Clinical copper deficiency is seen mainly in malnourished and recovering children, in premature babies, in patients receiving total parenteral nutrition (TPN) and as a consequence of malabsorption. Copper deficiency also occurs as the result of Menkes syndrome, a rare inherited defect of copper transport. Malnourished children are reported to be at particular risk of copper deficiency. A diet consisting exclusively or predominantly of cow's milk, with its poor bioavailability of copper, increases the likelihood of copper malabsorption. During nutritional recovery, growth rate can be 5-10 times the normal rate, increasing copper requirements beyond the dietary intake.3 Copper deficiency during this period has been shown to impair growth rate18 and to be associated with increased incidence of respiratory infection.19
Preterm babies are also at particular risk of copper deficiency, for several reasons. Copper stores are acquired late in foetal development, as metallothionein-bound copper accumulates in the foetal hepatocyte nuclei over the last trimester.11 Although neonates appear not to absorb copper well, particularly from highly-refined carbohydrate-based diets or cow's milk20, full-term infants have well-developed copper stores which can be mobilised during the first six months' rapid growth, to supplement dietary intake.21 Full-term infants are therefore independent of dietary intake for the first weeks of life.22 Premature babies, especially those with very low birth-weight, do not have such a resource. They also have higher growth rate than full-term babies, with accordingly higher copper requirements.23
Clinical copper deficiency in adults was unknown until the introduction of TPN, which is now well known to result in elevated urinary copper output and a net depletion of copper status.20 Although copper is now usually added to TPN infusates, it is often withheld from cholestatic patients since their impaired biliary excretion is expected to result in reduced intestinal losses. The complex interactions between disease states and copper metabolism, however, make individuals' requirements difficult to anticipate, and TPN-related copper deficiency continues to occur.24,25
Anumber of malabsorption syndromes have been reported to result in increased intestinal copper losses leading to deficiency. Such conditions include coeliac disease26, cystic fibrosis27, shortened intestine following surgery28, and chronic or recurrent diarrhoea.29,30 Menkes disease is an X-linked recessive disorder of copper metabolism in which mutations in the MNK gene impair copper transport from cells. The disease is manifest as copper deficiency, because although copper is absorbed by gut cells, very little is transported to the tissues where it is required for enzyme function. Symptoms usually appear within the first months of life, and can result in death in early childhood.31 In clinical copper deficiency, the most common defects are: cardiovascular and haematological disorders including iron-resistant anaemia, neutropenia and thrombocytopenia; bone abnormalities including osteoporosis and fractures; and alterations to skin and hair texture and pigmentation.23 Immunological changes have also been indicated.19,32 These changes may be accompanied by depressed serum copper and blood cupro-enzymes, with caeruloplasmin concentrations observed at 30% of normal.6
It has been clearly demonstrated that very many of the changes induced by severe copper deficiency are also risk factors for ischaemic heart disease in humans. Human copper depletion studies have produced impaired glucose clearance,33 blood pressure changes,34 electrocardiographic irregularities and significantly increased LDL cholesterol with decreased HDL cholesterol.21 In copper-deficient animals, cardiovascular disorders observed include lesion and rupture of blood vessels, cardiac enlargement, myocardial degeneration and infarction (MI).33 It has been argued that copper deficiency is the only nutritional deficit known to affect adversely so many risk factors for ischaemic heart disease.35 The proposed link between copper deficiency and cardiovascular disease is supported by data gathered from studies of cardiovascular patients. Post-mortem measurement of tissue copper has revealed lower-than-normal copper concentrations in ischaemic hearts, in the liver and heart of individuals with severe atherosclerosis, and in leucocytes of patients with highly occluded coronary arteries.33
A variety of mechanisms may contribute to the cardiovascular effects of copper deficiency. There is evidence for alterations in the activity of copper-dependent enzymes, increased oxidative stress and damage to biomolecules, and interference with the maintenance of blood pressure. An interaction of these three mechanisms of damage has been proposed to have even further potential for harm,36 which need not be limited to cardiovascular defects. The adverse effects elicited by copper deficiency are numerous and as varied as the roles of copper in health. In the light of this, it has been proposed that long-term sub-clinical copper deficiency may contribute to the pathogenesis of a number of degenerative and inflammatory conditions.37
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