Metabolomics profiles of patients with Wilson disease reveal a distinct metabolic signature

Introduction: Wilson disease (WD) is characterized by excessive intracellular copper accumulation in liver and brain due to defective copper biliary excretion. With highly varied phenotypes and a lack of biomarkers for the different clinical manifestations, diagnosis and treatment can be difficult. Objective: The aim of the present study was to analyze serum metabolomics profiles of patients with Wilson disease compared to healthy subjects, with the goal of identifying differentially abundant metabolites as potential biomarkers for this condition. Methods: Hydrophilic interaction liquid chromatography-quadrupole time of flight mass spectrometry was used to evaluate the untargeted serum metabolome of 61 patients with WD (26 hepatic and 25 neurologic subtypes, 10 preclinical) compared to 15 healthy subjects. We conducted analysis of covariance with potential confounders (body mass index, age, sex) as covariates and partial least-squares analysis. Results: After adjusting for clinical covariates and multiple testing, we identified 99 significantly different metabolites (FDR < 0.05) between WD and healthy subjects. Subtype comparisons also revealed significantly different metabolites compared to healthy subjects: WD hepatic subtype (67), WD neurologic subtype (57), WD hepatic-neurologic combined (77), and preclinical (36). Pathway analysis revealed these metabolites are involved in amino acid metabolism, the tricarboxylic acid cycle, choline metabolism, and oxidative stress. Conclusions: Patients with WD are characterized by a distinct metabolomics profile providing new insights into WD pathogenesis and identifying new potential diagnostic biomarkers.