Copper health benefits
Since the discovery in 1928 that copper is an essential nutrient, hundreds of experiments to clarify its function have been performed with several species of animals and, under very controlled conditions, with adult human volunteers. People respond to copper depletion similar to animals.
The earliest experiments involved hematology, which preoccupied nutritional scientists for decades.
Gradually, evidence for the adverse effects of copper deficiency on the cardiovascular and skeletal systems accumulated. Cardiovascular research related to copper deficiency, including associated lipid metabolism and cardiovascular
physiology, now exceeds that on hematology. Early work on bone structure and function is being collected and extended. Methods for assessing nutritional status for copper are poorly developed. However, there are a sufficient number of reports of low activities of enzymes dependent on copper and low copper values in important organs to suggest that a considerable number of people may be
too low in this element. These data complement measurements of dietary copper suggesting that the Western diet, which is frequently low in copper, may be the source of this abnormal biochemistry. Some people with abnormal gastrointestinal physiology may absorb too little copper as well.
Copper is an essential and versatile nutrient that operates as the active site in 10 to 15 enzymes. These proteins moderate the chemistry of this metallic element to enhance various metabolic processes related to oxidation. There also are several other copper-binding proteins of physiological importance in addition to some newly discovered proteins called metallochaperones. The latter proteins act in the intracellular transport of metallic elements and help to ensure that free copper ion is nonexistent in the body.
ACTIONS, BIOCHEMISTRY, AND PHYSIOLOGY
The essentiality of copper for mammals, including people, was discovered when rats fed a milk diet with
adequate iron became anemic and grew poorly. Copper proved to be the active material in several foods that were curative and could prevent the condition. All the classic deficiency experiments with animals were performed with milk diets. Adequate copper permits normal utilization of dietary iron. In addition to preventing anemia, it assists in blood coagulation and blood pressure control cross linking of connective tissues of arteries, bones, and heart, defense against oxidative damage, energy transformations, myelination of brain and spinal cord, reproduction, and synthesis of hormones. Inadequate copper produces adverse effects on the metabolism of cholesterol and glucose, on blood pressure control and heart function, on mineralization of bones, and on immunity. Isoprostanes are increased in deficiency.
Hypercholesterolemia in copper deficiency has been found in at least 30 independent laboratories, most recently in studies by Galhardi et al., Kaya et al., and Rosario et al. since the original observation.
Glutathione is an effective regulator of 3-hydroxy-3-methylglutaryl coenzyme A activity (22,23). Copper deficiency disrupts glutathione metabolism, leading to increased activity of this enzyme and contributing to the hypercholesterolemia that occurs. In contrast, decreased activities of lecithin: cholesterol acyltransferase and lipoprotein lipase also contribute to the hypercholesterolemia of deficiency. Electrocardiograms of animals deficient in copper reveal human cardiovascular risk factors such as branch block and abnormalities of the ST segment other heart blocks and wave pathologies are numerous. The heart blocks are probably caused by decreased activity of an ATPase isoform localized to the conduction system of the heart.
Copper deficiency depresses vasodilation via alterations in nitric oxide physiology. The mechanism has been reviewed and may involve, inter alia, guanylate cyclase, which contains copper. Paraoxonase, sometimes called PON1, is a homocysteine thiolactone hydrolase activity of which is decreased by copper deficiency. The lactone accumulates when homocysteine is elevated and irreversibly inhibits lysyl oxidase, which depends on copper for crosslinking of connective tissue in arteries and bone. There seems to be little doubt that copper deficiency can affect desaturase (and elongase) enzymes, but agreement is lacking on the details and directions of all the changes. Some of the data have been reviewed. These enzymes can alter the number of double bonds in a fatty acid and can also increase its length. Prostaglandin metabolism is also affected.
Copper Food Sources and Supplementation
As far as is known, food source does not affect copper absorption, in marked contrast to iron and zinc, which are more easily absorbed from animal, than from plant, products. Higher concentrations of copper in many plant foods can compensate if fractional absorption is slightly
lower. Vegetarian diets are high in copper. Phytates either have no inhibitory effect on copper, or have a markedly smaller effect than that on zinc. At intestinal pH, copper complexes with phytates are soluble
whereas zinc complexes are not. Phytates can thus enhance the utilization of copper.
Copper absorption at 55% to 75% is considerably higher than that of other trace elements; absorption occurs mainly in the upper small intestine, but stomach and colon may absorb the element as well. Thus, the concentration of copper in foods is an important characteristic that determines nutritional usefulness. In order of increasing concentration on a weight basis, fats and oils, dairy products, sugar, tuna, and lettuce are low in copper; legumes, mushrooms, chocolate, nuts and seeds, and liver are high in copper. Bread, potatoes, and tomatoes are consumed in sufficiently large amounts by U.S. adults for these foods to contribute substantially to copper intake, although they are not considered to be high-copper foods. Copper and magnesium are highly correlated in U.S. diets. Food groups high in folate tend to be high in copper. The Western diet typical of the United States, parts of Europe, and wealthy enclaves in the developing world is often low in copper. Approximately one-third of these
diets are low in comparison with those used in successful depletion experiments of men and women under controlled conditions and in comparison to the estimated average requirement and recommended dietary allowance (RDA) of the National Academy of Sciences.
Estimations of dietary copper intakes based on calculations,
for example, about Canadian octogenarians from the amount of copper in individual foods are too high according to eight published comparisons to chemical analysis of composite diets; the mean error from
calculation is an excess of 77%. The calculated 25th, median, and 75th percentiles
for intakes of 51- to 70-year-old men in a statistical sample of the U.S. population are 1.19,
1.47, and 1.81 mg copper daily. Corrections based on the mean excess in copper found by calculation decrease these estimates to 0.67, 0.83, and 1.02 mg daily. Although younger men seem to eat more copper, women eat less.
Data from several publications on dietary intakes of copper based on chemical analyses were pooled and a frequency distribution curve was derived for 849 analyzed diets; approximately one-third of the diets contained less than 1 mg of copper daily. Further analytical confirmation of diets low in copper is available from men and women randomly selected in Baltimore. Thirty-six percent and 62% of the diets were below the respective dietary reference intakes for copper.
Three approaches to supplementation are available. Diets below the EAR and the RDA can be improved by avoiding foods low in copper and by selecting foods high in copper. A copper-deficient salad (lettuce, mayonnaise,oil, tuna, etc.) can be improved by adding sunflower seeds, mushrooms, legumes, etc. Soy products are increasingly popular and are high in copper, as are nuts and chocolate. Beer enhances the utilization of copper in rats fed a deficient diet, resulting in a sixfold increase in longevity, with less cardiac damage and lower plasma cholesterol.
In contrast to iron, fortification of foods with copper is uncommon. Some new snacks and drinks promoted as products with exceptional nutritional properties are fortified with copper. A variety of tablets and capsules containing copper are available commercially. Copper gluconate is the only copper supplement listed by the United States Pharmacopeial Convention and probably is the best supplement for oral use. We have used copper sulfate effectively in experiments with animals and human volunteers. Others have used copper salts of amino acids. Other compounds containing copper, such as the orotate, for which there are no data on bioavailability should not be used. It is not easy to identify the chemical form of copper in some of the available supplements. Cupric oxide is contained in some vitamin–mineral supplements; this form is no longer used in animal nutrition because the copper is utilized poorly. Cupric oxide is used in the preparations with many ingredients because of its high concentration of copper, not because of demonstrated efficacy.
Deficient people should be supplemented with several times the EAR or RDA. Daily supplements of 3 to 7 mg of copper have been tolerated for long periods.
INDICATIONS AND USAGE
The Western diet is associated with rapid growth in infancy,
increasingly early sexual maturation, tall adults,
and low rates of infection. This diet is also associated
with common diseases of affluence such as cancer, heart
disease, obesity, and osteoporosis etc. Numerous
anatomical, chemical, and physiological characteristics
of people with some of these latter diseases have been
found in several species of animals deficient in copper.
No single indicator provides an adequate assessment
of copper nutriture (nutritional status). Indices
useful in experiments with animals have sometimes been
helpful in depletion studies of people, but most do not
seem to be altered by marginal deficiency. Circulating copper
may not reflect the actions of enzymes inside cells in
various organs where the metabolic processes affected by
copper take place. Liver copper, generally impossible to
assess in people, is the best indicator in animal experiments
(62). Experiments with animals reveal that plasma
copper can be normal or increased even though copper in
liver or other organs may be low. Thus, normal
or high plasma copper values in people may not be an
accurate reflection of copper nutriture.
According to the Oxford Textbook of Medicine,
low nutrient intakes can reduce nutrient concentrations in
tissues and compromise metabolic pathways.
then is relatively straightforward upon measurement of
the nutrient in suitable tissues or testing of metabolic pathways.
Numerous medical publications (some of which are
summarized here) reveal low copper concentrations and
impaired enzymatic pathways dependent on copper in
people. As “nutritional state often alters the expression
and course” of illness, extra copper should be provided
if low measurements related to copper values are
found whether or not they are the cause or the result of
the pathology under consideration.
Interpretation of copper or ceruloplasmin in serum
or plasma in the assessment of nutriture may be difficult.
Low values indicate impairment. Pepys describes the
acute phase response to acute and chronic inflammation:
a number of plasma proteins, such as ceruloplasmin, are
synthesized in liver under the influence of cytokines and
are secreted into the circulation. Thus, any illness with a
large inflammatory component may have falsely high values. Normal or high values cannot provide assurance that copper deficiency is not present. Clearly people with myelodysplasia and the new syndrome resembling the neurology of pernicious anemia (below) can be considered for supplementation. Possibly deficient people should be evaluated with some of the newer, potentially more sensitive, indices of copper status such as erythrocyte and extracellular superoxide dismutases, leukocyte copper, platelet cytochrome c oxidase or serum lysyl oxidase.
Data on which to base dietary reference intakes for copper are elusive and, often, absent. Consequently, some of the values in Table 1 are rounded and values for males and females are combined. The adequate intake (AI) values are based on intakes of apparently healthy, full-term infants whose sole source of copper was human milk. Values for pregnancy are based on the amount of copper in the fetus and other products of conception. Those for lactation are the amounts needed to replace the average amount secreted in human milk. EARs are values estimated to meet the requirement of half of the healthy individuals of the group. Copper RDAs are based on the EAR plus an assumed coefficient of variation of 15%, which is larger than the 10% assumed for some other nutrients.
In the United States, dietary reference intakes are median values with an assumed symmetry of distribution. However, there is virtually no information about the. Daily Adequate Intake (AI), Estimated Average Requirement
(EAR), and Recommended Dietary Allowance (RDA) for Copper (mg)
Age AI (mg) EAR (mg) RDA (mg)
0–6 mo 0.20 or 30 (g/kg)
7–12 mo 0.22 or 24 (g/kg)
1–3 yr 0.26 0.34
4–8 yr 0.34 0.44
9–13 yr 0.54 0.70
14–18 yr 0.685 0.89
19–70 yr 0.70 0.90
Pregnancy 0.80 1.00
Lactation 1.00 1.30
shape of the copper distribution; distributions for most
nutrients are skewed to the high end. People who are
deficient in copper without obvious cause (below) probably
have a personal requirement for copper considerably
higher than the median requirements reflected in the
It seems clear that there is little or no copper deficiency
in the industrialized world if one relies on traditional
criteria of deficiency such as anemia with decreased
plasma copper or ceruloplasmin. However, these markers
are affected by the acute phase response and are easily
increased by non dietary variables, such as inflammation,
oral contraceptives, and pregnancy etc. Copper depletion
experiments with men and women reveal unfavorable alterations
in biochemistry and physiology with minimal
or no changes in circulating copper and without anemia
(above). Copper deficiency is the leading nutritional deficiency
of agricultural animals worldwide; can people
be far behind?
A 2001 report on dietary reference intakes and
its predecessors, for example in Ref. summarize
the reasons why people may decide to take (or avoid)
nutrient supplements. Growth and function are improved
when nutrients are increased above levels just sufficient
to prevent deficiency. There is little evidence that small
surpluses of nutrients are detrimental, while small deficits
will lead to deficiency over time. There is no evidence
of unique health benefits from the consumption of a
large excess of any one nutrient. Meeting recommended
intakes for nutrients will not provide for malnourished individuals.
There seems to be little or no anemia responsive to copper in the United States, although this phenomenon does not seem to have been studied adequately in the last six decades. Copper deficiency can masquerade as the
myelodysplastic syndrome, however. Supplementation of middle-aged Europeans with copper protected their red blood cells from oxidative hemolysis in vitro, indicating that extra copper improved the quality of the cells.
Alzheimer’s disease is the leading cause of dementia
in the elderly and is of unknown etiology. It is hypothesized
that deficiency of dietary copper is the simplest
and most general explanation for the etiology and pathophysiology
of this disease because, inter alia, of numerous
reports of low copper in the brain and low activity of enzymes
dependent on copper in these patients. These
findings are consonant with Golden’s criteria for diagnosing
deficiency. Kumar has reviewed and expanded upon a copper
deficiency syndrome resembling the neuropathy of
pernicious anemia (vitamin B12 deficiency). Supplementation
with cyanocobalamin is useless, but extra copper
generally arrests the decline and sometimes reverses some
of the signs.
Several of the classical risk factors for ischemic heart
disease have been produced in animals deficient in copper.
Similar changes have been found in more than 30 men
and women in successful copper depletion experiments
using conventional foods and have been reversed by copper
supplementation. Copper intakes of 0.65 to
1.02 mg daily in these experiments were insufficient. Criteria
of depletion included abnormal electrocardiograms and blood pressure regulation (51), dyslipidemia, glucose intolerance, and hypercholesterolemia. Two of these experiments were interrupted prematurely
with early repletion with copper because of abnormal
electrocardiography; all of the metabolic and physiological
abnormalities disappeared with copper repletion.
Low paraoxonase activity is found in conditions associated
with increased risk of ischemic heart disease
isoprostanes are increased.
In contrast is a balance experiment using a formula
diet that failed to confirm these results. Applesauce,
cheese, chicken, cornflakes, crackers, lettuce, margarine,
milk, orange juice, and rice provided less than 31% to
34% of dietary energy (calculated at 2400 kcal/day).
As actual energy intake ranged from 2415 to 3553 kcal, the food part of the formula was probably about
26%. Because formula diets are known to lower serum
cholesterol (96), the potential increase in cholesterolemia
from the low copper intake may have been obscured.
Activities of enzymes dependent on copper and organ copper concentrations (104–113) have
been found to be decreased in people with cardiovascular
(mostly ischemic) diseases. There is a positive correlation
between cardiac output and copper in heart tissue of patients
with coronary heart disease. Decreased copper in organs and decreased enzyme activities are evidence of impaired copper nutriture.
Nolong-term copper supplementation has been performed
in patients with cardiac arrhythmia, dyslipidemia, glucose intolerance, hypercholesterolemia, or hypertension. However, some dietary regimens found to alleviate some of these conditions may have included an increase in copper intake as a hidden variable: for example, the
Lifestyle Trial (116), the protective effect of legumes on
cholesterol, blood pressure, and diabetes (117) and the
benefit of whole grain foods on coronary heart disease
(118). Spencer (119) described two men and a woman
whose premature ventricular beats, which had persisted
for years, were thought to be due to coronary heart disease.
These premature beats disappeared after they ingested 4
mg of copper (as copper gluconate) per day.
Witte et al. (120) explain how deficiencies of micronutrients,
copper among them, can contribute to cardiovascular
disease. Patients with heart failure in their
supplementation trial had improved ventricular function
and quality of life (121); copper in the supplement may
have contributed (122). Supplementation trials with vitamins
to lower homocysteine may show clinical benefit if
extra copper is included (123); copper supplementation
(with zinc) improved survival in a long-term, doubleblind
study of ocular disease (124).
Copper-deficient people have osteoporosis that can
be cured with extra copper (reviewed in Ref. 16). This
phenomenon has been found mainly in young children.
Adults may have skeletal pathology from low copper
status as well. Copper is decreased in bone in both osteoarthritis
and ischemic necrosis of the femoral head
(125). Low serum copper in patients with fractures of
the femoral neck (126) or decreased lumbar bone density
(14,127,128) may indicate covert copper deficiency.
Plasma copper and bone mineral density are correlated
(129). Healthy men fed a diet low in copper (0.7 mg/day)
experienced increased bone resorption that returned to
normal when copper was replaced (130).
There can be no medical doubt that copper deficiency
can cause osteoporosis in people. These references
on osteoporosis from copper deficiency (131–141) have
been found since the earlier review (16) of 17 articles. If
copper deficiency turns out to be a major component of the
osteoporosis of middle age, supplementation with copper
alone is unlikely to be effective. If copper deficiency is
corrected, another nutrient, particularly calcium and possibly
zinc, may become limiting (77). Two double-blind,
placebo-controlled trials have shown that trace element
supplements including copper improved bone mineral
density in postmenopausal women (65,142).
Premature infants and people with extensive burns
may need extra copper. The former (143) are sometimes
born before their mothers can load them with copper in
the last trimester (12). Premature infants have lower superoxide
dismutase activity in erythrocytes and plasma
copper after 100 days of life than term infants (144); premature
placentas are low in copper and copper-dependent
In analogy to vitamin B12 deficiency, any disruption
of the gastrointestinal tract has the potential to impair copper
nutriture. Copper deficiency is being reported with
increasing frequency in patients who have had bariatric
surgery (90,92,146–149). Some people with cystic fibrosis
or pancreatic insufficiency may need extra copper (150–
152). Copper-dependent enzyme activity and copper concentration
have been found to be decreased in ulcerative
colitis biopsies (153). Supplementation of people with
these conditions should be performed under medical supervision.
If adults have unmet needs for copper to provide
cardiovascular, hematopoietic, or skeletal benefit, neither
the dose nor the duration of therapy is clear. A potential
role for copper supplements in the treatment of rheumatoid
arthritis and psoriasis has not been proved. There is
probably no reason to exceed the tolerable upper intake
level (UL) of 10 mg daily (Table 2).
Potential Toxicity and Precautions
All chemicals, including essential nutrients, are toxic if
the dose is excessive. It seems that people have a 50- to
400-fold safety factor for copper considering usual dietary
intakes and the tolerance level found with several species
of experimental animals.
The UL connotes an intake
Table 2 Daily Tolerable Upper Intake Level
(UL) for Copper (mg)
Age group UL (mg)
1–3 yr 1.00
4–8 yr 3.00
9–13 yr 5.00
14–18 yr 8.00
19–70+ yr 10
that can, with high probability, be tolerated biologically
by almost all individuals.
Gastrointestinal signs and symptoms such as nausea
are prominent in the setting of this limit. A small,
double-blind study has revealed that adults are unaffected
in 12 weeks by a daily supplement of 10 mg of copper . The UL values in Table 2 are based on this experiment;
no value is available for infants less than 1-year old.
van Ravesteyn administered 38 mg of copper daily to people for as long as 14 days; toxicity was not
mentioned. Copper supplements should be taken with food and should not be taken by people with
biliary disease, liver disease, idiopathic copper toxicosis
or Wilson’s disease, or by people taking penicillamine or
trientine. Although copper can interfere with zinc utilization,
this phenomenon does not seem to be of practical importance
to people. In contrast, copper deficiency has been
induced in people (and in numerous species of pets and
animals in zoos) by the ingestion of recently minted pennies
(United States), which are almost pure zinc.
The dose of supplemental zinc that is excessive for adults
is ill-defined, but the adult UL for zinc, 40 mg daily, is
based on reduced copper nutriture from zinc in food,
water, and supplements combined. A case of copper responsive
anemia has been reported in a patient with
acrodermatitis enteropathica overtreated with zinc.
This potential exists for patients with Wilson’s disease
treated with zinc, particularly children. Demyelination
of the central nervous system has been reported from
overzealous treatment of Wilson’s disease with zinc.
Denture creams high in zinc have led to copper deficiency, but its UL of 2 g daily is not based
on copper effects. Adverse effects on blood pressure regulation
and copper utilization were found in women fed
1.5 g vitamin C daily (51). Simple sugars such as fructose, glucose, and sucrose interfere with the utilization
of copper (169,170): High-fructose corn syrup is found in many processed foods and beverages. Excessive ingestion
of soft drinks has contributed to copper deficiency.
High iron intakes can disrupt copper utilization. People with iron overload and
lead poisoning may benefit from copper supplementation. Copper supplements should not be used as
The Western diet often is low in copper. Statements to
the contrary are based on dietary calculations, which are
falsely high. The best way to ensure an AI of copper is to
minimize the intake of foods low in copper and to increase
that of foods high in it, such as cereals, grains, legumes,
mushrooms, nuts, and seeds. Dietary copper can be increased
by using the food pyramid as a guide. Only a
few foods are fortified with copper. Copper gluconate is
probably the best supplement.
There seems to be little copper deficiency inWestern
society if one considers anemia as its only sign. However,
adults with diseases of the cardiovascular, gastrointestinal,
and skeletal systems have repeatedly been found to
have low concentrations of copper in important organs
and to have low activities of enzymes dependent on copper.
These signs are consonant with deficiency. Premature
infants may also be deficient in copper. Large intakes of vitamin
C or zinc can impair the proper utilization of copper
People deficient in copper are being reported with
increasing frequency. Although many circumstances seem
without explanation and because the clinical signs differ
fromthose traditionally associated with copper deficiency,
the reports are often scattered in medical journals that do
not have the word “nutrition” in their titles.
Recognition of copper deficiency in the general
population still seems rare enough to be published,
but deficiency also is common enough that 10 cases
are reported from one neurological clinic. The index
of suspicion should be increased among those providing
primary care. When obvious explanations such as
bariatric surgery, dental adhesives high in zinc, hemochromatosis,
lead poisoning, and soft drink excess are
excluded one should consider the possibility that the patient
has a dietary requirement higher than those mentioned
among the dietary reference intakes. Some cases of
myelodysplastic syndrome and heart failure respond to
Evaluations should not rely only on plasma copper
or ceruloplasmin. Supplementation should be done with
substantial doses of easily absorbed, copper salts under
Some successful experiments in human copper
depletion, particularly in relation to the cardiovascular
system, are summarized here, as are some unsuccessful experiments.
Others have been reviewed (181). Depletion experiments
with positive results illustrate what is possible
in the wider world, particularly when the potentially adverse
effects were eliminated on repletion. Seemingly contrary
or incongruous experiments should not promote denial
or negativism; rather they should stimulate searches
for explanations of differences.
Individual animals and individual people fed the
same depleted diets do not respond uniformly. Signs of
deficiency are variable in experimental pellagra and in
animal experiments on biotin, thiamin, or copper deficiencies.
Our success rate in inducing copper depletion in
people resembles that of Goldberger in inducing pellagra.
One should not expect all people to respond uniformly to
a diet low in copper.
There is no information available on how copper
requirements vary from person to person; dietary recommendations
are based on assumptions of narrow variability.
The amount of copper in the body and its variability
are known, only inaccurately. Copper absorption is reasonably
well defined, but data on copper losses are scant.
Aside from some obvious causes of deficiency mentioned
here, causes of human deficiency in some recent, medical
reports are unknown. These reports have increased since
the first edition and illustrate opportunities for research;
it seems likely that people with unidentified high requirements
for copper are eating too little. The field of copper
nutrition is far from stagnant.