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Copper

GlossarySuccess Chemistry Staff

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.

GENERAL DESCRIPTION

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.

Diagnosis

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

RDAs.

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

enzymes (145).

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)

Children

1–3 yr 1.00

4–8 yr 3.00

9–13 yr 5.00

Adolescents

14–18 yr 8.00

Adults

19–70+ yr 10

Pregnancy 8.00

Lactation 8.00–10.00

Copper 179

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

emetics.

 

CONCLUSIONS

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

in people.

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

copper.

Evaluations should not rely only on plasma copper

or ceruloplasmin. Supplementation should be done with

substantial doses of easily absorbed, copper salts under

medical supervision.

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.