Abstract
Importance
Sex is a well-recognized factor associated with hepatocellular carcinoma (HCC) incidence, but its association with mortality is unclear.
Objective
To assess the association between sex and the risk of overall, liver-related, and non–liver-related mortality among patients with HCC.
Design, Setting, and Participants
This retrospective cohort study was conducted among patients with HCC in 17 centers from 5 countries and regions (2000-2023). Male and female patients with HCC who had balanced baseline characteristics via inverse probability of treatment weighting (IPTW) were included, with a propensity score–matched cohort included for sensitivity analyses. Data were analyzed between July 10 and September 8, 2025.
Exposures
Male vs female sex.
Main Outcomes and Measures
Overall, liver-related, and non–liver-related mortality.
Results
Among 8594 patients with HCC (mean [SD] age, 63.3 [10.9] years; 6214 male [72.3%]; 5644 Asian [65.7%], 458 Black [5.3%], 615 Hispanic [7.2%], and 1784 White [20.8%]), 4567 were from Asia (53.1%), 6327 had cirrhosis (73.6%), and 6617 had viral etiology (77.0%). In the unmatched cohort, males had a higher overall mortality rate per 100 person-years than females in the total cohort (15.9 [95% CI, 15.3-16.4] vs 13.3 [95% CI, 12.5-14.1];
P
< .001) and in Asian (14.1 [95% CI, 13.5-14.7] vs 11.1 [95% CI, 10.3-12.0];
P
< .001), Asia region (14.4 [95% CI, 13.6-15.2] vs 10.8 [95% CI, 9.9-11.8];
P
< .001), cirrhosis (17.6 [95% CI, 16.9-18.3] vs 14.4 [95% CI, 13.5-15.4];
P
< .001), and hepatitis B (13.6 [95% CI, 12.7-14.5] vs 10.0 [95% CI, 8.6-11.5];
P
< .001) and C (15.8 [95% CI, 15.0-16.6] vs 13.4 [95% CI, 12.4-14.6];
P
< .001) subgroups. In the IPTW-matched cohort, male sex was associated with increased overall mortality in the full cohort (adjusted hazard ratio [aHR], 1.14 [95% CI, 1.05-1.23];
P
= .002) and in Asian (aHR, 1.22 [95% CI, 1.10-1.36];
P
< .001), Asia region (aHR, 1.23 [95% CI, 1.09-1.39];
P
< .001), cirrhosis (aHR, 1.18 [95% CI, 1.08-1.29];
P
< .001), and viral (aHR, 1.15 [95% CI, 1.05-1.26];
P
= .004) subgroups. Additionally, sex differences varied by liver disease etiology, with male sex having the highest aHR in the association with overall mortality among individuals with alcohol-associated liver disease (aHR, 1.90 [95% CI, 1.02-3.54];
P
= .04), followed by those with hepatitis B (aHR, 1.22 [95% CI, 1.01-1.47];
P
= .04) or C (aHR, 1.13 [95% CI, 1.02-1.26];
P
= .03), but there was no association in patients with metabolic dysfunction–associated steatotic liver disease. There was no significant sex difference for non–liver-related mortality.
Conclusions and Relevance
In this study, sex disparities in HCC mortality existed but were heterogeneous across ethnic background and liver disease etiologies. These findings support incorporation of sex-based considerations in HCC management.