Diagnosis and Current Therapy of Wilson's Disease

P. Ferenci

Disclosures

Aliment Pharmacol Ther. 2004;19(2) 

In This Article

Summary and Introduction

Summary

Wilson's disease is an autosomal recessive inherited disorder of hepatic copper metabolism resulting in liver disease and/or neuropsychiatric disease. The diagnosis of neurological disease is straightforward if the following symptoms are present: Kayser-Fleischer rings, typical neurological symptoms and low serum ceruloplasmin levels. The diagnosis is more complex in patients presenting with liver diseases. None of the commonly used parameters alone allows a diagnosis with certainty. A combination of various laboratory parameters is necessary to firmly establish the diagnosis. In the future, limited mutation analysis may play an important diagnostic role. Recently, a group of international experts has proposed a score based on a variety of tests and clinical symptoms. The validity of this score needs to be assessed prospectively. Treatment requires life-long administration of copper chelators (D-penicillamine, trientine). A frequently used alternative is zinc. None of these treatments has been tested by prospective randomized controlled studies. Liver transplantation is reserved for severe or treatment-resistant cases with advanced liver disease, whilst experience with refractory neuropsychiatric disease is limited.

Wilson's disease is an autosomal recessive inherited disorder of hepatic copper metabolism resulting in the accumulation of copper in many organs and tissues. The hallmarks of the disease are the presence of liver disease, neurological symptoms and Kayser-Fleischer corneal rings.

Copper is an essential dietary nutrient and is needed for such diverse processes as mitochondrial respiration, melanin biosynthesis, dopamine metabolism, iron homeostasis, antioxidant defence, connective tissue formation and peptide amidation. Specific pathways allow the intracellular trafficking and compartmentalization of copper, ensuring adequate cuproprotein synthesis whilst avoiding cellular toxicity. Biliary excretion is the only mechanism for copper elimination, and the amount of copper excreted in the bile is directly proportional to the size of the hepatic copper pool. Trafficking of copper in the hepatocytes is complex and involves several transport proteins. The copper transporter 1 transports copper with high affinity in a metal-specific, saturable fashion at the hepatocyte plasma membrane.[1,2] Metallothioneins, a group of cysteine-rich intracellular proteins capable of binding metal ions, including copper, cadmium and zinc,[3] have a critical role in protecting intracellular proteins from copper toxicity.[4] Metallochaperones transfer copper to the site of synthesis of copper-containing proteins.[5,6] The cytoplasmic copper chaperone atox1 is required for copper delivery to the Wilson ATPase (ATP7B) in the hepatocyte secretory pathway[7] by direct protein-protein interaction.[7,8,9] In the copper-limiting environment of the cell, the delivery of copper by atox1 is responsible for initiating the catalytic activity and the intracellular trafficking of ATP7B.[10] ATP7B is the gene product of the Wilson's disease gene (see Figure 1) located on chromosome 13 and is a polytopic membrane protein containing several motifs characteristic of P-type ATPases.[11] The histidine residue in the SEHPL motif within the cytoplasmic loop is the site of the H1069Q missense mutation, a common disease allele found in northern, central and eastern European populations with Wilson's disease.[12,13,14,15] In hepatocytes, this ATPase resides in the trans-Golgi network transporting copper into the secretory pathway for incorporation into apoceruloplasmin and excretion into the bile[16] (see Figure 2). Molecular genetic analysis of affected patients reveals over 200 distinct mutations (database maintained at the University of Alberta (http://www.medgen.med.ualberta.ca)). About one-half of these mutations are missense, with most confined to recognized consensus motifs or predicted transmembrane domains. A detailed review of hepatic copper transport has recently been published.[17]

Figure 1.

Schematic presentation of the Wilson ATPase (ATP7B).

Figure 2.

Roles of the Wilson ATPase (ATP7B) in hepatic copper transport. CPL, ceruloplasmin; CTR1, copper transporter 1; MT, metallothionein.

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