{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T22:37:19Z","timestamp":1792103839944,"version":"4.4.0"},"reference-count":38,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,9,6]],"date-time":"2026-09-06T00:00:00Z","timestamp":1788652800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science and Technology Council","award":["NSTC 112-2314-B-002-209-MY3"],"award-info":[{"award-number":["NSTC 112-2314-B-002-209-MY3"]}]},{"award":["NSTC 112-2314-B-002-209-MY3"],"award-info":[{"award-number":["NSTC 112-2314-B-002-209-MY3"]}],"id":[{"id":"https:\/\/ror.org\/02kv4zf79","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background and Aims: Until now, according to the EASL Clinical Practice Guidelines on the management of chronic hepatitis B (CHB), the relationship between steatotic liver disease (SLD) and the risk of hepatocellular carcinoma (HCC) in CHB patients still yields conflicting results, with some data suggesting an increased risk of HCC, while several cohort studies have indicated a reduced risk in CHB patients with SLD. Sex is a predominant factor in the development and severity of chronic liver diseases. We aimed to understand the effect modification by sex in this association using a large population-based cohort study with long-term follow-up of patients with CHB. Approach and Results: This population-based study from Taiwan\u2019s National Health Insurance Research Database (2009\u20132022) comprised two cohorts of patients with CHB aged 40\u201375 years: (1) 53,888 patients treated with entecavir or tenofovir, and (2) 525,109 antiviral-naive patients. HCC was identified in 4245 and 9491 patients in the treated and untreated cohorts, respectively. After adjusting for competing risk of death and relevant covariates, SLD was associated with a lower risk of HCC in males but a higher risk in females, and this sex difference (p &lt; 0.0001 for sex\u2013SLD interaction) was identified in both treated (subdistribution hazard ratio [SHR] [95% CI]: 0.85 [0.74\u20130.96] in males and 1.42 [1.17\u20131.73] in females) and untreated (0.75 [0.67\u20130.84] in males and 1.34 [1.14\u20131.56] in females) patients. Using propensity score matching with stratification by sex, further accounting for differences in medication use between SLD and non-SLD groups, yielded consistent results. The excess risk of HCC with SLD among females was mainly in those aged\u226555 years, and even existed in the presence of diabetes, whereas among males, SLD exhibited an inverse association with HCC, regardless of age or diabetes. Conclusions: There was a sex disparity in the association between SLD and CHB-related HCC. Future studies and management of SLD for CHB should consider the sex disparity.<\/jats:p>","DOI":"10.3390\/cancers18172880","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T09:23:37Z","timestamp":1788773017000},"page":"2880","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Sex Difference in the Impact of Steatotic Liver Disease on Incident Hepatocellular Carcinoma in Patients with Chronic Hepatitis B"],"prefix":"10.3390","volume":"18","author":[{"given":"Wan-Jung","family":"Wu","sequence":"first","affiliation":[{"name":"Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei 10055, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9869-5698","authenticated-orcid":false,"given":"Chih-Hsuan","family":"Tien","sequence":"additional","affiliation":[{"name":"Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei 10055, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9890-7596","authenticated-orcid":false,"given":"Chih-Lin","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Ren-Ai Branch, Taipei City Hospital, Taipei 10629, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6202-0993","authenticated-orcid":false,"given":"Chun-Jen","family":"Liu","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei 10048, Taiwan"},{"name":"Hepatitis Research Center, National Taiwan University Hospital, Taipei 100229, Taiwan"},{"name":"Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei 10048, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Jui-Ting","family":"Hu","sequence":"additional","affiliation":[{"name":"Liver Center, Cathay General Hospital Medical Center, School of Medicine, Fu-Jen Catholic University College of Medicine, Taipei 24352, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Jyh-Ming","family":"Liou","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei 10048, Taiwan"},{"name":"Department of Internal Medicine, National Taiwan University College of Medicine, Taipei 10051, Taiwan"},{"name":"Department of Internal Medicine, National Taiwan University Cancer Center, Taipei 106037, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8371-6236","authenticated-orcid":false,"given":"Ming-Whei","family":"Yu","sequence":"additional","affiliation":[{"name":"Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei 10055, 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treatment","volume":"406","author":"Chan","year":"2025","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"5576","DOI":"10.1200\/JCO.2008.16.1075","article-title":"Body-mass index and progression of hepatitis B: A population-based cohort study in men","volume":"26","author":"Yu","year":"2008","journal-title":"J. Clin. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"301","DOI":"10.2147\/JHC.S355540","article-title":"Impact of PNPLA3 p.I148M and hepatic steatosis on long-term outcomes for hepatocellular carcinoma and HBsAg seroclearance in chronic hepatitis B","volume":"9","author":"Hsueh","year":"2022","journal-title":"J. Hepatocell. Carcinoma"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Yu, M.W., Lin, C.L., Liu, C.J., Wu, W.J., Hu, J.T., and Huang, Y.W. (2022). Metabolic-associated fatty liver disease, hepatitis B surface antigen seroclearance, and long-term risk of hepatocellular carcinoma in chronic hepatitis B. Cancers, 14.","DOI":"10.3390\/cancers14236012"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1093\/infdis\/jiaa739","article-title":"Association between fatty liver and cirrhosis, hepatocellular carcinoma, and hepatitis B surface antigen seroclearance in chronic hepatitis B","volume":"224","author":"Li","year":"2021","journal-title":"J. Infect. Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1007\/s12072-021-10205-7","article-title":"Controlled attenuation parameter value and the risk of hepatocellular carcinoma in chronic hepatitis B patients under antiviral therapy","volume":"15","author":"Oh","year":"2021","journal-title":"Hepatol. Int."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Yendewa, G.A., Elangovan, A., Olasehinde, T., Mulindwa, F., Cater, M.G., Salata, R.A., and Jacobson, J.M. (2025). Impact of hepatic steatosis on mortality, hepatocellular carcinoma, end-stage liver disease and HBsAg seroclearance in chronic hepatitis B: A United States cohort study. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1566925"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1007\/s12072-021-10218-2","article-title":"Reduced hepatic steatosis is associated with higher risk of hepatocellular carcinoma in chronic hepatitis B infection","volume":"15","author":"Mak","year":"2021","journal-title":"Hepatol. Int."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1735","DOI":"10.1002\/hep.32792","article-title":"Steatosis, HBV-related HCC, cirrhosis, and HBsAg seroclearance: A systematic review and meta-analysis","volume":"77","author":"Mao","year":"2023","journal-title":"Hepatology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2668","DOI":"10.1002\/ijc.29321","article-title":"Hyperglycemia and chronic liver diseases on risk of hepatocellular carcinoma in Chinese patients with type 2 diabetes--National cohort of Taiwan Diabetes Study","volume":"136","author":"Li","year":"2015","journal-title":"Int. J. Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.3350\/cmh.2024.1070","article-title":"Impacts of metabolic syndrome diseases on long-term outcomes of chronic hepatitis B patients treated with nucleos(t)ide analogues","volume":"31","author":"Huang","year":"2025","journal-title":"Clin. Mol. Hepatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"320","DOI":"10.3350\/cmh.2022.0422","article-title":"Chronic hepatitis B with concurrent metabolic dysfunction-associated fatty liver disease: Challenges and perspectives","volume":"29","author":"Huang","year":"2023","journal-title":"Clin. Mol. Hepatol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1016\/j.cgh.2023.09.040","article-title":"Metabolic dysfunction-associated steatotic liver disease facilitates hepatitis B surface antigen seroclearance and seroconversion","volume":"22","author":"Huang","year":"2024","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Sayaf, K., Gabbia, D., Russo, F.P., and De Martin, S. (2022). The role of sex in acute and chronic liver damage. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231810654"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.1053\/j.gastro.2011.12.061","article-title":"Epidemiology of viral hepatitis and hepatocellular carcinoma","volume":"142","year":"2012","journal-title":"Gastroenterology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.1093\/jnci\/92.24.2023","article-title":"Androgen-receptor gene CAG repeats, plasma testosterone levels, and risk of hepatitis B-related hepatocellular carcinoma","volume":"92","author":"Yu","year":"2000","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1644","DOI":"10.1093\/jnci\/93.21.1644","article-title":"Hormonal markers and hepatitis B virus-related hepatocellular carcinoma risk: A nested case-control study among men","volume":"93","author":"Yu","year":"2001","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.1111\/jgh.12934","article-title":"Gender disparity in chronic hepatitis B: Mechanisms of sex hormones","volume":"30","author":"Wang","year":"2015","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1392","DOI":"10.1002\/hep.23163","article-title":"Identification of androgen response elements in the enhancer I of hepatitis B virus: A mechanism for sex disparity in chronic hepatitis B","volume":"50","author":"Wang","year":"2009","journal-title":"Hepatology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"32ra35","DOI":"10.1126\/scitranslmed.3001143","article-title":"Androgen receptor promotes hepatitis B virus-induced hepatocarcinogenesis through modulation of hepatitis B virus RNA transcription","volume":"2","author":"Wu","year":"2010","journal-title":"Sci. Transl. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1038\/s41574-020-00431-8","article-title":"Sexual dimorphism in cardiometabolic health: The role of adipose tissue, muscle and liver","volume":"17","author":"Goossens","year":"2021","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1126","DOI":"10.1016\/j.molmed.2024.05.013","article-title":"Sexual dimorphism of metabolic dysfunction-associated steatotic liver disease","volume":"30","author":"Cherubini","year":"2024","journal-title":"Trends Mol. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.jhep.2025.08.007","article-title":"Sex-related variations in liver homeostasis and disease: From zonation dynamics to clinical implications","volume":"84","author":"Berg","year":"2026","journal-title":"J. Hepatol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"101511","DOI":"10.1016\/j.jhepr.2025.101511","article-title":"Impact of tenofovir vs. entecavir treatment on progression of chronic hepatitis B: A nationwide cohort study","volume":"7","author":"Wu","year":"2025","journal-title":"JHEP Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"349","DOI":"10.2147\/CLEP.S196293","article-title":"Taiwan\u2019s National Health Insurance Research Database: Past and future","volume":"11","author":"Hsieh","year":"2019","journal-title":"Clin. Epidemiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1906","DOI":"10.1001\/2012.jama.11975","article-title":"Association between nucleoside analogues and risk of hepatitis B virus\u2013related hepatocellular carcinoma recurrence following liver resection","volume":"308","author":"Wu","year":"2012","journal-title":"JAMA"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"102065","DOI":"10.1016\/j.eclinm.2023.102065","article-title":"Daily aspirin associated with a reduced risk of hepatocellular carcinoma in patients with non-alcoholic fatty liver disease: A population-based cohort study","volume":"61","author":"Lee","year":"2023","journal-title":"EClinicalMedicine"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1002\/hep.31726","article-title":"Administrative coding in electronic health care record-based research of NAFLD: An expert panel consensus statement","volume":"74","author":"Adams","year":"2021","journal-title":"Hepatology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1016\/j.jhep.2019.06.021","article-title":"The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: A systematic review and meta-analysis","volume":"71","author":"Younossi","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"51","DOI":"10.3350\/cmh.2022.0095","article-title":"Development and prognosis of hepatocellular carcinoma in patients with diabetes","volume":"29","author":"Nakatsuka","year":"2023","journal-title":"Clin. Mol. Hepatol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"372","DOI":"10.2337\/dc17-1902","article-title":"Nonalcoholic fatty liver disease and risk of incident type 2 diabetes: A meta-analysis","volume":"41","author":"Mantovani","year":"2018","journal-title":"Diabetes Care"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.1016\/j.numecd.2023.05.018","article-title":"The bidirectional relationship between NAFLD and type 2 diabetes: A prospective population-based cohort study","volume":"33","author":"Wang","year":"2023","journal-title":"Nutr. Metab. Cardiovasc. Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/s12072-020-10121-2","article-title":"How does hepatic lipid accumulation lead to lipotoxicity in non-alcoholic fatty liver disease?","volume":"15","author":"Geng","year":"2021","journal-title":"Hepatol. Int."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e16202","DOI":"10.1111\/liv.16202","article-title":"HBV-induced carcinogenesis: Mechanisms, correlation with viral suppression, and implications for treatment","volume":"45","author":"Tu","year":"2025","journal-title":"Liver Int."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"101391","DOI":"10.1016\/j.jhepr.2025.101391","article-title":"Prediction of long-term HBsAg seroclearance in patients with HBeAg-negative chronic hepatitis B","volume":"7","author":"Lee","year":"2025","journal-title":"JHEP Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.cgh.2020.04.067","article-title":"Women have a lower risk of nonalcoholic fatty liver disease but a higher risk of progression vs men: A systematic review and meta-analysis","volume":"19","author":"Balakrishnan","year":"2021","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1080\/00365521.2023.2185475","article-title":"Administrative coding for non-alcoholic fatty liver disease is accurate in Swedish patients","volume":"58","author":"Wester","year":"2023","journal-title":"Scand. J. Gastroenterol."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/17\/2880\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T04:29:28Z","timestamp":1788841768000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/17\/2880"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,6]]},"references-count":38,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["cancers18172880"],"URL":"https:\/\/doi.org\/10.3390\/cancers18172880","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,6]]}}}