Authors: Venu Julapalli, MD, Andrea Duchini, MDSeries Editor: Richard Goodgame, MD


February 03, 2003


Wilson's disease is an autosomal recessive inherited disorder of copper overload. It was first described by the London neurologist Samuel Wilson in 1912 as a familial syndrome presenting with progressive degeneration of the lenticular nuclei and liver cirrhosis at autopsy. The prevalence of the disease is approximately 1:30,000, with the frequency of gene mutations in the general population approximately 1:90.[1] There are many different associated mutations described, with worldwide distribution. Most patients are compound heterozygotes. The altered gene has been isolated to chromosome 13 and encodes the ATP7B-ATPase. This ATPase is expressed in hepatocytes and plays a dual role: (1) it is localized to the trans-Golgi network where it enables copper to enter the secretory pathway, incorporate into ceruloplasmin, and become exported into the plasma; and (2) it controls the excretion of excess copper into the bile via a vesicular-apical membrane route.[2] Biliary excretion represents the predominant mechanism of copper excretion from the liver. As copper accumulates in Wilson's disease, cytoplasmic injury results, manifested by microvesicular and macrovesicular steatosis and alterations of various organelles.[1] Eventually, cell death occurs, with release of copper into the plasma, hemolysis from oxidative injury to red blood cells, and deposition in nonhepatic tissues.[1,2]

Early treatment is essential in reversing and preventing organ damage in Wilson's disease.[9] Compliance must be emphasized, as rapid deterioration to fulminant hepatic failure is well described after abrupt discontinuation of therapy.[2] A minor role in the management of Wilson's disease is played by a low-copper diet, involving avoidance of liver, shellfish, nuts, mushrooms, and chocolate. The mainstay of treatment is life-long pharmacologic therapy with chelating substances -- penicillamine, trientine, or tetrathiomolybdate -- and zinc.

Liver transplantation is advocated in patients with wilsonian fulminant hepatic failure (with its inherent high mortality) and in those with advanced cirrhosis unresponsive to an adequate trial of chelation therapy (defined as anywhere from < 1 to 3 months). In a series of 55 patients with Wilson's disease who underwent liver transplantation, the 1-year survival rate was 79%, and overall survival was 72%, ranging from 3 months to 20 years.[10]

Screening of patients' siblings for possible Wilson's disease is imperative. Some authorities advocate screening of all first-degree relatives. The screening evaluation should include a thorough history and physical examination, corneal slit-lamp examination, liver function tests, and a serum ceruloplasmin level; a liver biopsy for quantitative hepatic copper measurement may be necessary for diagnostic dilemmas.[4] Genetic testing may obviate the need for liver biopsy in families in which the culprit mutation is well defined, but such testing is complicated by the molecular heterogeneity and compound heterozygosity found in Wilson's disease.[2]


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