Biochemical Markers for the Diagnosis and Monitoring of Wilson Disease

Abstract

Wilson disease (WD) is an autosomal recessively-inherited disorder of copper metabolism and characterised by a pathological accumulation of copper. The ATP7B gene encodes for a transmembrane copper transporter essential for biliary copper excretion. Depending on time of diagnosis, severity of disease can vary widely. Almost all patients show evidence of progressive liver disease. Neurological impairments or psychiatric symptoms are common in WD patients not diagnosed during adolescence. WD is a treatable disorder, and early treatment can prevent the development of symptoms in patients diagnosed while still asymptomatic. This is why the early diagnosis of WD is crucial. The diagnosis is based on clinical symptoms, abnormal measures of copper metabolism and DNA analysis. Available treatment includes chelators and zinc salts which increase copper excretion and reduce copper uptake. In severe cases, liver transplantation is indicated and accomplishes a phenotypic correction of the hepatic gene defect. Recently, clinical development of the new copper modulating agent tetrathiomolybdate has started and direct genetic therapies are being tested in animal models. The following review focuses especially on biochemical markers and how they can be utilised in diagnosis and drug monitoring.

Figure 1

Milestones in the history of Wilson disease.

Figure 2

A schematic representation of human ATP7B protein. ATP7B belongs to class 1B of the highly conserved P-type ATPase superfamily responsible for the transport of copper and other heavy metals across cellular membranes (M). The protein contains 1465 amino acids including eight transmembrane fractions (Tm). The N-terminal metal-binding domain (NH2) is composed of six copper binding sites (Cu), which play a central role in accepting copper from copper chaperone ATOX1 through protein-protein interactions. Unique amino acid motifs are present at the core structure of each domain, such as TGDN and SEHPL. The SEHPL domain functions as a phosphorylation domain, the TGDN as an ATP binding site. (Adapted from Fanni D et al. Eur J Histochem 2005;49:371–8.) NH2, N (nucleotide)-terminal metal-binding domain; Cu, copper; Tm, transmembrane domain; M, phospholipidic bilayer of the membrane; PD, Phosphorylation domain.

Figure 3

Copper homeostasis in the hepatocyte. Role of Wilson ATPase (ATP7B) in the hepatocellular disposition of copper: a hepatocyte is shown, with one side connected with the bile canaliculus, the other connected with the sinusoidal membrane. Starting at the left side of the diagram, copper (small green dots) is taken up by CTR1 (grey square), picked up and carried by ATOX1 to the Wilson ATPase (ATP7B; red square) in the trans-Golgi network (TGN). The Wilson ATPase either directs copper to production of caeruloplasmin (Cp; blue round shaped) or to excretion into bile. When intracellular copper concentrations are low or normal, the Wilson ATPase participates in the production of holocaeruloplasmin (HoloCp-Copper) in the Golgi apparatus; holocaeruloplasmin is then secreted into the blood. When intracellular copper concentrations are elevated, the Wilson ATPase expedites biliary excretion of copper.

Figure 4

Clinical manifestations in the pathogenesis of Wilson disease.