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Key Features

Essentials of Diagnosis

  • Acute or chronic liver disease

  • Deteriorating neurologic status

  • Kayser-Fleischer rings

  • Elevated liver copper

  • Abnormalities in levels of ceruloplasmin and serum and urine copper

General Considerations

  • Caused by mutations in the gene ATP7B on chromosome 13 coding for a specific P-type adenosine triphosphatase involved in copper transport; this results in impaired bile excretion of copper and incorporation of copper into ceruloplasmin by the liver

  • Accumulated hepatic copper causes oxidant (free-radical) damage to the liver

  • Subsequently, copper accumulates in the basal ganglia and other tissues

Demographics

  • Disease should be considered in all children older than age 2 years with evidence of liver disease (especially with hemolysis) or with suggestive neurologic signs

  • A family history is often present, and 25% of patients are identified by screening asymptomatic homozygous family members

  • Disease is autosomal recessive

  • Occurs in 1:30,000 live births in all populations

Clinical Findings

Symptoms and Signs

  • Hepatic involvement may present as

    • Acute liver failure

    • Acute hepatitis

    • Chronic liver disease

    • Cholelithiasis

    • Fatty liver disease

    • Cirrhosis with portal hypertension

  • Jaundice

  • Hepatomegaly early in childhood

  • Splenomegaly

  • Kayser-Fleischer rings

    • Brown band at the junction of the iris and cornea, generally requiring slit-lamp examination for detection

    • Absence does not exclude diagnosis

  • Neurologic or psychiatric manifestations after age 10 years may include

    • Tremor

    • Dysarthria

    • Drooling

Differential Diagnosis

  • Acute or chronic viral hepatitis

  • α1-Antitrypsin deficiency

  • Autoimmune hepatitis

  • Drug-induced hepatitis

  • Nonalcoholic steatohepatitis (NASH)

  • Indian childhood cirrhosis

  • Tyrolean childhood cirrhosis

  • Idiopathic copper toxicosis

Diagnosis

Laboratory Findings

  • Acute disease characterized by

    • Anemia

    • Hemolysis

    • Very high serum bilirubin levels (> 20–30 mg/dL)

    • Low alkaline phosphatase

    • Low uric acid

  • Plasma ceruloplasmin levels (measured by the oxidase method)

    • Usually < 20 mg/dL

    • Low values, however, occur normally in infants <3 months

  • Serum copper levels

    • Low, but overlap with normal is too great for satisfactory discrimination

    • Markedly elevated in acute fulminant Wilson disease, owing to hepatic necrosis and release of copper

  • Urine copper excretion in children older than 3 years

    • Normally < 30 μg/d

    • In Wilson disease, generally > 100 μg/d although it can be as low as > 40 μg/d

  • Glycosuria and aminoaciduria have been reported

  • Hemolysis and gallstones may be present

  • Bone lesions simulating those of osteochondritis dissecans have also been found

  • Presence of Mallory bodies is strongly suggestive of Wilson disease

Diagnostic Procedures

  • Tissue content of copper from a liver biopsy

    • Normally <40–50 μg/g dry tissue

    • In most patients with Wilson disease, >250 μg/g

    • May be as low as > 75 μg/d when characteristic liver histology is present

  • Electron microscopy findings of abnormal mitochondria may be helpful

  • Genetic testing (haplotype analysis or ATP7B genotyping) is available for family members ...

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