Associations of heavy metal exposure with NAFLD and the potential mediating role of the TyG index

Environmental exposure to heavy metals has been associated with the development of nonalcoholic fatty liver disease (NAFLD). Insulin resistance, a key driver of hepatic steatosis, may be involved in the association between metal exposure and NAFLD; however, this potential mediation remains insufficiently characterized. This study examined associations between plasma heavy metals and HSI-defined probable NAFLD and evaluated whether the TyG index statistically mediates these associations. We conducted a cross-sectional analysis of 3,442 adults from a cohort in Guangxi, China. Plasma concentrations of 11 metals were determined using inductively coupled plasma–mass spectrometry (ICP–MS). HSI-defined probable NAFLD was defined as an HSI > 36. Associations between individual metals and HSI-defined probable NAFLD were analyzed using multivariable logistic regression, restricted cubic spline (RCS), and Bayesian kernel machine regression (BKMR) models. Associations between metals and the TyG index were examined using linear regression and RCS models. Exploratory mediation analysis was performed to estimate the proportion of the Co–HSI-defined probable NAFLD association statistically explained by the TyG index. Cobalt (Co) exhibited an inverse linear association with HSI-defined probable NAFLD, whereas molybdenum (Mo) showed a nonlinear relationship. Findings were consistent across regression, RCS, and BKMR models. After adjustment for covariates, plasma Co was inversely associated with HSI-defined probable NAFLD (OR = 0.62, 95% CI 0.45–0.84, P = 0.002). Mo showed a nonlinear association with HSI-defined probable NAFLD ( P for nonlinearity < 0.001). Co was also inversely associated with the TyG index, and the exploratory mediation analysis suggested that the TyG index statistically explained 18.82% of the association between Co and HSI-defined probable NAFLD. Co and Mo showed distinct metal-specific associations with HSI-defined probable NAFLD. The TyG index may partly explain the inverse association between plasma Co and HSI-defined probable NAFLD. Prospective and mechanistic studies are needed to clarify the temporal and biological basis of these associations.