Copper is now well established as an essential trace element; the estimated safe and adequate adult daily intake is 2.5 – 3 mg/day (39 -47 µmol). Copper – containing metalloenzymes are important in iron and catecholamine metabolism, haemoglobin, elastin and collagen synthesis and free radical scavenging. About 30% of ingested copper is absorbed in the intestine, bound to albumin and transported to the liver, where it is stored. The major circulating form is the blue glycoprotein, caeruloplasmin, synthesised in the liver, which contains 6 – 8 atoms of copper per molecule. The functions of this protein are still unclear, but it is important in iron metabolism as a ferroxidase and may have a role in regulating copper transport. It is an acute phase reactant and can increase greatly in response to infection, injury, chronic inflammatory conditions or steroid hormones (pregnancy, certain contraceptive pills and oestrogen therapy). Serum copper and caeruloplasmin are both increased in these circumstances, as caeruloplasmin normally carries about 95% of the circulating copper. Excess copper is excreted in the bile, only small amounts being found in urine, unless renal damage is present, or substances which bind copper are excreted.
Copper deficiency presents as a microcytic hypochromic anaemia with marked neutropenia, which is resistant to iron therapy. Children and neonates on diets deficient in copper have ineffective collagen synthesis, and may develop bone disease. As the liver contains substantial stores of copper, frank clinical copper deficiency is unusual, but has been reported in malnourished children and in adults on long term parenteral nutrition. Reduced copper absorption is common in diarrhoea and when zinc intake is increased. Subclinical copper deficiency may be more widespread then previously thought and has been suggested as a risk factor for cardiovascular disease through reduced antioxidant activity altered lipoprotein and catecholamine metabolism and vascular changes. The rare sex linked recessive disorder, Menkes ‘steely hair’ disease, is characterised by a failure of copper transport across the intestinal mucosa. The hair changes are similar to those occurring in copper deficient sheep. Although copper levels are low in brain and liver, copper accumulates in many tissues of the body. The intake into cells appears to be normal but there is defective utilisation intracellularly. The condition is therefore one of functional copper deficiency as a result of impaired function of copper dependent enzymes. Patients show mental retardation, depigmentation, severe anaemia, hypotonia and scorbutic changes in bone. Serum copper and caeruloplasmin concentrations are extremely low; intravenous treatment with copper histidine may be effective if initiated early in life. Diagnosis can be confirmed by measuring the accumulation of copper in cultured fibroblasts from skin biopsy, or prenatally, by measuring the copper content of chorionic villi in the first trimester.
Wilson’s disease (hepatolenticular degeneration) is an autosomal recessive disorder, the frequency being of the order of 1 in 100,000 live births. Copper cannot be excreted via the bile, or incorporated into caeruloplasmin, and consequently accumulates within the liver. Later it is probable that the copper ‘overflows’ and accumulates more slowly in other tissues, especially the brain. The classical presentation is of adults with progressive neurological symptoms, low serum concentrations of copper and caeruloplasmin, raised urinary copper excretion, and characteristic copper deposits in the corneas (Kayser-Fleischer rings). It is now recognised that children and adolescents frequently present with a variety of hepatic symptoms including fulminant hepatic failure.
Depending on the stage of the disorder, plasma copper may be normal or even increased, as in acute hepatic conditions, and caeruloplasmin, an acute phase reactant, normal. Measurement of the liver copper content, or of the urinary output of copper following a penicillamine challenge may be necessary to diagnose difficult cases.
Acute ingestion of copper salts produces nausea, vomiting, diarrhoea, circulatory collapse and intravascular haemolysis. Cases have been reported following the ingestion of copper sulphate solutions, either deliberately or by accident; in patients on maintenance haemodialysis following leaching of the element from copper containing dialysis membranes (Cuprophan); inhalation of fumes from the burning of chromate-copper-arsenic (CCA) treated wood; use of Bordeaux mixture for crop spraying. In situations of acute toxicity serum copper concentration will be high, but the caeruloplasmin concentration will be normal.
Chronic poisoning with copper leads to gross hepatic copper overload with severe liver disease in young children. Indian childhood cirrhosis has been ascribed to storage of milk in copper vessels and there are reports of poisoning in young children as a result of high copper content in well water. Liver copper content in such cases can exceed that found in overload due to Wilson’s disease but the storage mechanisms and histological appearance will be different.
The copper content of betel nuts has been suggested as the causative agent for the oral fibrosis found in habitual chewers of this fruit.
Laboratory Indices of Copper Status
Some of the problems of interpreting the serum copper concentration, particularly in the diagnosis of Wilson’s disease, have been mentioned above. It is always advisable to measure serum copper and caeruloplasmin and the urinary copper excretion. ‘Free’ or non-caeruloplasmin copper can be derived from the serum measurements. This increases as Wilson’s disease progresses, but is also raised in other liver disorders. It is of diagnostic value in fulminant hepatic failure due to Wilson’s disease and in copper poisoning. Measuring urinary copper excretion before and during administration of 2 x 500 mg oral doses of penicillamine at 12 hour intervals can help to distinguish children with Wilson’s disease (over 25 µmol/24h post penicillamine) from those with liver disease due to other causes. Determination of copper content and the histological examination of a needle biopsy of liver is frequently of value in establishing the diagnosis. However, bile is a major copper excretion route and biliary impairment in other liver conditions, such as primary biliary cirrhosis, may result in elevated liver copper.
In neonates, serum copper and caeruloplasmin levels are low and rise during the early weeks of life, reaching adult levels after 1 to 2 years. This makes the diagnosis of Wilson’s disease difficult during the first six months. Copper concentrations which fail to rise above 5 µmol/L after the first few weeks may indicate copper deficiency.
Copper deficiency may be masked by increased caeruloplasmin synthesis as part of an ‘acute phase’ response to infection, injury or chronic inflammatory disease. The degree of such a response should be considered. An increase in caeruloplasmin following copper supplementation may be a method for confirming deficiency.
Liver Biopsies (or other tissues) for Copper Determination.
Protocol for collection and transport is given in the COPPER – yellow pages.
Danks DM. Disorders of copper transport. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic Basis of Inherited Disease, 7th edn. New York: McGraw-Hill, 1995: 2211-35
Taylor A. Detection and monitoring for disorders of essential trace elements. Annals of Clinical Biochemistry 1996; 33: 486-510