Iron homeostasis links the association between alcohol consumption and liver steatosis/fibrosis: a multi-cohort analysis

The relationship between alcohol consumption - particularly at low-to-moderate levels - and liver steatosis or fibrosis remains controversial, and the potential pathways involved are incompletely understood. Given that iron homeostasis is frequently disturbed in individuals who consume alcohol and may contribute to liver injury, we aimed to investigate whether alterations in iron metabolism link alcohol intake to hepatic injury. We analyzed data from the National Health and Nutrition Examination Survey (NHANES) and UK Biobank to examine associations between alcohol consumption and liver steatosis/fibrosis. Associations were assessed using multivariate logistic, Cox proportional hazards, restricted cubic spline, and Mendelian randomization (MR) analysis, where appropriate. Mediation analysis was conducted to evaluate the role of iron-related biomarkers. We observed a J-shaped association between daily pure alcohol intake and liver fat (proton density fat fraction, PDFF), where a low intake is inversely associated and a moderate-to-heavy intake is positively associated. Higher alcohol consumption increased the risks of incident steatosis (HR = 1.16, 95% CI: 1.13-1.19) and fibrosis (HR = 1.47, 95% CI: 1.42-1.52). Iron homeostasis biomarkers partially mediated these associations, with liver iron showing the strongest mediation effect (19.44%). MR analysis further supported a causal link between genetically predicted alcohol intake and elevated liver iron and PDFF. These findings indicate that alcohol consumption is associated with higher liver fat and a detrimental impact on fibrosis risk, in part through disruption of iron homeostasis. Monitoring iron metabolism in individuals with alcohol exposure may, therefore, offer clinically relevant insights for identifying individuals at higher risk and informing strategies to prevent alcohol-related liver disease progression.