Sex Difference in the Impact of Steatotic Liver Disease on Incident Hepatocellular Carcinoma in Patients with Chronic Hepatitis B

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’s National Health Insurance Research Database (2009–2022) comprised two cohorts of patients with CHB aged 40–75 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 < 0.0001 for sex–SLD interaction) was identified in both treated (subdistribution hazard ratio [SHR] [95% CI]: 0.85 [0.74–0.96] in males and 1.42 [1.17–1.73] in females) and untreated (0.75 [0.67–0.84] in males and 1.34 [1.14–1.56] 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≥55 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.