Elsevier

The Lancet

Volume 369, Issue 9559, 3–9 February 2007, Pages 397-408
The Lancet

Seminar
Wilson's disease

https://doi.org/10.1016/S0140-6736(07)60196-2Get rights and content

Summary

Progressive hepatolenticular degeneration, or Wilson's disease, is a genetic disorder of copper metabolism. Knowledge of the clinical presentations and treatment of the disease are important both to the generalist and to specialists in gastroenterology and hepatology, neurology, psychiatry, and paediatrics. Wilson's disease invariably results in severe disability and death if untreated. The diagnosis is easily overlooked but if discovered early, effective treatments are available that will prevent or reverse many manifestations of this disorder. Studies have identified the role of copper in disease pathogenesis and clinical, biochemical, and genetic markers that can be useful in diagnosis. There are several chelating agents and zinc salts for medical therapy. Liver transplantation corrects the underlying pathophysiology and can be lifesaving. The discovery of the Wilson's disease gene has opened up a new molecular diagnostic approach, and could form the basis of future gene therapy.

Section snippets

Hepatic pathology

In the early stages of the disease, diffuse cytoplasmic copper accumulation can be seen only by special immunohistochemical stains for detecting copper, which are not routinely available. This early accumulation of copper is associated with macrosteatosis, microsteatosis, and glycogenated nuclei which are features that can be seen in various other disorders—eg, nonalcoholic steatohepatitis.2 The ultrastructural abnormalities range from enlargement and separation of the mitochondrial inner and

Molecular pathogenesis

The gene responsible for Wilson's disease (on chromosome 13) was identified almost simultaneously by three separate laboratories.8, 9, 10, 11 The gene (ATP7B) is highly expressed in the liver, kidney, and placenta. ATP7B encodes a transmembrane protein ATPase (ATP7B), which functions as a copper-dependent P-type ATPase. The ATP7B transporter has dual synthetic and excretory roles, functioning in the transport of copper into the trans-Golgi compartment, for incorporation into the plasma protein

Clinical applications of Wilson's disease genetics

The Human Genome Organisation (HUGO) database for Wilson's disease lists roughly 300 different mutations described in the disease, which are distributed across the ATP7B gene. As a result, the distribution of ATP7B genotypes is complex and most patients are compound heterozygotes, having two different mutations of the ATP7B gene. In general, a few mutations predominate, depending on the population tested. Therefore, in molecular diagnosis, selected exons are chosen for initial screening

Clinical manifestations and range of disease

The clinical range of Wilson's disease is wide, and knowledge of the various disease presentations is important (panel 1). In broad terms, patients can present acutely with liver failure, haemolysis, or both, or more chronically with liver disease, neurological disease, or both.

Patients who first present with neurological or psychiatric signs tend to be older than those with hepatic features alone. Most patients with CNS involvement are believed to have liver disease at the time of presentation

Establishing a diagnosis

There is no one test for the diagnosis of Wilson's disease (panel 2). The diagnostic challenge is that the symptoms are often non-specific and the disease affects many different organ systems, which results in confusion with other disorders. The diagnosis is easy to establish in individuals with neurological symptoms, K-F rings, and a low caeruloplasmin concentration. The absence of K-F rings does not necessarily exclude the possibility of this disease but in patients with predominantly

Family screening

First-degree relatives must be screened for Wilson's disease. The probability of finding a homozygote in siblings is 25% and in the children is roughly 0·5%. Liver function tests, serum copper and caeruloplasmin concentration, and urinary copper analysis are done for relatives. If necessary, investigations should be extended to test for K-F rings. 24-h urinary copper might be difficult to interpret in Wilson's disease heterozygotes.

The diagnosis could remain contentious when individuals without

Treatment

The drug treatment of Wilson's disease is based on the use of copper chelators to promote copper excretion from the body, or zinc to reduce copper absorption, or both. Liver transplantation is successful for patients with liver failure that is unresponsive to medical treatment.

Wilson's disease was progressive and fatal until 1951, when the first chelating agent dimercaprol given intramuscularly was used. In 1956, John Walshe90 reported the clinical benefit of the orally active chelator

The future

Why is there a need for a cure for a disease that has available medical therapy? Patients faced with a lifelong need for medication and physicians faced with the results of non-adherence to therapy are the two main arguments.

Genetic therapy and hepatocyte transplantation represent future curative treatments for Wilson's disease, along with currently available liver transplantation.115 However, both cell and liver transplants need immunosuppression to maintain grafted cells. Future use of

Search strategy and selection criteria

We searched the MEDLINE database from January, 1966, to June, 2006, for specific topics in relation to the search terms “Wilson disease” or “Wilson's disease” in combination with the terms “genetic”, “liver disease”, “neurology”, and “psychiatric”. We largely selected publications in the past 5 years, but did not exclude commonly referenced and highly regarded older publications. We also searched the reference lists of articles identified by this search strategy, and selected those we

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