Copper in health - AbsoluteAstronomy.com

Copper is a chemical element with the symbol Cu and atomic number 29. It is a ductile metal with very high thermal and electrical conductivity. Pure copper is soft and malleable; an exposed surface has a reddish-orange tarnish...

is an essential trace element

Trace element

In analytical chemistry, a trace element is an element in a sample that has an average concentration of less than 100 parts per million measured in atomic count, or less than 100 micrograms per gram....

that is vital to the health of all living things (humans, plants, animals, and microorganisms). In humans, copper is essential to the proper functioning of organs

Organ (anatomy)

In biology, an organ is a collection of tissues joined in structural unit to serve a common function. Usually there is a main tissue and sporadic tissues . The main tissue is the one that is unique for the specific organ. For example, main tissue in the heart is the myocardium, while sporadic are...

and metabolic

Metabolism

Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...

processes. The human body has complex homeostatic mechanisms which attempt to ensure a constant supply of available copper, while eliminating excess copper whenever this occurs. However, like all essential elements and nutrients, too much or too little nutrition

Nutrition

Nutrition is the provision, to cells and organisms, of the materials necessary to support life. Many common health problems can be prevented or alleviated with a healthy diet....

al ingestion of copper can result in a corresponding condition of copper excess or deficiency in the body, each of which has its own unique set of adverse health effects.

Daily dietary standards for copper have been set by various health agencies around the world. Standards adopted by some nations recommend different copper intake levels for adults, pregnant women, infants, and children, corresponding to the varying need for copper during different stages of life.

Copper deficiency and toxicity can be either of genetic

Genetics

Genetics , a discipline of biology, is the science of genes, heredity, and variation in living organisms....

or non-genetic origin. The study of copper’s genetic diseases, which are the focus of intense international research activity, has shed insight into how human bodies use copper, and why it is important as an essential micronutrient

Micronutrient

Micronutrients are nutrients required by humans and other living things throughout life in small quantities to orchestrate a whole range of physiological functions, but which the organism itself cannot produce. For people, they include dietary trace minerals in amounts generally less than 100...

. The studies have also resulted in successful treatments for genetic copper excess conditions, enabling patients whose lives were once jeopardized to live long and productive lives.

Researchers specializing in the fields of microbiology

Microbiology

Microbiology is the study of microorganisms, which are defined as any microscopic organism that comprises either a single cell , cell clusters or no cell at all . This includes eukaryotes, such as fungi and protists, and prokaryotes...

, toxicology

Toxicology

Toxicology is a branch of biology, chemistry, and medicine concerned with the study of the adverse effects of chemicals on living organisms...

, nutrition

Nutrition

Nutrition is the provision, to cells and organisms, of the materials necessary to support life. Many common health problems can be prevented or alleviated with a healthy diet....

, and health risk assessments are working together to define the precise copper levels that are required for essentiality, while avoiding deficient or excess copper intakes. Results from these studies are expected to be used to fine-tune governmental dietary recommendation programs which are designed to help protect public health.

Essentiality

Copper is an essential trace element (i.e., micronutrient

Micronutrient

) that is required for plant, animal, and human health. It is also required for the normal functioning of aerobic

Aerobic organism

An aerobic organism or aerobe is an organism that can survive and grow in an oxygenated environment.Faculitative anaerobes grow and survive in an oxygenated environment and so do aerotolerant anaerobes.-Glucose:...

(oxygen-requiring) microorganisms.

Copper is incorporated into a variety of proteins and metalloenzymes which perform essential metabolic functions; the micronutrient is necessary for the proper growth, development, and maintenance of bone, connective tissue

Connective tissue

"Connective tissue" is a fibrous tissue. It is one of the four traditional classes of tissues . Connective Tissue is found throughout the body.In fact the whole framework of the skeleton and the different specialized connective tissues from the crown of the head to the toes determine the form of...

, brain, heart, and many other body organs. Copper is involved in the formation of red blood cells, the absorption and utilization of iron, the metabolism of cholesterol

Cholesterol

Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...

and glucose

Glucose

Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...

, and the synthesis and release of life-sustaining proteins and enzymes. These enzymes in turn produce cellular energy and regulate nerve transmission, blood clotting, and oxygen transport.

Copper stimulates the immune system

Immune system

An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...

to fight infections, to repair injured tissues, and to promote healing. Copper also helps to neutralize "free-radicals", which can cause severe damage to cells.

Copper’s essentiality was first discovered in 1928, when it was demonstrated that rats fed a copper-deficient milk diet were unable to produce sufficient red blood cells. The anemia

Anemia

Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...

was corrected by the addition of copper-containing ash from vegetable or animal sources.

As an essential trace element, daily dietary requirements for copper have been recommended by a number of governmental health agencies around the world.

Fetuses, infants, and children

Copper is essential for the normal growth and development of human fetuses, infant

Infant

A newborn or baby is the very young offspring of a human or other mammal. A newborn is an infant who is within hours, days, or up to a few weeks from birth. In medical contexts, newborn or neonate refers to an infant in the first 28 days after birth...

s, and child

Child

Biologically, a child is generally a human between the stages of birth and puberty. Some vernacular definitions of a child include the fetus, as being an unborn child. The legal definition of "child" generally refers to a minor, otherwise known as a person younger than the age of majority...

ren. The human fetus accumulates copper rapidly in its liver

Liver

The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...

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

Cellular respiration

Cellular respiration is the set of the metabolic reactions and processes that take place in the cells of organisms to convert biochemical energy from nutrients into adenosine triphosphate , and then release waste products. The reactions involved in respiration are catabolic reactions that involve...

, melanin

Melanin

Melanin is a pigment that is ubiquitous in nature, being found in most organisms . In animals melanin pigments are derivatives of the amino acid tyrosine. The most common form of biological melanin is eumelanin, a brown-black polymer of dihydroxyindole carboxylic acids, and their reduced forms...

pigment and connective tissue synthesis, iron metabolism, free radical defense, gene expression

Gene expression

Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...

, and the normal functioning of the heart

Heart

The heart is a myogenic muscular organ found in all animals with a circulatory system , that is responsible for pumping blood throughout the blood vessels by repeated, rhythmic contractions...

and immune system

Immune system

s in infants.

Infants have special biochemical mechanisms for adequately managing copper in their bodies while permanent life-long mechanisms develop and mature.

Severe deficiency of copper in pregnant mothers increases the risk of health problems in their fetuses and infants. Health effects noted include low birth weights, muscle weaknesses, and neurologic problems. However, copper deficiencies in pregnant women can be avoided with a balanced diet.

Since copper availability in the body is hindered by an excess of iron

Iron

Iron is a chemical element with the symbol Fe and atomic number 26. It is a metal in the first transition series. It is the most common element forming the planet Earth as a whole, forming much of Earth's outer and inner core. It is the fourth most common element in the Earth's crust...

and zinc

Zinc

Zinc , or spelter , is a metallic chemical element; it has the symbol Zn and atomic number 30. It is the first element in group 12 of the periodic table. Zinc is, in some respects, chemically similar to magnesium, because its ion is of similar size and its only common oxidation state is +2...

intake, pregnant women prescribed iron supplements to treat anemia or zinc supplements to treat colds should consult doctors to be sure that the prenatal supplements they may be taking also have nutritionally-significant amounts of copper.

When newborn babies are breastfed, the babies’ livers and the mothers’ breast milk provide sufficient quantities of copper for the first 4–6 months of life. When babies are weaned, a balanced diet should provide adequate sources of copper.

Cow's milk and some older infant formula

Infant formula

Infant formula is a manufactured food designed and marketed for feeding to babies and infants under 12 months of age, usually prepared for bottle-feeding or cup-feeding from powder or liquid . The U.S...

s are depleted in copper. Most formulas are now fortified with copper to prevent depletion.

Most well-nourished children have adequate intakes of copper. Health-compromised children, including those who are premature, malnourished, have low birth weights, suffer from infections, and who experience rapid catch-up growth spurts, are at elevated risk for copper deficiencies. Fortunately, diagnosis of copper deficiency in children is clear and reliable once the condition is suspected. Supplements under a doctor’s supervision usually facilitate a full recovery.

Homeostasis

Copper is absorbed, transported, distributed, stored, and excreted in the body according to complex homeostatic processes which ensure a constant and sufficient supply of the micronutrient while simultaneously avoiding excess levels. If an insufficient amount of copper is ingested for a short period of time, copper stores in the liver will be depleted. Should this depletion continue, a copper health deficiency condition may develop. If too much copper is ingested, an excess condition can result. Both of these conditions, deficiency and excess, can lead to tissue injury and disease. However, due to homeostatic regulation, the human body is capable of balancing a wide range of copper intakes for the needs of healthy individuals.

Many aspects of copper homeostasis

Homeostasis

Homeostasis is the property of a system that regulates its internal environment and tends to maintain a stable, constant condition of properties like temperature or pH...

are known at the molecular level. Copper’s essentiality is due to its ability to act as an electron donor or acceptor as its oxidation state fluxes between Cu⁺¹(cuprous) and Cu⁺² (cupric). As a component of about a dozen cuproenzymes, copper is involved in key redox

Redox

Redox reactions describe all chemical reactions in which atoms have their oxidation state changed....

(i.e., oxidation-reduction) reactions in essential metabolic processes such as mitochondrial respiration, synthesis of melanin

Melanin

, and cross-linking of collagen

Collagen

Collagen is a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of mammals. It is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content...

. Copper is an integral part of the antioxidant enzyme, copper-zinc superoxide dismutase (Cu,Zn-SOD), and has a role in iron homeostasis as a cofactor in ceruloplasmin. A list of some key copper-containing enzymes and their functions is summarized below:

Key copper-containing enzymes and their functions
Enzymes	Function
Amine oxidase Amine oxidase Amine oxidase is an enzyme involved in the metabolism of histamine.-External links:... s	Group of enzymes oxidizing primary amines (e.g., tyramine, histidine and polylamines)
Ceruloplasmin Ceruloplasmin Ceruloplasmin is a ferroxidase enzyme that in humans is encoded by the CP gene.Ceruloplasmin is the major copper-carrying protein in the blood, and in addition plays a role in iron metabolism. It was first described in 1948... (ferroxidase Ferroxidase Ferroxidase also known as Fe:oxygen oxidoreductase is an enzyme that catalyzes the oxidization of iron II to iron III:- Examples :Human genes encoding proteins with ferroxidase activity include:* CP – Ceruloplasmin* FTH1 – Ferritin heavy chain... I)	Multi-copper oxidase in plasma, essential for iron transport
Cytochrome c oxidase Cytochrome c oxidase The enzyme cytochrome c oxidase or Complex IV is a large transmembrane protein complex found in bacteria and the mitochondrion.It is the last enzyme in the respiratory electron transport chain of mitochondria located in the mitochondrial membrane...	Terminal oxidase enzyme in mitochondrial respiratory chain, involved in electron transport
Dopamine ß-hydroxylase	Involved in catecholamine Catecholamine Catecholamines are molecules that have a catechol nucleus consisting of benzene with two hydroxyl side groups and a side-chain amine. They include dopamine, as well as the "fight-or-flight" hormones adrenaline and noradrenaline released by the adrenal medulla of the adrenal glands in response to... metabolism, catalyzes conversion of dopamine Dopamine Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their... to norepinephrine Norepinephrine Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
Hephaestin Hephaestin Hephaestin also known as HEPH is a protein which in humans is encoded by the HEPH gene.-Function:Hephaestin is involved in the metabolism and homeostasis of iron and possibly copper. It is a transmembrane copper-dependent ferroxidase responsible for transporting dietary iron from intestinal...	Multi-copper ferroxidase Ferroxidase Ferroxidase also known as Fe:oxygen oxidoreductase is an enzyme that catalyzes the oxidization of iron II to iron III:- Examples :Human genes encoding proteins with ferroxidase activity include:* CP – Ceruloplasmin* FTH1 – Ferritin heavy chain... , involved in iron transport across intestinal mucosa into portal circulation
Lysyl oxidase Lysyl oxidase Lysyl oxidase also known as protein-lysine 6-oxidase is a protein that, in humans, is encoded by the LOX gene. Its inhibition can cause lathyrism, but, at the same time, its upregulation by tumor cells may promote metastasis of the existing tumor, causing it to become malignant and cancerous.-...	Cross-linking of collagen Collagen Collagen is a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of mammals. It is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content... and elastin Elastin Elastin is a protein in connective tissue that is elastic and allows many tissues in the body to resume their shape after stretching or contracting. Elastin helps skin to return to its original position when it is poked or pinched. Elastin is also an important load-bearing tissue in the bodies of...
Peptidylglycine alpha-amidating mono-oxygenase (PAM)	Multifunction enzyme involved in maturation and modification of key neuropeptides (e.g., neurotransmitters, neuroendocrine peptides)
Superoxide dismutase Superoxide dismutase Superoxide dismutases are a class of enzymes that catalyze the dismutation of superoxide into oxygen and hydrogen peroxide. As such, they are an important antioxidant defense in nearly all cells exposed to oxygen... (Cu, Zn)	Intracellular Intracellular Not to be confused with intercellular, meaning "between cells".In cell biology, molecular biology and related fields, the word intracellular means "inside the cell".It is used in contrast to extracellular... and extracellular Extracellular In cell biology, molecular biology and related fields, the word extracellular means "outside the cell". This space is usually taken to be outside the plasma membranes, and occupied by fluid... enzyme involved in defense against reactive oxygen species (e.g., destruction of superoxide Superoxide A superoxide, also known by the obsolete name hyperoxide, is a compound that possesses the superoxide anion with the chemical formula O2−. The systematic name of the anion is dioxide. It is important as the product of the one-electron reduction of dioxygen O2, which occurs widely in nature... radicals)
Tyrosinase Tyrosinase Tyrosinase also known as monophenol monooxygenase is an enzyme that catalyses the oxidation of phenols and is widespread in plants and animals...	Enzyme catalyzing melanin and other pigment production

The transport and metabolism of copper in living organisms is currently the subject of much active research. Copper transport at the cellular level involves the movement of extracellular copper across the cell membrane

Cell membrane

The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...

and into the cell by specialized transporters. In the bloodstream, copper is carried throughout the body by albumin

Albumin

Albumin refers generally to any protein that is water soluble, which is moderately soluble in concentrated salt solutions, and experiences heat denaturation. They are commonly found in blood plasma, and are unique to other blood proteins in that they are not glycosylated...

, ceruloplasmin

Ceruloplasmin

Ceruloplasmin is a ferroxidase enzyme that in humans is encoded by the CP gene.Ceruloplasmin is the major copper-carrying protein in the blood, and in addition plays a role in iron metabolism. It was first described in 1948...

, and other proteins. The majority of blood copper (or serum copper) is bound to ceruloplasmin. The proportion of ceruloplasmin-bound copper can range from 70-95% and differs between individuals, depending, for example, on hormonal cycle, season, and copper status. Intracellular copper is routed to sites of synthesis of copper-requiring enzymes and to organelles by specialized proteins called metallochaperones. Another set of these transporters carries copper into subcellular compartments. Certain mechanisms exist to release copper from the cell. Specialized transporters return excess unstored copper to the liver for additional storage and/or biliary excretion. These mechanisms ensure that free unbound toxic ionic copper is unlikely to exist in the majority of the population (i.e., those without genetic copper metabolism defects).

Copper is imported into cells through the cell wall by the plasma membrane transport protein known as Copper Transporter 1, or Ctr1. Ctr1 rapidly binds to intracellular copper chaperone proteins. Atox1 delivers copper to the secretory pathway and docks with either copper-transporting ATPase ATP7B in the liver or ATP7A in other cells. ATP7B directs copper to plasma ceruloplasmin or to biliary excretion in concert with a newly discovered chaperone, Murr1, the protein missing in canine copper toxicosis. ATP7A directs copper within the trans-Golgi network to the proteins dopamine beta-monooxygenase

Dopamine beta-monooxygenase

In enzymology, a dopamine beta-monooxygenase is an enzyme that catalyzes the chemical reactionThe 3 substrates of this enzyme are 3,4-dihydroxyphenethylamine, ascorbate, and O2, whereas its 3 products are noradrenaline, dehydroascorbate, and H2O....

, peptidylglycine alpha-amidating monooxygenase

Peptidylglycine alpha-amidating monooxygenase

Peptidyl-glycine alpha-amidating monooxygenase is an enzyme that in humans is encoded by the PAM gene.-Interactions:Peptidylglycine alpha-amidating monooxygenase has been shown to interact with TSC2.-Further reading:...

, lysyl oxidase

Lysyl oxidase

Lysyl oxidase also known as protein-lysine 6-oxidase is a protein that, in humans, is encoded by the LOX gene. Its inhibition can cause lathyrism, but, at the same time, its upregulation by tumor cells may promote metastasis of the existing tumor, causing it to become malignant and cancerous.-...

, and tyrosinase

Tyrosinase

Tyrosinase also known as monophenol monooxygenase is an enzyme that catalyses the oxidation of phenols and is widespread in plants and animals...

, depending on the cell type. CCS

CCS (gene)

Copper chaperone for superoxide dismutase is a metalloprotein that in humans is encoded by the CCS gene.-Interactions:CCS has been shown to interact with SOD1 and APBA1.-Further reading:...

is the copper chaperone for the Cu/Zn-superoxide dismutase that protects cells against reactive oxygen species; it delivers copper in the cytoplasm

Cytoplasm

The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...

and intermitochondrial space. Cox17 delivers copper to mitochondria to cytochrome c oxidase

Cytochrome c oxidase

The enzyme cytochrome c oxidase or Complex IV is a large transmembrane protein complex found in bacteria and the mitochondrion.It is the last enzyme in the respiratory electron transport chain of mitochondria located in the mitochondrial membrane...

via the chaperones Cox11, Sco1, and Sco2. Other copper chaperones may exist and might include metallothionein

Metallothionein

Metallothionein is a family of cysteine-rich, low molecular weight proteins. They are localized to the membrane of the Golgi apparatus...

and amyloid precursor protein

Amyloid precursor protein

Amyloid precursor protein is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. Its primary function is not known, though it has been implicated as a regulator of synapse formation, neural plasticity and iron export...

(APP). Genetic and nutritional studies have illustrated the essential nature of these copper-binding proteins.

Absorption

In mammals, copper is absorbed in the stomach and small intestine, although there appear to be differences among species with respect to the site of maximal absorption. Copper is absorbed from the stomach and duodenum

Duodenum

The duodenum is the first section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear and the terms anterior intestine or proximal intestine may be used instead of duodenum...

in rats and from the lower small intestine in hamsters. The site of maximal copper absorption is not known for humans, but is assumed to be the stomach and upper intestine because of the rapid appearance of Cu64 in the plasma after oral administration.

Absorption of copper ranges from 15–97%, depending on copper content, form of the copper, and composition of the diet.

Various factors influence copper absorption. For example, copper absorption is enhanced by ingestion of animal protein

Protein

Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

, citrate

Citrate

A citrate can refer either to the conjugate base of citric acid, , or to the esters of citric acid. An example of the former, a salt is trisodium citrate; an ester is triethyl citrate.-Other citric acid ions:...

, and phosphate

Phosphate

A phosphate, an inorganic chemical, is a salt of phosphoric acid. In organic chemistry, a phosphate, or organophosphate, is an ester of phosphoric acid. Organic phosphates are important in biochemistry and biogeochemistry or ecology. Inorganic phosphates are mined to obtain phosphorus for use in...

. Copper salts, including copper gluconate

Copper gluconate

Copper gluconate is the copper salt of D-gluconic acid.- Uses :*Dietary supplement -- metabolizable copper to treat copper deficiency.*Used to treat acne vulgaris, common cold, hypertension, premature labor, Leishmaniasis, visceral postoperative complications.*Ingredient of Retsyn.- Side effects...

, copper acetate, or copper sulfate, are more easily absorbed than copper oxide

Copper oxide

Copper oxide is a compound from the two elements copper and oxygen.Copper oxide may refer to:*Copper oxide , a red powder;*Copper oxide , a black powder...

s. Elevated levels of dietary zinc

Zinc

, as well as cadmium

Cadmium

Cadmium is a chemical element with the symbol Cd and atomic number 48. This soft, bluish-white metal is chemically similar to the two other stable metals in group 12, zinc and mercury. Similar to zinc, it prefers oxidation state +2 in most of its compounds and similar to mercury it shows a low...

, high intakes of phytlate and simple sugars (fructose

Fructose

Fructose, or fruit sugar, is a simple monosaccharide found in many plants. It is one of the three dietary monosaccharides, along with glucose and galactose, that are absorbed directly into the bloodstream during digestion. Fructose was discovered by French chemist Augustin-Pierre Dubrunfaut in 1847...

, sucrose

Sucrose

Sucrose is the organic compound commonly known as table sugar and sometimes called saccharose. A white, odorless, crystalline powder with a sweet taste, it is best known for its role in human nutrition. The molecule is a disaccharide composed of glucose and fructose with the molecular formula...

) inhibit dietary absorption of copper. Furthermore, low levels of dietary copper inhibit iron absorption.

Some forms of copper are not soluble in stomach acids and cannot be absorbed from the stomach or small intestine. Also, some foods may contain indigestible fiber that binds with copper. High intakes of zinc

Zinc

can significantly decrease copper absorption. Extreme intakes of Vitamin C

Vitamin C

Vitamin C or L-ascorbic acid or L-ascorbate is an essential nutrient for humans and certain other animal species. In living organisms ascorbate acts as an antioxidant by protecting the body against oxidative stress...

or iron

Iron

can also affect copper absorption, reminding us of the fact that micronutrients need to be consumed as a balanced mixture. This is one reason why extreme intakes of any one single micronutrient are not advised. Individuals with chronic digestive problems may be unable to absorb sufficient amounts of copper, even though the foods they eat are copper-rich.

Several copper transporters have been identified that can move copper across cell membranes. Other intestinal copper transporters may exist. Intestinal copper uptake may be catalyzed by Ctr1. Ctr1 is expressed in all cell types so far investigated, including enterocytes, and it catalyzes the transport of Cu+1 across the cell membrane.

Excess copper (as well as other heavy metal ions like zinc or cadmium) is sequestered in enterocyte

Enterocyte

Enterocytes, or intestinal absorptive cells, are simple columnar epithelial cells found in the small intestines and colon. A glycocalyx surface coat contains digestive enzymes. Microvilli on the apical surface increase surface area for the digestion and transport of molecules from the intestinal...

(i.e., predominant cells in the small intestinal mucosa) metallothionein.

Distribution

Copper released from intestinal cells moves to the serosal (i.e., thin membrane lining) capillaries where it binds to albumin

Albumin

, glutathione

Glutathione

Glutathione is a tripeptide that contains an unusual peptide linkage between the amine group of cysteine and the carboxyl group of the glutamate side-chain...

, and amino acid

Amino acid

Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...

s in the portal blood. There is also evidence for a small protein, transcuprein, with a specific role in plasma copper transport Several or all of these copper-binding molecules may participate in serum copper transport. Copper from portal circulation is primarily taken up by the liver. Once in the liver, copper is either incorporated into copper-requiring proteins, which are subsequently secreted into the blood. Most of the copper (70 – 95%) is incorporated into ceruloplasmin

Ceruloplasmin

, the main copper carrier in blood. Copper is transported to extra-hepatic tissues by albumin

Albumin

and amino acid

Amino acid

s, or excreted into the bile

Bile

Bile or gall is a bitter-tasting, dark green to yellowish brown fluid, produced by the liver of most vertebrates, that aids the process of digestion of lipids in the small intestine. In many species, bile is stored in the gallbladder and upon eating is discharged into the duodenum...

. By regulating copper release, the liver exerts homeostatic control over extrahepatic copper.

Excretion

Bile is the major pathway for the excretion of copper and is vitally important in the control of liver copper levels. Most fecal copper results from biliary excretion; the remainder is derived from unabsorbed copper and copper from desquamated mucosal cells.

postulated spectrum of copper metabolism
Dose range	Approximate daily intakes	Health outcomes
		Death
		Gross dysfunction and disturbance of metabolism of other nutrients; hepatic “detoxification” and homeostasis overwhelmed
Toxic	>5.0 mg/kg body weight	Gastrointestinal metallothionein induced (possible differing effects of acute and chronic exposure)
	100 μg/kg body weight	Plateau of absorption maintained; homeostatic mechanisms regulate absorption of copper
Adequate	34 μg/kg body weight	Hepatic uptake, sequestration and excretion effect homeostasis; glutathione-dependent uptake of copper; binding to metallothionein; and lysosomal excretion of copper
	11 μg/kg body weight	Biliary excretion and gastrointestinal uptake normal
	9 μg/kg body weight	Hepatic deposit(s) reduced; conservation of endogenous copper; gastrointestinal absorption increased
Deficient	8.5 μg/kg body weight	Negative copper balance
	5.2 μg/kg body weight	Functional defects, such as lysyl oxidase and superoxide dismutase activities reduced; impaired substrate metabolism
	2 μg/kg body weight	Peripheral pools disrupted; gross dysfunction and disturbance of metabolism of other nutrients; death

Daily dietary copper requirements

Various national and international organizations concerned with nutrition and health have standards for copper intake at levels judged to be adequate for maintaining good health. These standards, or dietary reference values, are periodically changed and updated as new scientific data become available. The standards sometimes differ among regions and organizations.

Adults

The World Health Organization

World Health Organization

The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...

recommends a minimal acceptable intake of approximately 1.3 mg/day. These values are considered to be adequate and safe for most of the general population. In North America, the recommended intake of copper for healthy adult men and women is 900 micrograms/day (0.9 mg/day). Health benefits above the recommended adequate intake of 0.9 - 1.3 mg/day have not been established.

In North America, a maximum tolerable intake has been established at 10 mg/day. This is the highest level of copper intake that is not likely to pose a health risk to most adults in the general population. However, this daily intake level is not recommended by any authority.

Adolescents, children, and infants

The World Health Organization has not developed minimum daily intakes for these age groups. In North America, safe and acceptable daily intakes have been estimated from adult data and are as follows: 340 micrograms/day (0.34 mg/day) for children of 1–3 years; 440 micrograms/day (0.44 mg/day) for 4–8 years; 700 micrograms/day (0.7 mg/day) for 9–13 years; and 890 micrograms/day (0.89 mg/day) for 14–18 years.

In North America, tolerable intakes for these age groups (i.e., intakes not likely to pose a health risk for most children in the general population, but for which no additional health benefits are known) are: 1 mg/day for children of 1–3 years; 3 mg/day for 4–8 years; 5 mg/day for 9–13 years; and 8 mg/day for 14–18 years.

Full-term and premature infants are more sensitive to copper deficiency than adults. Since the fetus accumulates copper during the last 3 months of pregnancy, infants that are born prematurely have not had sufficient time to store adequate reserves of copper in their livers and therefore require more copper at birth than full-term infants.

For full-term infants, the North American recommended safe and adequate intake is approximately 0.2 mg/day. For premature babies, it is considerably higher: 1 mg/day. The World Health Organization has recommended similar minimum adequate intakes and advises that premature infants be given formula supplemented with extra copper to prevent the development of copper deficiency.

Pregnant women and mothers who breastfeed

Nature has devised a way for the fetus

Fetus

A fetus is a developing mammal or other viviparous vertebrate after the embryonic stage and before birth.In humans, the fetal stage of prenatal development starts at the beginning of the 11th week in gestational age, which is the 9th week after fertilization.-Etymology and spelling variations:The...

to get copper from the mother via the placenta

Placenta

The placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...

and for infants to get copper via breast milk. For these reasons, pregnancy and nursing increase the body's need for copper. The recommended oral intake in pregnant and nursing women is slightly higher than for non-pregnant, non-nursing healthy women (approximately 1 mg/day for pregnant women and 1.3 mg/day for nursing mothers aged 14–50 years).

The best source of copper and other essential micronutrients during the first year of life is human milk. If a full-term infant is not nursed, fortified baby formula is highly recommended. Cow's milk, however, contains very low amounts of bioavailable copper and should be supplemented with copper during the first year of life.

Dietary sources

Copper is an essential trace mineral that cannot be formed by the human body. It must be ingested from dietary sources.

Foods contribute virtually all of the copper consumed by humans. The best dietary sources include seafood

Seafood

Seafood is any form of marine life regarded as food by humans. Seafoods include fish, molluscs , crustaceans , echinoderms . Edible sea plants, such as some seaweeds and microalgae, are also seafood, and are widely eaten around the world, especially in Asia...

(especially shellfish

Shellfish

Shellfish is a culinary and fisheries term for exoskeleton-bearing aquatic invertebrates used as food, including various species of molluscs, crustaceans, and echinoderms. Although most kinds of shellfish are harvested from saltwater environments, some kinds are found only in freshwater...

), organ meats (e.g., liver), whole grain

Whole grain

Whole grains are cereal grains that contain cereal germ, endosperm, and bran, in contrast to refined grains, which retain only the endosperm. Whole grains can generally be sprouted while refined grains generally will not sprout. Whole-meal products are made by grinding whole grains in order to make...

s, legumes (e.g., bean

Bean

Bean is a common name for large plant seeds of several genera of the family Fabaceae used for human food or animal feed....

s and lentil

Lentil

The lentil is an edible pulse. It is a bushy annual plant of the legume family, grown for its lens-shaped seeds...

s) and chocolate

Chocolate

Chocolate is a raw or processed food produced from the seed of the tropical Theobroma cacao tree. Cacao has been cultivated for at least three millennia in Mexico, Central and South America. Its earliest documented use is around 1100 BC...

. Nuts, including peanut

Peanut

The peanut, or groundnut , is a species in the legume or "bean" family , so it is not a nut. The peanut was probably first cultivated in the valleys of Peru. It is an annual herbaceous plant growing tall...

s and pecan

Pecan

The pecan , Carya illinoinensis, is a species of hickory, native to south-central North America, in Mexico from Coahuila south to Jalisco and Veracruz, in the United States from southern Iowa, Illinois, Missouri, and Indiana east to western Kentucky, southwestern Ohio, North Carolina, South...

s, are especially rich in copper, as are grains such as wheat

Wheat

Wheat is a cereal grain, originally from the Levant region of the Near East, but now cultivated worldwide. In 2007 world production of wheat was 607 million tons, making it the third most-produced cereal after maize and rice...

and rye

Rye

Rye is a grass grown extensively as a grain and as a forage crop. It is a member of the wheat tribe and is closely related to barley and wheat. Rye grain is used for flour, rye bread, rye beer, some whiskeys, some vodkas, and animal fodder...

, and several fruits including lemon

Lemon

The lemon is both a small evergreen tree native to Asia, and the tree's ellipsoidal yellow fruit. The fruit is used for culinary and non-culinary purposes throughout the world – primarily for its juice, though the pulp and rind are also used, mainly in cooking and baking...

s and raisin

Raisin

Raisins are dried grapes. They are produced in many regions of the world. Raisins may be eaten raw or used in cooking, baking and brewing...

s. Other food sources that contain copper include cereal

Cereal

Cereals are grasses cultivated for the edible components of their grain , composed of the endosperm, germ, and bran...

s, potato

Potato

The potato is a starchy, tuberous crop from the perennial Solanum tuberosum of the Solanaceae family . The word potato may refer to the plant itself as well as the edible tuber. In the region of the Andes, there are some other closely related cultivated potato species...

es, pea

Pea

A pea is most commonly the small spherical seed or the seed-pod of the pod fruit Pisum sativum. Each pod contains several peas. Peapods are botanically a fruit, since they contain seeds developed from the ovary of a flower. However, peas are considered to be a vegetable in cooking...

s, red meat

Red meat

Red meat in traditional culinary terminology is meat which is red when raw and not white when cooked. In the nutritional sciences, red meat includes all mammal meat. Red meat includes the meat of most adult mammals and some fowl ....

, mushroom

Mushroom

A mushroom is the fleshy, spore-bearing fruiting body of a fungus, typically produced above ground on soil or on its food source. The standard for the name "mushroom" is the cultivated white button mushroom, Agaricus bisporus; hence the word "mushroom" is most often applied to those fungi that...

s, some dark green leafy vegetables (such as kale

Kale

Kale is very high in beta carotene, vitamin K, vitamin C, lutein, zeaxanthin, and reasonably rich in calcium. Kale, as with broccoli and other brassicas, contains sulforaphane , a chemical with potent anti-cancer properties. Boiling decreases the level of sulforaphane; however, steaming,...

), and fruits (coconut

Coconut

The coconut palm, Cocos nucifera, is a member of the family Arecaceae . It is the only accepted species in the genus Cocos. The term coconut can refer to the entire coconut palm, the seed, or the fruit, which is not a botanical nut. The spelling cocoanut is an old-fashioned form of the word...

s, papaya

Papaya

The papaya , papaw, or pawpaw is the fruit of the plant Carica papaya, the sole species in the genus Carica of the plant family Caricaceae...

and apple

Apple

The apple is the pomaceous fruit of the apple tree, species Malus domestica in the rose family . It is one of the most widely cultivated tree fruits, and the most widely known of the many members of genus Malus that are used by humans. Apple grow on small, deciduous trees that blossom in the spring...

s). Tea

Tea

Tea is an aromatic beverage prepared by adding cured leaves of the Camellia sinensis plant to hot water. The term also refers to the plant itself. After water, tea is the most widely consumed beverage in the world...

, rice

Rice

Rice is the seed of the monocot plants Oryza sativa or Oryza glaberrima . As a cereal grain, it is the most important staple food for a large part of the world's human population, especially in East Asia, Southeast Asia, South Asia, the Middle East, and the West Indies...

and chicken

Chicken

The chicken is a domesticated fowl, a subspecies of the Red Junglefowl. As one of the most common and widespread domestic animals, and with a population of more than 24 billion in 2003, there are more chickens in the world than any other species of bird...

are relatively low in copper, but can provide a reasonable amount of copper when they are consumed in significant amounts.

Eating a balanced diet with a range of foods from different food groups is the best way to avoid copper deficiency. In both developed and developing countries, adults, young children, and adolescents who consume diets of grain, millet

Millet

The millets are a group of small-seeded species of cereal crops or grains, widely grown around the world for food and fodder. They do not form a taxonomic group, but rather a functional or agronomic one. Their essential similarities are that they are small-seeded grasses grown in difficult...

, tuber

Tuber

Tubers are various types of modified plant structures that are enlarged to store nutrients. They are used by plants to survive the winter or dry months and provide energy and nutrients for regrowth during the next growing season and they are a means of asexual reproduction...

, or rice along with legumes (beans) or small amounts of fish or meat, some fruits and vegetables, and some vegetable oil are likely to obtain adequate copper if their total food consumption is adequate in calories. In developed countries where consumption of red meat is high, copper intake is also likely to be adequate.

As a natural element in the earth's crust, copper exists in most of the world's surface water and groundwater, although the actual concentration of copper in natural waters varies geographically. Drinking water can comprise 20-25% of dietary copper.

In many regions of the world, copper tubing that conveys drinking water can be a source of dietary copper. Copper tube can leach a small amount of copper, particularly in its first year or two of service. Afterwards, a protective surface usually forms on the inside of copper tubes that retards leaching.

Supplementation

Copper supplements can prevent copper deficiency, but supplements should be taken only under a doctor's supervision. Different forms of copper supplementation have different absorption rates. For example, the absorption of copper from cupric oxide supplements is lower than that from copper gluconate

Copper gluconate

, sulfate, or carbonate.

Supplementation is generally not recommended for healthy adults who consume a well-balanced diet which includes a wide range of foods. However, supplementation under the care of a physician may be necessary for premature infants or those with low birth weights, infants fed unfortified formula or cow's milk during the first year of life, and malnourished young children. Physicians may consider copper supplementation for 1) illnesses that reduce digestion (e.g., children with frequent diarrhea

Diarrhea

Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...

or infection

Infection

An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...

s; alcoholics), 2) insufficient food consumption (e.g., the elderly, the infirm, those with eating disorder

Eating disorder

Eating disorders refer to a group of conditions defined by abnormal eating habits that may involve either insufficient or excessive food intake to the detriment of an individual's physical and mental health. Bulimia nervosa, anorexia nervosa, and binge eating disorder are the most common specific...

s or on diets), 3) patients taking medications that block the body's use of copper, 4) anemia

Anemia

patients who are treated with iron supplements, 5) anyone taking zinc supplements, and 6) those suffering from osteoporosis

Osteoporosis

Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...

Copper deficiency and excess health conditions (non-genetic)

If insufficient quantities of copper are ingested, copper reserves in the liver will become depleted and a copper deficiency leading to disease or tissue injury (and in extreme cases, death) may result. Toxicity from copper deficiency can be treated with a balanced diet or supplementation under the supervision of a doctor. On the contrary, like all substances, excess copper intake at levels far above World Health Organization

World Health Organization

limits can become toxic. Acute copper toxicity is generally associated with accidental ingestion. These symptoms abate when the high copper food source is no longer ingested.

In 1996, the International Program on Chemical Safety, a World Health Organization-associated agency, stated “there is greater risk of health effects from deficiency of copper intake than from excess copper intake.” This conclusion was confirmed in recent multi-route exposure surveys.

The health conditions of non-genetic copper deficiency and copper excess are described below.

Copper deficiency

A number of nutrition surveys have indicated that the diets of approximately 25% of adolescents, adults, and people over 65, do not meet the recommended daily nutrient intake for copper. These studies also suggest that long-term acquired copper deficiency is under-diagnosed and is much more common than suspected.

Symptoms of copper deficiency include osteoporosis

Osteoporosis

, osteoarthritis

Osteoarthritis

Osteoarthritis also known as degenerative arthritis or degenerative joint disease, is a group of mechanical abnormalities involving degradation of joints, including articular cartilage and subchondral bone. Symptoms may include joint pain, tenderness, stiffness, locking, and sometimes an effusion...

, rheumatoid arthritis

Rheumatoid arthritis

Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...

, cardiovascular disease, colon cancer, and chronic conditions involving bone, connective tissue, heart, and blood vessels. Furthermore, acquired copper deficiency has recently been implicated in adult-onset progressive myeloneuropathy and in the development of severe blood disorders including myelodysplastic syndrome

Myelodysplastic syndrome

The myelodysplastic syndromes are a diverse collection of hematological medical conditions that involve ineffective production of the myeloid class of blood cells....

. Fortunately, copper deficiency can be confirmed by very low serum

Blood serum

In blood, the serum is the component that is neither a blood cell nor a clotting factor; it is the blood plasma with the fibrinogens removed...

metal and ceruloplasmin

Ceruloplasmin

concentrations in the blood.

Copper deficiency alters the role of other cellular constituents involved in antioxidant activities, such as iron, selenium

Selenium

Selenium is a chemical element with atomic number 34, chemical symbol Se, and an atomic mass of 78.96. It is a nonmetal, whose properties are intermediate between those of adjacent chalcogen elements sulfur and tellurium...

, and glutathione

Glutathione

Glutathione is a tripeptide that contains an unusual peptide linkage between the amine group of cysteine and the carboxyl group of the glutamate side-chain...

, and therefore plays an important role in diseases in which oxidant stress is elevated.

In both humans and animals, the major target organs for copper deficiency are the blood and hematopoietic system, the cardiovascular system, connective tissue

Connective tissue

and bone, the nervous system, and the immune system.

A marginal (i.e., ‘mild’) copper deficiency, believed to be more widespread than previously thought, can impair human health in subtle ways. Those affected suffer from lowered resistance to infection, general fatigue, impaired neurological function, and elevated risk for coronary heart disease and osteoporosis.

Populations susceptible to copper deficiency include those with genetic defects for Menkes disease

Menkes disease

Menkes disease , also called Menkes syndrome, copper transport disease, steely hair disease, kinky hair disease, or Menkes kinky hair syndrome, is a disorder that affects copper levels in the body, leading to copper deficiency...

, low-birth-weight infants, infants fed cow’s milk instead of breast milk or fortified formula, pregnant and lactating mothers, patients receiving total parenteral nutrition

Total parenteral nutrition

Parenteral nutrition is feeding a person intravenously, bypassing the usual process of eating and digestion. The person receives nutritional formulae that contain nutrients such as glucose, amino acids, lipids and added vitamins and dietary minerals...

, individuals with “malabsorption syndrome” (impaired dietary absorption), diabetics, individuals with chronic diseases that result in low food intake, such as alcoholics, and persons with eating disorders. The elderly and athletes may also be at higher risk for copper deficiency due to special needs that increase the daily requirements. Vegetarians may have decreased copper intake due to the consumption of plant foods in which copper bioavailability is low. Fetuses and infants of severely copper deficient women have increased risk of low birth weights, muscle weaknesses, and neurological problems. Copper deficiencies in these populations may result in anemia, bone abnormalities, impaired growth, weight gain, frequent infections (colds, flu, pneumonia), poor motor coordination, and low energy.

Copper excess

Copper excess is a subject of much current research. Distinctions have emerged from studies that copper excess factors are different in normal populations versus those with increased susceptibility to adverse effects and those with rare genetic diseases. This has led to statements from health organizations that could be confusing to the uninformed. For example, according to a U.S. Institute of Medicine report, the intake levels of copper for a significant percentage of the population are lower than recommended levels. On the other hand, the U.S. National Research Council

United States National Research Council

The National Research Council of the USA is the working arm of the United States National Academies, carrying out most of the studies done in their names.The National Academies include:* National Academy of Sciences...

concluded in its report Copper in Drinking Water that there is concern for copper toxicity in susceptible populations and recommended that additional research be conducted to identify and characterize copper-sensitive populations.

Excess copper intake causes stomach upset, nausea

Nausea

Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...

, and diarrhea and can lead to tissue injury and disease.

The oxidation potential of copper may be responsible for some of its toxicity in excess ingestion cases. At high concentrations copper is known to produce oxidative damage to biological systems, including peroxidation of lipids or other macromolecules.

While the cause and progression of Alzheimer's disease

Alzheimer's disease

Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...

are not well understood, research indicates that, among several other key observations, iron

Iron

, aluminum, and copper accumulate in the brains of Alzheimer’s patients. However, it is not yet known whether this accumulation is a cause or a consequence of the disease.

Research has been ongoing over the past two decades to determine whether copper is a causative or a preventive agent of Alzheimer’s disease, and whether copper accumulates due to a metal homeostasis

Homeostasis

Homeostasis is the property of a system that regulates its internal environment and tends to maintain a stable, constant condition of properties like temperature or pH...

disturbance that develops in individuals with Alzheimer’s disease. For example, as a possible causative agent or an expression of a metal homeostasis

Homeostasis

Homeostasis is the property of a system that regulates its internal environment and tends to maintain a stable, constant condition of properties like temperature or pH...

disturbance, studies indicate that copper may play a role in increasing the growth of protein clumps in Alzheimer’s disease brains, possibly by damaging a molecule that removes the toxic buildup of amyloid beta

Amyloid beta

Amyloid beta is a peptide of 36–43 amino acids that is processed from the Amyloid precursor protein. While it is most commonly known in association with Alzheimer's disease, it does not exist specifically to cause disease...

(Aβ) in the brain. On the other hand, studies also demonstrate potential beneficial roles of copper in treating rather than causing Alzheimer’s disease. For example, copper has been shown to 1) promote the non-amyloidogenic processing of amyloid beta precursor protein (APP), thereby lowering amyloid beta

Amyloid beta

(Aβ) production in cell culture systems 2) increase lifetime and decrease soluble amyloid production in APP transgenic mice, and 3) lower Aβ levels in cerebral spinal fluid in Alzheimer’s disease patients.

Furthermore, long-term copper treatment (oral intake of 8 mg copper (Cu-(II)-orotate-dihydrate)) was excluded as a risk factor for Alzheimer’s disease in a noted clinical trial on humans and a potentially beneficial role of copper in Alzheimer’s disease has been demonstrated on cerebral spinal fluid levels of Aβ42, a toxic peptide and biomarker of the disease. More research is needed to understand metal homeostasis disturbances in Alzheimer’s disease patients and how to address these disturbances therapeutically.

Copper toxicity from excess exposures

In humans, the liver is the primary organ of copper-induced toxicity. Other target organs include bone and the central nervous and immune systems. Excess copper intake also induces toxicity indirectly by interacting with other nutrients. For example, excess copper intake produces anemia by interfering with iron transport and/or metabolism.

The identification of genetic disorders of copper metabolism leading to severe copper toxicity (i.e., Wilson disease) has spurred research into the molecular genetics and biology of copper homeostasis (for further information, refer to the following section on copper genetic diseases). Much attention has focused on the potential consequences of copper toxicity in normal and potentially susceptible populations. Potentially susceptible subpopulations include hemodialysis

Hemodialysis

In medicine, hemodialysis is a method for removing waste products such as creatinine and urea, as well as free water from the blood when the kidneys are in renal failure. Hemodialysis is one of three renal replacement therapies .Hemodialysis can be an outpatient or inpatient therapy...

patients and individuals with chronic liver disease. Recently, concern was expressed about the potential sensitivity to liver disease of individuals who are heterozygote carriers of Wilson disease genetic defects (i.e., those having one normal and one mutated Wilson copper ATPase gene) but who do not have the disease (which requires defects in both relevant genes). However, to date, no data are available that either support or refute this hypothesis.

Acute exposures

In case reports of humans intentionally or accidentally ingesting high concentrations of copper salts (doses usually not known but reported to be 20–70 grams of copper), a progression of symptoms was observed including abdominal pain, headache, nausea, dizziness, vomiting and diarrhea, tachycardia

Tachycardia

Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...

, respiratory difficulty, hemolytic anemia

Hemolytic anemia

Hemolytic anemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells , either in the blood vessels or elsewhere in the human body . It has numerous possible causes, ranging from relatively harmless to life-threatening...

, hematuria

Hematuria

In medicine, hematuria, or haematuria, is the presence of red blood cells in the urine. It may be idiopathic and/or benign, or it can be a sign that there is a kidney stone or a tumor in the urinary tract , ranging from trivial to lethal...

, massive gastrointestinal bleeding, liver and kidney failure, and death.

Episodes of acute gastrointestinal upset following single or repeated ingestion of drinking water containing elevated levels of copper (generally above 3–6 mg/L) are characterized by nausea, vomiting, and stomach irritation. These symptoms resolve when copper in the drinking water source is reduced.

Three experimental studies were conducted that demonstrate a threshold for acute gastrointestinal upset of approximately 4–5 mg/L in healthy adults, although it is not clear from these findings whether symptoms are due to acutely irritant effects of copper and/or to metallic, bitter, salty taste. In an experimental study with healthy adults, the average taste threshold for copper sulfate and chloride in tap water, deionized water, or mineral water was 2.5–3.5 mg/L. This is just below the experimental threshold for acute gastrointestinal upset.

Chronic exposures

The long-term toxicity of copper has not been well studied in humans, but it is infrequent in normal populations that do not have a hereditary defect in copper homeostasis.

There is little evidence to indicate that chronic human exposure to copper results in systemic effects other than liver injury. Chronic copper poisoning leading to liver failure was reported in a young adult male with no known genetic susceptibility who consumed 30–60 mg/d of copper as a mineral supplement for 3 years. Individuals residing in U.S. households supplied with tap water containing >3 mg/L of copper exhibited no adverse health effects.

No effects of copper supplementation on serum liver enzymes, biomarkers of oxidative stress, and other biochemical endpoints have been observed in healthy young human volunteers given daily doses of 6 to 10 mg/d of copper for up to 12 weeks. Infants aged 3–12 months who consumed water containing 2 mg Cu/L for 9 months did not differ from a concurrent control group in gastrointestinal tract (GIT) symptoms, growth rate, morbidity, serum liver enzyme and bilirubin

Bilirubin

Bilirubin is the yellow breakdown product of normal heme catabolism. Heme is found in hemoglobin, a principal component of red blood cells. Bilirubin is excreted in bile and urine, and elevated levels may indicate certain diseases...

levels, and other biochemical endpoints.) Serum ceruloplasmin was transiently elevated in the exposed infant group at 9 months and similar to controls at 12 months, suggesting homeostatic adaptation and/or maturation of the homeostatic response.

Dermal exposure has not been associated with systemic toxicity but anecdotal reports of allergic responses may be a sensitization to nickel and cross-reaction with copper or a skin irritation from copper. Workers exposed to high air levels of copper (resulting in an estimated intake of 200 mg Cu/d) developed signs suggesting copper toxicity (e.g., elevated serum copper levels, hepatomegaly). However, other co-occurring exposures to pesticidal agents or in mining and smelting may contribute to these effects. Effects of copper inhalation are being thoroughly investigated by an industry-sponsored program on workplace air and worker safety. This multi-year research effort is expected to be finalized in 2011.

Measurements of elevated copper status

Although a number of indicators are useful in diagnosing copper deficiency, there are no reliable biomarkers of copper excess resulting from dietary intake. The most reliable indicator of excess copper status is liver copper concentration. However, measurement of this endpoint in humans is intrusive and not generally conducted except in cases of suspected copper poisoning. Increased serum copper or ceruolplasmin levels are not reliably associated with copper toxicity as elevations in concentrations can be induced by inflammation, infection, disease, malignancies, pregnancy, and other biological stressors. Levels of copper-containing enzymes, such as cytochrome c oxidase, superoxide dismutase, and diaminase oxidase, vary not only in response to copper state but also in response to a variety of other physiological and biochemical factors and therefore are inconsistent markers of excess copper status.

A new candidate biomarker for copper excess as well as deficiency has emerged in recent years. This potential marker is a chaperone protein, which delivers copper to the antioxidant protein SOD1 (copper, zinc superoxide dismutase). It is called “copper chaperone for SOD1” (CCS), and excellent animal data supports its use as a marker in accessible cells (e.g., erythrocytes) for copper deficiency as well as excess. CCS is currently being tested as a biomarker in humans.

Hereditary copper metabolic diseases

Several rare genetic diseases (Wilson disease, Menkes disease

Menkes disease

, idiopathic

Idiopathic

Idiopathic is an adjective used primarily in medicine meaning arising spontaneously or from an obscure or unknown cause. From Greek ἴδιος, idios + πάθος, pathos , it means approximately "a disease of its own kind". It is technically a term from nosology, the classification of disease...

copper toxicosis, Indian childhood cirrhosis) are associated with the improper utilization of copper in the body. All of these diseases involve mutations of genes

Gênes

Gênes is the name of a département of the First French Empire in present Italy, named after the city of Genoa. It was formed in 1805, when Napoleon Bonaparte occupied the Republic of Genoa. Its capital was Genoa, and it was divided in the arrondissements of Genoa, Bobbio, Novi Ligure, Tortona and...

containing the genetic code

Genetic code

The genetic code is the set of rules by which information encoded in genetic material is translated into proteins by living cells....

s for the production of specific proteins involved in the absorption and distribution of copper. When these proteins are dysfunctional, copper either builds up in the liver or the body fails to absorb copper.

These diseases are inherited and cannot be acquired. Adjusting copper levels in the diet or drinking water will not cure these conditions (although therapies are available to manage symptoms of genetic copper excess disease).

The study of genetic copper metabolism diseases and their associated proteins are enabling scientists to understand how human bodies use copper and why it is important as an essential micronutrient.

The diseases arise from defects in two similar copper pumps, the Menkes and the Wilson Cu-ATPases. The Menkes ATPase is expressed in tissues like skin-building fibroblasts, kidneys, placenta, brain, gut and vascular system, while the Wilson ATPase is expressed mainly in the liver, but also in mammary glands and possibly in other specialized tissues. This knowledge is leading scientists towards possible cures for genetic copper diseases.

Menkes disease

, a genetic condition of copper deficiency, was first described by Dr. John Menkes in 1962. It is a rare X-linked disorder that affects approximately 1/200,000 live births, primarily boys. Livers of Menkes disease patients cannot absorb essential copper needed for patients to survive. Death usually occurs in early childhood: most affected individuals die before the age of 10 years, although several patients have survived into their teens and early 20s.

The protein produced by the Menkes gene is responsible for transporting copper across the gastrointestinal tract

Gastrointestinal tract

The human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. ....

(GIT) mucosa and the blood-brain barrier

Blood-brain barrier

The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...

. Mutational defects in the gene encoding the copper ATPase cause copper to remain trapped in the lining of the small intestine. Hence, copper cannot be pumped out of the intestinal cells and into the blood for transport to the liver and consequently to rest of the body. The disease therefore resembles a severe nutritional copper deficiency despite adequate ingestion of copper.

Symptoms of the disease include coarse, brittle, depigmented hair and other neonatal problems, including the inability to control body temperature, mental retardation, skeletal defects, and abnormal connective tissue growth.

Menkes patients exhibit severe neurological abnormalities, apparently due to the lack of several copper-dependent enzymes required for brain development, including reduced cytochrome c oxidase activity. The brittle, kinky hypopigmented hair of steely appearance is due to a deficiency in an unidentified cuproenzyme. Reduced lysyl oxidase

Lysyl oxidase

activity results in defective collagen

Collagen

and elastin

Elastin

Elastin is a protein in connective tissue that is elastic and allows many tissues in the body to resume their shape after stretching or contracting. Elastin helps skin to return to its original position when it is poked or pinched. Elastin is also an important load-bearing tissue in the bodies of...

polymerization and corresponding connective-tissue abnormalities including aortic aneurisms, loose skin, and fragile bones.

With early diagnosis and treatment consisting of daily injections of copper histidine

Histidine

Histidine Histidine, an essential amino acid, has a positively charged imidazole functional group. It is one of the 22 proteinogenic amino acids. Its codons are CAU and CAC. Histidine was first isolated by German physician Albrecht Kossel in 1896. Histidine is an essential amino acid in humans...

intraperitoneally and intrathecal

Intrathecal

Intrathecal is an adjective that refers to something introduced into or occurring in the space under the arachnoid membrane of the brain or spinal cord...

ly to the central nervous system, some of the severe neurological problems may be avoided and survival prolonged. However, Menkes disease patients retain abnormal bone and connective-tissue disorders and show mild to severe mental retardation. Even with early diagnosis and treatment, Menkes disease is usually fatal.

Ongoing research into Menkes disease is leading to a greater understanding of copper homeostasis, the biochemical mechanisms involved in the disease, and possible ways to treat it. Investigations into the transport of copper across the blood/brain barrier, which are based on studies of genetically altered mice, are designed to help researchers understand the root cause of copper deficiency in Menkes disease. The genetic makeup of “transgenic mice” is altered in ways that help researchers garner new perspectives about copper deficiency. The research to date has been valuable: genes can be 'turned off' gradually to explore varying degrees of deficiency.

Researchers have also demonstrated in test tubes that damaged DNA

DNA

Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...

in the cells of a Menkes patient can be repaired. In time, the procedures needed to repair damaged genes in the human body may be found.

Wilson disease

Wilson disease is a rare autosomal (chromosome 13) recessive genetic disorder of copper transport that causes an excess of copper to build up in the liver. This results in liver toxicity, among other symptoms. The disease is now treatable.

Wilson disease is produced by mutational defects of a protein that transports copper from the liver to the bile for excretion. The disease involves poor incorporation of copper into ceruloplasmin and impaired biliary copper excretion and is usually induced by mutations impairing the function of the Wilson copper ATPase. These genetic mutations produce copper toxicosis due to excess copper accumulation, predominantly in the liver and brain and, to a lesser extent, in kidneys, eyes, and other organs.

The disease, which affects about 1/30,000 infants of both genders, may become clinically evident at any time from infancy through early adulthood. The age of onset of Wilson disease ranges from 3 to 50 years of age. Initial symptoms include hepatic, neurologic, or psychiatric disorders and, rarely, renal, skeletal, or endocrine symptomatology. The disease progresses with deepening jaundice

Jaundice

Jaundice is a yellowish pigmentation of the skin, the conjunctival membranes over the sclerae , and other mucous membranes caused by hyperbilirubinemia . This hyperbilirubinemia subsequently causes increased levels of bilirubin in the extracellular fluid...

and the development of encephalopathy

Encephalopathy

Encephalopathy means disorder or disease of the brain. In modern usage, encephalopathy does not refer to a single disease, but rather to a syndrome of global brain dysfunction; this syndrome can be caused by many different illnesses.-Terminology:...

, severe clotting abnormalities, occasionally associated with intravascular coagulation, and terminal renal insufficiency. A peculiar type of tremor in the upper extremities, slowness of movement, and changes in temperament become apparent. Kayser-Fleischer rings, a rusty brown discoloration at the outer rims of the iris due to copper deposition noted in 90% of patients, become evident as copper begins to accumulate and affect the nervous system.

Almost always, death occurs if the disease is untreated. Fortunately, identification of the mutations in the Wilson ATPase gene underlying most cases of Wilson disease has made DNA testing for diagnosis possible.

If diagnosed and treated early enough, patients with Wilson disease may live long and productive lives. Wilson disease is managed by copper chelation therapy with D-penicillamine (which picks up and binds copper and enables patients to excrete excess copper accumulated in the liver), therapy with zinc sulfate or zinc acetate, and restrictive dietary metal intake, such as the elimination of chocolate, oysters, and mushrooms. Zinc therapy is now the treatment of choice. Zinc produces a mucosal block by inducing metallothionein, which binds copper in mucosal cells until they slough off and are eliminated in the feces. and it competes with copper for absorption in the intestine by DMT1 (Divalent Metal transporter 1). More recently, experimental treatments with tetrathiomolybdate showed promising results. Tetrathiomolybdate appears to be an excellent form of initial treatment in patients who have neurologic symptoms. In contrast to penicillamine therapy, initial treatment with tetrathiomolybdate rarely allows further, often irreversible, neurologic deterioration.

Over 100 different genetic defects leading to Wilson disease have been described and are available on the Internet at http://www.uofa-medical-genetics.org/wilson/index.php. Some of the mutations have geographic clustering.

Many Wilson patients carry different mutations on each chromosome 13 (i.e., they are
compound heterozygotes). Even in individuals who are homozygous for a mutation, onset and severity of the disease may vary. Individuals homozygous for severe mutations (e.g., those truncating the protein) have earlier disease onset. Disease severity may also be a function of environmental factors, including the amount of copper in the diet or variability in the function of other proteins that influence copper homeostasis.

It has been suggested that heterozygote carriers of the Wilson disease gene mutation may be potentially more susceptible to elevated copper intake than the general population. A heterozygotic frequency of 1/90 people has been estimated in the overall population. However, there is no evidence to support this speculation. Further, a review of the data on single-allelic autosomal recessive diseases in humans does not suggest that heterozygote carriers are likely to be adversely affected by their altered genetic status.

Other copper-related hereditary syndromes

Other diseases in which abnormalities in copper metabolism appear to be involved include Indian childhood cirrhosis (ICC), Endemic Tyrolean Copper Toxicosis (ETIC), and idiopathic

Idiopathic

copper toxicosis (ICT), also known as non-Indian childhood cirrhosis. ICT is a genetic disease recognized in the early twentieth century primarily in the Tyrolean

County of Tyrol

The County of Tyrol, Princely County from 1504, was a State of the Holy Roman Empire, from 1814 a province of the Austrian Empire and from 1867 a Cisleithanian crown land of Austria-Hungary...

region of Austria

Austria

Austria , officially the Republic of Austria , is a landlocked country of roughly 8.4 million people in Central Europe. It is bordered by the Czech Republic and Germany to the north, Slovakia and Hungary to the east, Slovenia and Italy to the south, and Switzerland and Liechtenstein to the...

and in the Pune

Pune

Pune , is the eighth largest metropolis in India, the second largest in the state of Maharashtra after Mumbai, and the largest city in the Western Ghats. Once the centre of power of the Maratha Empire, it is situated 560 metres above sea level on the Deccan plateau at the confluence of the Mula ...

region of India

India

India , officially the Republic of India , is a country in South Asia. It is the seventh-largest country by geographical area, the second-most populous country with over 1.2 billion people, and the most populous democracy in the world...

.

ICC, ICT, and ETIC are infancy syndromes that are similar in their apparent etiology

Etiology

Etiology is the study of causation, or origination. The word is derived from the Greek , aitiologia, "giving a reason for" ....

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 exposures to elevated concentrations of copper are commonly found in both diseases, some cases appear to develop in children who are exclusively breastfed or who receive only low levels of copper in water supplies. The currently prevailing hypothesis is that ICT is due to a genetic lesion resulting in impaired copper metabolism combined with high copper intake. This hypothesis was supported by the frequency of occurrence of parental consanguinity

Consanguinity

Consanguinity refers to the property of being from the same kinship as another person. In that respect, consanguinity is the quality of being descended from the same ancestor as another person...

in most of these cases, which is absent in areas with elevated copper in drinking water and in which these syndromes do not occur.

ICT appears to be vanishing as a result of greater genetic diversity within the affected populations in conjunction with educational programs to ensure that tinned cooking utensils are used instead of copper pots and pans being directly exposed to cooked foods. The preponderance of cases of early childhood cirrhosis identified in Germany

Germany

Germany , officially the Federal Republic of Germany , is a federal parliamentary republic in Europe. The country consists of 16 states while the capital and largest city is Berlin. Germany covers an area of 357,021 km2 and has a largely temperate seasonal climate...

over a period of 10 years were not associated with either external sources of copper or with elevated hepatic metal concentrations Only occasional spontaneous cases of ICT arise today.

Plant and animal health

In addition to being an essential nutrient for humans, copper is vital for the health of animals and plants and plays an important role in agriculture

Agriculture

Agriculture is the cultivation of animals, plants, fungi and other life forms for food, fiber, and other products used to sustain life. Agriculture was the key implement in the rise of sedentary human civilization, whereby farming of domesticated species created food surpluses that nurtured the...

Plant health

Copper concentrations in soil are not uniform around the world. In many areas, soils have insufficient levels of copper. Soils that are naturally deficient in copper often require copper supplements before agricultural crops, such as cereals, can be grown.

Copper deficiencies in soil can lead to crop failure. Copper deficiency is a major issue in global food production, resulting in losses in yield and reduced quality of output. Nitrogen fertilizers can worsen copper deficiency in agricultural soils.

The world's two most important food crops, rice

Rice

and wheat

Wheat

, are highly susceptible to copper deficiency. So are several other important foods, including citrus

Citrus

Citrus is a common term and genus of flowering plants in the rue family, Rutaceae. Citrus is believed to have originated in the part of Southeast Asia bordered by Northeastern India, Myanmar and the Yunnan province of China...

, oats

OATS

OATS - Open Source Assistive Technology Software - is a source code repository or "forge" for assistive technology software. It was launched in 2006 with the goal to provide a one-stop “shop” for end users, clinicians and open-source developers to promote and develop open source assistive...

, spinach

Spinach

Spinach is an edible flowering plant in the family of Amaranthaceae. It is native to central and southwestern Asia. It is an annual plant , which grows to a height of up to 30 cm. Spinach may survive over winter in temperate regions...

and carrot

Carrot

The carrot is a root vegetable, usually orange in colour, though purple, red, white, and yellow varieties exist. It has a crisp texture when fresh...

s. On the other hand, some foods including coconut

Coconut

s, soybean

Soybean

The soybean or soya bean is a species of legume native to East Asia, widely grown for its edible bean which has numerous uses...

s and asparagus

Asparagus

Asparagus officinalis is a spring vegetable, a flowering perennialplant species in the genus Asparagus. It was once classified in the lily family, like its Allium cousins, onions and garlic, but the Liliaceae have been split and the onion-like plants are now in the family Amaryllidaceae and...

, are not particularly sensitive to copper-deficient soils.

The most effective strategy to counter copper deficiency is to supplement the soil with copper, usually in the form of copper sulfate. Sewage sludge is also used in some areas to replenish agricultural land with organics and trace metals, including copper.

Animal health

In livestock, cattle

Cattle

Cattle are the most common type of large domesticated ungulates. They are a prominent modern member of the subfamily Bovinae, are the most widespread species of the genus Bos, and are most commonly classified collectively as Bos primigenius...

and sheep commonly show indications when they are copper deficient. Swayback, a sheep disease associated with copper deficiency, imposes enormous costs on farmers worldwide, particularly in Europe

Europe

Europe is, by convention, one of the world's seven continents. Comprising the westernmost peninsula of Eurasia, Europe is generally 'divided' from Asia to its east by the watershed divides of the Ural and Caucasus Mountains, the Ural River, the Caspian and Black Seas, and the waterways connecting...

, North America

North America

North America is a continent wholly within the Northern Hemisphere and almost wholly within the Western Hemisphere. It is also considered a northern subcontinent of the Americas...

, and many tropical countries. For pig

Pig

A pig is any of the animals in the genus Sus, within the Suidae family of even-toed ungulates. Pigs include the domestic pig, its ancestor the wild boar, and several other wild relatives...

s, copper has been shown to be an outstanding growth promoter.

Essentiality

Fetuses, infants, and children

Homeostasis

Absorption

Distribution

Excretion

Daily dietary copper requirements

Adults

Adolescents, children, and infants

Pregnant women and mothers who breastfeed

Dietary sources

Supplementation

Copper deficiency and excess health conditions (non-genetic)

Copper deficiency

Copper excess

Copper toxicity from excess exposures

Acute exposures

Chronic exposures

Measurements of elevated copper status

Hereditary copper metabolic diseases

Menkes disease

Wilson disease

Other copper-related hereditary syndromes

Plant and animal health

Plant health

Animal health

See also