Trace mineral - Copper

Trace minerals

A trace element contributes less than 0.01% to the total body weight. It is a term that applies to those elements that are consistently present in human tissues and have one or more definite, probable, or possible physiologic roles. The total body content of trace elements is small, but concentrations in individual tissues can range up to many parts per thousand. Though the trace elements are present in the human body in such small quantities, they are analogous to their organic counterparts, the vitamins, in that they have multiple, indispensable roles in a variety of important metabolic pathways.  

What is Copper?

Copper is an essential trace element that is vital to the health of all living things. Copper is found in much of the natural environment, including water and soils. The amounts vary from location to location depending on specific conditions. Depending on the source of the biological material, copper content ranges from parts per billion (ppb) to parts per million (ppm). Copper ions undergo unique chemistry due to their ability to adopt distinct redox states, either oxidized (Cu⁺²) or in the reduced state (Cu⁺¹). Consequently, Cu ions serve as important catalytic cofactors in redox chemistry for proteins that carry out fundamental biological functions that are required for growth and development. In humans, copper is essential to the proper functioning of organs and metabolic processes.

What Is The Function Of Copper?

Copper is an essential component of many enzymes, known as copper enzymes– cytochrome c oxidase, lysyl oxidase, feroxidase, amine oxidase, catechol oxidase, tyrosinase, dopamine beta-monooxygenase, D-hexozo oxidoreductase, L-ascorbatoxidase, nitratreductase, peptidylglycine monooxygenase, flavonol 2,4-dioxygenase, superoxide dismutase, PHM (peptidylglycine monooxygenase hydroxylation). Each of the copper-containing enzymes has a distinct function (Table 1), indicating that copper plays a role in a wide range of physiological processes.  

Table 1: Functions of Copper-Dependent Enzymes

Enzyme	Function	Consequences of deficiency
Ceruloplasmin	Iron and copper transport	Decreased circulating copper levels, iron deficiency
Cytochrome C oxidase	Mitochondrial respiration	Hypothermia, muscle weakness
Dopamine β-hydroxylase	Catecholamine production	Hypothermia, neurological defects
Lysyl oxidase	Connective tissue formation	Laxity of skin and joints
Peptidylglycine α amidating monooxygenase	Peptide amidation	Neuroendocrine defects
Superoxide dismutase	Antioxidant defence	Diminished protection against oxidative stress
Tyrosinase	Pigment formation	Hypopigmentation of hair and skin

Copper for Foetuses, Infants, and Children

The human fetus

 accumulates copper rapidly in its liver during the third trimester of pregnancy. At birth, a healthy infant has four times the concentration of copper than a full-grown adult. Human milk is relatively low in copper, and the neonate’s liver stores falls rapidly after birth, supplying copper to the fast-growing body during the breast feeding period. These supplies are necessary to carry out such metabolic functions as cellular respiration, melanin pigment and connective tissue synthesis, iron metabolism, free radical defense, gene expression, and the normal functioning of the heart and immune systems in infants.

Medicinal Benefits of Organic Complexes of Copper In A Number Of Disease States

Ulcer and Wound-Healing Activities: Copper complexes such as copper aspirinate and copper tryptophanate, markedly increase healing rate of ulcers and wounds. For example, copper complexes heal gastric ulcers five days sooner than other reagents. NSAIDs, such as ibuprofen and enefenamic acid suppress wound healing, copper complexes of these drugs promote normal wound healing while at the same time retaining anti-inflammatory activity.

Anticonvulsant Activities: The brain contains more copper than any other organ of the body except the liver, where copper is stored. Copper plays a role in brain functions. With reports of seizures in humans following the protracted consumption of copper-deficient diets, it was reasoned that copper has a role to play in the prevention of seizures.

Anticancer Activities: Copper compounds have anticancer activity. Treatment of solid tumours with non-toxic doses of various organic complexes of copper markedly decreased tumour growth and metastasis and thus increased survival rate. These copper complexes did not kill cancer cells but caused them to revert to normal cells.

Radiation Protection and Radiation Recovery: Ionizing radiation induces massive systemic inflammation. Thus, pharmacological approaches to the repair of radiation-damaged tissue are needed. Copper metallo-organic complexes have radiation protection and radiation recovery activities. They are capable of causing rapid recovery of immunocompetence and recovery from radiation induced tissue changes. The mechanism of this activity appears to be tied to the ability of certain copper complexes to deactivate the superoxide, or "free," radicals liberated by ionizing radiation. Since these complexes may also have anticarcinogenic activity, it is suggested that there would be merit in using copper complexes in the treatment of cancer and in particular, treating patients undergoing ionizing radiation therapy for their cancer, accidental exposure to radiation, and astronauts undertaking space travel.

Heart Disease: Copper has a direct effect on the control of cholesterol. A metabolic imbalance between zinc and copper - with more emphasis on copper deficiency than zinc excess - is a major contributing factor to the etiology of CHD. Copper complexes also can have a valuable role in the minimization of damage to the aorta and heart muscle as oxygenated blood reperfuses into tissues following myocardial infarction. This action is based on the anti-inflammatory action of copper complexes. Use of copper dietary supplements as a means of preventing and controlling diseases such as atherosclerosis, CHD and myocardial infarction may be considered.

Factors Influencing Copper Absorption

• ·         Copper absorption is enhanced by ingestion of animal protein, citrate, and phosphate.
• ·         Some foods may contain indigestible fiber that binds with copper.
• ·         High intakes of zinc can significantly decrease copper absorption. High additional intake of zinc - 50 mg/d or more for an extended period of time can lead to copper deficiency. Zinc supplemented diet increases the intestinal synthesis of cellular proteins, called metallothioneins. They bind metals and do not allow their absorption by intestinal cells. Metallothioneins have a stronger affinity for copper than for zinc, so high levels of metallothioneins due to increased zinc can cause reduced absorption of copper.
• ·         Extreme intakes of Vitamin C or iron can also affect copper absorption. Individuals with chronic digestive problems may be unable to absorb sufficient amounts of copper, even though the foods they eat are copper-rich.
• ·         Zinc and cadmium appear to be the most potent inhibitors of copper absorption, possibly by competing with copper for transport.
• ·         Fructose and other carbohydrates, dietary cellulose fiber, and phytate were found to reduce the bioavailability of copper. 
• ·         Increased physical activity is also found to reduce the concentration of serum copper.

INBORN ERRORS OF COPPER METABOLISM

Menkes Disease

Menkes disease is an X-linked syndrome occurring at a frequency of approximately 1/200,000 live births. Although the disease primarily occurs in boys, it has also been reported in females. Menkes patients show a profound systemic copper deficiency that is often fatal in early childhood and accompanied by severe neurological abnormalities, apparently due to the lack of several copper-dependent enzymes required for brain development. Affected individuals present with hypopigmented hair due to tyrosinase deficiency, resulting in lack of melanin synthesis.

The hair of steely appearance is also brittle and kinky because of a deficiency in an unidentified cuproenzyme required for cross-linking keratin. This has led to the alternative designation “kinky hair disease.” Reduced lysyl oxidase activity results in defective collagen and elastin polymerization and corresponding connective-tissue abnormalities including loose skin, and fragile bones. The severe neurological defects are thought to be due to reduced cytochrome c oxidase activity.

Menkes disease patients show mild to severe mental retardation. Even with early diagnosis and treatment, Menkes disease is usually fatal; most affected individuals die before the age of 10 years. Individuals with Menkes disease absorb copper from the small intestine, but this copper cannot be pumped out of the intestinal cells into the blood for transport to the liver and consequently to rest of the body. The disease thus functionally resembles severe nutritional copper deficiency.

Wilson Disease

Wilson disease, also referred to as hepatolenticular degeneration, is an autosomal (chromosome 13) recessive inherited disorder of copper transport, which (1) involves poor incorporation of copper into ceruloplasmin and impaired biliary copper excretion and (2) is usually induced by mutations impairing the function of the Wilson copper ATPase. These mutations produce copper toxicosis due to excessive copper accumulation, predominantly in liver and brain.

The age on onset of Wilson disease ranges from 3 to 50 yr. Initial presentation of patients with Wilson disease involves hepatic, neurologic, or psychiatric manifestations. Hepatic symptoms may be acute and self-limited, mimicking acute hepatitis, or may progress rapidly, suggesting fulminant hepatitis. Alternatively, onset may resemble chronic active hepatitis or cirrhosis with hepatic insufficiency. Standard marker enzymes of liver damage are unreliable diagnostic markers in Wilson disease; aminotransferase activity levels are not markedly elevated and serum alkaline phosphatase activity values are almost always inappropriately low, despite severe hepatic insufficiency. The disease progresses with deepening jaundice and the development of encephalopathy, severe clotting abnormalities, occasionally associated with intravascular coagulation, and terminal renal insufficiency. Almost always, death occurs if the disease is untreated.

Copper accumulates in hepatocytes, and lysis occurs when their capacity is exceeded. The released metal then diffuses into the blood and is accumulated in extrahepatic tissues.

Other Copper-Related Hereditary Syndromes

Other diseases in which abnormalities in copper metabolism appear to be involved include Indian childhood cirrhosis (ICC) and idiopathic copper toxicosis (ICT), or non-Indian childhood cirrhosis. These are infancy syndromes that are similar in their apparent etiology and presentation. Both appear to have a genetic component and a contribution from elevated copper intake. In cases of ICC, the elevated copper intake is due to heating and/or storing milk in copper or brass vessels. ICT cases, on the other hand, are due to elevated copper concentrations in water supplies. Although exposure to elevated concentrations of copper is commonly found in both diseases, some cases appear to develop in children who are exclusively breast fed or who receive only low levels of copper in the water supply. The currently prevailing hypothesis is that ICT is due to a genetic lesion resulting in impaired copper metabolism combined with high copper intake. 

DAILY COPPER REQUIREMENTS

Table 2: Recommended Dietary Allowances (RDA) for Copper

Physiological Stage	RDA for Copper
0-6 months	200 micrograms
7-12 months	220 micrograms
1-3 years	340 micrograms
4-8 years	440 micrograms
Boys 9-13 years	700 micrograms
Girls 9-13 years	700 micrograms
Boys 14-18 years	890 micrograms
Girls 14-18 years	890 micrograms
Men and women 19-70 years	900 micrograms
Men and women greater than 70 years	900 micrograms
Pregnant women 14-50 years	1000 micrograms
Lactating women 14-50 years	1300 micrograms

                 

COPPER RICH FOODS

The best dietary sources include seafood (especially shellfish), organ meats (e.g., liver), whole grains, legumes (e.g., beans and lentils) and chocolate. Nuts, including peanuts, are especially rich in copper, as are grains such as wheat and several fruits including lemons and raisins. Other food sources that contain copper include cereals, potatoes, peas, red meat, mushrooms, some dark green leafy vegetables, and fruits (coconuts, papaya and apples). Tea, rice and chicken are relatively low in copper, but can provide a reasonable amount of copper when they are consumed in significant amounts.

Table 3: Sources of Copper in Diet

Sources
Excellent	Asparagus, turnip greens and molasses
Very good	Spinach, sesame seeds, mustard greens, shiitake mushrooms, cashews
Good	Tomatoes, green peas, garlic, sunflower seeds, green beans, beets, fennel, olives, sweet potato, barley, tempeh, tofu, soybeans, miso, shrimp, walnuts, pumpkin seeds, flaxseeds, peanuts, almonds, pineapple, raspberries, lentils, sesame seeds, kidney beans, ginger, black pepper

Table 4: Copper Content Of Foods

Food stuff	Edible portion/100 g
Cereals and pulses
Bajra	1.06
Barley	1.19
Maize (dry)	0.41
Ragi	0.47
Rice (raw) milled	0.72
Rice flakes	0.37
Wheatflour (whole)	0.51
Wheatflour (refined)	0.21
Bengal gram (whole)	1.18
Red gram (dal)	1.2
Green gram (dal)	0.39
Bengal gram (dal)	1.34
Khesari dal	0.77
Peas (dried)	1.29
Lentil (dal)	1.37
Soyabean (black)	1.38
Vegetables
Colocasia (leaves)	0.18
Coriander leaves	0.14
Beetroot	0.29
Potato	0.16
Tomato (green)	0.19
Fruits
Sitaphal	0.43
Orange	0.58
Banana	0.16
Pineapple	0.13
Sapota	0.08
Guava (country)	0.14
Pomegranate	0.34
Mango	0.11

Impact of Cooking, Storage and Processing

• ·         The leaching of copper from copper water pipes can increase the copper content of drinking water. Cooking with copper cookware can also increase the copper content of foods.
• ·         Foods that require long-term cooking can have their copper content substantially reduced. The processing of whole grains can also dramatically reduce copper content.   
• ·         Many vegetables and whole grains now appear to be lower in copper, which is believed to be due to depletion of copper from soils. 
• ·         When acidic foods are cooked in unlined copper cookware, or in lined cookware where the lining has worn through, toxic amounts of copper can leech into the foods being cooked. This effect is exacerbated if the copper has corroded, creating reactive salts. Actual cooking may not be required for copper to leach into acidic liquids if they are stored in copper for a period of time.

Table 5: Copper Supplementation Should be Considered for

	Conditions Requiring Copper Supplementation
1	Illnesses that reduce digestion (e.g., children with frequent diarrhea or infections; alcoholics)
2	Insufficient food consumption (e.g., the elderly, the infirm, those with eating disorders or on diets)
3	Patients taking medications that block the body's use of copper
4	Anemia patients who are treated with iron supplements
5	Anyone taking zinc supplements
6	Those suffering from osteoporosis

COPPER TOXICITY

The most common route of copper intoxication appears to be through the ingestion of contaminated drinking water. The usual epidemic of mass copper poisoning occurs when copper sulphate is used to reduce algae growth in reservoirs. The algae are killed; however, the population drinking the water is often intoxicated. Two other factors which substantially contribute to the daily intake of copper are multivitamin supplements and cigarette smoking. Cigarette smoking only adds to copper and cadmium poisoning. The copper accumulates in the body as smoke is inhaled. In humans, the liver is the primary organ of copper-induced toxicity.

Toxicity Symptoms

Excessive intake of copper can cause abdominal pain and cramps, nausea, diarrhea, vomiting, and liver damage. Elevated copper levels, especially when zinc levels are also low, may be a contributing factor in many medical conditions including schizophrenia, hypertension, autism, fatigue, muscle and joint pain, headaches, childhood hyperactivity, depression, insomnia and premenstrual syndrome.

Since excess copper is excreted through bile, copper toxicity is most likely to occur in individuals with liver disease or other medical conditions in which the excretion of bile is compromised.

CONSEQUNECES OF HYPERCUPREMIA

Wilson's Disease (Hepatolenticular degeneration): This disease is rare. Ceruloplasmin is deficient and excess copper is absorbed from the intestines. The serum copper level is low but the tissue level by liver biopsy is very high. The presenting symptoms of Wilson's disease in the adult may be psychosis, which if not diagnosed, results in death, and diagnosis by "sibling autopsy" since the other children in the family may also have the defect.

Renal and Hepatic Effects: Gross hepatic necrosis and destruction of the proximal tubule of the nephron evolve as the body attempts to eliminate excess copper. Although most copper is excreted in the bile, formation of an ultrafiltrate in the proximal tubule leaves this tissue susceptible to damage. The rupturing of lysosomes and the subsequent release of destructive enzymes are responsible for cell death and necrosis.

Hypertension: The most common manifestation of hypercupremia is hypertension. High copper levels in the tissues are positively correlated with CVD and hypertension. Melanin, the natural skin pigment, seems to be a factor in the etiology of some forms of hypertension, especially in the darker skinned populations.

Cancer: Elevated copper is related to cancer, either as a possible cause or as a sign of malignancy. Elevated copper levels enhance the biological damage of oxygen radicals leading to the loss of enzymatic activity, single or double standard breaks in DNA, and changes in protein properties.

Free radicals, whose production is catalyzed by free, unbound copper, have been linked to a number of the "diseases of aging." In addition to cancer, the cellular irritation generated by toxic radicals has been linked to atherosclerosis and immune deficiency. Copper may play an integral role in the degenerative processes of aging.

Dementia Dialytica: Is heavy metal poisoning resulting from the use of tap water for a dialysis of kidney patients. Symptoms of this acute intoxication range from psychosis and loss of reality to such fatal complications as cardiac failure and hemolytic anemia. Fortunately, the use of de-ionized water in standard dialysis has greatly reduced the threat of heavy metal intoxication in such treatments.

Aging: Copper accumulates with age as zinc declines, resulting in a higher risk of intoxication in the elderly than any other age group. Free unbound copper increases as the copper burden is elevated and is responsible for the formation of toxic oxygen radicals in the body. A growing number of "free radical diseases" are being identified and to date these include cancer, atherosclerosis, hypertension, senile dementia, and immune deficiency. Surprisingly, two cupric enzymes are responsible for the neutralization of such radicals, namely superoxide dismutase and ceruloplasmin. If elevated, free copper overwhelms these natural defenses.

Treatment

Drug treatment consists of chelating agents, namely penicillamine, which binds copper ions causing their excretion. The copper levels may be brought to the normal range, but zinc, molybdenum, manganese, and other cations may be depleted leading to numerous side effects such as anorexia, nausea, vomiting, epigastric pain, peptic ulcers, hepatic dysfunction, pancreatitis, loss of taste, hemolytic anemia, bone marrow depression, leukocytosis, proteinuria, alopecia, epidermal necrolysis, bronchiolitis, pulmonary fibrosis, bronchial asthma, and excessive wrinkling of the skin. Penicillamine therapy, therefore, should be avoided except for severe cases of acute poisoning, rheumatoid arthritis, and some cases of Wilson's disease.

Zinc has been shown to protect against copper toxicosis by inhibiting intestinal absorption while promoting excretion in the bile. Additional reports have documented copper deficiency anemia in humans suffering from zinc intoxication. Manganese is synergistic with zinc in copper elimination and therefore manganese should be combined with zinc therapy.