The American Journal of Medicine
Volume 122, Issue 10 , Pages 896-903 , October 2009

Long-term Safety Concerns with Proton Pump Inhibitors

References 

  1. Selye H. A syndrome produced by diverse nocuous agents. 1936 J Neuropsychiatry Clin Neurosci. 1998;10:230–231
  2. Garnett WR. Considerations for long-term use of proton-pump inhibitors. Am J Health Syst Pharm. 1998;55:2268–2279
  3. Curling TB. On acute ulceration of the duodenum in cases of burn. Medico-Chirurgical Transactions, London. 1842;25:260–281
  4. Nardino RJ, Vender RJ, Herbert PN. Overuse of acid-suppressive therapy in hospitalized patients. Am J Gastroenterol. 2000;95:3118–3122
  5. Naunton M, Peterson GM, Bleasel MD. Overuse of proton pump inhibitors. J Clin Pharm Ther. 2000;25:333–340
  6. Batuwitage BT, Kingham JG, Morgan NE, Bartlett RL. Inappropriate prescribing of proton pump inhibitors in primary care. Postgrad Med J. 2007;83:66–68
  7. Koop H. Review article: metabolic consequences of long-term inhibition of acid secretion by omeprazole. Aliment Pharmacol Ther. 1992;6:399–406
  8. Steinberg WM, King CE, Toskes PP. Malabsorption of protein-bound cobalamin but not unbound cobalamin during cimetidine administration. Dig Dis Sci. 1980;25:188–191
  9. Koop H, Bachem MG. Serum iron, ferritin, and vitamin B12 during prolonged omeprazole therapy. J Clin Gastroenterol. 1992;14:288–292
  10. Marcuard SP, Albernaz L, Khazanie PG. Omeprazole therapy causes malabsorption of cyanocobalamin (vitamin B12). Ann Intern Med. 1994;120:211–215
  11. Termanini B, Gibril F, Sutliff VE, et al. Effect of long-term gastric acid suppressive therapy on serum vitamin B12 levels in patients with Zollinger-Ellison syndrome. Am J Med. 1998;104:422–430
  12. den Elzen WP, Groeneveld Y, de Ruijter W, et al. Long-term use of proton pump inhibitors and vitamin B12 status in elderly individuals. Aliment Pharmacol Ther. 2008;27:491–497
  13. Hirschowitz BI, Worthington J, Mohnen J. Vitamin B12 deficiency in hypersecretors during long-term acid suppression with proton pump inhibitors. Aliment Pharmacol Ther. 2008;27:1110–1121
  14. Conrad ME, Schade SG. Ascorbic acid chelates in iron absorption: a role for hydrochloric acid and bile. Gastroenterology. 1968;55:35–45
  15. Cook JD, Brown GM, Valberg LS. The effect of achylia gastrica on iron absorption. J Clin Invest. 1964;43:1185–1191
  16. 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
  17. Nordin BE. Calcium and osteoporosis. Nutrition. 1997;13:664–686
  18. Sheikh MS, Santa Ana CA, Nicar MJ, et al. Gastrointestinal absorption of calcium from milk and calcium salts. N Engl J Med. 1987;317:532–536
  19. Carr CJ, Shangraw RF. Nutritional and pharmaceutical aspects of calcium supplementation. Am Pharm. 1987;2:49–50
  20. Chonan O, Takahashi R, Yasui H, Watanuki M. Effect of L-lactic acid on calcium absorption in rats fed omeprazole. J Nutr Sci Vitaminol. 1998;44:473–481
  21. 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
  22. Tuukkanen J, Vaananen HK. Omeprazole, a specific inhibitor of H+-K+-ATPase, inhibits bone resorption in vitro. Calcif Tissue Int. 1986;38:123–125
  23. 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
  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
  25. Yang YX, Lewis JD, Epstein S, Metz DC. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA. 2006;296:2947–2953
  26. Thorens J, Froehlich F, Schwizer W, et al. Bacterial overgrowth during treatment with omeprazole compared with cimetidine: a prospective randomised double blind study. Gut. 1996;39:54–59
  27. Zedtwitz-Liebenstein K, Wenisch C, Patruta S, et al. Omeprazole treatment diminishes intra- and extracellular neutrophil reactive oxygen production and bactericidal activity. Crit Care Med. 2002;30:1118–1122
  28. 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
  29. Williams C. Occurrence and significance of gastric colonization during acid-inhibitory therapy. Best Pract Res Clin Gastroenterol. 2001;15:511–521
  30. Cunningham R, Dale B, Undy B, Gaunt N. Proton pump inhibitors as a risk factor for Clostridium difficile diarrhoea. J Hosp Infect. 2003;54:243–245
  31. Pepin J, Valiquette L, Alary ME, et al. Clostridium difficile-associated diarrhea in a region of Quebec from 1991 to 2003: a changing pattern of disease severity. CMAJ. 2004;171:466–472
  32. Wilson KH, Sheagren JN, Freter R. Population dynamics of ingested Clostridium difficile in the gastrointestinal tract of the Syrian hamster. J Infect Dis. 1985;151:355–361
  33. Klingensmith ME, Neville LJ, Delpire E, et al. Gastrin-mediated effects of omeprazole on rat colon mucosa. Surgery. 1999;126:272–278
  34. Shah S, Lewis A, Leopold D, et al. Gastric acid suppression does not promote clostridial diarrhoea in the elderly. QJM. 2000;93:175–181
  35. 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
  36. Trey G, Marks IN, Louw JA, et al. Changes in acid secretion over the years (A 30-year longitudinal study). J Clin Gastroenterol. 1997;25:499–502
  37. Bliss DZ, Johnson S, Savik K, et al. Acquisition of Clostridium difficile and Clostridium difficile-associated diarrhea in hospitalized patients receiving tube feeding. Ann Intern Med. 1998;129:1012–1019
  38. Dial S, Delaney JA, Barkun AN, Suissa S. Use of gastric acid-suppressive agents and the risk of community-acquired Clostridium difficile-associated disease. JAMA. 2005;294:2989–2995
  39. 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
  40. Martinsen TC, Bergh K, Waldum HL. Gastric juice: a barrier against infectious diseases. Basic Clin Pharmacol Toxicol. 2005;96:94–102
  41. Hurst AF. The clinical importance of achlorhydria. Br Med J. 1934;2:665–669
  42. Neal KR, Briji SO, Slack RC, et al. Recent treatment with H2 antagonists and antibiotics and gastric surgery as risk factors for Salmonella infection. BMJ. 1994;308:176
  43. Neal KR, Scott HM, Slack RC, Logan RF. Omeprazole as a risk factor for campylobacter gastroenteritis: case-control study. BMJ. 1996;312:414–415
  44. 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
  45. Cook DJ, Reeve BK, Guyatt GH, et al. Stress ulcer prophylaxis in critically ill patients (Resolving discordant meta-analyses). JAMA. 1996;275:308–314
  46. Tryba M. Risk of acute stress bleeding and nosocomial pneumonia in ventilated intensive care unit patients: sucralfate versus antacids. Am J Med. 1987;83:117–124
  47. Driks MR, Craven DE, Celli BR, et al. Nosocomial pneumonia in intubated patients given sucralfate as compared with antacids or histamine type 2 blockers (The role of gastric colonization). N Engl J Med. 1987;317:1376–1382
  48. Faisy C, Guerot E, Diehl JL, et al. Clinically significant gastrointestinal bleeding in critically ill patients with and without stress-ulcer prophylaxis. Intensive Care Med. 2003;29:1306–1313
  49. Kantorova I, Svoboda P, Scheer P, et al. Stress ulcer prophylaxis in critically ill patients: a randomized controlled trial. Hepatogastroenterology. 2004;51:757–761
  50. Messori A, Trippoli S, Vaiani M, et al. Bleeding and pneumonia in intensive care patients given ranitidine and sucralfate for prevention of stress ulcer: meta-analysis of randomised controlled trials. BMJ. 2000;321:1103–1106
  51. Jalving M, Koornstra JJ, Gotz JM, et al. High-grade dysplasia in sporadic fundic gland polyps: a case report and review of the literature. Eur J Gastroenterol Hepatol. 2003;15:1229–1233
  52. Graham JR. Gastric polyposis: onset during long-term therapy with omeprazole. Med J Aust. 1992;157:287–288
  53. Attard TM, Yardley JH, Cuffari C. Gastric polyps in pediatrics: an 18-year hospital-based analysis. Am J Gastroenterol. 2002;97:298–301
  54. Jalving M, Koornstra JJ, Wesseling J, et al. Increased risk of fundic gland polyps during long-term proton pump inhibitor therapy. Aliment Pharmacol Ther. 2006;24:1341–1348
  55. Jalving M, Koornstra JJ, Boersma-van Ek W, et al. Dysplasia in fundic gland polyps is associated with nuclear beta-catenin expression and relatively high cell turnover rates. Scand J Gastroenterol. 2003;38:916–922
  56. Schenk BE, Kuipers EJ, Klinkenberg-Knol EC, et al. Hypergastrinaemia during long-term omeprazole therapy: influences of vagal nerve function, gastric emptying and Helicobacter pylori infection. Aliment Pharmacol Ther. 1998;12:605–612
  57. Verdu EF, Armstrong D, Fraser R, et al. Effect of Helicobacter pylori status on intragastric pH during treatment with omeprazole. Gut. 1995;36:539–543
  58. Sanduleanu S, Jonkers D, De Bruine A, et al. Double gastric infection with Helicobacter pylori and non-Helicobacter pylori bacteria during acid-suppressive therapy: increase of pro-inflammatory cytokines and development of atrophic gastritis. Aliment Pharmacol Ther. 2001;15:1163–1175
  59. Kuipers EJ. Proton pump inhibitors and gastric neoplasia. Gut. 2006;55:1217–1221
  60. Uemura N, Okamoto S, Yamamoto S, et al. Helicobacter pylori infection and the development of gastric cancer. N Engl J Med. 2001;345:784–789
  61. Wang TC, Koh TJ, Varro A, et al. Processing and proliferative effects of human progastrin in transgenic mice. J Clin Invest. 1996;98:1918–1929
  62. Watson SA, Durrant LG, Crosbie JD, Morris DL. The in vitro growth response of primary human colorectal and gastric cancer cells to gastrin. Int J Cancer. 1989;43:692–696
  63. Renga M, Brandi G, Paganelli GM, et al. Rectal cell proliferation and colon cancer risk in patients with hypergastrinaemia. Gut. 1997;41:330–332
  64. Thorburn CM, Friedman GD, Dickinson CJ, et al. Gastrin and colorectal cancer: a prospective study. Gastroenterology. 1998;115:275–280
  65. 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
  66. Singh M, Dhindsa G, Friedland S, Triadafilopoulos G. Long-term use of proton pump inhibitors does not affect the frequency, growth, or histologic characteristics of colon adenomas. Aliment Pharmacol Ther. 2007;26:1051–1061
  67. van Soest EM, van Rossum LG, Dieleman JP, et al. Proton pump inhibitors and the risk of colorectal cancer. Am J Gastroenterol. 2008;103:966–973
  68. Neal KR, Slack RC. Diabetes mellitus, anti-secretory drugs and other risk factors for campylobacter gastro-enteritis in adults: a case-control study. Epidemiol Infect. 1997;119:307–311
  69. Doorduyn Y, Van Den Brandhof WE, Van Duynhoven YT, et al. Risk factors for Salmonella Enteritidis and Typhimurium (DT 104 and non-DT 104) infections in The Netherlands: predominant roles for raw eggs in Enteritidis and sandboxes in Typhimurium infections. Epidemiol Infect. 2006;134:617–626

 Funding: None.

 Conflict of Interest: None of the authors have any conflicts of interest associated with the work presented in this manuscript.

 Authorship: All authors had access to the data and played a role in writing this manuscript.

PII: S0002-9343(09)00528-2

doi: 10.1016/j.amjmed.2009.04.014

The American Journal of Medicine
Volume 122, Issue 10 , Pages 896-903 , October 2009