Sex and gender differences in metabolic dysfunction-associated liver disease

Area of Science:

• Hepatology
• Endocrinology
• Public Health

Background:

• Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly NAFLD, is the leading cause of chronic liver disease worldwide.
• MASLD prevalence and complications like MASH and HCC are increasing globally.
• Sex and gender represent critical, yet underexplored, determinants of MASLD epidemiology and outcomes.

Purpose of the Study:

• To review the multifaceted roles of biological sex and gender in MASLD/MASH prevalence, disease progression, and clinical outcomes.
• To analyze age- and sex-specific trends in MASLD development and associated liver pathology.
• To explore the influence of lifestyle, hormonal factors, and gender-affirming hormone therapy on MASLD.

Main Methods:

• Comprehensive literature review of studies investigating sex and gender differences in MASLD.
• Analysis of epidemiological data on MASLD prevalence across different age groups and sexes.
• Examination of preclinical (animal) and clinical data on hormonal and behavioral influences.

Main Results:

• Males show higher rates of MASLD complications like HCC, while females exhibit increased MASH cirrhosis.
• Hormonal differences (estrogen, testosterone) and age-related changes (e.g., post-menopause) significantly modulate liver steatosis and inflammation.
• Gender-related behaviors (diet, exercise, alcohol) and gender-affirming hormone therapy influence MASLD progression and management.

Conclusions:

• Sex and gender are key determinants of MASLD pathophysiology, influencing disease risk, progression, and outcomes.
• Tailoring MASLD treatment strategies to account for sex and gender variations is essential for improved patient care.
• Further research is needed to elucidate the complex interplay of sexual dimorphism and gender in MASLD.