Copper & Disease Prevention

Cardiovascular diseases

While it is clear that severe copper deficiency results in heart abnormalities and damage (cardiomyopathy) in some animal species, the pathology differs from atherosclerotic cardiovascular diseases prevalent in humans. Studies in humans have produced inconsistent results, and their interpretation is hindered by the lack of a reliable marker of copper nutritional status. Outside the body, free copper is known to be a pro-oxidant and is frequently used to produce oxidation of low density lipoprotein (LDL) in the test tube. Recently, the copper-containing protein ceruloplasmin has been found to stimulate LDL oxidation in the test tube, leading some scientists to propose that increased copper levels could increase the risk of atherosclerosis by promoting the oxidation of LDL. However, there is little evidence that copper or ceruloplasmin promotes LDL oxidation in the human body. Additionally, the cuproenzymes, superoxide dismutase and ceruloplasmin, are known to have antioxidant properties, leading some experts to propose that copper deficiency rather than excess copper increases the risk of cardiovascular diseases.

Epidemiologic studies: Several epidemiologic studies have found increased serum copper levels to be associated with increased risk of cardiovascular disease. A recent prospective study in the U.S. examined serum copper levels in more than 4,400 men and women 30 years of age and older. During the following 16 years, 151 participants died from coronary heart disease (CHD). After adjusting for other risk factors of heart disease, those with serum copper levels in the two highest quartiles had a significantly greater risk of dying from CHD. Three other case-control studies conducted in Europe had similar findings. Serum copper largely reflects serum ceruloplasmin, and is not a sensitive indicator of copper nutritional status. Serum ceruloplasmin levels are known to increase by 50% or more under certain conditions of physical stress, such as trauma, inflammation, or disease. Because over 90% of serum copper is carried in ceruloplasmin, elevated serum copper may simply be a marker of the inflammation that accompanies atherosclerosis. In contrast to the serum copper findings, two autopsy studies found copper levels in heart muscle to be lower in patients who died of CHD than those who died of other causes. Additionally, the copper content of white blood cells has been positively correlated with the degree of patency of coronary arteries in CHD patients, and patients with a history of myocardial infarction (MI) had lower concentrations of extracellular superoxide dismutase (SOD) than those without a history of MI.

Experimental studies: While studies in very small numbers of adults fed experimental diets low in copper have demonstrated adverse changes in blood cholesterol levels, including increased total and LDL-cholesterol levels and decreased HDL-cholesterol levels, other studies have not confirmed those results. Copper supplementation of 2-3 mg/day for 4 to 6 weeks did not result in clinically significant changes in cholesterol levels. Recent research has also failed to find evidence that increased copper intake increases oxidative stress. In a multi-center placebo-controlled study, copper supplementation of 3 and 6 mg/day for 6 weeks did not result in increased susceptibility of LDL to oxidation induced outside the body (ex vivo) by copper or peroxynitrite (a reactive nitrogen species). Moreover, supplementation with 3 and 6 mg/day of copper decreased the in vitro oxidizability of red blood cells, indicating that relatively high intakes of copper do not increase the susceptibility of LDL or red blood cells to oxidation.

Summary: Although free copper and ceruloplasmin can promote LDL oxidation in the test tube, there is little evidence that increased dietary copper increases oxidative stress in humans. Increased serum copper levels have been associated with increased cardiovascular disease risk, but the significance of these findings is unclear due to the association between serum ceruloplasmin levels and inflammatory conditions. Clarification of the relationships between copper nutritional status, ceruloplasmin levels, and cardiovascular disease risk requires further research.

Immune system function

Copper is known to play an important role in the development and maintenance of immune system function, but the exact mechanism of its action is not yet known. Neutropenia (abnormally low numbers of white blood cells called neutrophils) is a clinical sign of copper deficiency in humans. Adverse effects of insufficient copper on immune function appear most pronounced in infants. Infants with Menkes disease, a genetic disorder that results in severe copper deficiency, suffer from frequent and severe infections. In a study of 11 malnourished infants with evidence of copper deficiency, the ability of certain white blood cells to engulf pathogens increased significantly after one month of copper supplementation. More recently, 11 men on a low-copper diet (0.66 mg copper/day for 24 days and 0.38 mg/day for another 40 days) showed a decreased proliferation response when white blood cells called mononuclear cells isolated from their blood were presented with an immune challenge in cell culture. While severe copper deficiency has adverse effects on immune function, the effects of marginal copper insufficiency in humans are not yet clear.

Osteoporosis

The copper-dependent enzyme, lysyl oxidase, is required for the maturation (cross-linking) of collagen, a key element in the organic matrix of bone. Osteoporosis has been observed in infants and adults with severe copper deficiency, but it is not clear whether marginal copper deficiency contributes to osteoporosis. Research regarding the role of copper nutritional status in age-related osteoporosis is limited. Serum copper levels of 46 elderly patients with hip fractures were reported to be significantly lower than matched controls. A small study in perimenopausal women, who consumed an average of 1 mg of dietary copper daily, reported decreased loss of bone mineral density (BMD) from the lumbar spine after copper supplementation of 3 mg/day for 2 years. Marginal copper intake of 0.7 mg/day for 6 weeks significantly increased a measurement of bone resorption (breakdown) in healthy adult males. However, copper supplementation of 3 to 6 mg/day for 6 weeks had no effect on biochemical markers of bone resorption or bone formation in a study of healthy adult men and women. Although severe copper deficiency is known to adversely affect bone health, the effects of marginal copper deficiency and copper supplementation on bone metabolism and age-related osteoporosis require further research before conclusions can be drawn.

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