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Copper is a component of many body proteins; almost all of the body's copper is bound to copper proteins. Unbound (free) copper ions are toxic. Genetic mechanisms control the incorporation of copper into apoproteins and the processes that prevent toxic accumulation of copper in the body. Copper absorbed in excess of metabolic requirements is excreted through bile.
Acquired Copper Deficiency
If the genetic mechanisms controlling copper metabolism are normal, dietary deficiency rarely causes clinically significant copper deficiency. The only reported causes are kwashiorkor, persistent infantile diarrhea (usually associated with a diet limited to milk), severe malabsorption (as in sprue), and excessive zinc intake.
Deficiency may cause neutropenia, impaired bone calcification, and hypochromic anemia not responsive to iron supplements.
Diagnosis is based on low serum levels of copper and ceruloplasmin, although these tests are not always reliable. Treatment is directed at the cause, and copper 1.5 to 3 mg/day po (usually as copper sulfate) is given.
Inherited Copper Deficiency
(Menkes syndrome)
Inherited copper deficiency occurs in male infants who inherit a mutant X-linked gene. Incidence is about 1 in 50,000 live births. Copper is deficient in the liver, serum, and essential copper proteins, including cytochrome-c oxidase, ceruloplasmin, and lysyl oxidase.
Symptoms are severe mental retardation, vomiting, diarrhea, protein-losing enteropathy, hypopigmentation, bone changes, and arterial rupture; the hair is sparse, steely, or kinky.
Diagnosis
Diagnosis is based on low copper and ceruloplasmin levels in serum, although these tests are not always reliable. Because early diagnosis and treatment seem to result in a better prognosis, the disorder is ideally detected before age 2 wk. However, diagnostic accuracy of these tests is limited. Thus, infants at risk (eg, those with a family history) can be screened by measuring dopamine, norepinephrine, dihydroxyphenylacetic acid, and dihydroxyphenylglycol in serum. A dihydroxyphenylacetic acid:dihydroxyphenylglycol ratio of > 4 seems to indicate deficiency, and a dopamine:norepinephrine ratio of > 0.2 seems to confirm it.
Treatment
Parenteral copper is usually given as copper histidine 250 μg sc bid to age 1 yr, then 250 μg sc once/day until age 3 yr; monitoring of kidney function is essential during treatment. Despite early treatment, many children have abnormal neurodevelopment.
Acquired Copper Toxicity
Acquired copper toxicity can result from ingesting or absorbing excess copper (eg, from ingesting an acidic food or beverage that has had prolonged contact with a copper container). Self-limited gastroenteritis with nausea, vomiting, and diarrhea may occur.
More severe toxicity results from ingestion (usually with suicidal intent) of gram quantities of a copper salt (eg, copper sulfate) or from absorption of large amounts through the skin (eg, if compresses saturated with a solution of a copper salt are applied to large areas of burned skin). Hemolytic anemia and anuria can result and may be fatal.
Indian childhood cirrhosis, non-Indian childhood cirrhosis, and idiopathic copper toxicity are probably identical disorders in which excess copper causes cirrhosis. All appear to be caused by ingesting milk that has been boiled or stored in corroded copper or brass vessels. Recent studies suggest that idiopathic copper toxicity may develop only in infants with an unknown genetic defect.
Diagnosis usually requires liver biopsy, which shows Mallory hyalin bodies.
Treatment
For copper toxicity due to ingesting grams of copper, prompt gastric lavage is done. Copper toxicity that causes complications such as hemolytic anemia, anuria, or hepatotoxicity is also treated with either oral penicillamine 250 mg q 6 h to 750 mg q 12 h (1000 to 1500 mg/day in 2 to 4 doses) or dimercaprol 3 to 5 mg/kg IM q 4 h for 2 days, then q 4 to 6 h (see also Table 4: Poisoning: Guidelines for Chelation Therapy and copper salts in Table 8: Poisoning: Symptoms and Treatment of Specific Poisons ). If used early, hemodialysis may be effective. Occasionally, copper toxicity is fatal despite treatment.
Inherited Copper Toxicity
(Wilson's Disease)
Inherited copper toxicity 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 chelation, usually with penicillamine or dimercaprol.
Wilson's disease is a progressive disorder of copper metabolism that affects 1 person in 30,000. 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 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 in Descemet's membrane of the cornea, causing Kayser-Fleischer rings.
Symptoms and Signs
Symptoms usually develop between ages 5 and 40. 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 first 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
Wilson's disease should be suspected in people < 40 with any of the following:
If Wilson's 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's 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's 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
Despite the copper accumulation in the body, serum copper levels are decreased because of the decreased ceruloplasmin levels.
Urinary copper excretion
In Wilson's 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
Because early treatment is most effective, screening is indicated for anyone who has a sibling, cousin, or parent with Wilson's 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 is usually good, unless disease is advanced before treatment begins. Untreated Wilson's disease is fatal, usually by age 30.
Treatment
Continual, lifelong treatment is mandatory regardless of whether symptoms are present. Accumulated copper should be removed with chelating drugs. A low-copper diet (eg, avoiding beef liver, cashews, black-eyed peas, vegetable juice, shellfish, mushrooms, and cocoa) and use of either low-dose chelation therapy or oral zinc can prevent copper from accumulating.
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/d) 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 prevent 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 given with 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's disease and fulminant hepatic failure or severe hepatic insufficiency refractory to drugs.
Last full review/revision August 2008 by Larry E. Johnson, MD, PhD
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