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Wilson Disease

(Wilson's Disease; Inherited Copper Toxicity)

By Larry E. Johnson, MD, PhD

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Wilson disease results in accumulation of copper in the liver and other organs. Hepatic or neurologic symptoms develop. Diagnosis is based on a low serum ceruloplasmin level, high urinary excretion of copper, and sometimes liver biopsy results. Treatment consists of a low-copper diet and drugs such as penicillamine or trientine.

Wilson disease is a disorder of copper metabolism that affects men and women; about 1 person in 30,000 has the disorder. Affected people are homozygous for the mutant recessive gene, located on chromosome 13. Heterozygous carriers, who constitute about 1.1% of the population, are asymptomatic.

Pathophysiology

The genetic defect in Wilson disease impairs copper transport. The impaired transport decreases copper secretion into the bile, thus causing the copper overload and resultant accumulation in the liver, which begins at birth. The impaired transport also interferes with incorporation of copper into the copper protein ceruloplasmin, thus decreasing serum levels of ceruloplasmin.

Hepatic fibrosis develops, ultimately causing cirrhosis. Copper diffuses out of the liver into the blood, then into other tissues. It is most destructive to the brain but also damages the kidneys and reproductive organs and causes hemolytic anemia. Some copper is deposited around the rim of the cornea and edge of the iris, causing Kayser-Fleischer rings. The rings appear to encircle the iris.

Symptoms and Signs

Symptoms of Wilson disease usually develop between ages 5 and 35 but can develop from age 2 to 72 yr.

In almost half of patients, particularly adolescents, the first symptom is

  • Hepatitis—acute, chronic active, or fulminant

But hepatitis may develop at any time.

In about 40% of patients, particularly young adults, the first symptoms reflect

  • CNS involvement

Motor deficits are common, including any combination of tremors, dystonia, dysarthria, dysphagia, chorea, drooling, and incoordination. Sometimes the CNS symptoms are cognitive or psychiatric abnormalities.

In 5 to 10% of patients, the first symptom is incidentally noted gold or greenish gold Kayser-Fleischer rings or crescents (due to copper deposits in the cornea), amenorrhea or repeated miscarriages, or hematuria.

Diagnosis

  • Slit-lamp examination for Kayser-Fleischer rings

  • Serum ceruloplasmin and 24-h urinary copper excretion

  • Sometimes confirmation by penicillamine provocation test or liver biopsy

Wilson disease should be suspected in people < 40 with any of the following:

  • An unexplained hepatic, neurologic, or psychiatric disorder

  • An unexplained persistent elevation in hepatic transaminases

  • A sibling, parent, or cousin with Wilson disease

  • Fulminant hepatitis

If Wilson disease is suspected, slit-lamp examination for Kayser-Fleischer rings is required, and serum ceruloplasmin and copper levels and 24-h urinary copper excretion are measured. Transaminase levels are also often measured; high levels are consistent with the diagnosis.

Kayser-Fleischer rings

These rings plus typical motor neurologic abnormalities or a decrease in ceruloplasmin are nearly pathognomonic for Wilson disease. Rarely, these rings occur in other liver disorders (eg, biliary atresia, primary biliary cirrhosis), but ceruloplasmin levels should be unaffected.

Ceruloplasmin

Serum ceruloplasmin (normally 20 to 35 mg/dL) is usually low in Wilson disease but can be normal. It can also be low in heterozygous carriers and those with other liver disorders (eg, viral hepatitis, drug- or alcohol-induced liver disease). A low ceruloplasmin level in a patient with a Kayser-Fleischer ring is diagnostic. Also, a level of < 5 mg/dL is highly suggestive regardless of clinical findings.

Serum copper

Serum copper levels may be high, normal, or low.

Urinary copper excretion

In Wilson disease, 24-h urinary copper excretion (normally, 30 μg/day) is usually > 100 μg/day. If serum ceruloplasmin is low and urinary copper excretion is high, diagnosis is clear. If levels are equivocal, measuring urinary copper excretion after penicillamine is given (penicillamine provocation test) may confirm the diagnosis; this test is not usually done in adults because cutoff values are not well-established.

Liver biopsy

In unclear cases (eg, elevated transaminases, no Kayser-Fleischer rings, indeterminate values for ceruloplasmin and urinary copper), the diagnosis is made by doing a liver biopsy to measure hepatic copper concentration. However, false-negative results may occur because of a sampling error (due to large variations in copper concentrations in the liver) or fulminant hepatitis (causing necrosis that releases large amounts of copper).

Screening for Wilson disease

Because early treatment is most effective, screening is indicated for anyone who has a sibling, cousin, or parent with Wilson disease. Screening consists of a slit-lamp examination and measurement of transaminase levels, serum copper and ceruloplasmin, and 24-h urine copper excretion. If any results are abnormal, liver biopsy is done to measure hepatic copper concentration. Infants should not be tested until after age 1 yr because ceruloplasmin levels are low during the first few months of life. Children < 6 yr with normal test results should be retested 5 to 10 yr later.

Genetic testing is under investigation.

Prognosis

Prognosis for patients with Wilson disease is usually good, unless disease is advanced before treatment begins.

Untreated Wilson disease is fatal, usually by age 30.

Treatment

  • Penicillamine or trientine

  • Low-copper diet

  • For maintenance, lifelong low-dose penicillamine or trientine, or oral zinc

Continual, lifelong treatment of Wilson disease is mandatory regardless of whether symptoms are present. A low-copper diet (eg, avoiding beef liver, cashews, black-eyed peas, vegetable juice, shellfish, mushrooms, and cocoa) and use of penicillamine, trientine, and sometimes oral zinc can prevent copper from accumulating. Copper content in drinking water should be checked, and people should be advised not to take any vitamin or mineral supplements containing copper.

Penicillamine is the most commonly used chelating drug but has considerable toxicity (eg, fever, rash, neutropenia, thrombocytopenia, proteinuria). Cross-reactivity may occur in people with penicillin allergy. Patients > 5 yr are given oral doses of 62.5 mg q 6 h to 250 mg q 12 h (250 to 500 mg/day in 2 to 4 doses) and slowly increased to a maximum of 250 mg q 6 h to 750 mg q 12 h (1000 to 1500 mg/day in 2 to 4 doses). Younger children are given 10 mg/kg bid or 6.7 mg/kg tid (20 mg/kg/day) po. Pyridoxine 25 mg po once/day is given with penicillamine. Occasionally, use of penicillamine is associated with worsening neurologic symptoms.

Trientine hydrochloride is an alternative treatment to penicillamine. Doses are 375 to 750 mg po bid or 250 to 500 mg po tid (750 to 1500 mg/day).

Zinc acetate 50 mg po tid can reduce intestinal copper absorption, thus preventing reaccumulation of copper in patients who cannot tolerate penicillamine or trientine or who have neurologic symptoms that do not respond to the other drugs. (Caution: Penicillamine or trientine must not be taken at the same time as zinc because either drug can bind zinc, forming a compound with no therapeutic effect. )

Poor long-term adherence to drug therapy is common. After 1 to 5 yr of therapy, lower dose maintenance drug therapy can be considered. Regular follow-up care with an expert in liver disease is recommended.

Liver transplantation may be lifesaving for patients who have Wilson disease and fulminant hepatic failure or severe hepatic insufficiency refractory to drugs.

Key Points

  • Wilson disease is a rare, autosomal recessive disorder in which copper accumulates in various organs.

  • The disease manifests during childhood or adulthood, usually between ages 5 and 35.

  • Suspect the disorder in people with a family history of the disorder or unexplained hepatic, neurologic, or psychiatric abnormalities (including elevated transaminase levels).

  • Confirm the diagnosis primarily with a slit-lamp examination (for Kayser-Fleischer rings) and measurement of serum ceruloplasmin (which is low) and 24-h urinary copper excretion (which is high).

  • Advise patients to follow a low copper diet, and treat them with penicillamine, trientine, or, if these drugs are intolerable or ineffective, oral zinc.

Drugs Mentioned In This Article

  • Drug Name
    Select Trade
  • CUPRIMINE
  • SYPRINE

* This is the Professional Version. *