Association between blood copper and nonalcoholic fatty liver disease according to sex

Nonalcoholic fatty liver disease (NAFLD) is a common disease with potential sex-based difference in the prevalence and prognosis. Copper deficiency may affect the antioxidant defense system and lead to the progression of NAFLD. This study aimed to evaluate the association between blood copper and NAFLD according to sex difference.A case-control study of 1816 cases of NAFLD and 1111 sex- and age-matched control cases was conducted in Tangshan, China, from January 1, 2016, to December 31, 2017, based on the Kailuan cohort. In men and women, logistic regression analysis was separately applied to determine the risk of NAFLD, severity of NAFLD based on hepatic steatosis, the NAFLD fibrosis score, and fibrosis-4 score, for each quartile of blood copper with the lowest quartile as the reference. In addition, the effect of metabolic syndrome on the association between copper and NAFLD was assessed.In men, blood copper concentration was lower in the NAFLD group (mean ± SD: 0.617 ± 0.117 μg/mL) than in the control group (mean ± SD: 0.655 ± 0.133 μg/mL) (P < 0.001). After adjustment for possible confounders, the odds ratio of NAFLD at the highest quartile of copper compared to the lowest quartile was 0.57 (95% CI: 0.41-0.80) and the protective effect of higher blood copper was increased with the severity of NAFLD. In the results of stratified analysis, lower copper concentration was a significant additional factor that contributed to higher risk of NAFLD in male subjects with metabolic syndrome. However, no significant association was observed between copper and NAFLD in women with different characteristics, except an NAFLD fibrosis score < -1.455 and moderate hepatic steatosis.Higher copper levels achieved significant protective effect against NAFLD in men but not in women. Sex-specific intervention is a potential tool for the prevention of development of NAFLD.