Sex differences in alcohol-related liver disease, viral hepatitis, metabolic dysfunction-associated steatotic liver disease, and hepatocellular carcinoma

Females are more susceptible to alcohol-related liver disease (ALD) owing to increased risk of alcohol dependence; decreased gastric first-pass effect and increased risk of producing hepatotoxic metabolites, higher alcohol bioavailability, and hormonal fluctuations affecting ethanol metabolism. Male sex is independently associated with hepatitis B virus (HBV) infection and hypertransaminasemia in HBV chronic infection. Compared to women, men have higher risks of being hepatitis B surface antigen (HBsAg) carriers, exhibit higher non-response and lower long-term immunity after prophylactic vaccination, have a higher risk of chronic hepatitis, and fibrotic and hepatocellular carcinoma (HCC). Females have higher spontaneous hepatitis C virus (HCV) clearance and reduced risk of fibrosis, cirrhosis, and HCC than men. However, post-menopausal women experience more rapid progression of hepatic fibrosis and HCC development and lower response rates to antiviral regimens compared to younger women. Hormonal and immunological mechanisms explain these sex differences observed in chronic viral hepatitis B and C. Sex and reproductive status affect the risk of metabolic dysfunction-associated steatotic liver disease (MASLD) development and progression. Genetic sex and sex hormones are involved in the pathogenesis of sex differences in MASLD by differential effects on body fat distribution, insulin sensitivity, and oxidative stress. HCC may arise as a complication of ALD, HBV, HCV, and MASLD and has a definite prevalence in the male sex because of the most robust inflammatory response of the male sex and the anti-inflammatory activity of estrogens. We conclude that those major sex differences which are identifiable in the epidemiology and clinical course of ALD, viral hepatitis owing to HBV and HCV, MASLD, and HCC. These sex disparities are explained by biological sex and sex hormones affecting metabolism, immunity, fibrogenesis, and cancer, and are the foundations for precision medicine approaches in these common hepatological conditions.