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Reviews

Safety of proton pump inhibitors and risk of gastric cancers: review of literature and pathophysiological mechanisms

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References

  • Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers.
  • Ward RM, Kearns GL. Proton pump inhibitors in pediatrics. Mechanism of action, pharmacokinetics, pharmacogenetics, and pharmacodynamics. Pediatric Drugs. 2013;15(2):119–131.
  • Waldum HL, Brenna E, Sandvik AK. Long-term safety of proton pump inhibitors: risk of gastric neoplasia and infections. Expert Opin Drug Saf. 2002;1(1):29–38.
  • Roche VF. The chemically elegant proton pump inhibitors. Am J Pharm Educ. 2006;70(5):1–11.
  • Shin JM, Munson K, Vagin O, et al. The gastric HK-ATPase: structure, function, and inhibition. Pflugers Arch. 2009;457(3):609–622.
  • Devlin JW, Welage LS, Olsen KM. Proton pump inhibitor formulary considerations in the acutely ill. Part 2: clinical efficacy, safety, and economics. Ann Pharmacother. 2005;39:1844–1851.
  • Forgacs I. Overprescribing proton pump inhibitors. BMJ. 2008;33(6):p. 2.
  • Batuwitage B, Kingham JGC, Morgan NE, et al. Inappropriate prescribing of proton pump inhibitors in primary care. Postgrad Med J. 2007;83:66–68.
  • Grant K, Al-Adhami N, Tordoff J, et al. Continuation of proton pump inhibitors from hospital to community. Pharm World Sci. 2006;28:189–193.
  • Targownik LE, Lix LM, Leung S, et al. Proton-pump inhibitor use is not associated with osteoporosis or accelerated bone mineral density loss. Gastroenterology. 2010;138:896–904.
  • Targownik LE, Lix LM, Metge CJ. Use of proton pump inhibitors and risk of osteoporosis-related fractures. CMAJ. 2008;179:319–326.
  • Aseeri M, Schroeder T, Kramer J, et al. Gastric acid suppression by proton pump inhibitors as a risk factor for Clostridium difficile-associated diarrhea in hospitalized patients. Am J Gastroenterol. 2008;103(9):2308–2313.
  • Cunningham R, Dale B, Undy B, et al. Proton pump inhibitors as a risk factor for Clostridium difficile diarrhoea. J Hosp Infect. 2003;54(3):234–235.
  • Dial S, Alrasadi K, Manoukian C, et al. Risk of Clostridium difficile diarrhea among hospital inpatients prescribed proton pump inhibitors: cohort and case-control studies. CMAJ. 2004;171(1):33–38.
  • 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 Int Med. 2007;167:950–955.
  • Laheij RJF, Sturkenboom MCJM, Hassing RJ, et al. Risk of community-acquired pneumonia and use of gastric acid-suppressive drugs. JAMA. 2004;292:1955–1960.
  • Shubert ML, Peura DA. Reviews in basic and clinical gastroenterology: control of gastric acid secretion in health and disease. Gastroenterology. 2008;134:1842–1860.
  • Song H, Zhu J, Lu DH. Long-term proton pump inhibitor (PPI) use and the development of gastric pre-malignant lesions. Cochrane Database Syst Rev. 2014;(12):CD010623. doi:10.1002/14651858.CD010623.pub2.

•• This Cochrane review is the only Cochrane review to date regarding PPI use and associations with gastric adenocarcinomas and neuroendocrine tumors.

  • Lundell L, Vieth M, Gibson F, et al. Systematic review: the effects of long-term proton pump inhibitor use on serum gastrin levels and gastric histology. Aliment Pharmacol Ther 2015. Accessed on 15 July 2015: doi:10.1111/apt.13324.
  • Ahn JS, Eom CS, Jeon CY, et al. Suppressive drugs and gastric cancer: a meta-analysis of observational studies. World J Gastroenterol. 2013;19(16):2560–2568.

• This is the first meta-analysis of observational study investigating the association between PPIs and gastric cancers; observational studies may provide longer follow-up time of cancers compared to RCTs.

  • Eslami L, Nasseri-Moghaddam S. Meta-analyses: does long-term PPI use increase the risk of gastric premalignant lesions? Arch Iran Med. 2013;16(8):449–458.
  • Lawrence B, Kidd M, Svejda B, et al. A clinical perspective on gastric neuroendocrine neoplasia. Curr Gastroenterol Rep. 2011;13:101–109.
  • Hwang JH, Rulyak SD, Kimmey MB. American Gastroenterological Association Institute technical review on the management of gastric subepithelial masses. Gastroenterology. 2006;130:2217–2228.
  • Berna MJ, Annibale B, Marignani M, et al. A prospective study of gastric carcinoids and enterochromaffin-like cell changes in multiple endocrine neoplasia type 1 and Zollinger–Ellison syndrome: identification of risk factors. J Clin Endocrinol Metab. 2008;93:1582–1591.
  • Yao JC, Hassan M, Phan A, et al. One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008;26(18):3063–3072.
  • Bordi C, Azzoni C, Ferraro G, et al. Sampling strategies for analysis of enterochromaffin-like cell changes in Zollinger–Ellison syndrome. Am J Clin Pathol. 2000;114:419–425.
  • Walsh JW, Richardson CT, Fordtran JS. pH dependence of acid secretion and gastrin release in normal and ulcer subjects. J Clin Invest. 1975;55:462–468.
  • Havu N, Mattsson H, Ekman L, et al. Enterochromaffin-like cell carcinoids in the rat gastric mucosa following long-term administration of ranitidine. Digestion. 1990;45:189–195.
  • Graham DY, Genta RM. Long term proton pump inhibitor use and gastrointestinal cancer. Curr Gastroenterol Rep. 2008;10(6):543–547.
  • Orlando LA, Lenard L, Orlando RC. Chronic hypergastrinemia: causes and consequences. Dig Dis Sci. 2007;52:2482–2489.
  • Corleta V, Festa S, Giulioa ED, et al. Proton pump inhibitor therapy and potential long-term harm. Curr Opin Endocrinol Diabetes Obes. 2014;21:3–8.
  • Rindi G, Solcia E. Endocrine hyperplasia and dysplasia in the pathogenesis of gastrointestinal and pancreatic endocrine tumors. Gastroenterol Clin North Am. 2007;36:851–865.
  • Langhans N, Rindi G, Chiu M, et al. Abnormal gastric histology and decreased acid production in cholescytokinin-B/gastrin receptor-deficient mice. Gastroenterology. 1997;112:280–286.
  • Fiocca R, Mastracci L, Attwood SE, et al. Gastric exocrine and endocrine cell morphology under prolonged acid inhibition therapy: results of a 5-year follow-up in the LOTUS trial. Aliment Pharmacol Ther. 2012;36:959–971.
  • Jianu CS, Fossmark R, Viset T, et al. Gastric carcinoids after long-term use of a proton pump inhibitor. Aliment Pharmacol Ther. 2012;36(7):644–649.
  • Dawson R, Manson JMK. Omeprazole in oesophageal reflux disease. Lancet. 2000;356(9243):1770–1771.
  • Jianu CS, Lange OJ, Viset T, et al. Gastric neuroendocrine carcinoma after long-term use of proton pump inhibitor. Scand J Gastroenterol. 2012;47:64–67.
  • Haga Y, Nakatsura T, Shibata Y, et al. Human gastric carcinoid detected during long-term antiulcer therapy of H2 receptor antagonist and proton pump inhibitor. Dig Dis Sci. 1998;43:253–257.
  • Havu N. Enterochromaffin-like cell carcinoids of gastric mucosa in rats after life-long inhibition of gastric secretion. Digestion. 1986;35(Suppl. 1):42–55.
  • Poynter D, Pick CR, Harcourt RA, et al. Association of long lasting unsurmountable histamine H2 blockade and gastric carcinoid tumours in the rat. Gut. 1985;26:1284–1295.
  • Brunner G, Athmann C, Schneider A. Long-term, open-label trial: safety and efficacy of continuous maintenance treatment with pantoprazole for up to 15 years in severe acid-peptic disease. Aliment Pharmacol Ther. 2012;36:37–47.

• The longest follow-up period by an RCT investigating PPI and association with gastric cancers.

  • Kokkola A, Sjöblom SM, Haapiainen R, et al. The risk of gastric carcinoma and carcinoid tumours in patients with pernicious anaemia. A prospective follow-up study. Scand J Gastroenterol. 1998;33(p):88–92.
  • Stockbrugger RW, Menon GG, Belby JOW, et al. Gastroscopic screening in 80 patients with pernicious anemia. Gut. 1983;24:1141–1147.
  • Mcguican JE, Trudeau WL. Serum gastrin concentration in pernicious anemia. N Engl J Med. 1970;282:358–361.
  • Creutzfeldt W, Lamberts R, Stockmann F, et al. Quantitative studies of gastric endocrine cells in patients receiving long term treatment with omeprazole. Scand. J. Gastroenterol. 1989;24:122–128.
  • Waldum HL, Haugen OA, Isaksen C, et al. Are diffuse gastric carcinomas neuroendocrine tumours (ECL-omas)? Euro J Gastroenterol HEpatol. 1991;3:245–249.
  • Waldum HL, Aase S, Kvtnoi I, et al. Neuroendocrine differentiation in human gastric carcinomas. Cancer. 1998;83:435–444.
  • Fossmark R, Sørdal Ø, Jianu CS, et al. Treatment of gastric carcinoids type 1 with the gastrin receptor antagonist netazepide (YF476) results in regression of tumours and normalisation of serum chromogranin A.. Aliment Pharmacol Ther. 2012;36:1067–1075.
  • Von Rosenvinge EC, Wank SA, Lim RM. Gastric masses in multiple endocrine neoplasia type I-associated Zollinger-Ellison syndrome. Gastroenterology. 2009;137(4):1222.
  • Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893–2917.
  • Jemal A, Center MM, DeSantis C, et al. Global patterns of cancer incidence and mortality rates and trends. Cancer Epidemiol Biomarkers Prev. 2010;19(8):1893–1907.
  • Shin A, Kim J, Park S. Gastric cancer epidemiology in Korea. J Gastric Cancer. 2011;11:135–140.
  • Wroblewski LE, Peek RM, Wilson KT. Helicobacter pylori and gastric cancer: factors that modulate disease risk. Clin Microbiol Rev. 2010;23:713–739.
  • Correa P. Human gastric carcinogenesis: a multistep and multifactorial process first American Cancer Society award lecture on cancer epidemiology and prevention. Cancer Res. 1992;52:6735–6740.

• Article outlining Correa’s human gastric carcinogenesis sequence.

  • Posselt G, Backert S, Wessler S. The functional interplay of Helicobacter pylori factors with gastric epithelial cells induces a multi-step process in pathogenesis. Cell Commun Signal. 2013;11:77.
  • Hansen S, Vollset SE, Derakhshan MH, et al. Two distinct aetiologies of cardia cancer; evidence from premorbid serological markers of gastric atrophy and Helicobacter pylori status. Gut. 2007;56:918–925.
  • Meining A, Riedl B, Stolte M. Features of gastritis predisposing to gastric adenoma and early gastric cancer. J Clin Pathol. 2002;55:770–773.
  • El-Omar EM, Rabkin CS, Gammon MD, et al. 2003. Increased risk of noncardia gastric cancer associated with proinflammatory cytokine gene polymorphisms. Gastroenterology. 124;1193–1201.
  • Kuipers EJ. Proton pump inhibitors and gastric neoplasia. Gut. 2006;55:1217–1221.
  • Xia HH, Kalantar JS, Talley NJ, et al. Antral-type mucosa in the gastric incisura, body, and fundus (antralization): a link between Helicobacter pylori infection and intestinal metaplasia? Am J Gastroenterol. 2000;95:114–121.
  • Lind T, Cederberg C, Ekenved G, et al. EVect of omeprazole—a gastric acid pump inhibitor—on pentagastrin stimulated acid secretion in man. Gut. 1983;24:270–277.
  • Scott D, Weeks D, Melchers K, et al. The life and death of Helicobacter pylori. Gut. 1998;43(Suppl):S56–S60.
  • Graham DY, Opekun AR, Yamaoka Y, et al. Early events in proton pump inhibitor–associated exacerbation of corpus gastritis. Aliment Pharmacol Ther. 2003;17:193–200.
  • Sanduleanu S, Jonkers D, De Bruïne 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.
  • Sugano K. Premalignant conditions of gastric cancer. J Gastroenterol Hepatol. 2013;28:906–911.
  • Shin VY, Jin HC, Ng EKO, et al. 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone promoted gastric cancer growth through prostaglandin E receptor (EP2 and EP4) in vivo and in vitro. Cancer Sci. 2011;102:926–933.
  • Lewis SJ, Young G, O’Keefe SJD. Proton pump inhibitor formulary considerations in the acutely ill. Part 1: pharmacology, pharmacodynamics, and available formulations. Aliment Pharmacol Ther. 1996;10:557–561.
  • Bektas M, Saraç N, Çetinkaya H, et al. Effects of Helicobacter pylori infection and long-term proton pump inhibitor use on enterochromaffin-like cells. Ann Gastroenterol. 2012;25(12):123–127.
  • Eissele R, Brunner GORIK, Simon B, et al. Gastric mucosa during treatment with lansoprazole: Helicobacter pylori is a risk factor for argyrophil cell hyperplasia. Gastroenterology. 1997;1997:707–717.
  • Kuipers EJ, Lundell L, Klinkenberg-Knol EC, et al. Atrophic gastritis and Helicobacter pylori infection in patients with reflux esophagitis treated with omeprazole or fundoplication. N Engl J Med. 1996;334:1018–1022.
  • Poulsen AH, Christensen S, McLaughlin JK, et al. Proton pump inhibitors and risk of gastric cancer: a population-based cohort study. Br J Cancer. 2009;100:1503–1507.
  • Hawker PC, Muscroft TJ, Keighley MR. Gastric cancer after cimetidine in patient with two negative pre-treatment biopsies. Lancet. 1980;1:709–710.
  • Mullen PW. Gastric cancer in patients who have taken cimetidine. Lancet. 1979;1:1406.
  • Taylor TV, Lee D, Howatson AG, et al. Gastric cancer in patients who have taken cimetidine. Lancet. 1979;1:1135–1136.
  • Raghunath AS, O’Morain C, McLoughlin RC. Review article: the long-term use of proton-pump inhibitors. Aliment Pharmacol Ther. 2005;22:55–63.
  • Malfertheiner P, Megraud F, O’Morain C. et al. 2006. Current concepts in the management of Helicobacter pylori infection: The Maastricht III Consensus Report 2005.
  • Deans C, Yeo MSW, Soe MY, et al. Cancer of the gastric cardia is rising in incidence in an Asian Population and is associated with adverse outcome. World J Surg. 2011;35:617–624.
  • Anderson WF, Camargo MC, Fraumeni JF Jr, et al. Age-specific trends in incidence of noncardia gastric cancer in US adults. JAMA. 2010;303:1723–1728.
  • Rastogi A, Puli S, El-Serag HB, et al. Incidence of esophageal adenocarcinoma in patients with Barrett’s esophagus and high-grade dysplasia: a meta-analysis. Gastrointest Endosc. 2008;67:394–398.
  • Devesa SS, Blot WJ, Fraumeni JF. Changing patterns in the incidence of esophageal and gastric carcinoma in the United States. Cancer. 1998;83:2049–2053.
  • El-Serag HB, Aguirre TV, Davis S, et al. Proton pump inhibitors are associated with reduced incidence of dysplasia in Barrett’s esophagus. Am J Gastroenterol. 2004;99:1877–1883.
  • Cooper BT, Chapman W, Neumann CS, et al. Continuous treatment of Barrett’s oesophagus patients with proton pump inhibitor up to 13 years: observations on regression and cancer incidence. Aliment Pharmacol Ther. 2006;23:727–733.
  • Romero Y. Do PPIs diminish Barrett’s esophagus length or cancer risk? Nat Clin Pract Gastroenterol Hepatol. 2006;3:658–659.
  • McCarthy D. Adverse effects of proton pump inhibitor drugs: clues and conclusions. Curr Opin Gastroenterol. 2010;26:624–631.
  • Harris JC, Clarke PA, Awan A, et al. An antiapoptotic role for gastrin and the gastrin/CCK-2 receptor in Barrett’s esophagus. Cancer Res. 2004;64:1915–1919.
  • Haigh CR, Attwood S, Thompson DG, et al. Gastrin induces proliferation in Barrett’s metaplasia through activation of the CCK2 receptor. Gastroenterology. 2003;124:615–625.
  • Ferrand A, Wang T. Gastrin and cancer: a review. Cancer Lett. 2006;238:15–29.
  • Abdalla SI, Lao-Sirieix P, Novelli MR, et al. Gastrin-induced cyclooxygenase-2 expression in Barrett’s carcinogenesis. Clin Cancer Res. 2004;10:4784–4792.
  • Chueca E, Lanas A, Piazuelo E. Role of gastrin-peptides in Barrett’s and colorectal carcinogenesis. World J Gastroenterol. 2012;18:6560–6570.
  • Kaur BS, Khamnehei N, Iravani M, et al. Rofecoxib inhibits cyclooxygenase 2 expression and activity and reduces cell proliferation in Barrett’s esophagus. Gastroenterology. 2002;123:60–67.
  • Alsalahi O, Dobrian AD. Proton pump inhibitors: the culprit for Barrett’s esophagus? Front Oncol. 2014;4:373.
  • Wang JS, Varro A, Lightdale CJ, et al. Elevated serum gastrin is associated with a history of advanced neoplasia in Barrett’s esophagus. Am J Gastroenterol. 2010;105:1039–1045.

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