Sex and gender differences in MASLD: pathophysiological mechanisms, clinical implications, and future directions

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading and increasingly prevalent cause of chronic liver disease worldwide, with significant hepatic and extrahepatic consequences. Sex and gender are major, yet underrecognized, determinants of MASLD risk, progression, and related clinical events. This narrative review synthesizes evidence on (1) biological sex effects - including sex chromosomes, genetic variants, and the modulatory roles of estrogens and androgens on lipid metabolism, mitochondrial function, immune signalling, and fibrogenesis - and (2) gendered socio-behavioral influences such as diet, physical activity, alcohol and tobacco use, health-seeking behavior, pregnancy and lactation, and gender-affirming hormone therapy. We highlight sex differences in metabolic phenotypes (fat distribution, insulin resistance, dyslipidemia, and hypertension), emerging sex-specific gene-microbiome interactions in the gut-liver axis, and sex-dependent patterns of extrahepatic comorbidity (cardiovascular disease, chronic kidney disease, and selected cancers). Evidence also suggests that commonly used diagnostic tools and predictive algorithms - including non-invasive fibrosis scores and machine-learning models - may misclassify risk if sex and hormonal status are not considered, and that pharmacologic, surgical, and hormone-based therapies exhibit preliminary sex-specific effects. Based on these observations, we propose a conceptual framework in which sex and gender, individually and interactively, shape the MASLD burden. Critical knowledge gaps remain, particularly for premenopausal women, transgender, and non-binary populations. Incorporating sex and gender into study design, diagnostics, risk stratification, and clinical trials is essential to advance precision prevention and equitable care for MASLD.

Keywords

MASLD / sex differences / gender disparities / metabolic risk factors / estrogen / gut-liver axis / liver fibrosis / personalized medicine

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