Hereditary intoxication with copper: symptoms, diagnosis, treatment

Hereditary copper intoxication (Wilson's disease) leads to accumulation of copper in the liver and other organs. Hepatic or neurologic symptoms develop. The diagnosis is based on a low serum level of ceruloplasmin, a high level of copper excretion in the urine, and sometimes liver biopsy results. Treatment consists in chelation, usually with penicillamine.

Hepatolenticular degeneration (Wilson's disease) is a progressive disorder of copper metabolism that develops in 1 person out of 30 000. People who are affected by this disease are homozygous for a recessive mutant gene located in the 13th chromosome. In heterozygous carriers, which make up approximately 1.1% of the population, the disease does not appear.

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Pathophysiology of hereditary intoxication with copper

Since birth, copper accumulates in the liver. Serum ceruloplasmin levels are reduced. Develops hepatic fibrosis and, ultimately, cirrhosis. Copper diffuses from the liver into the bloodstream, and then into other tissues. This leads, mainly, to destructive lesions of the brain, but also affects the kidneys, reproductive organs and hemolytic anemia. A certain amount of copper settles in the Descemet's membrane of the cornea.

Symptoms of hereditary intoxication with copper

Symptoms usually develop between the ages of 6 and 30 years. Almost half of patients, especially teenagers, the first symptom - hepatitis, acute, chronic active or lightning. But hepatitis can develop at any time. In approximately 40% of patients, especially at a young age, the first symptoms reflect involvement in the CNS process. Typical motor disorders, including any combination of tremors, dystonia, dysarthria, dysphagia, trochees, drooling and impaired coordination. Sensory disturbances are not observed. Sometimes the first symptoms are behavioral or cognitive abnormalities. In 5-10% of patients, the first symptom is the accidentally observed gold or greenish-gold Kaiser-Fleischer rings or crescents (due to the deposition of copper in the cornea), amenorrhea, repeated spontaneous abortions, hematuria.

Diagnosis of hereditary intoxication with copper

Wilson's disease (hepatolenticular degeneration) should be suspected in a person under 40 years of age in any of the following cases: no other unexplained liver, neurological or psychiatric pathology; nothing else unexplained constant increase in hepatic trans -aminase; Sibs, parent or cousin with Wilson's disease; fulminant hepatitis and Coombs-negative hemolytic anemia (see page 1336).

If Wilson's disease is suspected, it is necessary to use a slit lamp to identify the Kaiser-Fleischer rings, measure the levels of copper and ceruloplasmin in the blood serum and excrete copper in the daily urine.

Ceruloplasmin in serum (norm 20-35 mg / dL) is usually lowered with hepatolenticular degeneration, but it can be normal. It can also be false-low, especially in heterozygous carriers. If the serum ceruloplasmin is low, and the excretion of copper in the urine is high, then the diagnosis is clear. If the levels are doubtful, then the diagnosis can be confirmed by measuring the excretion of copper in the urine after taking penicillamine (penicillamine provocation test). If this sample is not performed, then you need to take a liver biopsy to measure the concentration of copper in the liver.

A low level of ceruloplasmin usually means that the total amount of copper in the blood serum is reduced. However, the level of free (unbound) copper is usually elevated. The amount of free copper can be calculated by subtracting the amount of copper in the ceruloplasmin from the total copper level in the blood serum, or it can be measured directly.

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

In Wilson's disease (hepatolenticular degeneration), the excretion of copper in the urine (normally <30 μg / day) usually exceeds 100 μg / day. Administration of penicillamine at a dose of 500 mg 2 or 4 times a day increases the excretion to 1200 μg / day or more in patients with hepatolenticular degeneration and does not allow to exceed 500 μg / day in patients with no Wilson's disease. In borderline cases, the diagnosis is made on the basis of reduced inclusion of radioactive copper in ceruloplasmin.

The concentration of copper in the liver (normally <50 μg / g dry body weight) usually exceeds 250 μg / g of dry body weight in patients with Wilson's disease. However, there may be false-negative results due to a sampling error (copper concentrations in the liver vary very much) or lightning-induced hepatitis (causes necrosis, which results in the release of large amounts of copper).

The level of uric acid in the blood serum can be low, because its urinary excretion is increased.

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Treatment of hereditary intoxication with copper

Continuous, lifelong treatment is necessary, regardless of whether symptoms are present. The accumulated copper should be removed with the help of chelating agents. The accumulation of copper should be prevented by a low-content diet containing copper [for example, avoiding beef liver, cashew nuts, Chinese cowweed (cow peas), vegetable juices, molluscs, mushrooms and cocoa] or by treatment with low doses of chelating agents or zinc orally.

Chelate-forming drug of choice is penicillamine. Patients over the age of 5 years are appointed in a dose of 500 mg orally 2 or 4 times a day on an empty stomach (> 1 hour before meals and at bedtime).

To younger children the drug is prescribed in a dose of 50 mg / kg orally 4 times a day. Sometimes with the use of penicillamine, worsening of neurologic symptoms is associated. Together with penitsillaminom is given and pyridoxin at a dose of 25 mg orally once a day.

Trientin hydrochloride is less potent than penicillamine. It is administered immediately at a dose of 500 mg orally 2 times a day if penicillamine is canceled due to an adverse effect.

Oral administration of zinc acetate in a dose of 50 mg 2 times a day can prevent the re-accumulation of copper in those patients who can not tolerate penicillamine or trientine, or in those who have neurologic symptoms that are not removed by other drugs.

Warning

Penicillamine or triene should not be taken with zinc, because any of these drugs can bind zinc to form a compound that does not have a therapeutic effect.

Ammonium tetramothiomolybdate is currently being evaluated as well as a drug for the treatment of Wilson's disease. It reduces the absorption of copper by binding to it in blood plasma, and is relatively non-toxic. It is especially useful in the presence of neurologic symptoms, because, unlike penicillamine, does not aggravate neurologic symptoms during treatment.

Liver transplantation can be a rescue for patients who have Wilson's disease with fulminant liver damage or severe liver failure that is not sensitive to drugs.

Prognosis and screening of hereditary intoxication with copper

The prognosis is usually favorable if the disease has not progressed much before the treatment began. An untreated Wilson's disease is fatal and leads to death usually in the age of up to 30 years.

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