Lipid peroxidation mediates the association between iron overload and liver injury: Cross-sectional and longitudinal analyses in general Chinese urban adults

Abstract Background: Iron overload has been associated with acute/chronic organ failure, but whether iron overload induces liver injury remain unclear. Objectives: To assess the relationship between urinary iron and serum alanine aminotransferase (ALT, a biomarker for liver injury), and investigate the potential mediating roles of lipid peroxidation and oxidative DNA damage in such association. Methods: Levels of urinary iron, serum ALT, and urinary biomarkers of lipid peroxidation (8-iso-prostaglandin-F2α [8-iso-PGF2α]) and oxidative DNA damage (8-hydroxy-deoxyguano-sine [8-OHdG]) were measured among 5386 observations of 4220 participants from the Wuhan-Zhuhai cohort. The relationships between urinary iron and serum ALT as well as risk of hyperALT were separately evaluated by linear mixed models and logistic regression models. The mediating roles of 8-iso-PGF2α and 8-OHdG were assessed by mediation analyses. Results: In cross sectional analysis, urinary iron was positively associated with ALT (β=0.032; 95% CI: 0.020, 0.044) and hyperALT (OR=1.127; 95% CI: 1.065, 1.192). After 3 years of follow-up, participants with persistent high iron level had increased risk of developing hyperALT (RR=3.800; 95% CI: 1.464, 9.972) when compared with those with persistent low iron level. In addition, each 1% increase in urinary iron was associated with a 0.146% (95% CI: 0.128%, 0.164%) and 0.192% (95% CI: 0.154%, 0.229%) increase in 8-iso-PGF2α and 8-OHdG, respectively. Urinary 8-iso-PGF2α (β=0.056; 95% CI: 0.039, 0.074) rather than 8-OHdG was positively associated with ALT, and increased 8-iso-PGF2α significantly mediate 22.48% of the urinary iron-associated ALT increment. Conclusions: Our study demonstrated that iron overload was significantly associated with liver injury, which was partly mediated by lipid peroxidation.