I. Pathophysiology

  1. An autosomal recessive defect in a copper-transporting ATP-ase that leads to impaired biliary excretion of copper
  2. The result is copper accumulation in the liver, and in later stages, the brain, cornea, and kidneys as well

II. Clinical presentation

  1. Accumulation begins in infancy but usually presents clinically during adolescence
  2. Hepatic manifestations
  1. Most often presents with cirrhosis and portal hypertension
  2. 10-30% will have chronic active hepatitis
  3. Rarely, get fulminant hepatic failure
  4. Often get a pattern of recurrent mild hepatitis
  1. In some cases, liver injury is subclinical and dysfunction of other organs becomes apparent earlier
  1. Neuropsychiatric sx-motor sx (tremor, chorea, decreased movement), loss of coordination of fine movements; personality changes; sz are infrequent; sensory abnormalities don't seem to occur
  2. Hemolytic anemia (occurs when copper is released from liver into circulation in large amounts; usually accompanied by overt liver disease)-brief, self-limited
  1. Uniformly fatal if untreated

III. Diagnosis

  1. No single biochemical test is diagnostic
  2. Serum ceruloplasmin
    1. In a study in 4- asymptomatic children with Wilson Disease (confirmed with abnromal liver copper levels plus a confirmed mutation associated with Wilson Disease) and 58 age- and sex-matched controls with non-Wilson hepatic disease, serum ceruloplasmin < 20mg/dL was 95% sensitive and 84.5% specific for WD; 24h urine copper excretion performed less well. (Hepatol. 52:1948, 2010-JW)
    2. Can increase even in pts with Wilson's during inflammation, estrogen rx, and pregnancy.
  3. Kaiser-Fleisher rings are typical, but often absent-brown or greenish rings at the limbus of the cornea, composed of copper-containing granules, often visible only with slit-lamp
  4. Liver biopsy to evaluate copper content may be helpful (> 250ug/g of dry liver tissue plus either Kaiser-Fleisher rings or low ceruloplasmin is considered diagnostic); specific histological appearance of liver is nonspecific
  5. Urinary copper excretion in response to oral penicillamine challenge is sometimes used (?)

IV. Treatment

  1. Copper chelation improves survival but does not reverse cirrhosis
  1. Must be continued for life; discontinuation can result in rapid hepatic decompensation
  2. d-Penicillamine is drug of choice; can cause rash, fever, adenopathy, neutropenia, thrombocytopenia early; late side effects include nephrotic sd., SLE, Goodpasture's sd, and a variety of chronic skin diseases; often reversible by temporarily discontinuing the drug
  3. Pyridoxine, trientine, and zinc also used
  1. Zinc (inhibits copper uptake in GI tract)-Some evidence of benefit in uncontrolled trials (Hepatol. 50:1442, 2009-JW)

  2. Liver transplantation when liver failure ensues

(Source: Cecil's 20th ed.)