Sex and gender differences in metabolic dysfunction-associated liver disease.

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously termed non-alcoholic fatty liver disease (NAFLD), is the most prevalent cause for chronic liver disease globally, with a rising incidence of metabolic-associated steatohepatitis (MASH) and its complications. This review examines the critical role of sex and gender in MASLD/MASH prevalence, progression and clinical outcomes. Biological sex affects MASLD significantly with males exhibiting higher rates of downstream complications such as hepatocellular carcinoma (HCC). In comparison, females tend to develop progressive disease with higher rates of MASH cirrhosis. Gender, influenced by social and cultural factors, influences disease progression through behaviors such as diet, exercise and alcohol consumption. As the prevalence of gender-fluid and gender diverse patients increases, this has additional influences on MASLD. Age-related trends demonstrate MASLD prevalence in men increases from young adulthood, whereas in women, rates rise mainly after menopause, affecting liver fibrosis and inflammation differently. Animal studies reveal sex-specific differences in steatosis, inflammatory cytokines, oxidative stress and the role of sex hormones such as estrogen and testosterone in modulating disease progression. Lifestyle behaviors linked to gender also contribute; women generally follow healthier diets and respond better to exercise in reducing liver fat. While estrogen plays a protective role in liver metabolism, its effects on MASLD progression are complex, particularly in post-menopausal women. This review also explores the emerging area of gender-affirming hormone therapy (GAHT) in transgender individuals, showing potential benefits in managing comorbid MASLD/MASH. Ultimately, understanding these sex and gender-based variations is essential for optimizing MASLD treatment strategies, highlighting the need for more research on how sexual dimorphism and gender influence the disease.