Plasma homocysteine levels associated with increased risk of incident metabolic dysfunction-associated steatotic liver disease

ObjectiveMetabolic dysfunction-associated steatotic liver disease (MASLD) is defined by hepatic steatosis accompanied by metabolic abnormalities. Prior cross-sectional studies on the association between plasma homocysteine (Hcy) and MASLD, often limited by small sample sizes, have reported conflicting results.MethodsThis study included 5,184 adults from the Dalian Health Management Cohort (DHMC; 2014–2023), excluding those with baseline MASLD or severe comorbidities. MASLD was diagnosed using liver ultrasonography and metabolic criteria. Hyperhomocysteinemia (HHcy) was defined as a plasma Hcy level >15 μmol/L. Cox proportional hazards models and restricted cubic spline (RCS) analyses evaluated linear and nonlinear associations between baseline Hcy levels and incident MASLD. Subgroup and sensitivity analyses ensured result robustness.ResultsOver a median follow-up of 2.66 years, 1,204 participants developed MASLD. After multivariable adjustment, each standard deviation (SD) increase in Hcy level was associated with a 18% higher risk of incident MASLD (hazard ratio [HR] = 1.18, 95% confidence interval [CI]: 1.11–1.25). Participants with HHcy had a 45% greater risk of developing MASLD compared to those without (HR = 1.45, 95% CI: 1.26–1.68). RCS analysis revealed a U-shaped relationship, with an approximate inflection point around 10 μmol/L identified by restricted cubic spline analysis. Subgroup and sensitivity analyses confirmed these findings.ConclusionPlasma Hcy levels demonstrated a U-shaped, independent association with the risk of incident MASLD, suggesting that both very low and high concentrations may adversely impact hepatic metabolic health.