Wilson Disease: Update on Pathophysiology and Treatment

Abstract

Wilson disease (WD) is a potentially fatal genetic disorder with a broad spectrum of phenotypic presentations. Inactivation of the copper (Cu) transporter ATP7B and Cu overload in tissues, especially in the liver, are established causes of WD. However, neither specific ATP7B mutations nor hepatic Cu levels, alone, explain the diverse clinical presentations of WD. Recently, the new molecular details of WD progression and metabolic signatures of WD phenotypes began to emerge. Studies in WD patients and animal models revealed the contributions of non-parenchymal liver cells and extrahepatic tissues to the liver phenotype, and pointed to dysregulation of nuclear receptors (NR), epigenetic modifications, and mitochondria dysfunction as important hallmarks of WD pathogenesis. This review summarizes recent advances in the characterization of WD pathophysiology and discusses emerging targets for improving WD diagnosis and treatment.

Keywords: ATP7B; Wilson disease; copper; liver; nuclear receptor.

FIGURE 1

Cu homeostasis in liver (A) and Cu-handling proteins in liver cells (B). (A) Cu enters liver via portal circulation and transported into liver cells primarily by the high affinity uptake protein, CTR1. Cytosolic Cu chaperones shuttle Cu to specific intracellular targets; CCS transports Cu to SOD1, ATOX1 - to the Cu-transporting ATPase ATP7B. ATP7B transports Cu into the trans-Golgi network (TGN) for incorporation into ceruloplasmin (CP) and to the apical membrane for excretion. Inactivation of ATP7B causes Cu overload, which manifests clinically as WD (ATP7B-ATPase Cu(I) transporting beta polypeptide; CTR1-high affinity Cu uptake protein 1; MT-Metallothionein; GSH-Glutathione, ATOX1-antioxidant protein 1; SOD1-Superoxide dismutase; CCS-Cu Chaperone for SOD, COX17-Cytochrome C oxidase) (Lutsenko 2016; Członkowska et al., 2018). (B) Expression of ATP7B, CP and CTR in liver cells. The figure is generated using Liver Cell Atlas (https://www.livercellatlas.org/), which aggregates single cells sequencing data for human and animal livers.

FIGURE 2

Summary of main pathologic changes in WD liver. ATP7B mutations result in hepatic accumulation of copper (green circle). In the cytosol, Cu is sequestered by metallothioneins (MT1/2), whereas excess Cu causes glutathione oxidation (lower GSH:GSSG ration), contributing to redox stress. Cu elevation in nuclei, alters RNA processing, including splicing (Burkhead et al., 2011) inhibits NR function and induces epigenetic changes. Downstream effects include dysregulation of metabolic profiles in hepatocytes. Hepatocyte injury and possibly Cu accumulation in non-parenchymal cells stimulates immune cells and stellate cells, resulting in inflammation and fibrosis. The figure was generated using BioRender.