Sex Differences in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): Epidemiology, Pathophysiology,...

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects 25-58% of the worldwide population across all continents and ethnicities. The liver exhibits marked sexual dimorphism, resulting in clinically significant sex-based differences in disease epidemiology, pathophysiology, and outcomes that warrant a comprehensive global synthesis. This narrative review synthesizes evidence from population-based studies conducted across Asia, Europe, North America, the Middle East, and other regions, examining epidemiological data, pathophysiological mechanisms, diagnostic considerations, and therapeutic responses across diverse geographic and ethnic populations. Global epidemiological data consistently show a higher MASLD prevalence in men (23-41%) than in premenopausal women (13-21%) across populations in China, Japan, Korea, Taiwan, India, Israel, Spain, the Netherlands, the United Kingdom, and the United States. The sex disparity diminishes after menopause; postmenopausal women face a 12-fold increased risk of metabolic dysfunction-associated steatohepatitis and advanced fibrosis as estrogen levels decline. Sex-specific pathophysiological drivers include differential adipose tissue distribution (visceral predominance in men versus gynoid/femoral in premenopausal women), distinct gut microbiota profiles (a higher Firmicutes/Bacteroidetes ratio in women), and genetic variants such as patatin like phospholipase domain containing 3 I148M, with sex-biased risk associations. Hormonal influences-testosterone, ER-α-mediated estrogen signaling, and postmenopausal hormonal shifts-critically modulate insulin resistance, lipid metabolism, and hepatic inflammation. Clinically, women exhibit lower alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels across populations, potentially contributing to underdiagnosis. Men demonstrate faster fibrosis progression and a higher hepatocellular carcinoma incidence, whereas postmenopausal women experience heightened cardiovascular mortality. Pregnancy-related factors including gestational diabetes and maternal high-fat diets, confer sex-specific transgenerational MASLD risk. These globally consistent findings support sex-tailored management strategies. Evidence suggests differential treatment responses, with pioglitazone showing greater efficacy in women with prediabetes/type 2 diabetes. Lifestyle interventions, diagnostic thresholds, and risk-stratification tools require sex-specific calibration. Sex and gender differences in MASLD are evident globally. Integrating sex and reproductive status into MASLD management is essential for advancing personalized medicine worldwide.