Hereditary copper intoxication: symptoms, diagnosis, treatment

Hereditary copper toxicity (Wilson's disease) results in accumulation of copper in the liver and other organs. Liver or neurologic symptoms develop. Diagnosis is based on low serum ceruloplasmin, high urinary copper excretion, and sometimes liver biopsy. Treatment is chelation, usually with penicillamine.

Hepatolenticular degeneration (Wilson's disease) is a progressive disorder of copper metabolism that affects 1 in 30,000 people. People affected by the disease are homozygous for a recessive mutant gene located on chromosome 13. Heterozygous carriers, who make up approximately 1.1% of the population, do not develop the disease.

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Pathophysiology of hereditary copper intoxication

Beginning at birth, copper accumulates in the liver. Serum ceruloplasmin levels are reduced. Liver fibrosis and eventually cirrhosis develop. Copper diffuses from the liver into the blood and then into other tissues. This leads primarily to destructive lesions of the brain, but also to damage of the kidneys, reproductive organs, and hemolytic anemia. Some copper is deposited in Descemet's membrane of the cornea.

Symptoms of Hereditary Copper Intoxication

Symptoms usually develop between 6 and 30 years of age. In about half of patients, especially adolescents, the first symptom is hepatitis, either acute, chronic active, or fulminant. But hepatitis may develop at any time. In about 40% of patients, especially young adults, the first symptoms reflect CNS involvement. Movement disturbances are typical, including any combination of tremor, dystonia, dysarthria, dysphagia, chorea, salivation, and incoordination. Sensory disturbances are not observed. Sometimes the first symptoms are behavioral or cognitive abnormalities. In 5-10% 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, recurrent spontaneous abortions, or hematuria.

Diagnosis of hereditary copper intoxication

Wilson's disease (hepatolenticular degeneration) should be suspected in a person under 40 years of age in any of the following situations: otherwise unexplained hepatic, neurologic, or psychiatric pathology; otherwise unexplained persistent elevation of hepatic transaminase; a sibling, parent, or cousin with Wilson's disease; fulminant hepatitis and Coombs-negative hemolytic anemia (see p. 1336).

If Wilson's disease is suspected, slit-lamp examination for Kayser-Fleischer rings, measurement of serum copper and ceruloplasmin levels, and 24-hour urinary copper excretion are necessary.

Serum ceruloplasmin (normal 20-35 mg/dL) is usually low in hepatolenticular degeneration but may be normal. It may also be falsely low, especially in heterozygous carriers. If serum ceruloplasmin is low and urinary copper excretion is high, the diagnosis is clear. If levels are equivocal, the diagnosis can be confirmed by measuring urinary copper excretion after penicillamine administration (penicillamine provocation test). If this test is not done, a liver biopsy should be taken to measure the liver copper concentration.

Low ceruloplasmin levels usually mean that total serum copper is also low. However, free (unbound) copper levels are usually elevated. Free copper can be calculated by subtracting the amount of copper in ceruloplasmin from the total serum copper level, or it can be measured directly.

Kayser-Fleischer rings are occasionally seen in other liver diseases (eg, biliary atresia, primary biliary cirrhosis). However, Kayser-Fleischer rings in combination with motor neurological abnormalities or decreased ceruloplasmin are pathognomonic for hepatolenticular degeneration (Wilson's disease).

In Wilson's disease (hepatolenticular degeneration), urinary copper excretion (normally <30 μg/day) usually exceeds 100 μg/day. Oral penicillamine 500 mg 2 or 4 times daily increases excretion to 1200 μg/day or more in patients with hepatolenticular degeneration and does not exceed 500 μg/day in patients without Wilson's disease. In borderline cases, the diagnosis is based on decreased incorporation of radioactive copper into ceruloplasmin.

Liver copper concentrations (normally < 50 μg/g dry body weight) are usually greater than 250 μg/g dry body weight in patients with Wilson's disease. However, false negative results may occur due to sampling error (liver copper concentrations vary greatly) or fulminant hepatitis (causes necrosis, resulting in the release of large amounts of copper).

Serum uric acid levels may be low because urinary excretion is increased.

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Treatment of hereditary copper intoxication

Continuous, lifelong treatment is essential, whether or not symptoms are present. Accumulated copper must be removed with chelating agents. Copper accumulation should be prevented by a diet low in copper-containing foods [e.g., avoid beef liver, cashews, cowpeas, vegetable juices, shellfish, mushrooms, and cocoa] or by treatment with low doses of chelating agents or oral zinc.

The chelating agent of choice is penicillamine. For patients over 5 years of age, it is prescribed at a dose of 500 mg orally 2 or 4 times a day on an empty stomach (> 1 hour before meals and at bedtime).

For younger children, the drug is prescribed at a dose of 50 mg/kg orally 4 times a day. Sometimes, worsening of neurological symptoms is associated with penicillamine administration. Pyridoxine is also given together with penicillamine at a dose of 25 mg orally once a day.

Trientine hydrochloride is a less potent drug than penicillamine. It is given immediately at a dose of 500 mg orally twice daily if penicillamine is discontinued because of an adverse effect.

Oral zinc acetate 50 mg twice daily may prevent copper reaccumulation in patients who cannot tolerate penicillamine or trientine or who have neurologic symptoms that are not relieved by other drugs.

Warning

Penicillamine or trientine should not be taken with zinc because either drug can bind zinc, forming a compound that has no therapeutic effect.

Ammonium tetrathiomolybdate is also currently being evaluated for the treatment of Wilson's disease. It reduces copper absorption by binding to it in plasma and is relatively nontoxic. It is particularly useful in the presence of neurological symptoms because, unlike penicillamine, it does not worsen neurological symptoms during treatment.

Liver transplantation can be lifesaving for patients with Wilson's disease, which has fulminant liver damage or severe liver failure that is unresponsive to drugs.

Prognosis and screening of hereditary copper intoxication

The prognosis is usually good unless the disease has progressed too far before treatment is started. Untreated Wilson's disease is fatal, usually causing death before age 30.

Because early treatment is most effective, screening is performed for anyone who has a sibling, cousin, or parent with Wilson disease. Screening includes slit-lamp examination, liver function tests, measurement of serum copper and ceruloplasmin levels, and 24-hour urinary copper excretion. If any results are abnormal, a liver biopsy is done to assess liver copper concentrations. Infants should not be tested until age 1 year because ceruloplasmin levels are low during the first few months of life. Children younger than 6 years with normal test results should be retested in 5 to 10 years. Genetic testing is not feasible.