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Key Features

Essentials of Diagnosis

  • Rare autosomal recessive disorder that usually manifests in persons under age 40

  • Excessive deposition of copper in the liver and brain

  • Serum ceruloplasmin, the plasma copper-carrying protein, is low

  • Urinary excretion and hepatic concentration of copper are high

General Considerations

  • The genetic defect, localized to chromosome 13, affects a copper-transporting adenosine triphosphatase (ATP7B) in the liver and leads to oxidative damage of hepatic mitochondria

  • Over 500 different mutations in the Wilson disease gene have been identified

  • The major physiologic aberration is excessive absorption of copper from the small intestine and decreased excretion of copper by the liver, resulting in increased tissue deposition, especially in the liver, brain, cornea, and kidney

Demographics

  • Usually manifests in adolescents and young adults but can occur in persons over age 40

Clinical Findings

Symptoms and Signs

  • Consider the diagnosis in any child or young adult with the following

    • Hepatitis, splenomegaly with hypersplenism, portal hypertension

    • Coombs-negative hemolytic anemia

    • Neurologic or psychiatric abnormalities

    • Chronic or fulminant hepatitis

  • Hepatic involvement may range from elevated liver tests (although the alkaline phosphatase may be low) to fulminant hepatitis, cirrhosis and portal hypertension

  • Neurologic manifestations

    • Dysarthria, dysphagia, incoordination, and spasticity

    • Migraines, insomnia, and seizures

    • Related to basal ganglia dysfunction

  • Psychiatric features include behavioral and personality changes and emotional lability

  • Corneal Kayser-Fleischer ring

    • Pathognomonic sign

    • Brownish or gray-green pigmented granular deposits in Descemet membrane in the cornea close to the endothelial surface

    • Usually most marked at the superior and inferior poles of the cornea

    • Sometimes seen with the naked eye; readily detected by slit-lamp examination

    • It may be absent in patients with hepatic manifestations only but is usually present in those with neuropsychiatric disease

  • Other manifestations

    • Renal calculi

    • Aminoaciduria

    • Renal tubular acidosis

    • Hypoparathyroidism

    • Infertility

    • Hemolytic anemia

    • Subcutaneous lipomas

Differential Diagnosis

  • Acute hepatitis

  • Cholestasis

  • Acute hepatic failure

  • Chronic hepatitis

  • Cirrhosis

  • Hepatomegaly

  • Other cause of liver disease, eg, viral infections, toxins, hemochromatosis

  • Tremor due to other causes, eg, Parkinson disease, essential tremor

  • Dementia due to other causes, eg, Huntington disease

  • Behavior change due to other medical illness, eg, neurosyphilis, brain tumor

Diagnosis

Laboratory Tests

  • Increased urinary copper excretion (> 40 mcg/24 h and usually > 100 mcg/24 h); low serum ceruloplasmin levels (< 14 mg/dL [< 140 mg/L] usually and < 5 mg/dL [< 50 mg/L] diagnostic); and elevated hepatic copper concentration (> 210–250 mcg/g of dry liver)

  • However, increased urinary copper and low serum ceruloplasmin levels are not completely sensitive or specific for Wilson disease; an enzymatic assay for ceruloplasmin appears to be more accurate

  • In equivocal cases (eg, when the serum ceruloplasmin level is normal), the diagnosis may require demonstration of a rise in urinary copper after a penicillamine challenge; however, this test is ...

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