Elevated Homocysteine is Associated With Liver Fibrosis in Metabolic Dysfunction-Associated Steatotic Liver Disease in a Sex- and Menopause-Specific Manner.

Background and Aims: Elevated hepatic homocysteine (Hcy) contributes to hepatic inflammation and fibrogenesis in metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to evaluate the association between serum Hcy levels and the risk of MASLD and hepatic fibrosis in a large, diverse population, accounting for clinical confounders and effect modifiers such as sex and reproductive status. Methods: We analyzed 1999-2006 National Health and Nutrition Examination Survey data for 8253 adults (≥18 years) without hepatitis B/C, excessive alcohol use, or pregnancy. MASLD was defined using the fatty liver index (≥30), and fibrosis risk was assessed using age-adjusted Fibrosis-4 and nonalcoholic fatty liver disease fibrosis score among MASLD subjects (N = 5328). Associations between serum Hcy and MASLD/fibrosis risk were evaluated using multivariable linear regression adjusting for confounders, with stratification by sex and menopausal status. Results: Serum Hcy levels were higher among those with MASLD (fatty liver index ≥30), though the association was attenuated after covariate adjustment. Among MASLD individuals, those at higher fibrosis risk (based on Fibrosis-4 or nonalcoholic fatty liver disease fibrosis score) had significantly elevated Hcy levels. This association remained significant in men and postmenopausal women, but not in premenopausal women. Conclusion: Elevated serum Hcy is independently associated with hepatic fibrosis risk in MASLD, particularly in men and postmenopausal women. These findings underscore the importance of accounting for sex and menopausal status in future Hcy-lowering interventions targeting MASLD.