{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T13:58:58Z","timestamp":1793973538499,"version":"4.8.0"},"reference-count":44,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","license":[{"start":{"date-parts":[[2021,4,19]],"date-time":"2021-04-19T00:00:00Z","timestamp":1618790400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2021,4,19]],"date-time":"2021-04-19T00:00:00Z","timestamp":1618790400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2021,6]]},"abstract":"<jats:sec>\n            <jats:title>Background and Aims<\/jats:title>\n            <jats:p>Long\u2010term antiviral therapy can effectively suppress viral replication and improve clinical outcomes in patients with chronic hepatitis B (CHB), but it cannot eliminate risk of HCC. We investigated the association of metabolic risk factors with the risks of cancer and all\u2010cause mortality in patients with CHB.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results<\/jats:title>\n            <jats:p>This nationwide population\u2010based study from the Korean National Health Insurance Service database consisted of adults with CHB who underwent health examinations from 2007 through 2012. We collected baseline data on metabolic risk factors, including obesity, high blood pressure, hypercholesterolemia, and diabetes. The risks of developing HCC, non\u2010HCC cancer, and overall death were analyzed according to the metabolic risk profile. The study population composed of 317,856 patients (median age, 46\u00a0years [interquartile range, 37\u201054\u00a0years]; 219,418 men [69.0%]) had 2,609,523.8 person\u2010years of follow\u2010up. A total of 18,850 HCCs, 22,164 non\u2010HCC cancers, and 15,768 deaths were observed during a median follow\u2010up period of 8.5\u00a0years. The metabolic risk factor burden was positively associated with the risks of HCC, non\u2010HCC cancer, and all\u2010cause mortality (all <jats:italic toggle=\"yes\">P<\/jats:italic>\u00a0&lt;\u00a00.0001 for trend). Patients with \u22653 metabolic risk factors, compared with those without metabolic risk factors, showed adjusted hazard ratios of 1.23 (95% CI, 1.16\u20101.31) for HCC, 1.34 (95% CI, 1.27\u20101.41) for non\u2010HCC cancer, and 1.31 (95% CI, 1.23\u20101.39) for all\u2010cause mortality. Among patients receiving antiviral therapy for over 5\u00a0years, the risk\u2010increasing association of the sum of metabolic risk factors with the risks of HCC and overall death was consistent.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>The metabolic risk factor burden was associated with increased risks of HCC, non\u2010HCC cancer, and all\u2010cause mortality in patients with CHB.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.31612","type":"journal-article","created":{"date-parts":[[2020,11,3]],"date-time":"2020-11-03T03:27:07Z","timestamp":1604374027000},"page":"2266-2277","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":64,"title":["Association of Metabolic Risk Factors With Risks of Cancer and All\u2010Cause Mortality in Patients With Chronic Hepatitis B"],"prefix":"10.1097","volume":"73","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3193-9745","authenticated-orcid":false,"given":"Yun Bin","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Internal Medicine and Liver Research Institute,Seoul National University College of Medicine,Seoul,Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyemi","family":"Moon","sequence":"additional","affiliation":[{"name":"Department of Biostatistics,College of Medicine,Korea University,Seoul,Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0315-2080","authenticated-orcid":false,"given":"Jeong\u2010Hoon","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Liver Research Institute,Seoul National University College of Medicine,Seoul,Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2677-3189","authenticated-orcid":false,"given":"Eun Ju","family":"Cho","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Liver Research Institute,Seoul National University College of Medicine,Seoul,Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8888-7977","authenticated-orcid":false,"given":"Su Jong","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Liver Research Institute,Seoul National University College of Medicine,Seoul,Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9141-7773","authenticated-orcid":false,"given":"Yoon Jun","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Liver Research Institute,Seoul National University College of Medicine,Seoul,Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabien","family":"Zoulim","sequence":"additional","affiliation":[{"name":"Cancer Research Centre of Lyon,INSERM U1052,Lyon University,Hospices Civils de Lyon, Lyon,France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juneyoung","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Biostatistics,College of Medicine,Korea University,Seoul,Korea"},{"name":"BK21 FOUR R&E Center for Learning Health Systems,Korea University,Seoul,Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9128-3610","authenticated-orcid":false,"given":"Jung\u2010Hwan","family":"Yoon","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Liver Research Institute,Seoul National University College of Medicine,Seoul,Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2021,4,19]]},"reference":[{"key":"hep31612-bib-0001-20250824","doi-asserted-by":"crossref","first-page":"1546","DOI":"10.1016\/S0140-6736(15)61412-X","article-title":"Estimations of worldwide prevalence of chronic hepatitis B virus infection: a systematic review of data published between 1965 and 2013","volume":"386","year":"2015","journal-title":"Lancet"},{"key":"hep31612-bib-0002-20250824","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.1056\/NEJMoa033364","article-title":"Lamivudine for patients with chronic hepatitis B and advanced liver disease","volume":"351","year":"2004","journal-title":"N Engl J Med"},{"key":"hep31612-bib-0003-20250824","doi-asserted-by":"crossref","first-page":"2673","DOI":"10.1056\/NEJMoa042957","article-title":"Long\u2010term therapy with adefovir dipivoxil for HBeAg\u2010negative chronic hepatitis B","volume":"352","year":"2005","journal-title":"N Engl J Med"},{"key":"hep31612-bib-0004-20250824","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1016\/S0140-6736(12)61425-1","article-title":"Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5\u2010year open\u2010label follow\u2010up study","volume":"381","year":"2013","journal-title":"Lancet"},{"key":"hep31612-bib-0005-20250824","doi-asserted-by":"crossref","first-page":"755","DOI":"10.3851\/IMP2754","article-title":"Efficacy of entecavir in chronic hepatitis B patients with persistently normal alanine aminotransferase: randomized, double\u2010blind, placebo\u2010controlled study","volume":"19","year":"2014","journal-title":"Antivir Ther"},{"key":"hep31612-bib-0006-20250824","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1002\/hep.28280","article-title":"Antiviral therapy for chronic hepatitis B viral infection in adults: A systematic review and meta\u2010analysis","volume":"63","year":"2016","journal-title":"Hepatology"},{"key":"hep31612-bib-0007-20250824","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1053\/j.gastro.2014.03.048","article-title":"Association of nucleos(t)ide analogue therapy with reduced risk of hepatocellular carcinoma in patients with chronic hepatitis B\u2014A nationwide cohort study","volume":"147","year":"2014","journal-title":"Gastroenterology"},{"key":"hep31612-bib-0008-20250824","doi-asserted-by":"crossref","first-page":"1705","DOI":"10.1053\/gast.2002.36572","article-title":"AGA technical review on nonalcoholic fatty liver disease","volume":"123","year":"2002","journal-title":"Gastroenterology"},{"key":"hep31612-bib-0009-20250824","doi-asserted-by":"crossref","first-page":"1640","DOI":"10.1161\/CIRCULATIONAHA.109.192644","article-title":"Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity","volume":"120","year":"2009","journal-title":"Circulation"},{"key":"hep31612-bib-0010-20250824","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1002\/hep.28431","article-title":"Global epidemiology of nonalcoholic fatty liver disease\u2014Meta\u2010analytic assessment of prevalence, incidence, and outcomes","volume":"64","year":"2016","journal-title":"Hepatology"},{"key":"hep31612-bib-0011-20250824","doi-asserted-by":"crossref","first-page":"2263","DOI":"10.1001\/jama.2015.5370","article-title":"Nonalcoholic fatty liver disease: A systematic review","volume":"313","year":"2015","journal-title":"JAMA"},{"key":"hep31612-bib-0012-20250824","doi-asserted-by":"crossref","first-page":"1174","DOI":"10.1002\/hep.26717","article-title":"Extrahepatic complications of nonalcoholic fatty liver disease","volume":"59","year":"2014","journal-title":"Hepatology"},{"key":"hep31612-bib-0013-20250824","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.jhep.2017.09.012","article-title":"Association between non\u2010alcoholic fatty liver disease and cancer incidence rate","volume":"68","year":"2018","journal-title":"J Hepatol"},{"key":"hep31612-bib-0014-20250824","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1038\/nrgastro.2013.34","article-title":"NAFLD in Asia\u2013As common and important as in the West","volume":"10","year":"2013","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"hep31612-bib-0015-20250824","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1136\/gut.2008.157735","article-title":"Metabolic syndrome increases the risk of liver cirrhosis in chronic hepatitis B","volume":"58","year":"2009","journal-title":"Gut"},{"key":"hep31612-bib-0016-20250824","doi-asserted-by":"crossref","first-page":"52","DOI":"10.3350\/cmh.2018.0040","article-title":"Association between hepatic steatosis and the development of hepatocellular carcinoma in patients with chronic hepatitis B","volume":"25","year":"2019","journal-title":"Clin Mol Hepatol"},{"key":"hep31612-bib-0017-20250824","doi-asserted-by":"crossref","first-page":"1178636120918878","DOI":"10.1177\/1178636120918878","article-title":"Presence of hepatic steatosis does not increase the risk of hepatocellular carcinoma in patients with chronic hepatitis B over long follow\u2010up","volume":"13","year":"2020","journal-title":"Microbiol Insights"},{"key":"hep31612-bib-0018-20250824","doi-asserted-by":"crossref","first-page":"2038","DOI":"10.1158\/1055-9965.EPI-19-0303","article-title":"The Influence of metabolic syndrome on the risk of hepatocellular carcinoma in patients with chronic hepatitis B infection in mainland China","volume":"28","year":"2019","journal-title":"Cancer Epidemiol Biomarkers Prev"},{"key":"hep31612-bib-0019-20250824","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1053\/j.gastro.2017.07.001","article-title":"Influence of metabolic risk factors on risk of hepatocellular carcinoma and liver\u2010related death in men with chronic hepatitis B: A large cohort study","volume":"153","year":"2017","journal-title":"Gastroenterology"},{"key":"hep31612-bib-0020-20250824","first-page":"799","article-title":"Data resource profile: The national health information database of the National Health Insurance Service in South Korea","volume":"46","year":"2017","journal-title":"Int J Epidemiol"},{"key":"hep31612-bib-0021-20250824","doi-asserted-by":"crossref","first-page":"6163","DOI":"10.7314\/APJCP.2012.13.12.6163","article-title":"A comparison of the cancer incidence rates between the National Cancer Registry and insurance claims data in Korea","volume":"13","year":"2012","journal-title":"Asian Pac J Cancer Prev"},{"key":"hep31612-bib-0022-20250824","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1080\/01621459.1999.10474144","article-title":"A proportional hazards model for the subdistribution of a competing risk","volume":"94","year":"1999","journal-title":"J Am Stat Assoc"},{"key":"hep31612-bib-0023-20250824","doi-asserted-by":"crossref","first-page":"4391","DOI":"10.1002\/sim.7501","article-title":"Practical recommendations for reporting Fine\u2010Gray model analyses for competing risk data","volume":"36","year":"2017","journal-title":"Stat Med"},{"key":"hep31612-bib-0024-20250824","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.1016\/j.jhep.2015.01.020","article-title":"Causes of death in people with chronic HBV infection: A population\u2010based cohort study","volume":"62","year":"2015","journal-title":"J Hepatol"},{"key":"hep31612-bib-0025-20250824","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1002\/hep.24199","article-title":"American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: An update","volume":"53","year":"2011","journal-title":"Hepatology"},{"key":"hep31612-bib-0026-20250824","doi-asserted-by":"crossref","first-page":"800","DOI":"10.1016\/j.jhep.2015.11.035","article-title":"PAGE\u2010B predicts the risk of developing hepatocellular carcinoma in Caucasians with chronic hepatitis B on 5\u2010year antiviral therapy","volume":"64","year":"2016","journal-title":"J Hepatol"},{"key":"hep31612-bib-0027-20250824","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1053\/j.gastro.2019.06.026","article-title":"Trends in mortality from extrahepatic complications in patients with chronic liver disease, from 2007 through 2017","volume":"157","year":"2019","journal-title":"Gastroenterology"},{"key":"hep31612-bib-0028-20250824","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1002\/hep.30034","article-title":"Extrahepatic cancers are the leading cause of death in patients achieving hepatitis B virus control or hepatitis C virus eradication","volume":"68","year":"2018","journal-title":"Hepatology"},{"key":"hep31612-bib-0029-20250824","doi-asserted-by":"crossref","first-page":"717","DOI":"10.3390\/ijms17050717","article-title":"Non\u2010alcoholic fatty liver disease and extra\u2010hepatic cancers","volume":"17","year":"2016","journal-title":"Int J Mol Sci"},{"key":"hep31612-bib-0030-20250824","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1146\/annurev-med-121211-091527","article-title":"Cytokines, obesity, and cancer: New insights on mechanisms linking obesity to cancer risk and progression","volume":"64","year":"2013","journal-title":"Annu Rev Med"},{"key":"hep31612-bib-0031-20250824","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1016\/j.jaci.2005.02.023","article-title":"Adipose tissue, adipokines, and inflammation","volume":"115","year":"2005","journal-title":"J Allergy Clin Immunol"},{"key":"hep31612-bib-0032-20250824","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1002\/hep.20280","article-title":"Beyond insulin resistance in NASH: TNF\u2010alpha or adiponectin?","volume":"40","year":"2004","journal-title":"Hepatology"},{"key":"hep31612-bib-0033-20250824","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1038\/nrmicro3344","article-title":"The gut microbiota, bacterial metabolites and colorectal cancer","volume":"12","year":"2014","journal-title":"Nat Rev Microbiol"},{"key":"hep31612-bib-0034-20250824","doi-asserted-by":"crossref","first-page":"1625","DOI":"10.1056\/NEJMoa021423","article-title":"Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults","volume":"348","year":"2003","journal-title":"N Engl J Med"},{"key":"hep31612-bib-0035-20250824","doi-asserted-by":"crossref","first-page":"2402","DOI":"10.2337\/dc12-0336","article-title":"Metabolic syndrome and risk of cancer: A systematic review and meta\u2010analysis","volume":"35","year":"2012","journal-title":"Diabetes Care"},{"key":"hep31612-bib-0036-20250824","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1001\/jama.295.1.65","article-title":"Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level","volume":"295","year":"2006","journal-title":"JAMA"},{"key":"hep31612-bib-0037-20250824","doi-asserted-by":"crossref","first-page":"3631","DOI":"10.1002\/cncr.29537","article-title":"Impact of long\u2010term tenofovir disoproxil fumarate on incidence of hepatocellular carcinoma in patients with chronic hepatitis B","volume":"121","year":"2015","journal-title":"Cancer"},{"key":"hep31612-bib-0038-20250824","doi-asserted-by":"crossref","first-page":"318","DOI":"10.7326\/M18-2753","article-title":"Lipophilic statins and risk for hepatocellular carcinoma and death in patients with chronic viral hepatitis: Results from a nationwide Swedish population","volume":"171","year":"2019","journal-title":"Ann Intern Med"},{"key":"hep31612-bib-0039-20250824","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1053\/j.gastro.2012.10.005","article-title":"Statins are associated with a reduced risk of hepatocellular cancer: a systematic review and meta\u2010analysis","volume":"144","year":"2013","journal-title":"Gastroenterology"},{"key":"hep31612-bib-0040-20250824","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1136\/gutjnl-2011-301708","article-title":"Metformin decreases hepatocellular carcinoma risk in a dose\u2010dependent manner: Population\u2010based and in vitro studies","volume":"62","year":"2013","journal-title":"Gut"},{"key":"hep31612-bib-0041-20250824","doi-asserted-by":"crossref","first-page":"1556","DOI":"10.1002\/hep.29318","article-title":"Antiplatelet therapy and the risk of hepatocellular carcinoma in chronic hepatitis B patients on antiviral treatment","volume":"66","year":"2017","journal-title":"Hepatology"},{"key":"hep31612-bib-0042-20250824","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1001\/jamainternmed.2018.8342","article-title":"Association of daily aspirin therapy with risk of hepatocellular carcinoma in patients with chronic hepatitis B","volume":"179","year":"2019","journal-title":"JAMA Intern Med"},{"key":"hep31612-bib-0043-20250824","doi-asserted-by":"crossref","first-page":"1018","DOI":"10.1056\/NEJMoa1912035","article-title":"Association of aspirin with hepatocellular carcinoma and liver\u2010related mortality","volume":"382","year":"2020","journal-title":"N Engl J Med"},{"key":"hep31612-bib-0044-20250824","doi-asserted-by":"crossref","first-page":"93","DOI":"10.3350\/cmh.2019.1002","article-title":"KASL clinical practice guidelines for management of chronic hepatitis B","volume":"25","year":"2019","journal-title":"Clin Mol Hepatol"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/hep.31612","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/hep.31612","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/10.1002\/hep.31612","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,25]],"date-time":"2025-08-25T00:04:43Z","timestamp":1756080283000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/10.1002\/hep.31612"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,19]]},"references-count":44,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2021]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.31612","relation":{},"ISSN":["0270-9139","1527-3350"],"issn-type":[{"value":"0270-9139","type":"print"},{"value":"1527-3350","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,19]]},"assertion":[{"value":"2020-06-20","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-10-13","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}