|
About half of ingested copper is absorbed. Copper absorbed in excess of metabolic requirements is excreted through bile. Copper is a component of many body proteins; almost all of the body's copper is bound within 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.
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. Treatment is directed at the deficiency's cause, and copper 1.5 to 3 mg/day po (usually as copper sulfate) is given.
Inherited
Copper Deficiency
Inherited copper deficiency (Menkes' syndrome) 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; arterial rupture; and sparse, steely, or kinky hair. Diagnosis is based on low copper and ceruloplasmin levels, usually in infants < 2 wk old. Parenteral copper (given as cupric sulfate) 20 to 30 mg/kg IV once/day is the usual treatment. However, parenteral copper does not enter the copper-containing enzymes. Copper histidine 100 to 600 mg sc once/day may be more effective; monitoring is essential during treatment.
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 followed by daily IM injections of at least 300 mg of dimercaprol may prevent death. The chelating drug penicillamine binds copper, facilitating its excretion. Doses of 1 to 4 g/day po may promote excretion of copper absorbed from burned skin (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.
For Indian childhood cirrhosis, treatment with penicillamine may be curative.
Inherited
Copper Toxicity
Inherited
copper toxicity (Wilson's 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 chelation, usually with penicillamine.
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
Beginning at birth, copper accumulates in the liver. Serum levels of the copper protein ceruloplasmin decrease. Hepatic fibrosis develops, ultimately producing 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.
Symptoms and Signs
Symptoms usually develop between ages 6 and 30. 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. Sensory disturbances do not occur. Sometimes the first symptoms are behavioral or cognitive 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 a person < 40 with any of the following: an otherwise unexplained hepatic, neurologic, or psychiatric disorder; an otherwise unexplained persistent elevation in hepatic transaminase; a sibling, parent, or cousin with Wilson's disease; or fulminant hepatitis and Coombs'-negative hemolytic anemia (see Anemias Caused by Hemolysis: Diagnosis).
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.
Serum ceruloplasmin (normally 20 to 35 mg/dL) is usually low in Wilson's disease but can be normal. It can also be falsely low, particularly in heterozygous carriers. 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. If it does not, biopsy to measure hepatic copper concentration is necessary.
A low ceruloplasmin level usually means that total serum copper is low. However, the free (unbound) copper level is usually increased. Free copper can be calculated by subtracting the amount of copper in ceruloplasmin from total serum copper, or it can be measured directly.
Kayser-Fleischer rings rarely occur in other liver disorders (eg, biliary atresia, primary biliary cirrhosis). However, Kayser-Fleischer rings combined with typical motor neurologic abnormalities or a decrease in ceruloplasmin are nearly pathognomonic for Wilson's disease.
In Wilson's disease, urinary copper excretion (normally, ≤ 30 μg/day) is usually > 100 μg/day. Administration of penicillamine 500 mg po tid or qid increases excretion to > 1200 μg/day in patients with Wilson's disease but to < 500 μg/day in patients without Wilson's disease. In borderline cases, the diagnosis is made by detecting a decreased incorporation of radioactive copper into ceruloplasmin.
Hepatic copper concentration (normally, < 50 μg/g dry weight) is usually > 250 μg/g dry weight in patients with Wilson's disease. 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).
The serum uric acid level may be low because its excretion in urine is increased.
Treatment
Continual, lifelong treatment is mandatory regardless of whether symptoms are present. Accumulated copper should be removed with chelating drugs. Copper accumulation should be prevented by a low copper diet (eg, avoiding beef liver, cashews, black-eyed peas, vegetable juice, shellfish, mushrooms, and cocoa) and by either low-dose chelation therapy or oral zinc.
Penicillamine is the chelating drug of choice. Patients aged > 5 yr receive 500 mg po tid or qid on an empty stomach (> 1 h before meals and at bedtime). Younger children receive 50 mg/kg po qid. Occasionally, use of penicillamine is associated with worsening neurologic symptoms. Pyridoxine 25 mg po once/day is given with penicillamine .
Trientine hydrochloride is less potent than penicillamine . It is started immediately at 500 mg po bid, given on an empty stomach, if penicillamine is discontinued because of an adverse effect.
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.
Ammonium tetrathiomolybdate has an evolving role. It decreases copper absorption, binds with plasma copper, and is relatively nontoxic. It is particularly useful for neurologic symptoms because, unlike penicillamine , it does not appear to worsen neurologic symptoms during treatment.
Liver transplantation may be lifesaving for patients who have Wilson's disease with fulminant hepatic failure or severe hepatic insufficiency unresponsive to drugs.
Prognosis and
Screening
Prognosis is usually good, unless disease is advanced before treatment begins. Untreated Wilson's disease is fatal, usually by age 30.
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, liver function tests, and measurement of 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 not feasible.
Last full review/revision November 2005
Content last modified November 2005
| 
