Chapter 360

Wilson's disease is an autosomal recessive disorder caused by mutations in the ATP7Bgene, a membrane-bound, copper-transporting ATPase. Clinical manifestations are caused by copper toxicity and primarily involve the liver and the brain. Because effective treatment is available, it is important to make this diagnosis early.

The frequency of Wilson's disease in most populations is about 1 in 30,000–40,000, and the frequency of carriers of ATP7B mutations is ˜1%. Siblings of a diagnosed patient have a 1 in 4 risk of Wilson's disease, whereas children of an affected patient have about a 1 in 200 risk. Because a large number of inactivating mutations have been reported in the ATP7Bgene, mutation screening for diagnosis is not routine, although this may be practical in the future. DNA haplotype analysis can be used to genotype siblings of an affected patient.

Pathogenesis

ATP7B protein deficiency impairs biliary copper excretion, resulting in positive copper balance, hepatic copper accumulation, and copper toxicity from oxidant damage. Excess hepatic copper is initially bound to metallothionein, but as this storage capacity is exceeded, liver damage begins as early as three years of age. Defective copper incorporation into apoceruloplasmin leads to excess catabolism and low blood levels of ceruloplasmin. Serum copper levels are usually lower than normal because of low blood ceruloplasmin, which normally binds >90% of serum copper. As the disease progresses, nonceruloplasmin serum copper (“free” copper) levels increase, resulting in copper buildup in other parts of the body, such as the brain, leading to neurologic and psychiatric disease.

Clinical Presentation

Hepatic

Wilson's disease may present as hepatitis, cirrhosis, or as hepatic decompensation, typically in the mid to late teenage years in western countries, although the age of presentation is quite broad and extends into the fifth decade of life.

An episode of hepatitis may occur, with elevated blood transaminase enzymes, with or without jaundice, and then spontaneously regress. Hepatitis often reoccurs, and most of these patients eventually develop cirrhosis.

Hepatic decompensation is associated with elevated serum bilirubin, reduced serum albumin and coagulation factors, ascites, peripheral edema, and hepatic encephalopathy. In severe hepatic failure, hemolytic anemia may occur because large amounts of copper derived from hepatocellular necrosis are released into the bloodstream. The association of hemolysis and liver disease makes Wilson's disease a likely diagnosis.

Neurologic

The neurologic manifestations of Wilson's disease typically occur in patients in their early twenties, although the age of onset extends into the sixth decade of life. MRI and CT scans reveal damage in the basal ganglia and occasionally in the pons, medulla, thalamus, cerebellum, and subcortical areas. The three main movement disorders include dystonia, incoordination, and tremor. Dysarthria and dysphagia are common. In some patients, the clinical picture closely resembles that of Parkinson's disease. Dystonia can involve any part of the body and ...

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