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

Abstract

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.

Sugar Alcohols Have a Key Role in Pathogenesis of Chronic Liver Disease and Hepatocellular Carcinoma in Whole Blood and Liver Tissues

“…A similar spill-over effect of glycolysis has been established as an ancillary pathway in type 2 diabetes mellitus [77][78][79][80]. Increased activity of the polyol pathway was also reported in other liver diseases such as Wilson's disease that is characterized by copper accumulation in the liver and other organs [81]. Activation of the polyol pathway was also reported in ovarian and cervical cancer cell lines [82,83], lung tumors [75], and colon [75,84], breast, ovary, cervix, and rectum cancers [85].…”

mtDNA depletion‐like syndrome in Wilson disease

“…Thirty-seven healthy controls and 61 patients with a diagnosis of WD according to Leipzig criteria were previously described in detail [25][26][27] and included in the metabolomic study; of these, 47 WD were included in the mtDNA study ( Figure S3; Table S3). Informed written consent was obtained from all subjects and patients, and the study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the Institutional Review Board at the University of California, Davis.…”

Oxylipin Profiles in Plasma of Patients with Wilson’s Disease

“…Understanding the variations in the metabolome may help in identifying variations in the biochemical pathways leading to different manifestations of the disease. High-throughput techniques, such as metabolomic profiling, can deepen our understanding of the disease's pathogenesis and biology of WD manifestation [12,13], and therefore lead to new therapeutic approaches.…”

“…Moreover, the number of some lipid-related nuclear receptors, such as retinoid X receptor (RXR), peroxisome proliferator-activated receptor α (PPARα), and hepatocyte nuclear factor 4 alpha (HNF4A), is generally decreased in WD animal models and humans [9,[21][22][23][24][25]. It is important to note that although oxylipins exhibit multiple effects, they somehow change the state of the innate immunity system [13][14][15]. Oxylipins are important markers of activation of the system, including the regulation of inflammatory resolution processes [13,16].…”

“…It is important to note that although oxylipins exhibit multiple effects, they somehow change the state of the innate immunity system [13][14][15]. Oxylipins are important markers of activation of the system, including the regulation of inflammatory resolution processes [13,16]. Despite these facts, the role of the innate immunity system, and oxylipins as parts of the system, is still underestimated in many diseases.…”