Sex disparity in hepatocellular carcinoma owing to NAFLD and non-NAFLD etiology: epidemiological findings and pathobiological mechanisms

Nonalcoholic fatty liver disease (NAFLD) exhibits sexual dimorphism, with men being more exposed than women to the risk of simple steatosis, nonalcoholic steatohepatitis fibrosis, and hepatocellular carcinoma (HCC), while the protection conferred to women seemingly disappears with aging and reproductive senescence (i.e., menopause). HCC, the most common primary liver cancer, which carries an ominous prognosis, may result from various genetic and non-genetic risk factors. NAFLD is now projected to become the most common cause of HCC. HCC also exhibits a definite sexual dimorphism in as much as it has a worldwide high male-to-female ratio. In this review article, we focus on sex differences in the epidemiological features of HCC. Moreover, we discuss sex differences in the clinical outcome and molecular pathobiology of NAFLD-HCC. By highlighting the research gaps to be filled, the aim of this review is to prompt future research of sex differences in HCC and facilitate developing personalized cancer prevention strategies, detection, and treatments to achieve better patient outcomes in NAFLD-HCC, considering sex differences in HCC pathobiology