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Contents
Copper (Cu) is an essential trace element for humans and other mammals. In biological systems, copper readily shifts between the cuprous (Cu1+) and cupric (Cu2+) forms. The redox properties of copper underlie its important role in oxidation-reduction reactions and in scavenging free radicals (1). Although Hippocrates is said to have prescribed copper compounds to treat diseases as early as 400 B.C. (2), scientists are still uncovering new information regarding the functions of copper in the human body (3).
Copper is critical for the function of several essential enzymes known as cuproenzymes, which are integral parts of various metabolic pathways (4, 5). Physiologic functions of these copper-dependent enzymes, and the biochemical pathways in which they function (6, 7), are outlined below.
The copper-dependent enzyme cytochrome c oxidase (CCO) plays a critical role in cellular energy production in mitochondria by catalyzing the reduction of molecular oxygen (O2) to water (H2O), thereby generating an electrical gradient that is required for ATP production (8). Redox-active copper contained within the CCO enzyme complex is required for the electron transfer reactions that are critical for its function.
Another cuproenzyme, lysyl oxidase (LOX), is required for the cross-linking of collagen and elastin fibers, which is essential for the formation of strong and flexible connective tissue. LOX function is critical for bone formation and maintenance of connective tissue in the heart and blood vessels (2).
Multi-copper oxidases (MCOs) are copper-dependent ferroxidases that function in iron homeostasis. MCOs oxidize ferrous iron (Fe2+) to the ferric (Fe3+) form, which enables binding to transferrin (the main iron carrier) in the blood, thus allowing iron transport to sites of utilization (e.g., the bone marrow). The MCOs include: (1) ceruloplasmin (CP), which contains 60%-95% of plasma copper; (2) a membrane-bound form of CP (GPI-CP), expressed in brain and other tissues; and (3) the membrane-bound ferroxidases hephaestin (HEPH) and zyklopen, which function in the intestine and placenta, respectively (9, 10). CP knockout (Cp-/-) mice accumulate excess hepatic iron but have normal copper status (11, 12). Similarly, humans with aceruloplasminemia, who lack functional CP, display iron overload in liver, brain, and retina but have no observable defects in copper homeostasis (13). Moreover, absorption of dietary iron and iron mobilization from storage sites (e.g., liver) are impaired in copper deficiency, when CP and HEPH activity is reduced, further supporting a role for the MCOs in iron metabolism (14).
Several physiological processes within the brain and nervous system, including neurotransmitter synthesis and formation and maintenance of myelin, depend upon catalysis mediated by cuproenzymes. Dopamine β-hydroxylase, for example, catalyzes the conversion of dopamine to the neurotransmitter norepinephrine (15). Also, CCO is required for the biosynthesis of phospholipids, which are critical structural components of the myelin sheath (2).
The cuproenzyme tyrosinase (TYR) is required for the biosynthesis of melanin in melanocytes, which is critical for normal pigmentation of hair, skin, and eyes (2). Low TYR activity most likely explains the achromotrichia seen in copper-deficient laboratory and agricultural animals, and the depigmentation noted in severely copper-depleted patients with Menkes disease.
Superoxide dismutase (SOD) functions as an antioxidant by catalyzing the conversion of reactive oxygen species, such as the superoxide anion (O2-) and the hydroxyl radical (•OH), to hydrogen peroxide (H2O2), which is subsequently reduced to water by other antioxidant systems (16). Two forms of SOD contain copper: copper/zinc SOD (SOD1), which is expressed in most cells, including red blood cells; and extracellular SOD (EcSOD), which is highly expressed in the lungs and found at lower levels in plasma (2). Also, as outlined above, ceruloplasmin has antioxidant properties relating to iron metabolism. The ferroxidase activity of ceruloplasmin may prevent ferrous iron (Fe2+) from participating in harmful free-radical-generating reactions via Fenton chemistry (16).
Copper-related gene expression pathways seem to be mainly regulated at a post-translation level, in some cases via protein trafficking-related mechanisms that respond to intracellular copper levels (17). Cytosolic copper may also influence mRNA expression levels of specific genes, in a dose-dependent manner (18-20), implicating possible transcriptional regulation. For example, intracellular copper may alter the redox state of cells and thus induce oxidative stress, which can activate signal transduction pathways that increase the expression of genes encoding proteins involved in the detoxification of reactive oxygen species (21).
Adequate copper nutritional status is necessary for normal iron metabolism and red blood cell production and function. Copper depletion results in an iron deficiency-like anemia, and iron accumulates in the livers of copper-deficient animals. The development of anemia during copper deficiency may be linked to low CP activity, impaired iron release from stores in the liver, and reduced iron delivery to the erythroid marrow, thus leading to iron-restricted erythropoiesis (see Iron metabolism) (2). However, this may not be the whole story, as was recently suggested by longtime copper researcher, Dr. Joseph R. Prohaska (Univ. of Minnesota, Duluth) (22). Copper depletion also reduces CP activity in humans, leading to hepatic iron overload and thus increasing risk for oxidative damage and liver cirrhosis (14). Oral copper supplementation restored normal serum CP levels and plasma ferroxidase activity, and corrected iron metabolism defects in a copper-deficient subject (23). Moreover, infants fed a formula with a high-iron content absorbed less copper than infants fed a low-iron formulation, suggesting that high iron intakes may interfere with copper absorption in infants (24). This observation was also confirmed in rats and mice, where high dietary iron caused copper depletion, thus increasing the copper nutritional requirement (25, 26).
Excess intake of supplemental zinc, at doses of 50 mg/day or more for extended periods of time, may result in copper depletion. The mechanism may relate to increased synthesis of metallothionein (MT), an intracellular zinc- and copper-binding protein. MT has a stronger affinity for copper than zinc, so high levels of MT induced by excess zinc may trap copper within enterocytes thus limiting its bioavailability. This postulate, however, was called into question by studies done in MT-deficient mice, in which high enteral zinc still decreased copper absorption, suggesting that high zinc may block a copper transporter (27). Conversely, elevated copper intakes have not been found to affect zinc nutritional status (2, 24). Moreover, zinc supplementation at 10 mg/day for eight weeks restored normal plasma copper/zinc ratios in 65 subjects on long-term hemodialysis who initially exhibited low serum zinc and high copper. Whether improving zinc and copper status of hemodialysis patients can impact clinical outcomes, however, needs to be assessed (28).
Evidence of copper-fructose interactions comes mainly from studies using experimental animals. High-fructose diets exacerbated copper deficiency in male rats, but not in pigs whose gastrointestinal system is anatomically and functionally more like humans. Also, very high levels of dietary fructose (20% of total calories) did not result in copper depletion in humans, suggesting that fructose intake does not result in copper depletion at levels relevant to normal diets (2, 24). However, high fructose consumption and low copper availability may be risk factors for functional copper deficiency in patients with non-alcoholic fatty liver disease (29).
Although vitamin C supplements have produced copper deficiency in guinea pigs (30), the effect of vitamin C supplementation on copper nutritional status in humans is less clear. Two small studies in healthy, young adult men indicated that ceruloplasmin oxidase activity may be impaired by relatively high doses of supplemental vitamin C. In one study, vitamin C intakes of 1,500 mg/day for two months resulted in a significant decline in CP oxidase activity (31). In the other study, supplements of 605 mg/day of vitamin C for three weeks resulted in decreased CP oxidase activity, although copper absorption did not decline (32). Neither of these studies found vitamin C supplementation to adversely affect copper nutritional status.
Clinically evident, or frank, dietary copper deficiency is relatively uncommon. Serum copper and CP levels may fall to 30% of normal in cases of severe copper deficiency. Hypocupremia is also observed in genetic disorders of copper metabolism, including Wilson disease (WD) and aceruloplasminemia; however, neither disorder has been linked to low dietary copper intake. One of the most common clinical signs of copper deficiency is an anemia that is unresponsive to iron therapy but is corrected by copper supplementation. It was hypothesized that this anemia could result from defective iron mobilization due to decreased CP activity, yet individuals with inherited aceruloplasminemia do not always develop overt anemia (33). Moreover, in copper-deficient swine, intestinal iron absorption is impaired but iron distribution among tissues/organs is normal (34-36). Low serum iron from reduced absorption is an unlikely cause of this anemia since intravenous provision of iron did not correct it. An alternative postulate is that copper-deficiency anemia is caused principally by impaired hemoglobin production and red blood cell proliferation, and a shortened erythrocyte lifespan. These physiological processes are thus likely to require copper. Copper deficiency may also lead to neutropenia, which can increase susceptibility to infection. Copper depletion studies demonstrated that low copper might affect erythroid and myeloid cell lineages, supporting a role for copper in the regulation of blood cell proliferation and maturation (37, 38). More research is clearly needed to further define the mechanisms underlying copper deficiency-induced anemia and neutropenia (4, 39). Furthermore, osteoporosis and other abnormalities of bone development have been described in copper-deficient, low-birth-weight infants and young children. Less common features of copper deficiency may include impaired growth, depigmentation, and development of neurological pathologies (2, 8).
Currently, there is not a sensitive and specific biomarker to detect copper inadequacy in humans (5, 40-42). Blood copper (43) and ceruloplasmin concentrations are reduced in severe copper deficiency (3, 6). However, both of these parameters are also influenced by pregnancy, inflammation, and infection (5), thus limiting the usefulness of these assays to estimate body copper status. Experimental work has recently identified other copper-related biomarkers, including erythrocyte copper Cu/Zn superoxide dismutase (SOD1) and copper chaperone for superoxide dismutase (44-46), but further experimental validation is required, including clinical testing in humans.
Bovine milk is relatively low in copper, and cases of copper deficiency have been reported in infants fed only cow's milk formula (47). Other individuals at elevated risk for copper deficiency include premature and low-birth-weight infants; individuals with severe burns (48) or prolonged diarrhea, which accelerate copper losses; infants and children recovering from malnutrition; and individuals with malabsorption syndromes, including celiac disease, Crohn’s disease, and short bowel syndrome, possibly due to surgical removal of large portions of the intestine (48-50). Also, gastric bypass surgery for morbid obesity significantly increases the risk for copper depletion (51-53). Individuals receiving intravenous total parenteral nutrition lacking copper or those on certain restricted diets may also require supplementation with copper (and other trace elements) (2, 8). Moreover, copper deficiency in infants with cholestasis has been linked to long-term parenteral nutrition lacking copper (54). Case reports indicated that cystic fibrosis patients may also be at increased risk of copper insufficiency (55, 56). And finally, excessive zinc intake has been associated with secondary copper deficiency in individuals taking zinc supplements or using zinc-enriched dental creams (57-59).
Copper deficiency is atypical in the general population; however, it was recently suggested that copper deficiency may be more widespread than currently recognized, and that (covert) pathophysiological links exist between low copper nutritional status and Alzheimer’s disease, ischemic heart disease (60), myelodysplastic syndrome, and postmenopausal osteoporosis (61). Part of the rationale for such an assertion relates to the difficulty in clinically evaluating the copper status of humans, so moderate to even severe copper deficiency is unlikely to be detected in individuals with no notable risk factors (62). Firmly establishing links between low copper status and increased risk for these, and possibly other, chronic diseases awaits further epidemiological and clinical testing. Furthermore, a neurological syndrome associated with copper deficiency was recently described in adults (63). The symptoms included central nervous system demyelination, polyneuropathy, myelopathy, and inflammation of the optic nerve. The etiology is unknown and risk factors have not been established (see Individuals at risk of deficiency). Case reports suggested that copper malabsorption underlies this disorder, but mutations in the gene encoding the main intestinal copper exporter, ATP7A, were not detected in affected patients (see Inherited copper deficiency) (64). Oral copper supplementation (2 mg/day) normalized serum copper and CP concentrations, and stabilized individuals afflicted with the disease and significantly improved their quality of life. Optimal duration and dose of copper administration has not, however, been experimentally evaluated (63).
ATPase copper transporting alpha, or ATP7A, is a dual function Cu1+-transporting ATPase that is expressed in most cell types, except for, notably, hepatocytes. ATP7A transports copper from the cytosol into the trans-Golgi (TGN), where cuproenzymes are synthesized within the secretory pathway, and exports copper from cells. Mutations in ATP7A, which underlie Menkes disease (MD), critically block copper export from enterocytes and vascular endothelial cells (65). Impaired absorption of dietary copper results in systemic copper deficiency in MD. Decreased cuproenzyme expression/activity is caused by low intracellular copper, and defective copper transport into the TGN. Copper accumulation in microvascular endothelial cells in the blood-brain barrier reduces copper transport into the brain, leading to low brain copper and reduced cuproenzyme activity in neurons. Other mutations in ATP7A have been linked to a less severe neurological copper deficiency disorder called occipital horn syndrome (OHS). The clinical features of MD include intractable seizures, connective tissue disorders, subdural hemorrhage, and hair abnormalities (so called "kinky hair"). OHS patients exhibit muscular hypotonia and connective tissue abnormalities, including formation of exostoses on occipital bones. Subcutaneous injections of copper-histidine improve copper-related metabolic functions in MD and OHS patients. Copper entry into the brain, however, remains limited (reviewed in 66). Furthermore, gene therapy approaches have been recently validated in a pre-clinical mouse model of MD, with long-term goals of using such treatments in humans with the disease (67, 68). Recently, another inherited copper-deficiency disorder was described in identical twin male infants, who were homozygous for a novel missense variant in the gene encoding copper transporter 1 (CTR1) (69). This genetic aberration caused a distinctive autosomal recessive syndrome of infantile seizures and neurodegeneration, consistent with profound central nervous system copper deficiency. Disease pathology was most likely caused by defective intestinal copper transport which resulted in severe systemic copper deficiency. This outcome is supported by experimental laboratory studies which demonstrated that intestine-specific ablation (deletion) of CTR1 significantly impaired absorption of dietary copper in mice (70).
Patients with Wilson disease (WD) may have increased risk for copper toxicosis even at copper intakes in the normal range. WD is an autosomal recessive disorder that is typified by defective copper distribution and storage (71). The disease is caused by mutations in the ATP7B gene, which encodes a copper-transporting ATPase that is highly expressed in liver and brain. Dysfunctional ATP7B disrupts copper flux in these organs. A recent review provides a nice summary of this devastating human disease (72). WD prevalence is ~1:30,000 individuals globally (73), although much higher prevalence rates have been reported. It was suggested that differences in the penetrance of disease-causing genetic variants explain the apparent discrepancy between epidemiological and genetic prevalence studies of WD (74).
In WD, redox-active copper accumulates in liver, brain, and cornea due to impaired ATP7B-mediated copper excretion, which increases oxidative stress leading to eventual tissue and organ damage. Untreated WD patients are likely to develop liver damage, cancer, and eventual hepatic failure, and severe hemolytic crisis. Elevated brain copper content can lead to neurological damage, and copper accumulation in the eye in so-called Kayser-Fleisher rings can result in abnormal eye movements. Blood concentrations of ceruloplasmin are characteristically low in WD patients, since hepatic ATP7B is required for its biosynthesis, and urinary copper losses may be enhanced. Early intervention can prevent development of some of the most severe pathophysiological outcomes. Treatments for WD include zinc supplementation, which attenuates enteral copper absorption, and/or copper chelation therapy with penicillamine or trientine (75).
Additional pathologies associated with liver copper loading include Indian childhood cirrhosis (ICC) and idiopathic copper toxicosis (ICT). In ICC, notable liver copper loading and progressive liver failure are observed (76). In contrast to Wilson disease when ceruloplasmin is low, in ICC, ceruloplasmin is normal or elevated. ICC is most likely caused by inadvertent excess copper ingestion, possibly from the use of copper-lined, food/beverage storage containers in a genetically susceptible individual. It seems likely that the unknown genetic defect in ICC relates to the efficiency of excretion of excess copper in the bile, but this has not been definitively established. Also, about one-third of ICC patients have α-1-antitrypsin deficiency, which calls into question a primary role for copper in disease outcomes (77). ICT is another hepatic copper overload disorder that predominantly afflicts infants and children. ICT displays autosomal recessive inheritance, and an unidentified genetic aberration results in defective copper metabolism leading to an increased susceptibility to excess copper. Affected individuals are at increased risk for copper-related, hepatic toxicosis due to inadvertent consumption of excess copper. However, the source of extra copper remains unidentified in many ICT patients, perhaps suggesting a more complex disease pathogenesis (78).
A variety of bioindicators were used to establish the RDA for copper, including plasma copper concentration, serum ceruloplasmin activity, superoxide dismutase activity in red blood cells, and platelet copper concentration (24). However, whether these are accurate and sensitive biomarkers of copper nutritional status uncertain (40). Also, estimates of copper concentrations in various foods and water sources may not be accurate and reliable (40, 62). The RDA for copper reflects the results of depletion-repletion studies and is based on the prevention of deficiency (Table 1). For infants up to one year of age, an adequate intake (AI) was established due to the lack of experimental evidence to set a requirement.
| Life Stage | Age Range | Males (μg/day) | Females (μg/day) |
|---|---|---|---|
| Infants | 0-6 months | 200 (AI) | 200 (AI) |
| Infants | 7-12 months | 220 (AI) | 220 (AI) |
| Children | 1-3 years | 340 | 340 |
| Children | 4-8 years | 440 | 440 |
| Children | 9-13 years | 700 | 700 |
| Adolescents | 14-18 years | 890 | 890 |
| Adults | ≥19 years | 900 | 900 |
| Pregnancy | all ages | - | 1,000 |
| Breast-feeding | all ages | - | 1,300 |
Severe copper deficiency results in cardiomyopathy in some animal species (79); however, this pathology differs from the atherosclerotic cardiovascular disease that is prevalent in humans (24). Outcomes of cardiovascular disease (CVD)-related clinical studies in humans are inconsistent, possibly since the copper status of participants is uncertain given the lack of reliable biomarkers of copper nutritional status. Ionic copper is a pro-oxidant, and it can oxidize low-density lipoprotein (LDL) in the test tube. CP can also stimulate LDL oxidation in the laboratory setting (80). As such, some researchers have proposed that excess copper could increase the risk for developing atherosclerosis by promoting the oxidation of LDL in vivo. However, there is scant experimental evidence to support this possibility. Moreover, superoxide dismutase and ceruloplasmin have known antioxidant properties, leading some experts to propose that copper deficiency, rather than copper excess, increases the risk for cardiomyopathy (81, 82). Outcomes of observational and intervention studies relating copper nutritional status to relative risk for CVD are summarized below.
Observational studies have linked elevated serum copper levels to an increased risk for developing CVD. For example, a prospective cohort study examined serum copper levels in more than 4,500 men and women 30 years of age and older in the United States (83). During the subsequent 16 years, 151 participants died from coronary heart disease (CHD). After adjusting for other risk factors, those with serum copper levels in the two highest quartiles had a significantly greater risk of dying from CHD. Case-control studies conducted in Europe also had similar outcomes. For example, a case-cohort study of 2,087 adults in Germany reported an association between higher serum copper concentrations and increased risk of incident CVD, including myocardial infarction and stroke (84). Another study in 60 patients with chronic heart failure or ischemic heart disease reported that serum copper was a predictor of short-term outcomes (85). Higher serum copper was also linked to an increased risk of heart failure in a prospective cohort study of 1,866 middle-aged and older men in Finland (86). Another prospective cohort study in 4,035 middle-aged men in France reported that high serum copper levels were significantly related to a 50% increase in all-cause mortality; however, serum copper was not significantly associated with CVD mortality in this study (87). Serum copper was also elevated in patients with rheumatic heart disease (88). In sum, these studies may indicate that high serum copper reflects elevated body copper content, which increases oxidative stress and accelerates tissue/organ damage and disease development. Importantly, however, most copper in the serum is contained within CP, up to 90% depending upon the species, with the remaining, smaller proportion of serum copper bound to albumin or α2-macroglobulin (89, 90). Serum CP is an acute-phase reactant protein, with levels increasing by up to 50% as a result of trauma or infection and during chronic inflammatory states. Changes in circulating CP are associated with proportional changes in serum copper levels, independent of body copper status. Therefore, elevated serum copper in CHD patients may simply reflect increased CP production due to the inflammation that typifies atherosclerosis. Collectively, these observations raise concerns about linking elevated serum copper to increased tissue copper content and chronic disease development in humans (91).
In contrast to the observational findings discussed above linking high serum copper levels to heart disease, two autopsy studies found copper levels in cardiac muscle were actually lower in patients who died of CHD than in those who died of other causes (92). Additionally, the copper content of white blood cells has been positively correlated with the degree of patency of coronary arteries in CHD patients (93, 94). Further, patients with a history of myocardial infarction (MI) had lower concentrations of copper-dependent, extracellular superoxide dismutase than those without a history of MI (95). Thus, due to the lack of specific, reliable biomarkers of copper nutritional status, it is not clear whether copper is related to cardiovascular disease. It is also important to note that altered copper metabolism may be symptomatic of a cardiovascular condition, rather than a factor that primarily influences its development.
Studies examining dietary intake of copper are scarce. In a prospective cohort study in Japan, which included 58,646 participants followed for a median of 19 years, dietary copper intake — measured by a food frequency questionnaire — was not associated with CHD mortality (96). Yet, this study associated higher copper intakes with an increased risk of mortality from stroke and other cardiovascular diseases (96).
Notably, it was suggested that elevated plasma copper concentrations could be linked to high circulating homocysteine levels in individuals with cardiovascular disease (97-99). Increased blood homocysteine may precipitate development of arterial wall lesions and increase risk of CVD (100); however, this matter is currently open to debate (101). In animal models, copper-homocysteine interactions were linked to impaired vascular endothelial function (102, 103). Copper restriction in experimental animals decreased homocysteine levels and reduced incidence of atherogenic lesions (104, 105), but it is not known whether copper imbalance contributes to a possible atherogenic effect of homocysteine in humans (106).
Small studies in adults deprived of dietary copper documented adverse changes in blood cholesterol, including increased total and LDL cholesterol concentrations and decreased HDL cholesterol concentrations (107), but these outcomes were not confirmed in other studies (108). For example, in one recent study, copper supplementation of 2 to 3 mg/day for 4 to 8 weeks did not result in clinically significant changes in blood cholesterol levels (81, 109, 110). Additionally, 8 mg/day of copper for six months had no effect on blood cholesterol levels (111). Interpretation of these outcomes is, however, challenging since the copper status of participants was presumably not well defined. Additional research failed to link increased copper intake to elevated oxidative stress. In a multi-center, placebo-controlled clinical trial, copper supplementation of 3 or 6 mg/day for six weeks did not result in increased susceptibility of LDL to oxidation by copper (112). Moreover, supplementation with 3 or 6 mg/day of copper did not increase oxidative damage to red blood cells (113). Collectively, these studies indicated that copper intakes several times above the RDA do not increase oxidative stress, at least as measured by these assays in these populations.
Although free copper and CP can promote LDL oxidation in the laboratory, there is little evidence that high dietary copper increases oxidative stress in the human body. Increased serum copper levels have been associated with increased CVD risk, as outlined above, but the significance of these findings is unclear due to the complex association among serum copper, CP, and inflammatory mediators. Clarification of the relationships of copper intake, copper nutritional status, CP levels, and CVD risk thus requires further research.
Copper is known to play several important roles in the development and maintenance of immune system function, including innate and adaptive immunity (reviewed in 114). Neutropenia is a clinical sign of copper deficiency in humans. Adverse effects of insufficient copper on immune system function appear most pronounced in infants. For example, infants with Menkes disease, a genetic copper-deficiency disorder, suffer from frequent and severe infections (115, 116). Moreover, in a study of 11 malnourished infants with evidence of copper deficiency, the ability of white blood cells to engulf pathogens increased significantly after one month of copper supplementation (117). Moreover, 11 men on a low-copper diet (0.66 mg/day of copper for 24 days and 0.38 mg/day for another 40 days) showed an impaired monocyte proliferative response in an ex vivo immune challenge assay (118). Mechanistic studies also support a role for copper in the innate immune response to bacterial and viral infections (reviewed in 119, 120). Severe copper deficiency thus has adverse effects on immune system function; however, whether marginal copper insufficiency impairs immunity in humans has not been established.
Progressive decrease of bone mineral density (BMD) is commonly observed in the elderly, frequently leading to development of osteopenia (pre-osteoporosis) and osteoporosis. Women are more often affected by osteoporosis than men, (e.g., prevalence ratio is 5:1 in non-Hispanic whites) (121), primarily due to the postmenopausal reduction in the production of estrogen, which is essential for maintaining strength of muscle, bone, and connective tissue (122). Osteoporosis is associated with an increased risk of falls, bone fracture, and mortality in individuals over 65 years of age (123).
Osteoporosis has been reported in infants with severe copper deficiency (124, 125), but how copper depletion affects bone and connective tissue health in adults is less certain. One recent investigation documented bone resorption (breakdown) in 11 healthy adult males consuming marginal copper for six weeks (0.7 mg/day) (126). Also, supplementation of 3 to 6 mg/day of copper for six weeks had no effect on biochemical markers of bone resorption or bone formation in two studies of healthy adult men and women (127, 128). An effect of copper deficiency on bone integrity seems likely, since a copper-dependent enzyme, lysyl oxidase (LOX), is required for the maturation (cross-linking) of collagen, a key element in the organic matrix of bone. In individuals with marginal copper intake and less efficient copper absorption, such as the elderly, it seems plausible that LOX activity is decreased, possibly increasing risk for bone and connective tissue effects.
Collectively, research examining the role of copper nutritional status in age-related osteoporosis is limited. An early study found that serum copper levels in 46 elderly patients with hip fractures were significantly lower than those of age-matched controls (129). Another study, however, found no differences in serum copper levels among postmenopausal women with normal BMD (N=40), osteopenia (N=40), or osteoporosis (N=40) (130). A cross-sectional study showed that blood copper concentrations were lower than the normal reference range in postmenopausal women with osteopenia (N=28) and osteoporosis (N=23) (131). In another cross-sectional study in 728 postmenopausal women, 491 of which had confirmed osteoporosis, lower serum copper concentrations were associated with osteoporosis in the younger women (ages 40-59 years) but not the older women (ages 60-80 years) (132). Furthermore, in a national survey in the US, including 8,224 adults (compiling data from NHANES 2007-2010, 2013-2014, and 2017-2018), higher daily copper intakes (from diet and supplements) were associated with higher BMD at the femur and lumbar spine and a lower risk of osteoporosis (133).
Limited studies of copper supplementation and bone health outcomes have been undertaken. A small study in perimenopausal women, who consumed ~1 mg of dietary copper daily, reported decreased loss of BMD from the lumbar spine after copper supplementation of 3 mg/day for two years (134). Additionally, a two-year, double-blind, placebo-controlled trial in 59 postmenopausal women found that daily intake of supplemental calcium plus trace minerals, including 2.5 mg of copper, resulted in maintenance of spinal BMD. Supplemental calcium or trace minerals, alone, were not as effective at preventing loss of bone density (135). Another randomized, double-blind, placebo-controlled study in 224 healthy, postmenopausal women ages 51 to 80 years, found daily supplementation with 600 mg of calcium, 2 mg of copper, and 12 mg of zinc for two years decreased whole-body BMD compared to supplemental calcium alone. Another trial showed that BMD was reduced in subjects with dietary copper intakes below the RDA (0.9 mg/day), but copper supplementation did not prevent the progressive loss of BMD as well as a calcium regimen alone (136). Finally, several studies have suggested that tooth loss might be related to defects in the maintenance of BMD (137, 138). When compared with 20 healthy-matched controls, 50 patients (mean age, 47.5 years) with low spinal BMD and advanced tooth wear were found to have significantly lower copper content in tooth enamel. However, despite evidence of bone demineralization, serum copper levels in this population were similar to those of the healthy group (139). In sum, additional research is required to draw meaningful conclusions regarding the effects of marginal copper depletion and copper supplementation on bone metabolism and risk for developing age-related osteoporosis.
Cognitive deterioration in individuals with Alzheimer’s disease (AD) is linked to the presence of β-amyloid plaques and abnormal Tau protein-forming aggregates. The possibility that copper imbalance is involved in the onset of AD is under investigation. A recent meta-analysis of case-control studies described higher blood concentrations of copper in AD patients (N=2,929) as compared to healthy subjects (N=3,547), from a total of 46 studies reviewed (140). Also, ‘free’ serum copper (i.e., not bound to CP) was higher in AD patients (N=1,595) than in healthy control subjects (N=2,399), representing 18 total studies. These observations were confirmed in another recent review of published studies (141). An additional meta-analysis of 12 case-control studies revealed AD patients had lower copper concentrations in various brain regions compared to healthy controls (142), further exemplifying dysregulation of copper homeostasis in Alzheimer’s disease.
Among the many hypotheses supporting a role for copper in AD onset or progression includes copper involvement in the formation of senile plaques through hypermetallation of the β-amyloid peptides, possibly leading to zinc depletion, enhanced oxidative stress, and brain damage (143-145). Recent research has also identified polymorphisms in the ATP7B gene that may be associated with the risk of developing copper imbalance and AD (140, 142). ATP7B is a copper-transporting ATPase expressed in the liver and brain. Impairment of ATP7B function causes Wilson disease, which is typified by elevated ‘free’ copper level in blood and copper accumulation in liver and brain.
Additional research is required to determine whether genetic variation could influence individual susceptibility to environmental exposure of high copper levels. Copper administered in drinking water was associated with development of enhanced pathological features in animal models of AD (146, 147). One study in a rabbit model reported that combining a high-cholesterol diet and copper (0.12 mg/L in drinking water) impaired cognition (146). A prospective cohort study in 3,718 elderly participants in the Chicago Health and Aging Project, followed for 5.5 years, evaluated the impact of fat and copper intakes using food frequency questionnaires on cognitive function. For individuals with high intakes of saturated and trans fat, cognitive decline was greater for those in the highest quintile of total copper intake compared to the lowest quintile (median intake of 2.75 vs. 0.88 mg copper per day) (148).
Although dysfunctional copper metabolism is suggested as a risk factor for AD, it could also be symptomatic of the disease, rather than causative. Moreover, it is still unclear whether copper supplementation or restriction could delay the progression of AD. A small, double-blind, placebo-controlled trial in 68 individuals with mild AD found that supplementation of 8 mg/day of copper for one year delayed the decrease of the β-amyloid peptide Aβ42 in cerebrospinal fluid; a decrease in Aβ42 has been linked to cognitive deterioration (149). This delay, however, was not associated with improved cognitive performance (150). Relating to the use of zinc supplementation to block copper absorption in Wilson disease, slow-release zinc acetate administration (150 mg/day for six months) in a randomized, placebo-controlled study of 60 patients with mild-to-moderate AD resulted in a decrease in serum ‘free’ copper and stabilization of cognition deficits (143). A specific role for copper was not, however, determined in these notable outcomes. In summary, additional human studies are needed to clarify the role of copper in AD prevention, development, and progression.
Neurologically presenting Wilson disease and inherited aceruloplasminemia are characterized by copper accumulation in the brain and development of neurological symptoms, including dystonia and cognitive impairment, that resemble Parkinson’s disease (PD) (151). Disruption of copper homeostasis has been documented in PD (152). Copper depletion occurs in brain regions with loss of neurons in PD patients (153, 154). Moreover, some studies have documented lower serum copper and/or CP concentrations in PD patients compared to healthy controls (155-157). Dietary copper intake did not, however, relate to the risk of developing PD in two small case-control studies (158, 159). As in AD, further research is required to elucidate whether copper imbalance contributes to the pathogenesis of PD.
Similar to findings from animal models (160), human studies have documented low circulating copper (161, 162) or low hepatic copper content (161, 163, 164) in adults and children with nonalcoholic fatty liver disease. An inverse association between hepatic copper content and liver disease severity has also been observed (163, 165). However, it is not known whether low dietary intake of copper might be a contributor to disease pathogenesis or whether dysregulated copper metabolism is only a manifestation of liver disease.
Copper is found in a wide variety of foods and is most plentiful in organ meats, shellfish, nuts, and seeds. Wheat-bran cereals and whole-grain products are also good sources of copper. According to national surveys (NHANES), the mean dietary intake of copper in the US is 1.1 mg/day for adult women and 1.3 mg/day for adult men (166), levels that exceed the established RDA for copper for adults of 900 µg/day (see Table 1). The estimated copper content of some foods that are relatively rich in copper is listed in Table 2. For more information on the nutrient content of foods, search USDA's FoodData Central.
Identification of those at risk for copper depletion is challenging since sensitive and specific, copper nutrition-related bioindicators have yet to be identified. Nonetheless, a range of copper supplements are available for purchase, including cupric oxide, copper gluconate, copper sulfate, and copper amino acid chelates (167). The relative bioavailability of these different chemical forms of copper, however, has not yet been established in humans (168). Copper supplements may contain a few µg up to 15 mg of elemental copper, which exceeds the UL for copper by 1.5 fold (169). Moreover, copper is typically included in multivitamin/mineral supplements (169) and added to fortified breakfast cereals. Supplementation of adults with 10 mg/day of cupric gluconate for 12 weeks did not cause copper toxicity (170). Importantly, however, higher copper intakes could be detrimental in some at-risk (unknown) individuals. Copper supplementation of infants should be approached with caution since homeostatic regulators of copper absorption and excretion are not fully developed, thus increasing the potential for copper toxicosis. From a clinical perspective, copper overload most frequently presents in biliary atresia, biliary cirrhosis and in WD patients, and as such, individuals suffering from these conditions should avoid taking supplemental copper.
Copper toxicity is rare in the general population. Acute copper poisoning has occurred by storing beverages in copper-containing containers, as well as from contaminated water supplies (171). Guideline values for copper in drinking water have been set by the US Environmental Protection Agency (1.3 mg/liter) and by the World Health Organization (2 mg/liter) (172). Symptoms of acute copper toxicity include abdominal pain, nausea, vomiting, and diarrhea; such symptoms help prevent additional ingestion and absorption of copper. More serious signs of acute copper toxicity include severe liver damage, kidney failure, coma, and death.
Of more concern from a nutritional standpoint is the possibility of liver damage resulting from long-term exposure to lower doses of copper. In generally healthy individuals, daily doses of up to 10,000 μg (10 mg) have not resulted in liver damage. The US Food and Nutrition Board has thus set the tolerable upper intake level (UL) in adults at 10 mg/day of copper from food and supplements combined (Table 3) (24). It should be noted that individuals with genetic disorders affecting copper metabolism (e.g., Wilson disease, Indian childhood cirrhosis, and idiopathic copper toxicosis) may be at risk for adverse effects of chronic copper toxicity at significantly lower intake levels. There is some concern that the UL of 10 mg/day might be too high. For example, one study in adult men who consumed 7.8 mg/day of copper for 147 days showed that they loaded excess copper during that time, and some indices of immune function and antioxidant status suggested that these functions were adversely affected by the high intakes of copper (173, 174). However, another study did not report any adverse effects in individuals supplemented with 8 mg/day of copper for six months (150).
Relatively little is known about the interaction of copper with drugs. Penicillamine is used to bind copper and enhance its elimination in Wilson disease, a genetic disorder resulting in hepatic copper overload. Because penicillamine dramatically increases the urinary excretion of copper, individuals taking the medication for reasons other than copper overload may have an increased dietary copper requirement. Additionally, antacids may interfere with copper absorption when used in very high amounts (2). Also, the anti-tuberculosis drug ethambutol may chelate copper in mitochondria and reduce cytochrome c oxidase activity specifically in optic nerve axons, possibly contributing to optic neuropathy which is a documented side-effect of this drug (175).
The RDA for copper (900 μg/day for adults) is sufficient to prevent deficiency, but the lack of clear biomarkers of copper nutritional status in humans makes it difficult to determine the level of copper intake most likely to promote optimum health or prevent chronic disease. A varied diet should provide enough copper for most people. For those who are concerned that their diet may not provide adequate copper, a multivitamin/mineral supplement will generally provide at least the RDA for copper.
Because aging has not been associated with significant changes in the requirement for copper, our recommendation for older adults is the same as that for adults 50 and younger (176).
Originally written in 2001 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University
Updated in April 2003 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University
Updated in January 2008 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University
Updated in December 2013 by:
Barbara Delage, Ph.D.
Linus Pauling Institute
Oregon State University
Updated in October 2022 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University
Reviewed and updated in July 2024 by:
James F. Collins, Ph.D.
Food Science & Human Nutrition department
University of Florida
Reviewed in July 2023 by:
Jason Burkhead, Ph.D.
Biological Sciences department
University of Alaska, Anchorage
Copyright 2001-2024 Linus Pauling Institute
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