{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T05:38:37Z","timestamp":1768282717013,"version":"3.49.0"},"reference-count":31,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2022,5,19]],"date-time":"2022-05-19T00:00:00Z","timestamp":1652918400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research Foundation of Korea (NRF)","award":["2021R1F1A1063346"],"award-info":[{"award-number":["2021R1F1A1063346"]}]},{"name":"Korea government","award":["2021R1F1A1063346"],"award-info":[{"award-number":["2021R1F1A1063346"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>(1) Background: The association between proton pump inhibitor (PPI) use and hepatocellular carcinoma (HCC) has been controversial, especially in the general population. We aimed to determine the impact of PPI on HCC risk in participants without liver cirrhosis or chronic hepatitis virus infection. (2) Methods: We assessed 406,057 participants from the Korean National Health Insurance Service database who underwent health screening from 2003 to 2006. We evaluated exposure to PPI before the index date using a standardized daily defined dose (DDD) system. The association of proton pump inhibitor use with the risk of HCC was evaluated using multivariable-adjusted Cox proportional hazards regression. (3) Results: Compared with non-users, PPI use was not associated with the HCC risk in low (&lt;30 DDDs; aHR, 1.07; 95% CI, 0.91\u20131.27), intermediate (30 \u2264 PPI &lt; 60 DDDs; aHR, 0.96; 95% CI, 0.73\u20131.26), and high (\u226560 DDDs; aHR, 0.86; 95% CI, 0.63\u20131.17) PPI groups in the final adjustment model. In addition, risks of cirrhosis-associated HCC and non-cirrhosis-associated HCC were not significantly associated with PPI use. The results remained consistent after excluding events that occurred within 1, 2, and 3 years to exclude pre-existing conditions that may be associated with the development of HCC. We also found no PPI-associated increase in HCC risk among the selected population, such as those with obesity, older age, and chronic liver diseases. (4) Conclusions: PPI use may not be associated with HCC risk regardless of the amount. We call for future studies conducted in other regions to generalize our findings.<\/jats:p>","DOI":"10.3390\/jcm11102865","type":"journal-article","created":{"date-parts":[[2022,5,19]],"date-time":"2022-05-19T12:25:57Z","timestamp":1652963157000},"page":"2865","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Association between Proton Pump Inhibitor Use and Risk of Hepatocellular Carcinoma: A Korean Nationally Representative Cohort Study"],"prefix":"10.3390","volume":"11","author":[{"given":"Soungmun","family":"Kim","sequence":"first","affiliation":[{"name":"Graduate School of Data Science, Seoul National University, Seoul 08826, Korea"},{"name":"Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seogsong","family":"Jeong","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics, CHA University School of Medicine, Seongnam 13488, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8205-9556","authenticated-orcid":false,"given":"Sun Jae","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8586-0645","authenticated-orcid":false,"given":"Jooyoung","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seulggie","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoosun","family":"Cho","sequence":"additional","affiliation":[{"name":"Total Healthcare Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul 06351, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph C.","family":"Ahn","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1910-9658","authenticated-orcid":false,"given":"Gyeongsil","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea"},{"name":"Estherformula Medical Food R&D Center, Seoul 06019, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2460-3378","authenticated-orcid":false,"given":"Joung Sik","family":"Son","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Hallym University Sacred Heart Hospital, Anyang 14068, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sang Min","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea"},{"name":"Estherformula Medical Food R&D Center, Seoul 06019, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1002\/ijc.32723","article-title":"International trends in hepatocellular carcinoma incidence, 1978\u20132012","volume":"147","author":"Petrick","year":"2019","journal-title":"Int. J. Cancer"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1007\/s12029-017-9959-0","article-title":"Global Epidemiology of Hepatocellular Carcinoma (HCC Epidemiology)","volume":"48","author":"Ozakyol","year":"2017","journal-title":"J. Gastrointest. Cancer"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"512","DOI":"10.3350\/cmh.2021.0171","article-title":"Hepatocellular carcinoma statistics in South Korea","volume":"27","author":"Chon","year":"2021","journal-title":"Clin. Mol. Hepatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"4300","DOI":"10.3748\/wjg.14.4300","article-title":"Hepatocellular carcinoma: Epidemiology, risk factors and pathogenesis","volume":"14","author":"Gomaa","year":"2008","journal-title":"World J. Gastroenterol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1093\/annonc\/mdn565","article-title":"The impact of obesity and diabetes mellitus on the risk of hepatocellular carcinoma","volume":"20","author":"Polesel","year":"2008","journal-title":"Ann. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"S2","DOI":"10.1097\/MCG.0b013e3182872f29","article-title":"Epidemiology of Hepatocellular Carcinoma: Consider the population","volume":"47","author":"Mittal","year":"2013","journal-title":"J. Clin. Gastroenterol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3030","DOI":"10.1002\/ijc.21731","article-title":"The global health burden of infection-associated cancers in the year 2002","volume":"118","author":"Parkin","year":"2006","journal-title":"Int. J. Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/j.jhep.2006.05.013","article-title":"The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide","volume":"45","author":"Perz","year":"2006","journal-title":"J. Hepatol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1093\/aje\/155.4.323","article-title":"Alcohol and Hepatocellular Carcinoma: The Effect of Lifetime Intake and Hepatitis Virus Infections in Men and Women","volume":"155","author":"Donato","year":"2002","journal-title":"Am. J. Epidemiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.cgh.2010.08.019","article-title":"Cirrhosis Is Present in Most Patients With Hepatitis B and Hepatocellular Carcinoma","volume":"9","author":"Yang","year":"2011","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Hwang, I.C., Chang, J., and Park, S.M. (2018). Association between proton pump inhibitor use and the risk of pancreatic cancer: A Korean nationwide cohort study. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0203918"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1111\/apt.14835","article-title":"Association between proton pump inhibitors and the risk of hepatocellular carcinoma","volume":"48","author":"Shao","year":"2018","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1001\/jamainternmed.2015.7927","article-title":"Adverse Effects Associated With Proton Pump Inhibitors","volume":"176","author":"Schoenfeld","year":"2016","journal-title":"JAMA Intern. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1097\/JCMA.0000000000000157","article-title":"Use of proton pump inhibitors and the risk of hepatocellular carcinoma","volume":"82","author":"Chang","year":"2019","journal-title":"J. Chin. Med. Assoc."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1007\/s00228-020-02854-8","article-title":"Proton pump inhibitors and risk of liver cancer and mortality in patients with chronic liver disease: A systematic review and meta-analysis","volume":"76","author":"Song","year":"2020","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_17","first-page":"799","article-title":"Data Resource Profile: The National Health Information Database of the National Health Insurance Service in South Korea","volume":"46","author":"Seong","year":"2017","journal-title":"Int. J. Epidemiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e016640","DOI":"10.1136\/bmjopen-2017-016640","article-title":"Cohort profile: The National Health Insurance Service-National Health Screening Cohort (NHIS-HEALS) in Korea","volume":"7","author":"Seong","year":"2017","journal-title":"BMJ Open"},{"key":"ref_19","unstructured":"World Health Organization (2000). Collaborating Centre for Drug Statistics Methodology, Guide-Lines for ATC Classification and DDD Assignment, WHO Collaborating Centre for Drug Statistics Methodology."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1136\/gutjnl-2017-314605","article-title":"Long-term proton pump inhibitors and risk of gastric cancer development after treatment for Helicobacter pylori: A population-based study","volume":"67","author":"Cheung","year":"2017","journal-title":"Gut"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1136\/gutjnl-2021-325097","article-title":"Proton pump inhibitors and risk of gastric cancer: Population-based cohort study","volume":"71","author":"Abrahami","year":"2021","journal-title":"Gut"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Hwang, I.C., Chang, J., and Park, S.M. (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.","DOI":"10.1371\/journal.pone.0189114"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1080\/14740338.2020.1715939","article-title":"Exposure to proton pump inhibitors and risk of pancreatic cancer: A meta-analysis","volume":"19","author":"Alkhushaym","year":"2020","journal-title":"Expert Opin. Drug Saf."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1007\/s00535-019-01652-z","article-title":"Long-term proton pump inhibitor usage and the association with pancreatic cancer in Sweden","volume":"55","author":"Brusselaers","year":"2019","journal-title":"J. Gastroenterol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1111\/apt.14796","article-title":"Proton pump inhibitor and histamine-2 receptor antagonist use and risk of liver cancer in two population-based studies","volume":"48","author":"Tran","year":"2018","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1046\/j.1365-2036.1996.d01-506.x","article-title":"Altered bowel function and duodenal bacterial overgrowth in patients treated with omeprazole","volume":"10","author":"Lewis","year":"1996","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1136\/gut.39.1.54","article-title":"Bacterial overgrowth during treatment with omeprazole compared with cimetidine: A prospective randomised double blind study","volume":"39","author":"Thorens","year":"1996","journal-title":"Gut"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1016\/j.jhep.2007.06.001","article-title":"Endogenous bile acids as carcinogens","volume":"47","author":"Jansen","year":"2007","journal-title":"J. Hepatol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/S0168-8278(99)80114-7","article-title":"Expression and processing of gastrin in hepatocellular carcinoma, fibrolamellar carcinoma and cholangiocarcinoma","volume":"30","author":"Caplin","year":"1999","journal-title":"J. Hepatol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1111\/apm.12380","article-title":"Hypergastrinemia is associated with adenocarcinomas in the gastric corpus and shorter patient survival","volume":"123","author":"Fossmark","year":"2015","journal-title":"APMIS"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"911","DOI":"10.2165\/00002512-200219120-00003","article-title":"Treatment of acid-related diseases in the elderly with emphasis on the use of proton pump inhibitors","volume":"19","author":"Thjodleifsson","year":"2002","journal-title":"Drugs Aging"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/11\/10\/2865\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:14:37Z","timestamp":1760138077000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/11\/10\/2865"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,19]]},"references-count":31,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["jcm11102865"],"URL":"https:\/\/doi.org\/10.3390\/jcm11102865","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,19]]}}}