Impact of sexual dimorphism on liver damage in patients with metabolic-dysfunction associated steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a sexually dimorphic condition, characterized by a high prevalence in men compared to premenopausal women, but the reverse is true after menopause. Steroids, including glucocorticoids and sex hormones, regulate both glucose and lipid metabolism, and their perturbation may exert a detrimental effect on metabolic pathways promoting liver damage. The aim of this study was to shed light on sexual dimorphism in patients with MASLD through a targeted steroidomic approach. We enrolled 463 consecutive patients (males n=275 [59%]; females n=188 [41%]) with biopsy-proven MASLD and 112 healthy controls (HC) (males n=55 [49%]; females n=57 [51%]). A panel of 26 steroids (including glucocorticoids, androgens and their representative glucuro- and sulpho-conjugated metabolites) was measured by liquid chromatography coupled to tandem mass spectrometry. For statistical analysis, we stratified the whole cohort according to sex and age, using 50 years(y) as a cut-off. Advanced fibrosis was defined as F≥3. By comparing MASLD subjects and HC, we observed an increase in glucocorticoid levels in MASLD men<50y, and an increase in testosterone levels in MASLD women ≥50y compared to the corresponding HC groups. Concerning MASLD group, the prevalence of F≥3 was 36% (men/women 31%/45%, p=0.061). Similarly, we observed an increase in glucocorticoids levels in both MASLD men and women <50y with F≥3 compared to those without advanced hepatic fibrosis. In addition, in MASLD women with F≥3, regardless of age, we observed an increase in androgens metabolites, but a decrease in sulphate compounds. In patients with MASLD, we identified different steroids profiles according to gender and age that varied according to the severity of hepatic fibrosis. Further studies are needed to understand the molecular basis of sexual dimorphism in the context of MASLD. Funded by HORIZON-HLTH-2023-ENVHLTH-02 program for the consortium EDC-MASLD, g.a. n. 101136259. [ABSTRACT FROM AUTHOR]