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The association between acid-suppressive agent use and the risk of cancer: a systematic review and meta-analysis

  • Pharmacoepidemiology and Prescription
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Abstract

Background

Acid-suppressive agents (ASAs) may be associated with cancer; previous studies reported that the risk of cancer with acid suppressants has differed depending on the site of cancer. Here, we conducted a systematic review and meta-analysis of the association between ASA use and the type of cancer risk.

Methods

MEDLINE, EMBASE, and Cochrane library databases were searched for publications up to the end of September 2019 for MeSH terms and text words related to cancer and ASAs. Studies on the association between ASAs and cancer risk, which included a control group and reported the relative risk of cancer, were included. The inverse-variance random effect model was used to estimate the pooled relative risk (RR) and 95% confidence interval (CI), and subgroup analysis for type of acid suppressants, drug uptake duration, and cumulative doses was performed. Heterogeneity was assessed using the I2 test and Q statistic.

Results

Thirty-nine cohort and case–control studies were included. ASA use was found to be significantly associated with a 46% higher risk of gastric cancer (RR, 1.46; 95% CI, 1.18–1.80) and a 53% higher risk of liver cancer (RR, 1.53; 95% CI, 1.31–1.78) compared with nonuse; however, there was no significant association for esophageal, colorectal, pancreatic, lung, breast, prostate, and kidney cancer; melanoma; and lymphoma.

Conclusions

ASAs were significantly associated with an increased risk of gastric and liver cancer; therefore, special attention of ASA use considering the potential risk of gastric and liver cancer is needed.

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References

  1. Antony Q (2009) Preventing stress ulcers with acid suppression. Pharmacy Times. https://www.pharmacytimes.com/publications/issue/2009/2009-05/hspstressulcers-0509.

  2. Modlin IM, Sandor A (1997) An analysis of 8305 cases of carcinoid tumors. Cancer 79:813–829. https://doi.org/10.1002/(sici)1097-0142(19970215)79:4<813::aid-cncr19>3.0.co;2-2

    Article  CAS  PubMed  Google Scholar 

  3. Thorburn CM, Friedman GD, Dickinson CJ, Vogelman JH, Orentreich N, Parsonnet J (1998) Gastrin and colorectal cancer: a prospective study. Gastroenterology 115:275–280. https://doi.org/10.1016/s0016-5085(98)70193-3

    Article  CAS  PubMed  Google Scholar 

  4. Smith JP, Nadella S, Osborne N (2017) Gastrin and gastric cancer. Cell Mol Gastroenterol Hepatol 4:75–83. https://doi.org/10.1016/j.jcmgh.2017.03.004

    Article  PubMed  PubMed Central  Google Scholar 

  5. Dacha S, Razvi M, Massaad J, Cai Q, Wehbi M (2015) Hypergastrinemia. Gastroenterol Rep (Oxf) 3:201–208. https://doi.org/10.1093/gastro/gov004

    Article  Google Scholar 

  6. Rosen R, Amirault J, Liu H, Mitchell P, Hu L, Khatwa U, Onderdonk A (2014) Changes in gastric and lung microflora with acid suppression: acid suppression and bacterial growth. JAMA Pediatr 168:932–937. https://doi.org/10.1001/jamapediatrics.2014.696

    Article  PubMed  PubMed Central  Google Scholar 

  7. Bajaj JS (2019) Alcohol, liver disease and the gut microbiota. Nat Rev Gastroenterol Hepatol 16:235–246. https://doi.org/10.1038/s41575-018-0099-1

    Article  PubMed  Google Scholar 

  8. Bajaj JS, Heuman DM, Hylemon PB, Sanyal AJ, White MB, Monteith P, Noble NA, Unser AB, Daita K, Fisher AR, Sikaroodi M, Gillevet PM (2014) Altered profile of human gut microbiome is associated with cirrhosis and its complications. J Hepatol 60:940–947. https://doi.org/10.1016/j.jhep.2013.12.019

    Article  CAS  PubMed  Google Scholar 

  9. Li M, Yuan J, Wen S, Chen J (2018) Alteration of gut microbiome in lung cancer patients. J Thorac Oncol 13:S947. https://doi.org/10.1016/j.jtho.2018.08.1772

    Article  Google Scholar 

  10. Islam MM, Poly TN, Walther BA, Dubey NK, Anggraini Ningrum DN, Shabbir SA, Jack Li YC (2018) Adverse outcomes of long-term use of proton pump inhibitors: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol 30:1395–1405. https://doi.org/10.1097/MEG.0000000000001198

    Article  CAS  PubMed  Google Scholar 

  11. Tran-Duy A, Spaetgens B, Hoes AW, de Wit NJ, Stehouwer CD (2016) Use of proton pump inhibitors and risks of fundic gland polyps and gastric cancer: systematic review and meta-analysis. Clin Gastroenterol Hepatol 14:1706–1719.e5. https://doi.org/10.1016/j.cgh.2016.05.018

    Article  CAS  PubMed  Google Scholar 

  12. Ahn JS, Eom CS, Jeon CY, Park SM (2013) Acid suppressive drugs and gastric cancer: a meta-analysis of observational studies. World J Gastroenterol 19:2560–2568. https://doi.org/10.3748/wjg.v19.i16.2560

    Article  PubMed  PubMed Central  Google Scholar 

  13. Qiu T, Zhou J, Zhang C (2018) Acid-suppressive drugs and risk of kidney disease: a systematic review and meta-analysis. J Gastroenterol Hepatol 33:1566–1573. https://doi.org/10.1111/jgh.14157

    Article  CAS  Google Scholar 

  14. Lambert AA, Lam JO, Paik JJ, Ugarte-Gil C, Drummond MB, Crowell TA (2015) Risk of community-acquired pneumonia with outpatient proton-pump inhibitor therapy: a systematic review and meta-analysis. PLoS One 10:e0128004. https://doi.org/10.1371/journal.pone.0128004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Trifan A, Stanciu C, Girleanu I, Stoica OC, Singeap AM, Maxim R, Chiriac SA, Ciobica A, Boiculese L (2017) Proton pump inhibitors therapy and risk of Clostridium difficile infection: systematic review and meta-analysis. World J Gastroenterol 23:6500–6515. https://doi.org/10.3748/wjg.v23.i35.6500

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, Clarke M, Devereaux PJ, Kleijnen J, Moher D (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Ann Intern Med 151:W65–W94. https://doi.org/10.1016/j.jclinepi.2009.06.006

    Article  PubMed  Google Scholar 

  17. Kim SY, Park JE, Lee YJ, Seo HJ, Sheen SS, Hahn S, Jang BH, Son HJ (2013) Testing a tool for assessing the risk of bias for nonrandomized studies showed moderate reliability and promising validity. J Clin Epidemiol 66:408–414. https://doi.org/10.1016/j.jclinepi.2012.09.016

    Article  PubMed  Google Scholar 

  18. Davies HT, Crombie IK, Tavakoli M (1998) When can odds ratios mislead? BMJ 316:989–991. https://doi.org/10.1136/bmj.316.7136.989

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Stare J, Maucort-Boulch D (2016) Odds ratio, hazard ratio and relative risk. Metodoloski zvezki 13:59–67

    Google Scholar 

  20. Zhang J, Yu KF (1998) What’s the relative risk? A method of correcting the odds ratio in cohort studies of common outcomes. JAMA 280:1690–1691. https://doi.org/10.1001/jama.280.19.1690

    Article  CAS  PubMed  Google Scholar 

  21. Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327:557–560. https://doi.org/10.1136/bmj.327.7414.557

    Article  PubMed  PubMed Central  Google Scholar 

  22. Suleiman UL, Harrison M, Britton A, McPherson K, Bates T (2000) H2-receptor antagonists may increase the risk of cardio-oesophageal adenocarcinoma: a case-control study. Eur J Cancer Prev 9:185–191

    Article  CAS  PubMed  Google Scholar 

  23. Tan MC, El-Serag HB, Yu X, Thrift AP (2018) Acid suppression medications reduce risk of oesophageal adenocarcinoma in Barrett’s oesophagus: a nested case-control study in US male veterans. Aliment Pharmacol Ther 48:469–477. https://doi.org/10.1111/apt.14895

    Article  CAS  PubMed  Google Scholar 

  24. Duan L, Wu AH, Sullivan-Halley J, Bernstein L (2009) Antacid drug use and risk of esophageal and gastric adenocarcinomas in Los Angeles County. Cancer Epidemiol Biomark Prev 18:526–533. https://doi.org/10.1158/1055-9965.EPI-08-0764

    Article  CAS  Google Scholar 

  25. Farrow DC, Vaughan TL, Sweeney C, Gammon MD, Chow WH, Risch HA, Stanford JL, Hansten PD, Mayne ST, Schoenberg JB, Rotterdam H, Ahsan H, West AB, Dubrow R, Raumeni JF Jr, Blot WJ (2000) Gastroesophageal reflux disease, use of H2 receptor antagonists, and risk of esophageal and gastric cancer. Cancer Causes Control 11:231–238. https://doi.org/10.1023/a:1008913828105

    Article  CAS  PubMed  Google Scholar 

  26. Habel LA, Levin TR, Friedman GD (2000) Cimetidine use and risk of breast, prostate, and other cancers. Pharmacoepidemiol Drug Saf 9:149–155. https://doi.org/10.1002/(SICI)1099-1557(200003/04)9:2<149::AID-PDS481>3.0.CO;2-1

    Article  CAS  PubMed  Google Scholar 

  27. García Rodríguez LA, Lagergren J, Lindblad M (2006) Gastric acid suppression and risk of oesophageal and gastric adenocarcinoma: a nested case control study in the UK. Gut 55:1538–1544. https://doi.org/10.1136/gut.2005.086579

    Article  PubMed  Google Scholar 

  28. Cheung KS, Chan EW, Wong AYS, Chen L, Wong ICK, Leung WK (2018) Long-term proton pump inhibitors and risk of gastric cancer development after treatment for Helicobacter pylori: a population-based study. Gut 67:28–35. https://doi.org/10.1136/gutjnl-2017-314605

    Article  CAS  PubMed  Google Scholar 

  29. Johnson AG, Jick SS, Perera DR, Jick H (1996) Histamine-2 receptor antagonists and gastric cancer. Epidemiology 7:434–436. https://doi.org/10.1097/00001648-199607000-00016

    Article  CAS  PubMed  Google Scholar 

  30. La Vecchia C, Negri E, D’Avanzo B, Franceschi S (1990) Histamine-2-receptor antagonists and gastric cancer risk. Lancet 336:355–357. https://doi.org/10.1016/0140-6736(90)91888-h

    Article  PubMed  Google Scholar 

  31. Niikura R, Hayakawa Y, Hirata Y, Yamada A, Fujishiro M, Koike K (2018) Long-term proton pump inhibitor use is a risk factor of gastric cancer after treatment for Helicobacter pylori: a retrospective cohort analysis. Gut 67:1908–1910. https://doi.org/10.1136/gutjnl-2017-315710

    Article  CAS  PubMed  Google Scholar 

  32. Poulsen AH, Christensen S, McLaughlin JK, Thomsen RW, Sørensen HT, Olsen JH, Friis S (2009) Proton pump inhibitors and risk of gastric cancer: a population-based cohort study. Br J Cancer 100:1503–1507. https://doi.org/10.1038/sj.bjc.6605024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Tamim H, Duranceau A, Chen LQ, Lelorier J (2008) Association between use of acid-suppressive drugs and risk of gastric cancer. A nested case-control study. Drug Saf 31:675–684. https://doi.org/10.2165/00002018-200831080-00004

    Article  PubMed  Google Scholar 

  34. Chubak J, Boudreau DM, Rulyak SJ, Mandelson MT (2009) Colorectal cancer risk in relation to use of acid suppressive medications. Pharmacoepidemiol Drug Saf 18:540–544. https://doi.org/10.1002/pds.1749

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Hwang IC, Chang J, Park SM (2017) Emerging hazard effects of proton pump inhibitor on the risk of colorectal cancer in low-risk populations: a Korean nationwide prospective cohort study. PLoS One 12:e0189114. https://doi.org/10.1371/journal.pone.0189114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Robertson DJ, Larsson H, Friis S, Pedersen L, Baron JA, Sørensen HT (2007) Proton pump inhibitor use and risk of colorectal cancer: a population-based, case-control study. Gastroenterology 133:755–760. https://doi.org/10.1053/j.gastro.2007.06.014

    Article  PubMed  Google Scholar 

  37. Siersema PD, Yu S, Sahbaie P, Steyerberg EW, Simpson PW, Kuipers EJ, Triadafilopoulos G (2006) Colorectal neoplasia in veterans is associated with Barrett’s esophagus but not with proton-pump inhibitor or aspirin/NSAID use. Gastrointest Endosc 63:581–586. https://doi.org/10.1016/j.gie.2005.08.043

  38. Yang YX, Hennessy S, Propert K, Hwang WT, Sedarat A, Lewis JD (2007) Chronic proton pump inhibitor therapy and the risk of colorectal cancer. Gastroenterology 133:748–754. https://doi.org/10.1053/j.gastro.2007.06.022

    Article  CAS  PubMed  Google Scholar 

  39. van Soest EM, van Rossum LG, Dieleman JP, van Oijen MG, Siersema PD, Sturkenboom MC, Kuipers EJ (2008) Proton pump inhibitors and the risk of colorectal cancer. Am J Gastroenterol 103:966–973. https://doi.org/10.1111/j.1572-0241.2007.01665.x

    Article  PubMed  Google Scholar 

  40. Kao WY, Su CW, Chia-Hui Tan E, Lee PC, Chen PH, Tang JH, Huang YH, Huo TI, Chang CC, Hou MC, Lin HC, Wu JC (2019) Proton pump inhibitors and risk of hepatocellular carcinoma in patients with chronic hepatitis B or C. Hepatology 69:1151–1164. https://doi.org/10.1002/hep.30247

    Article  CAS  PubMed  Google Scholar 

  41. Li DK, Yan P, Abou-Samra AB, Chung RT, Butt AA (2018) Proton pump inhibitors are associated with accelerated development of cirrhosis, hepatic decompensation and hepatocellular carcinoma in noncirrhotic patients with chronic hepatitis C infection: results from ERCHIVES. Aliment Pharmacol Ther 47:246–258. https://doi.org/10.1111/apt.14391

    Article  CAS  PubMed  Google Scholar 

  42. Peng YC, Lin CL, Hsu WY, Chow WK, Lee SW, Yeh HZ, Chen CC, Kao CH (2018) Association between cholangiocarcinoma and proton pump inhibitors use: a nested case-control study. Front Pharmacol 9:718. https://doi.org/10.3389/fphar.2018.00718

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Shao YJ, Chan TS, Tsai K, Wu SY (2018) Association between proton pump inhibitors and the risk of hepatocellular carcinoma. Aliment Pharmacol Ther 48:460–468. https://doi.org/10.1111/apt.14835

    Article  CAS  PubMed  Google Scholar 

  44. Tran KT, McMenamin ÚC, Hicks B, Murchie P, Thrift AP, Coleman HG, Iversen L, Johnston BT, Lee AJ, Cardwell CR (2018) Proton pump inhibitor and histamine-2 receptor antagonist use and risk of liver cancer in two population-based studies. Aliment Pharmacol Ther 48:55–64. https://doi.org/10.1111/apt.14796

    Article  CAS  PubMed  Google Scholar 

  45. Bradley MC, Murray LJ, Cantwell MM, Hughes CM (2012) Proton pump inhibitors and histamine-2-receptor antagonists and pancreatic cancer risk: a nested case-control study. Br J Cancer 106:233–239. https://doi.org/10.1038/bjc.2011.511

    Article  CAS  PubMed  Google Scholar 

  46. Hicks B, Friis S, Pottegård A (2018) Use of proton pump inhibitors and risk of pancreatic cancer. Pharmacoepidemiol Drug Saf 27:926–930. https://doi.org/10.1002/pds.4576

    Article  CAS  PubMed  Google Scholar 

  47. Hwang IC, Chang J, Park SM (2018) Association between proton pump inhibitor use and the risk of pancreatic cancer: a Korean nationwide cohort study. PLoS One 13:e0203918. https://doi.org/10.1371/journal.pone.0203918

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Kearns MD, Boursi B, Yang YX (2017) Proton pump inhibitors on pancreatic cancer risk and survival. Cancer Epidemiol 46:80–84. https://doi.org/10.1016/j.canep.2016.12.006

    Article  PubMed  PubMed Central  Google Scholar 

  49. Lai SW, Sung FC, Lin CL, Liao KF (2014) Use of proton pump inhibitors correlates with increased risk of pancreatic cancer: a case-control study in Taiwan. J Kuwait Med Assoc 46:44–48

    Google Scholar 

  50. Peng YC, Lin CL, Hsu WY, Lu IT, Yeh HZ, Chang CS, Kao CH (2018) Proton pump inhibitor use is associated with risk of pancreatic cancer: a nested case-control study. Dose-Response 16(4):1559325818803283. https://doi.org/10.1177/1559325818803283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Hsu CL, Chang CH, Lin JW, Wu LC, Chuang LM, Lai MS (2013) Histamine-2 receptor antagonists and risk of lung cancer in diabetic patients – an exploratory analysis. Pharmacoepidemiol Drug Saf 22:632–640. https://doi.org/10.1002/pds.3441

    Article  CAS  PubMed  Google Scholar 

  52. Chen CH, Lee CZ, Lin YC, Kao LT, Lin HC (2019) Negative association of proton pump inhibitors with subsequent development of breast cancer: a nationwide population-based study. J Clin Pharmacol 59:350–355. https://doi.org/10.1002/jcph.1329

    Article  CAS  PubMed  Google Scholar 

  53. Coogan PF, Zhang Y, Palmer JR, Strom BL, Rosenberg L (2005) Cimetidine and other histamine 2-receptor antagonist use in relation to risk of breast cancer. Cancer Epidemiol Biomark Prev 14:1012–1015. https://doi.org/10.1158/1055-9965.EPI-04-0547

    Article  CAS  Google Scholar 

  54. Ding DC, Sung FC, Chen W, Wang JH, Lin SZ (2019) Proton pump inhibitors reduce breast cancer risk in gastric ulcer patients: a population-based cohort study. Breast J 26:474–478. https://doi.org/10.1111/tbj.13519

    Article  CAS  PubMed  Google Scholar 

  55. Hálfdánarson ÓÖ, Fall K, Ogmundsdottir MH, Lund SH, Steingrímsson E, Ogmundsdottir HM, Zoega H (2019) Proton pump inhibitor use and risk of breast cancer, prostate cancer, and malignant melanoma: an Icelandic population-based case-control study. Pharmacoepidemiol Drug Saf 28:471–478. https://doi.org/10.1002/pds.4702

    Article  CAS  PubMed  Google Scholar 

  56. Mathes RW, Malone KE, Daling JR, Porter PL, Li CI (2008) Relationship between histamine 2-receptor antagonist medications and risk of invasive breast cancer. Cancer Epidemiol Biomark Prev 17:67–72. https://doi.org/10.1158/1055-9965.EPI-07-0765

    Article  CAS  Google Scholar 

  57. Velicer CM, Dublin S, White E (2006) Cimetidine use and the risk for prostate cancer: results from the VITAL cohort study. Ann Epidemiol 16:895–900. https://doi.org/10.1016/j.annepidem.2006.03.003

    Article  PubMed  Google Scholar 

  58. Nayan M, Juurlink DN, Austin PC, Macdonald EM, Finelli A, Kulkarni GS, Hamilton RJ (2017) Canadian Drug Safety and Effectiveness Research Network (CDSERN). Medication use and kidney cancer risk: a population-based study. Eur J Cancer 83:203–210. https://doi.org/10.1016/j.ejca.2017.07.001

    Article  PubMed  Google Scholar 

  59. Beiderbeck AB, Holly EA, Sturkenboom MC, Coebergh JW, Stricker BH, Leufkens HG (2003) Prescription medications associated with a decreased risk of non-Hodgkin’s lymphoma. Am J Epidemiol 157:510–516. https://doi.org/10.1093/aje/kwg004

    Article  PubMed  Google Scholar 

  60. Chien LN, Huang YJ, Shao YH, Chang CJ, Chuang MT, Chiou HY, Yen Y (2016) Proton pump inhibitors and risk of periampullary cancers - a nested case-control study. Int J Cancer 138:1401–1409. https://doi.org/10.1002/ijc.29896

    Article  CAS  PubMed  Google Scholar 

  61. Langman MJ (1985) Antisecretory drugs and gastric cancer. Br Med J (Clin Res Ed) 290:1850–1852. https://doi.org/10.1136/bmj.290.6485.1850

    Article  CAS  Google Scholar 

  62. Freston JW (1982) Cimetidine: II. Adverse reactions and patterns of use. Ann Intern Med 97:728–734. https://doi.org/10.7326/0003-4819-97-5-728

    Article  CAS  PubMed  Google Scholar 

  63. Stockbruegger RW (1985) Bacterial overgrowth as a consequence of reduced gastric acidity. Scand J Gastroenterol Suppl 111:7–16. https://doi.org/10.3109/00365528509093749

    Article  CAS  PubMed  Google Scholar 

  64. Stockbrugger RW, Cotton PB, Eugenides N, Bartholomew BA, Hill MJ, Walters CL (1982) Intragastric nitrites, nitrosamines, and bacterial overgrowth during cimetidine treatment. Gut 23:1048–1054. https://doi.org/10.1136/gut.23.12.1048

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Rowland JR (1988) The toxicology of N-nitroso compounds. In: Hill MJ (ed) Nitrosamines-toxicology and microbiology. Ellis Horwood pp, London, pp 117–141

    Google Scholar 

  66. Klinkenberg-Knol EC, Festen HP, Jansen JB, Lamers CB, Nelis F, Snel P, Lückers A, Dekkers CP, Havu N, Meuwis-sen SG (1994) Long-term treatment with omeprazole for refractory reflux esophagitis: efficacy and safety. Ann Intern Med 121:161–167. https://doi.org/10.7326/0003-4819-121-3-199408010-00001

    Article  CAS  PubMed  Google Scholar 

  67. Lamberts R, Creutzfeldt W, Stöckmann F, Jacubaschke U, Maas S, Brunner G (1988) Long-term omeprazole treatment in man: effects on gastric endocrine cell populations. Digestion 39:126–135. https://doi.org/10.1159/000199615

    Article  CAS  PubMed  Google Scholar 

  68. Laine L, Ahnen D, McClain C, Solcia E, Walsh JH (2000) Review article: potential gastrointestinal effects of long-term acid suppression with proton pump inhibitors. Aliment Pharmacol Ther 14:651–668. https://doi.org/10.1046/j.1365-2036.2000.00768.x

    Article  CAS  PubMed  Google Scholar 

  69. Havu N (1986) Enterochromaffin-like cell carcinoids of gastric mucosa in rats after life-long inhibition of gastric secretion. Digestion 35:42–55. https://doi.org/10.1159/000199381

    Article  PubMed  Google Scholar 

  70. Smith JP, Wood JG, Solomon TE (1989) Elevated gastrin levels in patients with colon cancer or adenomatous polyps. Dig Dis Sci 34:171–174. https://doi.org/10.1007/bf01536047

    Article  CAS  PubMed  Google Scholar 

  71. Seitz JF, Giovannini M, Gouvernet J, Gauthier AP (1991) Elevated serum gastrin levels in patients with colorectal neoplasia. J Clin Gastroenterol 13:541–545. https://doi.org/10.1097/00004836-199110000-00013

    Article  CAS  PubMed  Google Scholar 

  72. Singh P, Indaram A, Greenberg R, Visvalingam V, Bank S (2000) Long term omeprazole therapy for reflux esophagitis: follow up in serum gastrin levels, EC cell hyperplasia and neoplasia. World J Gastroenterol 6:789–792. https://doi.org/10.3748/wjg.v6.i6.789

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Jalving M, Koornstra JJ, Wesseling J, Boezen HM, DE Jong S, Kleibeuker JH (2006) Increased risk of fundic gland polyps during long-term proton pump inhibitor therapy. Aliment Pharmacol Ther 24:1341–1348. https://doi.org/10.1111/j.1365-2036.2006.03127.x

    Article  CAS  PubMed  Google Scholar 

  74. Solcia E, Fiocca R, Havu N, Dalväg A, Carlsson R (1992) Gastric endocrine cells and gastritis in patients receiving long-term omeprazole treatment. Digestion 51:82–92. https://doi.org/10.1159/000200921

    Article  PubMed  Google Scholar 

  75. Pashankar DS, Israel DM (2002) Gastric polyps and nodules in children receiving long-term omeprazole therapy. J Pediatr Gastroenterol Nutr 35:658–662. https://doi.org/10.1097/00005176-200211000-00013

    Article  CAS  PubMed  Google Scholar 

  76. Cats A, Schenk BE, Bloemena E, Roosedaal R, Lindeman J, Biemond I, Klinkenberg-Knol EC, Meuwissen SG, Kuipers EJ (2000) Parietal cell protrusions and fundic gland cysts during omeprazole maintenance treatment. Hum Pathol 31:684–690. https://doi.org/10.1053/hupa.2000.7637

    Article  CAS  PubMed  Google Scholar 

  77. van Grieken NC, Meijer GA, Weiss MM, Bloemena E, Lindeman J, Baak JP, Meuwissen SG, Kuipers EJ (2001) Quantitative assessment of gastric corpus atrophy in subjects using omeprazole: a randomized follow-up study. Am J Gastroenterol 96:2882–2886. https://doi.org/10.1111/j.1572-0241.2001.04242.x

    Article  PubMed  Google Scholar 

  78. Zhao J, Hua L, Li N, An R, Liang C (2018) Letter: proton pump inhibitors use and risk of hepatocellular carcinoma: a meta-analysis of observational studies. Aliment Pharmacol Ther 48:886–888. https://doi.org/10.1111/apt.14962

    Article  PubMed  Google Scholar 

  79. Tran KT, McMenamin ÚC, Hicks B, Murchie P, Thrift AP, Coleman HG, Iversen L, Johnston BT, Lee AJ, Cardwell CR (2018) Proton pump inhibitor and histamine-2 receptor antagonist use and risk of liver cancer in two population-based studies. Aliment Pharmacol Ther 48:55–64. https://doi.org/10.1111/apt.14796

    Article  CAS  PubMed  Google Scholar 

  80. Caplin M, Khan K, Savage K, Rode J, Varro A, Michaeli D, Grimes S, Brett B, Pounder R, Dhillon A (1999) Expression and processing of gastrin in hepatocellular carcinoma, fibrolamellar carcinoma and cholangiocarcinoma. J Hepatol 30:519–526

    Article  CAS  PubMed  Google Scholar 

  81. Llorente C, Schnabl B (2015) The gut microbiota and liver disease. Cell Mol Gastroenterol Hepatol 1:275–284. https://doi.org/10.1016/j.jcmgh.2015.04.003

    Article  PubMed  PubMed Central  Google Scholar 

  82. Jansen PLM (2007) Endogenous bile acids as carcinogens. J Hepatol 47:434–435. https://doi.org/10.1016/j.jhep.2007.06.001

    Article  CAS  PubMed  Google Scholar 

  83. Komichi D, Tazuma S, Nishioka T, Hyogo H, Chayama K (2005) Glycochenodeoxycholate plays a carcinogenic role in immortalized mouse cholangiocytes via oxidative DNA damage. Free Radic Biol Med 39:1418–1427. https://doi.org/10.1016/j.freeradbiomed.2005.07.005

    Article  CAS  PubMed  Google Scholar 

  84. Llorente C, Jepsen P, Inamine T, Wang L, Bluemel S, Wang HJ, Loomba R, Bajaj JS, Schubert ML, Sikaroodi M, Gillevet PM, Xu J, Kisseleva T, Ho SB, DePew J, Du X, Sørensen HT, Vilstrup H, Nelson KE, Brenner DA, Fouts DE, Schnabl B (2017) Gastric acid suppression promotes alcoholic liver disease by inducing overgrowth of intestinal Enterococcus. Nat Commun 8:1–14. https://doi.org/10.1038/s41467-017-00796-x

    Article  CAS  Google Scholar 

  85. Hayashi H, Shimamoto K, Taniai E, Ishii Y, Morita R, Suzuki K, Shibutani M, Mitsumori K (2012) Liver tumor promoting effect of omeprazole in rats and its possible mechanism of action. J Toxicol Sci 37:491–501. https://doi.org/10.2131/jts.37.491

    Article  CAS  PubMed  Google Scholar 

  86. Dacha S, Razvi M, Massaad J, Cai Q. Wehbi M (2015) Hypergastrinemia. Gastroenterol Rep 3:201–208. https://doi.org/10.1093/gastro/gov004

  87. Hu Q, Sun TT, Hong J, Fang JY, Xiong H, Meltzer SJ (2017) Proton pump inhibitors do not reduce the risk of esophageal adenocarcinoma in patients with Barrett’s esophagus: a systematic review and meta-analysis. PLoS One 12:e0169691. https://doi.org/10.1371/journal.pone.0169691

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Katz PO, Gerson LB, Vela MF (2013) Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol 108:308–328. https://doi.org/10.1038/ajg.2012.444

    Article  PubMed  Google Scholar 

  89. Kleiman DA, Sporn MJ, Beninato T, Metz Y, Crawford C, Fahey TJ 3rd, Zarnegar R (2013) Early referral for 24-h esophageal pH monitoring may prevent unnecessary treatment with acid-reducing medications. Surg Endosc 27:1302–1309. https://doi.org/10.1007/s00464-012-2602-z

    Article  PubMed  Google Scholar 

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Acknowledgments

We would like to thank Caitlin E. Kantner for proofreading the manuscript.

Funding

This work was supported by the Postdoctoral Research Program of Sungkyunkwan University (2017).

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HJS was involved in the study concept and design, literature search, study selection, quality assessment, data extraction, data analysis, data interpretation, and manuscript writing. NJ was involved in the literature search, study selection, quality assessment, data extraction, and manuscript writing. PS was involved in the study selection, quality assessment, and manuscript writing. All authors reviewed and approved the final version.

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Correspondence to Hyun Jin Song.

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Song, H.J., Jeon, N. & Squires, P. The association between acid-suppressive agent use and the risk of cancer: a systematic review and meta-analysis. Eur J Clin Pharmacol 76, 1437–1456 (2020). https://doi.org/10.1007/s00228-020-02927-8

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