Abstract
Background: Copper is an essential trace element involved in antioxidant defense and mitochondrial function. Evidence suggests that copper homeostasis may also influence metabolic liver diseases. We investigated the association between hepatic copper levels (HCLs) and liver-related outcomes among patients with Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). Methods: In this retrospective cohort study, we analyzed 215 MASLD patients who underwent liver biopsy with copper quantification. Patients were categorized based on hepatic copper content; normal < 50 vs. high ≥ 50 μg/g dry tissue (165 vs. 50 patients, respectively). The primary outcomes were progression in non-invasive fibrosis score (FIB-4) and incidence of clinical events (cirrhosis, liver transplantation, cardiovascular events or death) during a median follow-up of 4.9 ± 4.2 years. Multivariable linear and logistic regression models were adjusted for metabolic and demographic confounders. Results: Both liver copper groups shared similar baseline characteristics. High hepatic copper levels independently predicted higher FIB-4 scores at the end of follow-up in the fully adjusted linear regression model (β = 0.41; 95% CI: 0.05-0.76; p = 0.026). Logistic regression confirmed that high HCLs were associated with significant FIB-4 deterioration (OR = 41.3; 95%; p = 0.008). Kaplan-Meier analysis revealed significantly reduced overall survival among patients with high HCLs (Log-Rank p = 0.034), and multivariable Cox regression showed a markedly increased mortality risk (HR = 18.51; 95%; p = 0.032). Subgroup analyses highlighted greater risk among females, patients with diabetes or dyslipidemia, and individuals of Arab ethnicity. Conclusions: Elevated hepatic copper levels are associated with long term worsened liver fibrosis and higher mortality in MASLD. These findings support hepatic copper as a potential nutritional biomarker for risk stratification. Further studies are needed to explore copper modulation as a therapeutic target in MASLD.