Low HDL cholesterol levels in women and hypertriglyceridemia in men: predictors of MASLD onset in individuals without steatosis.

Background: Individuals with metabolic-associated steatotic liver disease (MASLD) have a worse prognosis compared to patients without steatosis, and its prevalence is increasing. However, detailed risk factors based on obesity and sex remain unclear. We aimed to investigate the impact of cardiometabolic risk factors (CMRFs) on the risk of MASLD in individuals without pre-existing SLD.

Methods: SLD was diagnosed by ultrasonography. Non-SLD individuals were followed 65,657 person-years. Incidence rates of MASLD were assessed by Kaplan-Meier analysis. Furthermore, independent factors associated with the development of MASLD were identified using Cox regression analysis, stratified by four groups: obese men, non-obese men, obese women, and non-obese women.

Results: The overall incidence rate of MASLD was 39.3/1,000 person-years. The cumulative incidence was highest in obese men, followed by obese women, non-obese men, and non-obese women. Two or more CMRFs increased the risk of MASLD in all groups. Low HDL cholesterol level was the strongest independent risk factor in both obese and non-obese women and hypertriglyceridemia for both obese and non-obese men. The impact of these CMRFs was stronger in non-obese individuals. (HR [95% CI]: women non-obese 1.9 [1.5-2.4], obese 1.4 [1.1-1.8]; men non-obese 2.3 [1.9-2.9], obese 1.5 [1.2-2.0]).

Conclusions: Multiple CMRFs are important to MASLD development, regardless of sex and obesity. In this Japanese cohort, low HDL cholesterol in women and hypertriglyceridemia in men were the most significant risk factors, especially among the non-obese group. These findings suggest that sex-specific CMRFs may play a role in the development of MASLD.