Michael L SchilskyMD

Wilson's disease is an autosomal recessive disorder of copper metabolism present in approximately 1 in 30,000 individuals, with disease specific mutations of the Wilson's disease gene, ATP7B, located on chromosome 13. In patients with Wilson's disease, copper accumulates to toxic levels in the liver, brain, and other sites in the body. When discovered in a timely fashion, many of the toxic effects of copper accumulation can be prevented or reversed by medical therapy.

Wilson's disease must be considered in patients below the age of 45 years with unexplained liver disease or cirrhosis, and in patients with neurologic and psychiatric symptoms and evidence of liver disease. Wilson's disease should also be considered in those with hepatic histology suspicious for this disorder, pediatric patients with autoimmune features not responsive to steroids and in those lacking typical markers, patients with brain imaging demonstrating compatible findings, and in patients in whom Kayser-Fleischer (KF) rings were identified (Table 124-1).

Failure to initiate treatment or interruption of the necessary lifelong treatment can lead to liver injury, neurologic and psychiatric signs and symptoms, liver failure, and death. In patients with fulminant liver failure due to Wilson's disease or in those with advanced liver disease unresponsive to medical treatment, liver transplantation can be lifesaving and curative.

The age of symptomatic clinical presentation of Wilson's disease varies widely, but patients present mainly with hepatic or neurologic or psychiatric symptoms or signs of disease. Liver disease typically presents earlier on, typically within the first two decades of life. Neurologic or psychiatric signs and symptoms may predominate in older

TABLE 124-1. Diagnostic Testing for Wilson's Disease



Ophthalmologic slit lamp examination

Serum ceruloplasmin

Serum copper

24-hour urinary copper

Hepatic copper

Hepatic histology

Electron microscopy for hepatic ultrastructure Copper histochemistry

Radiological imaging of the brain: MRI or CT

Molecular studies Haplotype and mutation analysis

KF rings are often absent early on in patients with Wilson's disease; present in only 50% of patients with hepatic presentation but 98% of patients with neurological or psychiatric signs or symptoms. KF rings and sunflower cataracts abate with treatment of Wilson's disease. Sunflower cataracts may also be seen on slit lamp exam in patients with Wilson's disease.

Normal ~ 20-40 mg/dL; elevated with acute phase, pregnancy, and with use of estrogens. Less than 20 mg/dL in ~ 95% of patients, 20% of heterozygous carriers, and with severe hepatic insufficiency and in severe protein losing states. Physiologically decreased in newborns; undetectable in rare patients with aceruloplasminemia.

Normally ~ 100 ^g/dL. Decreased in most with Wilson's disease, typically < 80 ^g/dL. Proportion not bound to ceruloplasmin > 10% in untreated patients with Wilson's disease. Total serum copper markedly elevated above 200 ^g/dL in fulminant hepatitis due to Wilson's disease.

Normal < 50 ^g/24 h. Greater than 100 ^g/24 h in most symptomatic patients and following chelation treatment; < 100 ^g in patients on zinc therapy.

Normal < 40 ^g/g dry weight liver. Greater than 250 ^g/g dry weight liver in most patients with Wilson's disease. May be increased in other cholestatic disorders, idiopathic copper toxicosis.

Abnormal findings in patients include steatosis, glycogen nuclei, fibrosis, chronic hepatitis, and cirrhosis. Marked degeneration of hepatocytes, pleiocytosis, and nuclear irregularities in fulminant hepatitis.

Abnormal in untreated patients; dilatation of mitochondrial cristae and crystalline deposits (present when steatosis seen on light microscopy). Dense lysosomes later on.

Absent normally, but in some patients, positive staining is present in some but not all liver nodules. Absence of staining does not exclude Wilson's disease.

Normal in the absence of Wilson's disease and in many patients early on. Findings in Wilson's disease with neurologic or psychiatric symptoms include atrophy, alterations in basal ganglia, subcortical white matter, midbrain, and pons. Abnormalities can be present in some asymptomatic patients.

Haplotype: same as proband indicates Wilson's disease present, different in carriers and unaffected siblings. Mutations: patients have disease specific mutations on each allele; most useful in populations with dominant mutations.

CT = computed tomography; KF = Kayser-Fleischer; MRI = magnetic resonance imaging.

patients, but there are exceptions where these may be present earlier on, even under the age of 10 years, or are present in conjunction with symptoms of liver disease.

The diagnosis of Wilson's disease is established by the presence of KF rings and a decreased level of serum ceruloplasmin, KF rings and neurologic or psychiatric symptoms, and in those with liver disease and appropriate histology, an elevated hepatic copper (typically > 250 ^g/g dry weight). Urinary copper excretion is elevated above 100 ^g/24 h in most symptomatic patients, and in those with fulminant hepatic failure (FHF) due to Wilson's disease. Genetic studies, haplotype or polymorphism analysis can identify affected siblings with the caveat that the diagnosis must be first firmly established in the proband. Direct identification of ATP7B mutations is possible, but limited by the size of the gene and the greater than 250 disease causing mutations and the limited availability of this testing (http://www.uofa-medical-genetics.org/wilson/index.php). In populations with a high frequency of specific mutations, molecular diagnostic testing for these mutations is useful.

The management of Wilson's disease depends upon the firm establishment of the diagnosis because treatment is lifelong. Therapy is directed at the removal of copper or the prevention of its further accumulation in the liver and in other body sites where it may be injurious.

Treatment options for Wilson's disease include medical therapy with oral chelating agents or zinc, and liver transplantation. Dietary restrictions in copper intake are recommended along with medical therapy, especially during the initial phase of treatment. The chelating agents peni-cillamine and trientine promote renal copper excretion and are recommended as first line therapy for symptomatic patients with hepatic or neurological disease. These chelat-ing agents may be used at lower dosages for maintenance therapy. Tetrathiomolybdate is an effective copper chelator that is under investigation for initial treatment of patients with neurologic disease. Zinc functions by blocking copper absorption from the gut by induction of the endogenous chelator metallothionein in enterocytes. Zinc is mainly used for maintenance therapy or initial therapy for asymptomatic patients, but may also have a role as an adjunct to initial chelation therapy. Liver transplantation restores a normal phenotype with respect to copper metabolism, and therapy specific for Wilson's disease is no longer required.

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