Sex Differences in Liver Cancer Mortality Trends in the US: Role of Cancer Type, Aetiology, and Birth Cohort

Background and aims: Liver cancer mortality (HCC, iCCA) is rising in the U.S., with marked sex disparities linked to hormones and risk factor exposure. This study examines recent trends in mortality by subtype, aetiology, and generation, highlighting their roles in sex-based differences. Methods: Mortality data for U.S. residents (1999-2023) were obtained from the CDC WONDER database. Age-standardised mortality rates were analysed for HCC and iCCA, with HCC deaths further classified by aetiology. Mortality trends were assessed by sex using Joinpoint regression, and age-, period-, and birth-cohort effects were evaluated with constrained generalised linear models. Results: Between 1999 and 2023, 534 526 liver cancer deaths occurred (353 968 in men; 180 588 in women). Male mortality increased until 2013, plateaued, and declined after 2017, while female mortality continued to rise modestly. For HCC, HCV-related mortality peaked around 2013 and declined thereafter, coinciding with direct-acting antiviral introduction. Meanwhile, MASLD-related mortality rose steadily, becoming the leading reported aetiology in both sexes by 2023. ALD-related mortality also increased, while HBV-related mortality remained stable. Cohort analysis revealed excess HCC mortality among those born in the 1940s-1960s. In contrast, iCCA mortality rose continuously in both sexes and across birth cohorts, with sharp increases among women and younger adults. By 2023, iCCA accounted for 44% of female liver cancer deaths. Conclusions: Liver cancer mortality is declining in men but rising in women. These trends coincide with changes in HCC etiologies along with an increasing contribution of iCCA, particularly in women. Targeted prevention and equitable access to screening are pivotal to reducing mortality.