CLINICAL REVIEW: Disorders of Copper Metabolism

The essentials
* Copper is an essential component of many enzymes.
* Absorption of dietary copper mainly takes place in the small intestine.
* Menkes’ syndrome is an inherited X-linked copper deficiency disease.
* Wilson’s disease results in excess copper in the liver, brain, and elsewhere.
* The Institute of Food Research is studying copper regulation and absorption.
1. The need for dietary copper
The fact that copper is an essential element in the human diet is now well-established, but this has not always been the case. In the early 19th century the finding of copper in plant and animal tissues was thought to be due to contamination, either from the environment or in the sampling process. It wasn’t until 1928 that the pioneering work of Hart and his colleagues demonstrated that both copper and iron were necessary for haemoglobin synthesis and the prevention of anaemia.
An essential component
Since then copper has been identified as an essential component of many enzymes, including those involved in antioxidant defence, connective tissue formation and neurological function. Despite its essential nature, copper levels need to be tightly regulated to avoid cellular excess and prevent its participation in reactions that produce oxygen-free radicals.This is important because free radical damage is thought to contribute to the development of cancer and cardiovascular disease.
Sources of copper
Copper is present in nearly all foods at widely varying concentrations, with the richest sources including shellfish, liver, nuts and wholegrain cereals.The latest dietary survey of British adults (The National Diet and Nutrition Survey) was carried out in 2003. This reported that on average 31 per cent of dietary copper intake is supplied by cereals and cereal products. Milk and dairy products are among the poorest sources of copper in the diet.
Factors affecting levels
Factors affecting the copper content of food were published in the Journal of the American Dietetic Association in 1973. It was reported that differences in soil copper levels in association with food processing, such as flour milling and refining, could dramatically alter copper levels.
In one example from the Pune, India, cows’ milk was found to leach copper from the traditional brass storage bowls that were used in cooking. The resulting excess intake of copper led to a high incidence of liver disease that was termed Indian childhood cirrhosis.The problem was approached by a major health education campaign that was carried out between 1984 and 1987. This has virtually eliminated this cause of hepatic damage throughout India.
In the UK, drinking water has historically been considered a potentially valuable source of dietary copper, due to leaching from domestic pipework. It is likely that this will decline considerably as copper pipes are replaced by plastic alternatives.
Key points
*Copper levels in the body need to be tightly regulated.
* The richest sources include shellfish, liver, nuts and wholegrain cereals.
* Milk and dairy products are among the poorest sources of dietary copper.
* In the UK, drinking water has been a valuable source of dietary copper due to leaching from domestic pipes.
2. Absorption, storage and bioavailability
Absorption of dietary copper takes place in the small intestine and to a limited extent in the stomach. After absorption from the gut, it is predominantly bound to albumin and transported to the liver.
The amount of copper absorbed is dependent on a range of dietary factors including iron, zinc and ascorbic acid. These factors suppress absorption, while animal protein and fructose enhance it. But unlike other minerals such as iron and zinc, dietary fibre does not have an inhibitory effect on the absorption of copper.
Whole-body homeostasis
Whole-body copper homeostasis is maintained by a combination of changes in absorptive efficiency from the gastrointestinal tract balanced by the quantity of copper re-excreted back into it. The process of copper absorption can be regulated up or down in response to low and high dietary intakes, but adaptation is more rapid at low copper intakes.
Copper is stored in the liver, and is transported around the body via caeruloplasmin. As well as its role as a transporter of copper, caeruloplasmin is also involved in the release of iron from storage sites in the body. Excretion from the body is mainly achieved by secretion of bile from the gall bladder into the intestinal tract. About 2mg of copper a day is excreted this way.This means that most copper is lost from the body in the faeces. Only negligible amounts are lost in the urine, unless significant renal damage is present.
A recent study (Br J Nutr 2003, 90:161-8) has shown that in adult males, copper homeostasis can be maintained over a wide range of intakes, mainly through changes in endogenous secretion. The precise genetic control mechanisms of copper homeostasis have yet to be defined. More research is needed to establish the exact way in which this regulation is achieved.
Dietary requirements
The factors that affect copper bioavailability from the diet are poorly understood, and coupled with the lack of a sensitive status biomarker it has only been possible to make limited recommendations on dietary requirements.
Current UK guidelines published by the DoH in 1991 suggest a daily intake of 1.2mg of copper for most adults. No additional increase is recommended during pregnancy, but an increment of 0.3mg per day is suggested for breastfeeding mothers to replace that lost in milk secretion.
New molecular biology techniques may identify a novel biomarker of copper status, which would ultimately allow the setting of more specific dietary recommendations.
Key points
* The amount of copper absorbed is dependent on a range of dietary factors.
* Excretion from the body is mainly achieved by secretion of bile from the gall bladder into the intestinal tract.
* Current UK guidelines suggest a daily intake of copper of 1.2mg.
3. Acquired and inherited deficiencies
Acquired copper deficiency in humans is rare and generally results from inadequate dietary intake. The most common symptoms of deficiency are anaemia and poor wound healing. A reduction in the activity of the copper-containing enzyme lysyl oxidase – important for connective tissue formation – can result in muscle weakness and the formation of arterial aneurysms.
Malnourished children and pre-term infants are also at particular risk. People who suffer from a number of malabsorption syndromes are also at risk, as are those with inflammatory bowel disease such as ulcerative colitis.
Menkes’ syndrome
Menkes’ syndrome is an inherited X-linked condition which affects about one in 300,000 live births in the UK.
Patients have low levels of copper in the liver and in serum and,more significantly, deficiencies of the essential copper- containing enzymes including cytochrome-c oxidase and lysyl oxidase, and also of caeruloplasmin. The clinical features include mental retardation, growth retardation and abnormalities in bone formation. Children with this condition also have sparse, steely or kinky hair, and they rarely survive infancy. The diagnosis can be made prenatally in the first trimester by measuring the copper content of the chorionic villi.
The genetic defect lies with a copper transporter called ATP7a. One of its roles is to transport copper out of enterocytes and into the blood stream, but in Menkes’ syndrome it is inactive. The effect of this is that copper is trapped in the gut wall and cannot be released into the circulation.
Intracellular copper metabolism
A range of proteins are thought to be involved in the absorption, transport and intracellular trafficking of copper in the body.
Recent advances in research include the identification of intracellular copper chaperones and also ATP7a and ATP7b, two copper transporters implicated in inherited disorders of copper metabolism.This may lead to new insights into the control mechanisms of copper homeostasis, and perhaps one day a treatment for Menkes’ syndrome, for which there is currently no effective therapy.
Key points
* The symptoms of acquired copper deficiency are anaemia and poorwound healing.
* Menkes’ syndrome affects about one in 300,000 live births in the UK.
* Clinical features include mental retardation, abnormalities in bone formation and sparse, steely hair.
* Children with Menkes’ syndrome rarely survive infancy.
4. Wilson’s disease
Wilson’s disease is a rare autosomal recessive inherited disorder of copper metabolism that causes excessive absorption of copper from the small intestine, and decreased excretion by the liver. The result is excessive deposition of copper in the liver, brain, skin and elsewhere.
The defect is found in the gene for another copper transporter, ATP7b, which is found on chromosome 13. ATP7b is essential for the incorporation of copper into caeruloplasmin, and for the biliary excretion of copper. In Wilson’s disease, ATP7b is unable to incorporate copper into caeruloplasmin for export from the cell.
Patients present during their first decade, or with a neuropsychiatrie disorder in young adults in their late teens or early twenties.
Clinical features
Symptoms of neuropsychiatrie problems include difficulty in speaking, clumsiness, personality changes and excessive salivation. Late manifestations are seen less commonly because of effective treatment, and include spasticity and grand mal seizures. Emotional lability, disinhibition and self-injury are common psychiatric symptoms.
Kayser-Fleischer rings
These are formed by deposition of copper in Descemet’s membrane in the limbus of the cornea. They occur in up to 90 per cent of patients with symptomatic Wilson’s disease, and are usually a greenish gold or brown colour. They are not pathognomic, however, and can occur in some chronic cholestatic disorders.
Osteopaenia may be seen on X-ray, and a degenerative arthropathy causes joint symptoms in up to half of patients. Haematuria, nephrocalcinosis and proteinuria may be found. Kidney stones can also occur.
Physical findings are those to be expected in liver disease, including oesophageal and abdominal varices, jaundice, spider naevi and erythema of the palms.
Diagnosis and treatment
The diagnosis is confirmed by liver biopsy. Copper levels of more than 250g/g dry weight of tissue are diagnostic, even in asymptomatic patients.
Patients should avoid liver, mushrooms, legumes and shellfish. Chelating agents such as D-penicillamine that bind the excess copper are the mainstay of treatment, although there are newer drugs such as trientine available. D-penicillamine has a number of interactions and side-effects, and must be given with pyridoxine.
Key points
* Wilson’s disease is a rare autosomal recessive inherited disorder.
* The defect is found in the gene for a copper transporter, ATP7b.
* Kayser-Fleischer rings are formed by copper in the limbus of the cornea.
* Chelating agents are the mainstay of treatment.
5. Research on copper regulation
The role of copper chaperones
Because of its potential to cause oxidative damage, the existence of free copper in cells is tightly regulated by a group of small proteins known as copper chaperones. These distribute copper to specific compartments within the cell for incorporation into copper- requiring proteins.
Three copper chaperones have been identified to date. One delivers copper to the mitochondria for respiratory function, another delivers copper to the secretory compartment where it supplies copper to the Menkes’ or Wilson’s disease proteins, and a third directly interacts with cytoplasmic copper/zinc-superoxide dismutase. How these chaperones are orchestrated to maintain the critical balance of copper homeostasis and regulate the intracellular trafficking is currently not known.
Institute of Food Research study
A three-year research project, funded by the Biotechnology and Biological Sciences Research Council, is being conducted at the Institute of Food Research in Norwich. It will help in understanding how the human body regulates absorption of copper and maintains the correct balance in the body.
The study involves the use of post-genomic technologies including cell culture techniques. These technologies are complementary and will provide a more complete picture of cellular events.
Human cell lines from the gastrointestinal tract and the liver are being used to determine the response of genes at different levels of exposure to copper and how this might contribute to the control of copper absorption and excretion. A lymphocyte line is also being investigated, as single blood samples would be an ideal source of any novel biomarker that could be identified.
The results will ultimately inform the design of human studies that will investigate the direct effects of dietary copper intake on gene and protein expression in individuals.
Key points
* The existence of free copper in cells is tightly regulated by a group of small proteins known as copper chaperones.
* Three copper chaperones have been identified to date.
* Human cell lines are being studied to investigate the control mechanisms of copper absorption and excretion.
Nuts and wholegrain cereals are foods that are high in copper, milk and dairy products are poor sources
Absorption of copper is mostly in the small intestine
One of the most common problems of copper deficiency is that it may cause failure of wound healing
A Kayser-Fleischer ring is seen in Wilson’s disease
Genomic research is studying copper metabolism
Further resources
Further reading
MMO Pea, J Lee and D J Thiele. ‘A delicate balance: homeostatic control of copper uptake and distribution’. J Nutr 1999, 129:1,251- 60
Websites
See Medicine on the Web, page 40
Previously in Clinical Review
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* Normal variants in orthopaedics (15 April)
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Contributed by Dr Linda Harvey, senior research scientist, micronutrients group, Institute of Food Research, Norwich