Sex Differences in Mortality Among Patients With Hepatocellular Carcinoma.
Sex is a well-recognized factor associated with hepatocellular carcinoma (HCC) incidence, but its association with mortality is unclear.
To assess the association between sex and the risk of overall, liver-related, and non-liver-related mortality among patients with HCC.
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.
Male vs female sex.
Overall, liver-related, and non-liver-related mortality.
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.
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.
To assess the association between sex and the risk of overall, liver-related, and non-liver-related mortality among patients with HCC.
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.
Male vs female sex.
Overall, liver-related, and non-liver-related mortality.
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.
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.
Authors
Yan Yan, Yeh Yeh, Leong Leong, Toyoda Toyoda, Abe Abe, Jun Jun, Roberts Roberts, Tanaka Tanaka, Schwartz Schwartz, Hsu Hsu, Landis Landis, Vutien Vutien, Uojima Uojima, Honda Honda, Buti Buti, Trinh Trinh, Ogawa Ogawa, Yasuda Yasuda, Tseng Tseng, Maeda Maeda, Sola Sola, Suzuki Suzuki, Huang Huang, Tsai Tsai, Dai Dai, Huang Huang, Chuang Chuang, Cheung Cheung, Yu Yu, Nguyen Nguyen
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