scholar 

  26. Schenk BE, Festen HP, Kuipers EJ, et al.: Effect of short-and long-term treatment with omeprazole on the absorption and serum levels of cobalamin. Aliment Pharmacol Ther 1996, 10:541–545.

    PubMed  Article  CAS  Google Scholar 

  27. Koop H, Bachem MG: Serum iron, ferritin, and vitamin B12 during prolonged omeprazole therapy. J Clin Gastroenterol 1992, 14:288–292.

    PubMed  Article  CAS  Google Scholar 

  28. Valuck RJ, Ruscin JM: A case-control study on adverse effects: H2 blocker or proton pump inhibitor use and risk of vitamin B12 deficiency in older adults. J Clin Epidemiol 2004, 57:422–428.

    PubMed  Article  Google Scholar 

  29. Force RW, Meeker AD, Cady PS, et al.: Ambulatory care increased vitamin B12 requirement associated with chronic acid suppression therapy. Ann Pharmacother 2003, 37:490–493.

    PubMed  Article  CAS  Google Scholar 

  30. Hutchinson C, Geissler CA, Powell JJ, Bomford A: Proton pump inhibitors suppress absorption of dietary non-haem iron in hereditary haemochromatosis. Gut 2007, 56:1291–1295.

    PubMed  Article  CAS  Google Scholar 

  31. Stewart CA, Termanini B, Sutliff VE, et al.: Iron absorption in patients with Zollinger-Ellison syndrome treated with long-term gastric acid antisecretory therapy. Aliment Pharmacol Ther 1998, 12:83–98.

    PubMed  Article  CAS  Google Scholar 

  32. Larsson H, Carlsson E, Mattsson H, et al.: Plasma gastrin and gastric enterochromaffinlike cell activation and proliferation. Studies with omeprazole and ranitidine in intact and antrectomized rats. Gastroenterology 1986, 90:391–399.

    PubMed  CAS  Google Scholar 

  33. Rindi G, Luinetti O, Cornaggia M, et al.: Three subtypes of gastric argyrophil carcinoid and the gastric neuroendocrine carcinoma: a clinicopathologic study. Gastroenterology 1993, 104:994–1006.

    PubMed  CAS  Google Scholar 

  34. Peghini PL, Annibale B, Azzoni C, et al.: Effect of chronic hypergastrinemia on human enterochromaffin-like cells: insights from patients with sporadic gastrinomas. Gastroenterology 2002, 123:68–85.

    PubMed  Article  Google Scholar 

  35. Modlin IM, Lye KD, Kidd M: A 50-year analysis of 562 gastric carcinoids: small tumor or larger problem? Am J Gastroenterol 2004, 99:23–32.

    PubMed  Article  Google Scholar 

  36. Lamberts R, Brunner G, Solcia E: Effects of very long (up to 10 years) proton pump blockade on human gastric mucosa. Digestion 2001, 64:205–213.

    PubMed  Article  CAS  Google Scholar 

  37. Solcia E, Fiocca R, Havu N, et al.: Gastric endocrine cells and gastritis in patients receiving long-term omeprazole treatment. Digestion 1992, 51(Suppl 1):82–92.

    PubMed  Article  Google Scholar 

  38. Klinkenberg-Knol EC, Nelis F, Dent J, et al.: Long-term omeprazole treatment in resistant gastroesophageal reflux disease: efficacy, safety, and influence on gastric mucosa. Gastroenterology 2000, 118:661–669.

    PubMed  Article  CAS  Google Scholar 

  39. Eslick GD, Lim LL, Byles JE, et al.: Association of Helicobacter pylori infection with gastric carcinoma: a meta-analysis. Am J Gastroenterol 1999, 94:2373–2379.

    PubMed  Article  CAS  Google Scholar 

  40. Kuipers EJ, Nelis GF, Klinkenberg-Knol EC, et al.: Cure of Helicobacter pylori infection in patients with reflux oesophagitis treated with long term omeprazole reverses gastritis without exacerbation of reflux disease: results of a randomised controlled trial. Gut 2004, 53:12–20.

    PubMed  Article  CAS  Google Scholar 

  41. Kuipers EJ: Proton pump inhibitors and gastric neoplasia. Gut 2006, 55:1217–1221.

    PubMed  Article  CAS  Google Scholar 

  42. Watson SA, Smith AM: Hypergastrinemia promotes adenoma progression in the APC(Min-/+) mouse model of familial adenomatous polyposis. Cancer Res 2001, 61:625–631.

    PubMed  CAS  Google Scholar 

  43. Thorburn CM, Friedman GD, Dickinson CJ, et al.: Gastrin and colorectal cancer: a prospective study. Gastroenterology 1998, 115:275–280.

    PubMed  Article  CAS  Google Scholar 

  44. Yang YX, Hennessy S, Propert K, et al.: Chronic proton pump inhibitor therapy and the risk of colorectal cancer. Gastroenterology 2007, 133:748–754.

    PubMed  Article  CAS  Google Scholar 

  45. Robertson DJ, Larsson H, Friis S, et al.: Proton pump inhibitor use and risk of colorectal cancer: a population-based, case-control study. Gastroenterology 2007, 133:755–760.

    PubMed  Article  Google Scholar 

  46. Cahan MA, Balduf L, Colton K, et al.: Proton pump inhibitors reduce gallbladder function. Surg Endosc 2006, 20:1364–1367.

    PubMed  Article  CAS  Google Scholar 

  47. Chowdhury JR, Berkowitz JM, Praissman M, Fara JW: Effect of sulfated and non-sulfated gastrin and octapeptide-cholecystokinin on cat gall bladder in vitro. Experientia 1976, 32:1173–1175.

    PubMed  Article  CAS  Google Scholar 

  48. Geevasinga N, Coleman PL, Webster AC, Roger SD: Proton pump inhibitors and acute interstitial nephritis. Clin Gastroenterol Hepatol 2006, 4:597–604.

    PubMed  Article  CAS  Google Scholar 

  49. Sierra F, Suarez M, Rey M, Vela MF: Systematic review: proton pump inhibitor-associated acute interstitial nephritis. Aliment Pharmacol Ther 2007, 26:545–553.

    PubMed  CAS  Google Scholar 

  50. Cote GA, Ferreira MR, Rozenberg-Ben-Dror K, Howden CW: Programme of stepping down from twice daily proton pump inhibitor therapy for symptomatic gastro-oesophageal reflux disease associated with a formulary change at a VA medical center. Aliment Pharmacol Ther 2007, 25:709–714.

    PubMed  CAS  Article  Google Scholar 

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Authors and Affiliations

  1. Division of Gastroenterology, Northwestern University Feinberg School of Medicine, 676 North St. Clair Street, Suite 1400, Chicago, IL, 60611, USA

    Colin W. Howden

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  1. Gregory A. Coté
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  2. Colin W. Howden
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Correspondence to Colin W. Howden.

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Coté, G.A., Howden, C.W. Potential adverse effects of proton pump inhibitors. Curr Gastroenterol Rep 10, 208–214 (2008). https://doi.org/10.1007/s11894-008-0045-4

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  • DOI: https://doi.org/10.1007/s11894-008-0045-4

Keywords

  • Omeprazole
  • Proton Pump Inhibitor
  • Atrophic Gastritis
  • Cobalamin
  • Proton Pump Inhibitor Therapy