Copper deficiency

Copper deficiency or frank dietary copper deficiency is less common in healthy individuals because copper is a ubiquitous element and is present in almost all foods ¹, ², ³. Copper deficiency in the United States is believed to be relatively rare but has been described in the setting of zinc supplementation ⁴, myelodysplastic syndrome ⁵, use of total parenteral nutrition (TPN) ⁶ and chronic tube feeding ⁷ especially via jejunostomy ⁸ and in various malabsorption syndromes such as cystic fibrosis, celiac disease and in people who’ve had gastrectomy and roux-en-Y gastric bypass surgery for obesity and in infants exclusively fed cow-milk formulas ⁹. A rare X-linked genetic condition called Menkes kinky hair syndrome or Menkes disease is caused by a defect in the ATP7A gene ¹⁰, ¹¹. The defect makes it hard for the body to properly distribute (transport) copper throughout the body. As a result, the brain and other parts of the body do not get enough copper, while it builds up in the small intestine and kidneys of affected infants. Menkes disease, which affects primarily males, is associated with seizures, delayed development, abnormal artery development in the brain, and unusual gray brittle kinky hair ¹¹.

Based on studies in animals and humans, the effects of copper deficiency include anemia, hypopigmentation (a low amount of melanin in your skin), high blood cholesterol (hypercholesterolemia), connective tissue disorders, osteoporosis (condition in which bones become weak and brittle) and other bone defects, abnormal lipid metabolism, a lack of coordination or unsteadiness (ataxia), and increased risk of infection ¹², ¹³, ¹⁴. Features of copper deficiency include hematologic abnormalities (anemia, leukopenia, neutropenia, and thrombocytopenia) and myeloneuropathy (spinal cord and peripheral nerves damage in the lower limbs); the latter is a rarer and often unrecognized complication of copper deficiency ¹⁵, ², ⁹. A low copper level can affect the structure of bone, skin, hair, and blood vessels, and interfere with nerve function. Most importantly, the neurologic complications of copper deficiency may be irreversible, making early diagnosis and prompt treatment essential to successful outcomes.

One of the most common clinical signs of copper deficiency is an anemia that is unresponsive to iron therapy but is corrected by copper supplementation ¹⁶. It was hypothesized that this copper-deficiency anemia could result from defective iron mobilization due to decreased ceruloplasmin (CP) activity, yet individuals with inherited aceruloplasminemia (a rare inherited autosomal recessive genetic disorder in which a mutation in the ceruloplasmin (CP) gene leads to the absence or dysfunction of ceruloplasmin) do not always develop overt anemia ¹⁷. Ceruloplasmin (CP) plays a role in iron metabolism and carries more than 95% of the total copper in healthy human plasma ¹⁸. In copper-deficient pig, intestinal iron absorption is impaired but iron distribution among tissues or organs is normal ¹⁹, ²⁰, ²¹. Low serum iron from reduced absorption is an unlikely cause of this anemia since intravenous provision of iron did not correct it ¹⁶. An alternative hypothesis is that copper-deficiency anemia is caused principally by impaired hemoglobin production and red blood cell proliferation, and a shortened red blood cell lifespan. These physiological processes are thus likely to require copper. Copper deficiency may also lead to neutropenia, which can increase susceptibility to infection. Copper depletion studies demonstrated that low copper might affect erythroid and myeloid cell lineages, supporting a role for copper in the regulation of blood cell proliferation and maturation ²², ²³. More research is clearly needed to further define the mechanisms underlying copper deficiency-induced anemia and neutropenia ²², ²⁴. Furthermore, osteoporosis and other abnormalities of bone development have been described in copper-deficient, low-birth-weight infants and young children. Less common features of copper deficiency may include impaired growth, depigmentation, and development of neurological pathologies ²⁵, ²⁶.

Copper is an essential trace mineral present in all body tissues that is essential for adequate use of iron and zinc, two other essential transition metals by your body ²⁷. Copper is also a cofactor of proteins and enzymes called cuproenzymes (copper-dependent enzymes) that are involved in regulation of iron metabolism, formation of connective tissue, energy (ATP) production at the cellular level, oxygen transportation, formation of blood cells such as red blood cells, platelets, and white blood cells (hematopoiesis), the formation of new blood vessels (angiogenesis), neurohormone homeostasis, the production of melanin (the pigment that produces skin color), the function of the nervous system, brain development, aids in iron absorption, regulation of gene expression, immune system functioning, mitochondrial electron transport and free radical scavenging (redox reactions or oxidation-reduction reactions) ²⁸, ²⁹, ¹², ¹⁶, ³⁰. Furthermore, defense against oxidative damage depends mainly on the copper-containing superoxide dismutases ³¹, ³². Copper also helps keep the blood vessels, nerves, immune system, and bones healthy. Copper is vital to the normal function of the hematologic, vascular, skeletal, antioxidant, and neurologic systems ⁹, ¹⁶, ³⁰. Copper is therefore essential for living cells. Both the accumulation of copper and copper deficiency are associated with brain dysfunction.

More recently, new evidence shows that copper is involved in the pathogenesis of neurodegenerative disorders. Copper is an essential transition metal. Copper participates in critical cuproenzymes preventing neurodegeneration and regulating neurotransmission. Via the ferroxidase activity of ceruloplasmin, copper is a metabolic regulator of the contents of iron in the CNS (central nervous system). An excess of free copper is directly involved to neurodegeneration. Wilson’s disease, Alzheimer’s disease and Parkinson’s disease are major neurodegenerative disorders associated with copper dyshomeostasis ³³. Wilson disease is a rare inherited disorder that prevents your body from getting rid of extra copper, which can lead to excess storage of copper in the liver, brain, and other organs ³⁴, ³⁵. Copper excess (toxicity) can also occur when a person is exposed to and absorbs large amounts over a short period of time (acute exposure) or various amounts over a long period (chronic exposure).

Copper is found in many foods including nuts, chocolate, mushrooms, shellfish, whole grains, dried fruits, and liver. Drinking water may acquire copper as it flows through copper pipes, and food may acquire it when people cook or serve food in copper dishes. Normally, the body absorbs copper from food or liquids in the intestines, converts it to a non-toxic form by binding it to a protein, and transports it to the liver. The liver stores some of the copper and binds most of the rest to another protein called apoceruloplasmin to produce the enzyme ceruloplasmin. About 95% of the copper in the blood is bound to ceruloplasmin, and most of the rest is bound to other proteins such as albumin. Only a small amount is normally present in the blood in a free (unbound) state. The liver eliminates excess copper into the bile and it is removed from the body in the stool. Some copper is also eliminated in the urine.

The average daily intake of copper is approximately 1,400 mcg/day for men and 1,100 mcg/day for women, coming mainly from seeds, grains, shellfish, nuts, beans and liver ³⁶, ¹², ³, ³⁷, ³⁸, ³⁹. The current recommended dietary intake of copper in the USA is 900 mcg/day ⁴⁰, ⁴¹.

Copper is absorbed mainly from the duodenum and proximal jejunum, and partly from the stomach ⁴². Low dietary copper intake reduces immune response, which is not restored to normal levels even after several weeks of a high copper intake ⁴³. Only small amounts of copper are typically stored in your body, and the average adult has a total body content of 50–120 mg copper ¹², ³. Almost two-thirds of the body’s copper is located in the bone and muscle ¹², ⁴⁰.

Most copper is excreted in bile, and a small amount is excreted in urine. Total fecal losses of copper of biliary origin and nonabsorbed dietary copper are about 1 mg/day ¹², ³. Copper levels in your body are homeostatically maintained by copper absorption from the intestine and copper release by the liver into bile to provide protection from copper deficiency and copper toxicity ⁴⁰.

Copper status is not routinely assessed in clinical practice, and no biomarkers that accurately and reliably assess copper status have been identified ³. Human studies typically measure copper and cuproenzyme activity in plasma and blood cells because individuals with known copper deficiency often have low blood levels of copper and ceruloplasmin (an abundant cuproenzyme) ³. Serum copper and ceruloplasmin (CP) levels may fall to 30% of normal in cases of severe copper deficiency ¹⁶. However, plasma ceruloplasmin (CP) and copper levels can be influenced by other factors, such as estrogen status, pregnancy, infection, inflammation, and some cancers ³. Low serum copper level or hypocupremia is also observed in genetic disorders of copper metabolism, including Wilson disease and aceruloplasminemia (a rare inherited autosomal recessive genetic disorder in which a mutation in the ceruloplasmin (CP) gene leads to the absence or dysfunction of ceruloplasmin); however, neither disorder has been linked to low dietary copper intake ¹⁶.

Normal serum concentrations are 10–25 micromol/L (63.5–158.9 mcg/dL) for copper and 180–400 mg/L for ceruloplasmin (CP) ⁴⁴.

The treatment for copper deficiency is not yet developed and depends on the underlying cause of the copper deficiency ¹⁵. However, it is easy to consume food containing high amounts of copper as a copper supplement. Commercially available pure cocoa contains approximately 4 mg copper per 100 g and is easy to administer to tube‐feeding patients because it is in powder form. Experts recommended other copper‐rich foods such as nuts, shellfish, or liver to patients with diabetes mellitus because almost all patients add sugar to suppress the bitterness of cocoa. Experts also used other copper‐rich foods for patients who could not continue oral cocoa intake due to diarrhea because cocoa contains fibers ⁴⁵. For individuals with Menkes kinky hair syndrome or Menkes disease, there is no cure at this time, but treatment with parenteral copper histidinate (CuHis) can increase survival and lessen the neurological symptoms if initiated early, within approximately 28 days following birth ⁴⁶.

What is copper?

Copper is a cofactor of proteins and enzymes (called cuproenzymes) involved in fundamental mechanisms, such as energy generation, oxygen transportation, hematopoiesis, cellular metabolism and signal transduction ²⁸. Copper is therefore essential for living cells. Its metabolism is linked to the metabolism of iron and zinc, two other essential transition metals ⁴⁷. The bulk of evidence that copper is involved in the pathogenesis of neurodegenerative disorders is now huge. Copper is an essential transition metal. Copper participates in critical cuproenzymes preventing neurodegeneration and regulating neurotransmission. Via the ferroxidase activity of ceruloplasmin, copper is a metabolic regulator of the contents of iron in the CNS (central nervous system). An excess of free copper is directly involved to neurodegeneration. Wilson’s disease, Alzheimer’s disease and Parkinson’s disease are major neurodegenerative disorders associated with copper dyshomeostasis ³³.

Metabolism of copper

In the human body, most of the copper (Cu) is present as Cu+ (cuprous) and oxidized Cu2+ (cupric) compounds ³³. Copper is therefore an intermediary for electron transfer in redox reactions. The oxidation states, Cu3+ and Cu4+, are uncommon ⁴⁸. Copper is mainly absorbed in the duodenum and proximal jejunum, with a little bit of absorption occurring in the stomach and the distal portion of the small intestine ⁴⁹. The human copper transport protein 1 (hCTR1), located at the level of enterocytes, transfers the ion following the reduction of dietary Cu2+ into Cu+. In hepatocytes, copper binds to metallothioneins, to reduced glutathione or to one of the copper chaperones regulating the traffic of intracellular copper (chaperone for superoxide dismutase 1; SOD1, which is the sole cytosolic cuproenzyme; COX17: chaperone for cytochrome C oxygenase; ATOX1 antioxidant-1: chaperone for the ATPases, ATP7A and ATP7B). The group of transmembrane copper transporters includes CTR1, ATP7A and ATP7B. ATP7A (expressed in the placenta, gut and nervous system) and ATP7B (expressed in the hepatocytes, where it exports copper into the bile and provides copper to nascent ceruloplasmin, and in the nervous system) are linked to the enzyme, tyrosinase, and the ceruloplasmin, respectively. In blood, about 65%–90% of the copper Cu2+ is bound to ceruloplasmin. The remaining 10–35 percent participate in exchanges with albumin, transcuprein, alpha 2 macroglobulin, and low-molecular-weight compounds ⁵⁰.

In terms of storage, the total amount of copper in an adult is estimated to be about 90–110 mg. The organs with the highest concentrations are the liver, brain, kidney and heart ⁵¹. Bones and skeletal muscles contain about 47% and 27% of the copper, respectively ⁵². Both the liver and brain contain about 8%–11% of the total body copper. Figure 1 illustrates the metabolism of copper in the brain. Brain concentrations range from 3.1 to 5.1 mg/g wet weight ⁵³. Within the brain, the distribution of copper is heterogeneous. Concentrations are higher in the hippocampus, substantia nigra and locus coeruleus ⁴⁸. Glial cells are enriched in copper as compared to neurons ⁴⁸. The concentrations of copper in the synaptic cleft range from 0.2 to 1.7 µM. Some studies have shown concentrations higher than 200 µM ⁵⁴. Concentrations in cerebrospinal fluid (CSF) are 100-fold lower as compared to plasmatic levels, and intra-neuronal concentrations are kept very low ⁵⁵. Choroid plexus could serve as a storage compartment in the vicinity of the brain.

Copper is excreted endogenously in the saliva, the gastric fluids and intestinal liquids. Copper is excreted from the body either in a non-absorbed form or via the bile. The estimated amount of copper in feces is 1–1.5 mg/day. The quantities lost in urine, saliva and perspiration are even smaller.

Figure 1. Copper metabolism in the brain

Footnote:

(A) A blood vessel (in red on the left), the blood-brain barrier (BBB), the blood-CSF barrier (shown by a rectangle with two compartments), a choroid plexus (CP) and an astrocyte are illustrated;

(B) A neuron, a synapse and an astrocyte are shown. Copper is represented by a green circle. At the blood-CSF barrier, CTR1 (copper transporter 1), DMT1 (divalent metal transporter) and the ATPase, ATP7A, transport copper towards the blood, whereas the ATPase, ATP7B, and CTR1 transport copper in the opposite direction. Organelles and proteins involved in the cellular regulation of copper are represented. CTR1 is the main transporter for transferring copper within cells. Chaperones (ATOX1, COX17, CCS) deliver copper to the ATPases, ATP7A/ATP7B, and to cuproenzymes, including in the mitochondria. Metallothioneins (MT-1, MT-2, MT-3) exert a function as a buffer. Copper is also found in secretory granules.

Abbreviations: APP = amyloid precursor protein; GSH= glutathione; NMDA-R = NMDA receptor; AMPA-R = AMPA receptor; GABAA-R = GABAA receptor; TGN = trans-Golgi network.

[Source ³³ ]

Free Copper

The fact that cells contain one free copper ion or less highlights the tight regulation ⁵⁶. The redox capacities of free copper and its ability to initiate the production of free radicals are two important features. Free copper is a catalyst of the Fenton reaction (Cu+ and H2O2 generate Cu2+ + OH− + OH). The hydrogen peroxide is transformed into the very reactive hydroxyl radical, which combines with nucleic acids, proteins and lipids. An increase in free copper is potentially harmful for brain circuits, despite the presence of metallothioneins and chaperones (see below).

Ceruloplasmin

Ceruloplasmin is a multicopper-containing protein mainly synthesized by the liver. Although the rate of synthesis is not influenced by copper intake, ceruloplasmin lacking bound copper has a shorter half-life ⁵⁷. Ceruloplasmin plays important functions, acting as an iron oxidase, an amine oxidase, an antioxidant and a glutathione peroxidase ⁵⁸. As a multicopper oxidase, ceruloplasmin reduces dioxygen, O2, to two water molecules. Ceruloplasmin is a scavenger of reactive oxygen species (ROS). It can be considered that the genuine link between copper metabolism and iron metabolism is mediated by ceruloplasmin. Its soluble form controls the oxidation of iron to be included into transferrin. A deficit in copper reduces the ferroxidase activity of ceruloplasmin (Fe2+ to Fe3+). Dietary and recycled iron are in the Fe2+ oxidation state, but iron is transported in serum by transferrin only as Fe3+ after its export by ferroportin ⁴⁷. Iron itself contributes to the formation of reactive oxygen species (ROS). A deficit of dietary copper leads not only to an accumulation of iron in the liver, but also to an impaired distribution within the spinal cord (see zinc-induced myeloneuropathy in the next section). In the central nervous system (CNS), a glycosylphosphatidylinositol-linked ceruloplasmin bound to the cell membranes is the major isoform of this protein ⁵⁹. Astrocytes can synthesize their own ceruloplasmin. This glial ceruloplasmin controls also the process of iron oxidation, which allows the clearance of iron from the CNS (central nervous system) ⁶⁰. Overall, functional ceruloplasmin promotes the synthesis of proteins involved in iron efflux. The maintenance of the iron balance in the brain is thus closely linked to the metabolism of copper.

Copper and Synapses in the CNS

There is evidence that copper is enriched in synaptic levels and could even play a signaling role ⁶¹. Copper is found in secretary granules containing SOD3, in constitutive vesicles and in endosomes. Copper in the secretory pathway is released in a calcium-dependent manner. Copper interacts with glutamatergic and GABAergic synapses and modulates voltage-gated calcium channels ⁶¹. Stimulation of the NMDA receptor (NMDA-R) evokes the release of copper in hippocampal neurons and is associated with a repositioning of the ATP7A transporter towards the hyperactive sites ⁶². Copper interacts closely with the NMDA-R and may inhibit currents related to NMDA-R activation ⁶³. Copper acts on the S-nitrosylation of the NMDA receptor ⁶⁴. Copper also interacts with AMPA-R, but the IC50 for inhibition is higher (4.5 µM) as compared to the NMDA-R (0.27 µM) ⁶⁵. The transition metal modulates also GABAA-R, with an impact on Cl− currents ⁶⁶. The IC50 is 2.4 µM. It affects also the extra-synaptic GABA receptors ⁶⁷. Overall, the acute effects of copper on AMPA-R and GABAA-R is inhibitory ⁴⁸.

What is the function of copper?

Your body uses copper to carry out many important functions, including making energy, connective tissues, and blood vessels. Copper also helps maintain the nervous and immune systems, and activates genes ²⁴, ⁶⁸, ⁶⁹, ⁷⁰. Your body also needs copper for brain development. Physiologic functions of these copper-dependent enzymes, and the biochemical pathways in which they function, are outlined below.

Energy production

The copper-dependent enzyme cytochrome C oxidase (CCO) plays a critical role in cellular energy (ATP) production in mitochondria by catalyzing the reduction of molecular oxygen (O2) to water (H2O), thereby generating an electrical gradient that is required for ATP production ²⁶. Redox-active copper contained within the cytochrome C oxidase (CCO) enzyme complex is required for the electron transfer reactions that are critical for its function.

Connective tissue formation

Another cuproenzyme, lysyl oxidase (LOX), is required for the cross-linking of collagen and elastin fibers, which is essential for the formation of strong and flexible connective tissue. Lysyl oxidase (LOX) function is critical for bone formation and maintenance of connective tissue in the heart and blood vessels ²⁵.

Iron metabolism

Multi-copper oxidases (MCOs) are copper-dependent ferroxidases that function in iron homeostasis. Multi-copper oxidases (MCOs) oxidize ferrous iron (Fe²⁺) to the ferric (Fe3⁺) form, which enables binding to transferrin (the main iron carrier) in the blood, thus allowing iron transport to sites of utilization (e.g., the bone marrow). The multi-copper oxidases (MCOs) include: (1) ceruloplasmin (CP), which contains 60%-95% of plasma copper; (2) a membrane-bound form of ceruloplasmin (CP) (GPI-CP), expressed in brain and other tissues; and (3) the membrane-bound ferroxidases hephaestin (HEPH) and zyklopen, which function in the intestine and placenta, respectively ⁷¹, ⁷². Ceruloplasmin (CP) knockout (Cp-/-) mice accumulate excess iron in their liver but have normal copper status ⁷³, ⁷⁴. Similarly, humans with aceruloplasminemia, who lack functional ceruloplasmin (CP), display iron overload in liver, brain, and retina but have no observable defects in copper homeostasis ⁷⁵. Moreover, absorption of dietary iron and iron mobilization from storage sites (e.g., liver) are impaired in copper deficiency, when ceruloplasmin (CP) and membrane-bound ferroxidases hephaestin (HEPH) activity is reduced, further supporting a role for the multi-copper oxidases (MCOs) in iron metabolism ⁷⁶.

Central nervous system function

Several physiological processes within the brain and nervous system, including neurotransmitter synthesis and formation and maintenance of myelin, depend upon catalysis mediated by cuproenzymes. Dopamine beta-hydroxylase, for example, catalyzes the conversion of dopamine to the neurotransmitter norepinephrine ⁷⁷. Also, cytochrome C oxidase (CCO) is required for the biosynthesis of phospholipids, which are critical structural components of the myelin sheath ²⁵.

Melanin biosynthesis

The cuproenzyme tyrosinase (TYR) is required for the biosynthesis of melanin in melanocytes, which is critical for normal pigmentation of hair, skin, and eyes ²⁵. Low tyrosinase (TYR) activity most likely explains the absence or loss of pigmentation in the hair (achromotrichia) seen in copper-deficient laboratory and agricultural animals, and the depigmentation noted in severely copper-depleted patients with Menkes disease.

Antioxidation

Superoxide dismutase (SOD) functions as an antioxidant by catalyzing the conversion of reactive oxygen species, such as the superoxide anion (O2-) and the hydroxyl radical (•OH), to hydrogen peroxide (H2O2), which is subsequently reduced to water by other antioxidant systems ⁷⁸. Two forms of superoxide dismutase (SOD) contain copper: copper/zinc SOD (SOD1), which is expressed in most cells, including red blood cells; and extracellular SOD (EcSOD), which is highly expressed in the lungs and found at lower levels in plasma ²⁵. Also, ceruloplasmin (CP) has antioxidant properties relating to iron metabolism. The ferroxidase activity of ceruloplasmin (CP) may prevent ferrous iron (Fe2+) from participating in harmful free-radical-generating reactions via Fenton chemistry ⁷⁸.

Regulation of gene expression

Copper-related gene expression pathways seem to be mainly regulated at a post-translation level, in some cases via protein trafficking-related mechanisms that respond to intracellular copper levels ⁷⁹. Cytosolic copper may also influence mRNA expression levels of specific genes, in a dose-dependent manner, implicating possible transcriptional regulation ⁸⁰, ⁸¹, ⁸². For example, intracellular copper may alter the redox state of cells and thus induce oxidative stress, which can activate signal transduction pathways that increase the expression of genes encoding proteins involved in the detoxification of reactive oxygen species ⁸³.

Immune system function

Copper is known to play several important roles in the development and maintenance of immune system function, including innate and adaptive immunity ⁸⁴. Neutropenia is a clinical sign of copper deficiency in humans. Adverse effects of insufficient copper on immune system function appear most pronounced in infants. For example, infants with Menkes disease, a genetic copper-deficiency disorder, suffer from frequent and severe infections ⁸⁵, ⁸⁶. Moreover, in a study of 11 malnourished infants with evidence of copper deficiency, the ability of white blood cells to engulf pathogens increased significantly after one month of copper supplementation ⁸⁷. Moreover, 11 men on a low-copper diet (660 mcg/day of copper for 24 days and 380 mcg/day for another 40 days) showed an impaired monocyte proliferative response in an ex vivo immune challenge assay ⁴³. Mechanistic studies also support a role for copper in the innate immune response to bacterial and viral infections ⁸⁸, ⁸⁹. Severe copper deficiency thus has adverse effects on immune system function; however, whether marginal copper insufficiency impairs immunity in humans has not been established.

How much copper do I need?

The amount of copper you need each day depends on your age. Average daily recommended amounts are listed below in micrograms (mcg).

Intake recommendations for copper and other nutrients are provided in the Dietary Reference Intakes (DRIs) developed by the Food and Nutrition Board (FNB) at the National Academies of Sciences, Engineering, and Medicine ⁴⁰. Dietary Reference Intake (DRI) is the general term for a set of reference values used for planning and assessing nutrient intakes of healthy people. These values, which vary by age and sex, include:

• Recommended Dietary Allowance (RDA): Average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%–98%) healthy individuals; often used to plan nutritionally adequate diets for individuals.
• Adequate Intake (AI): Intake at this level is assumed to ensure nutritional adequacy; established when evidence is insufficient to develop an RDA.
• Estimated Average Requirement (EAR): Average daily level of intake estimated to meet the requirements of 50% of healthy individuals; usually used to assess the nutrient intakes of groups of people and to plan nutritionally adequate diets for them; can also be used to assess the nutrient intakes of individuals.
• Tolerable Upper Intake Level (UL): Maximum daily intake unlikely to cause adverse health effects.

According to the National Health and Nutrition Examination Survey (NHANES), the mean dietary intake of copper in the US is 1100 mcg/day for adult women and 1300 mcg/day for adult men, levels that exceed the established Recommended Dietary Allowance (RDA) for copper for adults of 900 mcg/day (see Table 1) ⁹⁰.

Table 1 lists the current Recommended Dietary Allowance (RDA) for copper ⁴⁰. For infants from birth to 12 months, the Food and Nutrition Board established an Adequate Intake (intake at this level is assumed to ensure nutritional adequacy; established when evidence is insufficient to develop an RDA). for copper that is equivalent to the mean intake of copper in healthy, breastfed infants.

Table 1. Recommended Dietary Allowances (RDAs) for Copper

Life Stage	Recommended Amount
Birth to 6 months	200 mcg
Infants 7–12 months*	220 mcg
Children 1–3 years	340 mcg
Children 4–8 years	440 mcg
Children 9–13 years	700 mcg
Teens 14–18 years	890 mcg
Adults 19 years and older	900 mcg
Pregnant teens and women	1,000 mcg
Breastfeeding teens and women	1,300 mcg

Footnote: *Adequate Intake (AI) = intake at this level is assumed to ensure nutritional adequacy; established when evidence is insufficient to develop an Recommended Dietary Allowance (RDA).

[Source ³⁰ ]

Food Sources of Copper

Many foods contain copper. You can get recommended amounts of copper by eating a variety of foods, including the following ⁹¹:

• Beef liver and shellfish such as oysters
• Nuts (such as cashews), seeds (such as sesame and sunflower), and chocolate
• Wheat-bran cereals and whole-grain products
• Potatoes, mushrooms, avocados, chickpeas, and tofu

The estimated copper content of some foods that are relatively rich in copper is listed in Table 2.

For more information on the nutrient content of foods, search USDA’s FoodData Central.

Typical diets in the United States meet or exceed the copper Recommended Dietary Allowance (RDA). Mean dietary intakes of copper from foods range from 800 to 1,000 mcg per day for children aged 2–19 ³⁶. In adults aged 20 and older, average daily intakes of copper from food are 1,400 mcg for men and 1,100 mcg for women. Total intakes from supplements and foods are 900 to 1,100 mcg/day for children and 1,400 to 1,700 mcg/day for adults aged 20 and over.

Table 2. Selected Foods Copper Content

Food	Micrograms (mcg) per serving	Percent DV*
Beef, liver, pan fried (3 ounces)	12400	1378
Oysters, eastern, wild, cooked, 3 ounces	4850	539
Baking chocolate, unsweetened, 1 ounce	938	104
Potatoes, cooked, flesh and skin, 1 medium potato	675	75
Mushrooms, shiitake, cooked, cut pieces, ½ cup	650	72
Cashew nuts, dry roasted, 1 ounce	629	70
Crab, Dungeness, cooked, 3 ounces	624	69
Sunflower seed kernels, toasted, ¼ cup	615	68
Turkey, giblets, simmered, 3 ounces	588	65
Chocolate, dark, 70%-85% cacao solids, 1 ounce	501	56
Tofu, raw, firm, ½ cup	476	53
Chickpeas, mature sees, ½ cup	289	32
Millet, cooked, 1 cup	280	31
Salmon, Atlantic, wild, cooked, 3 ounces	273	30
Pasta, whole wheat, cooked, 1 cup (not packed)	263	29
Avocado, raw, ½ cup	219	24
Figs, dried, ½ cup	214	24
Spinach, boiled, drained, ½ cup	157	17
Asparagus, cooked, drained, ½ cup	149	17
Sesame seeds, ¼ cup	147	16
Turkey, ground, cooked, 3 ounces	128	14
Cereals, Cream of Wheat, cooked with water, stove-top, 1 cup	104	12
Tomatoes, raw, chopped, ½ cup	53	6
Yogurt, Greek, plain, lowfat, 7-ounce container	42	5
Milk, nonfat, 1 cup	27	3
Apples, raw, with skin, ½ cup slices	17	2

Footnote: *DV = Daily Value. The U.S. Food and Drug Administration (FDA) developed Daily Values (DVs) to help consumers compare the nutrient contents of foods and dietary supplements within the context of a total diet. The Daily Value (DV) for copper is 0.9 mg (900 mcg) for adults and children age 4 years and older ⁹². The FDA does not require food labels to list copper content unless copper has been added to the food. Foods providing 20% or more of the DV are considered to be high sources of a nutrient, but foods providing lower percentages of the DV also contribute to a healthful diet.

[Source ³⁰ ]

Copper supplements

Copper is available in many multivitamin or multimineral supplements, in supplements that contain only copper, and in other dietary supplements in combination with other ingredients. Copper in dietary supplements is often in the forms of cupric oxide, cupric sulfate, copper amino acid chelates, and copper gluconate. To date, no studies have compared the bioavailability of copper from these and other forms ⁹³. The amount of copper in dietary supplements typically ranges from a few micrograms to 15 mg (about 17 times the Daily Value [DV] for copper) ³⁰.

Supplementation of adults with 10 mg/day of cupric gluconate for 12 weeks did not cause copper toxicity ⁹⁴. Importantly, however, higher copper intakes could be detrimental in some at-risk (unknown) individuals. Copper supplementation of infants should be approached with caution since homeostatic regulators of copper absorption and excretion are not fully developed, thus increasing the potential for copper toxicosis. From a clinical perspective, copper overload most frequently presents in biliary atresia, biliary cirrhosis and in Wilson’s disease patients, and as such, individuals suffering from these conditions should avoid taking supplemental copper.

According to an analysis of data from the 2009–2012 National Health and Nutrition Survey (NHANES), 6% to 15% of adults aged 19 and older who do not take dietary supplements containing copper have copper intakes below the Estimated Average Requirement (average daily level of intake estimated to meet the requirements of 50% of healthy individuals; usually used to assess the nutrient intakes of groups of people and to plan nutritionally adequate diets for them; can also be used to assess the nutrient intakes of individuals) ⁹⁵. In those who do use supplements, rates of adults with intakes below the copper Estimated Average Requirement (EAR) range from 2.2% to 7.2% ⁹⁵.

Should I be taking copper supplements or trying to get more copper in my diet?

In most cases, a regular diet satisfies the body’s requirements for copper. Talk to your healthcare provider before taking any supplements or changing your diet.

Can copper be harmful?

Yes, copper can be harmful if you get too much. Getting too much copper on a regular basis can cause liver damage, abdominal pain, cramps, nausea, diarrhea, and vomiting ⁴⁴. More serious signs of acute copper toxicity include severe liver damage, kidney failure, coma, and death ¹⁶. Copper toxicity is rare in healthy individuals who do not have a hereditary copper homeostasis defect (e.g., Wilson’s disease, a rare genetic disorder). Wilson’s diseaseis a rare, autosomal recessive disease, which is caused by a mutation in ATP7B, leads to abnormally high tissue levels of copper as a result of defective copper clearance ⁹⁶. People with Wilson’s disease can develop neurologic and liver damage that can result in cirrhosis ¹². Patients can also develop acute hepatitis, hemolytic crisis, and liver failure. Lifelong copper chelation therapy or high doses of zinc can prevent permanent organ damage in these patients.

Copper toxicity has been reported in people who consume water containing high levels of copper as a result of stagnant water in copper-containing pipes and fixtures as well as copper alloys in water distribution systems and household plumbing that allow copper to leach into water ⁴⁴, ⁹⁷. The Environmental Protection Agency has established a recommended upper limit for copper in public water systems of 1.3 mg/L ⁹⁷, ⁹⁸ and by the World Health Organization (2 mg/liter) ⁹⁹.

The daily upper limits (ULs) for copper include intakes from all sources—food, beverages, and supplements—and are listed below in micrograms (mcg). The Food and Nutrition Board has established Tolerable Upper Intake Level (maximum daily intake unlikely to cause adverse health effects) for copper from food and supplements for healthy individuals based on levels associated with liver damage ⁴⁴. The Tolerable Upper Intake Levels (ULs) do not apply to individuals who are receiving supplemental copper under medical supervision.

Table 3. Tolerable Upper Intake Levels (ULs) for Copper

Age	Male	Female	Pregnancy	Lactation
Birth to 6 months	None established*	None established*
7–12 months	None established*	None established*
1–3 years	1,000 mcg	1,000 mcg
4–8 years	3,000 mcg	3,000 mcg
9–13 years	5,000 mcg	5,000 mcg
14–18 years	8,000 mcg	8,000 mcg	8,000 mcg	8,000 mcg
19+ years	10,000 mcg	10,000 mcg	10,000 mcg	10,000 mcg

Footnote: * Breast milk, formula, and food should be the only sources of copper for infants.

[Source ³⁰ ]

Copper deficiency disease

Menkes disease

Menkes disease or Menkes syndrome (Menkes kinky hair syndrome) or copper transport disease, is an inherited disorder in which the body has a problem absorbing copper resulting in copper deficiency. Mutations in the ATP7A gene located on the X chromosome cause Menkes syndrome (Menkes kinky hair syndrome). The mutation leads to uneven distribution of copper in the body. It may build up in tissues of the intestines and kidneys, for example, but may be deficient in areas such as the brain.

Menkes disease affects development, both mental and physical. It is characterized by sparse, kinky hair; failure to gain weight and grow at the expected rate (failure to thrive); and developmental delay, nervous system deterioration. Additional signs and symptoms include weak muscle tone (hypotonia), sagging facial features, seizures, developmental delay, and intellectual disability. Children with Menkes disease (Menkes syndrome) typically begin to develop symptoms during infancy and often do not live past age 3. Early treatment with copper may improve the prognosis in some affected individuals. In rare cases, symptoms begin later in childhood.

Occipital horn syndrome (sometimes called X-linked cutis laxa) is a less severe form of Menkes disease that begins in early to middle childhood. It is characterized by wedge-shaped calcium deposits in a bone at the base of the skull (the occipital bone), coarse hair, and loose skin and joints.

The incidence of Menkes disease and occipital horn syndrome is estimated to be 1 in 100,000 newborns.

Outlook (Prognosis)

Most children with Menkes disease die within the first few years of life.

Menkes disease causes

Mutations in the ATP7A gene located on the X chromosome cause Menkes disease (Menkes kinky hair syndrome). The ATP7A gene provides instructions for making a protein that is important for regulating copper levels in the body. Copper is necessary for many cellular functions, but it is toxic when present in excessive amounts. Mutations in the ATP7A gene result in poor distribution of copper to the body’s cells. Copper accumulates in some tissues, such as the small intestine and kidneys, while the brain and other tissues have unusually low levels of copper. The decreased supply of copper can reduce the activity of numerous copper-containing enzymes that are necessary for the structure and function of bone, skin, hair, blood vessels, and the nervous system. The signs and symptoms of Menkes syndrome and occipital horn syndrome are caused by the reduced activity of these copper-containing enzymes.

Menkes disease inheritance pattern

Menkes disease is inherited in an X-linked recessive pattern. The gene associated with this condition is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause Menkes disease (Menkes kinky hair syndrome). In females (who have two X chromosomes), a mutation would have to occur in both copies of the gene to cause Menkes disease (Menkes kinky hair syndrome). Because it is unlikely that females will have two altered copies of this gene, males are affected by X-linked recessive disorders much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons because males receive the Y chromosome from their father.

In about one-third of cases, Menkes disease is caused by new mutations in the ATP7A gene. People with a new mutation do not have a history of the disorder in their family.

Menkes disease tests

Once Menkes disease is suspected, tests that may be done include:

• Ceruloplasmin blood test (substance that transports copper in the blood)
• Copper blood test
• Skin cell culture
• X-ray of the skeleton or x-ray of the skull
• Gene testing to check for defect of the ATP7A gene

Menkes disease treatment

Treatment usually only helps when started very early in the course of the disease. Injections of copper into a vein or under the skin have been used with mixed results and depends on whether the ATP7A gene still has some activity.

Zinc-induced myeloneuropathy

Copper and zinc are known to compete for absorption ¹⁰⁰. Study has confirmed a decline in serum zinc levels as copper supplementation continued and that monitoring of serum zinc levels is necessary when copper supplementation is performed. Zinc-induced myeloneuropathy is also caused by a deficit in copper ¹⁰¹. Zinc-induced myeloneuropathy is the human equivalent to the copper deficiency myelopathy occurring in ruminants (“enzootic ataxia”) ¹⁰². Zinc-induced myeloneuropathy occurs mainly after sustained zinc exposure ¹⁰³. Regular use of zinc-containing dental fixatives has been identified as a triggering factor ¹⁰⁴. Patients undergoing gastrojejunal bypass surgery are also at risk ¹⁰⁵. The first disturbances are sensory symptoms in the feet. After a few years, zinc-induced myeloneuropathy mimics the subacute combined degeneration of the spinal cord, a disorder due to a deficit in vitamin B12. MRI of the spinal cord demonstrates signal changes in the dorsal columns. Chronic zinc ingestion may also cause bone marrow suppression with anemia, thrombocytopenia and neutropenia. By contrast to Wilson’s disease, urinary copper levels are typically decreased ¹⁰⁶. Although copper replacement may revert cytopenias, neurological deficits are irreversible in 40% of cases, highlighting the importance of detecting the hypocupremic state as soon as possible.

Copper deficiency anemia

It was found in the 1930s that copper is vital for effective erythropoiesis ¹⁰⁷. The hematological manifestations of deficiency are typically anemia or neutropenia, or more rarely pancytopenia ¹⁰⁸. The anemia is usually normocytic or macrocytic, but may rarely be microcytic. A retrospective review of 40 patients with copper deficiency defined the typical bone marrow findings of hypocellularity, vacuolisation of granulocyte and erythroid precursors, iron-containing plasma cells and ring sideroblasts ¹⁰⁹. Owing to the similarity of the haematological findings, copper deficiency may be mistaken for a myelodysplastic syndrome. Some haematology textbooks do not list copper deficiency as a differential of myelodysplastic syndrome ¹¹⁰, and in cases with concomitant myelopathy the neurologist may be the first to consider copper deficiency as the unifying diagnosis.

The mechanisms underlying the hematological effects of copper deficiency have not been fully elucidated. The anemia appears to be partly attributable to impaired iron metabolism. Copper is an essential component of both ceruloplasmin and hephaestin, which are necessary for normal iron homeostasis. Both have enzymatic activity as ferroxidases and are involved in iron export from non-intestinal ¹¹¹ and intestinal cells ¹¹², respectively. In copper deficiency, iron is seen to accumulate in the liver and can be released by intravenous caeruloplasmin. Although the literature suggests that copper deficiency typically causes a microcytic anaemia akin to iron deficiency, this pattern was reported in only one of the cases reviewed herein. The remaining cases where mean corpuscular volume (MCV) was reported were either macrocytic (9 cases) or normocytic (3 cases). The difference between copper deficiency and iron deficiency anaemia may be due to iron utilisation being impaired only at certain steps or the contribution of other mechanisms. For example, copper deficiency seems to impair the production of heme from ferric iron and protoporphyrin, possibly because decreased energy production (cytochrome-c oxidase) in erythrocytes impinges on the synthetic pathway ¹¹³. In addition, alterations in erythrocyte membrane fluidity and oxidative damage cause reduced red cell lifespan in copper-deficient rats ¹¹⁴.

Suggestions for the mechanism leading to neutropenia include destruction of myeloid precursors and impaired maturation within the bone marrow, impaired release of mature neutrophils from the bone marrow and increased serum clearance of neutrophils ¹¹⁵. Indeed, the bone marrow of copper-deficient patients contains a decreased number of myeloid precursors which show vacuolisation ¹⁰⁹.

Familial benign copper deficiency

Familial benign copper deficiency is a rare disorder of mineral absorption and transport characterized by low blood copper level (hypocupremia) that manifests as failure to thrive, mild anemia, repeated seizures, hypotonia, and seborrheic skin ¹¹⁶. Spurring of the femur and tibia are also noted on radiographic imaging. Symptoms are reversible or improve with supplements of oral copper. There have been no further descriptions in the literature since 1988 ¹¹⁷.

Mehes and Petrovicz ¹¹⁸ found hypocupremia with normal ceruloplasmin levels in a 21-month-old boy admitted to hospital because of repeated seizures and failure to thrive. He had blond curly hair, spurring of the femurs and tibias, and mild anemia, but his mental development, electroencephalogram, and hair structure on microscopic examination were normal. His condition improved with supplements of oral copper, but as soon as these were reduced or stopped, hypocupremia and seizures recurred. Photographs showed curly hair and an appearance of the nose and lips reminiscent of that in the infantile hypercalcemia syndrome. The father and 2 brothers were physically and biochemically normal. The mother, aged 28, was notably thin, had always been pale and vulnerable to infections but had no seizures. Her face was seborrheic and her hair so thin that the top of the head was almost bald. Serum copper was low. The mother’s brother was also thin and had been frequently ill as a child but had never had seizures. He had had blond, ‘extremely curly’ hair, but had been bald since age 24 years. His skin was seborrheic and serum copper was low. His 2 sons were healthy with brown, slightly curly hair and normal serum copper levels. Deficient dietary intake of copper and excessive renal loss were excluded. The authors suggested either X-linked or autosomal dominant inheritance and a defect in intestinal absorption of copper. Mehes and Petrovicz ¹¹⁷ provided a 7-year follow-up. Low serum copper levels with marginally low/normal ceruloplasmin values persisted. It was thought that seborrhea improved with copper supplementation.

Copper deficiency causes

Upper gastrointestinal surgery

Certain types of upper gastrointestinal surgery can reduce the effective absorption area for particular micronutrients. Deficiencies of iron and vitamin B12 are especially common ¹¹⁹, with a lack of intrinsic factor contributing to the latter. Whilst neurological complications of gastrectomy for peptic ulcer disease have long been recognized, the underlying aetiology often remained obscure ¹²⁰. The association between a remote history of upper gastrointestinal surgery, copper deficiency and myelopathy was first described in 2001 ¹²¹, and has since been increasingly reported following both non-bariatric ¹²² and bariatric intervention ¹²³.

Partial gastrectomy has rarely been used to treat peptic ulcer disease since the advent of effective pharmacological therapy. The number of cases of gastrectomy-related copper deficiency is small relative to the number of past procedures. However, it is likely that many further cases will be diagnosed because undiagnosed hypocupraemia is common in patients with a history of gastrectomy ¹²⁴, copper deficiency may manifest over 40 years after the operation ¹²⁵ and awareness amongst physicians continues to increase.

The annual number of bariatric operations continues to grow, with the commonest procedure being a Roux-en-Y gastric bypass. Post-operatively, food bypasses most of the stomach and the entire duodenum. Copper deficiency tends to develop sooner after bariatric than after non-bariatric operations, probably due to the greater reduction in the effective absorption area for copper. Case numbers of copper deficiency will rise with the growing use of bariatric surgery and with the ageing of the present cohort.

Malabsorption

In half the cases of copper deficiency attributed to malabsorption, celiac disease was diagnosed; in the other half, no cause of malabsorption was established. In three cases of idiopathic copper malabsorption, no detailed investigation findings were reported ¹²⁰. In the fourth case, malabsorption was not specific to copper: the patient was cachectic and exhibited concomitant deficiencies of iron, vitamin D and vitamin E. A D-xylose absorption test was compatible with proximal intestinal malabsorption, but upper gastrointestinal endoscopy, duodenal biopsies and faecal microbiology failed to identify an underlying cause ¹²⁶.

Drug-induced copper deficiency

Rosa ¹²⁷ reviewed a series of cases of infants born to women who received d-penicillamine during pregnancy for a variety of conditions, including connective-tissue abnormalities and rheumatoid arthritis. Abnormalities observed in the infants included lax skin, hyperflexibility of the joints, fragility of the veins, and numerous soft tissue abnormalities. It was suggested that the malformations were in part due to a drug-induced copper deficiency during embryonic or fetal development. Similar abnormalities were produced with d-penicillamine in rodent models ¹²⁸, and the teratogenicity of the drug can be modulated by maternal dietary copper intake ¹²⁹. The above suggest that in humans maternal copper status should be monitored when d-penicillamine is taken during pregnancy.

Little is known about the influence of other copper chelating drugs such as captopril, disulfiram, dimercaptosuccinic acid, and triethylenetetramine on human prenatal development. Given the significant teratogenic effects that can be associated with similar drugs in experimental animals, it is reasonable to suggest that these drugs can pose a substantial risk to the conceptus if maternal dietary copper intake is low.

A condition of severe copper deficiency can be rapidly induced in experimental animals through the use of a number of chelating drugs, including disulfiram, D-penicillamine, triethylenetetramine, and dimercaptosuccinic acid ¹³⁰. Each of those drugs is known to be teratogenic. The abnormalities produced are reminiscent of those induced by dietary copper deficiency. Although the teratogenicity of D-penicillamine, triethylenetetramine, and dimercaptosuccinic acid can be modulated by the amount of copper in the mother’s diet (Cohen et al. 1983; Mark-Savage et al. 1983), it is important to note that drugs that bind copper typically also bind zinc. Thus, the teratogenic effects of those drugs might be due to a combination of copper and zinc deficiencies.

In contrast to the effects of zinc, drugs and chemicals that induce an acute-phase response in the mother do not necessarily influence copper uptake by the embryo or fetus, and in most cases, fetal copper concentrations are unaffected by chemicals that induce transitory acute-phase responses ¹³¹. That is not surprising, because maternal plasma copper concentrations are increased during an acute-phase response (due to the hepatic production and release of the cuproenzyme ceruloplasmin), and zinc concentrations are decreased. Ceruloplasmin has been postulated to be involved directly in copper transport to the embryo and fetus ¹³². It must be noted that the mechanisms underlying copper transport into the embryo and fetus is an area of active research.

Disease-induced copper deficiency

Copper deficiency can occur secondarily to such diseases as chronic diarrhea, diabetes, alcoholism, and hypertension ¹³³. In the case of maternal diabetes and alcoholism, disease-induced deficiencies of copper in the embryo or fetus have been postulated to contribute to the teratogenesis ¹³⁴. Mothers with diabetes are reported to have low concentrations of copper in erythrocytes ¹³⁵. In addition, maternal hypocupremia is often noted in cases of spontaneous abortion or rupture of the fetal and placental membranes ¹³⁶.

Copper-diet interactions

Zinc

Zinc intakes, well in excess of the amount normally found in the diet, can decrease copper absorption in adults ¹³⁷. In one case report, an infant who was given 16 to 24 mg/day of zinc developed copper deficiency ¹³⁸. Very high doses of zinc have been used to treat patients with Wilson’s disease, an inborn error of copper metabolism resulting in copper toxicity ¹³⁹. This zinc-induced inhibition of copper absorption could be the result of competition for a common, apically oriented transporter or the induction of metallothionein in intestinal cells by zinc. Because this protein has a higher binding affinity for copper than for zinc, copper is retained within enterocytes and its absorption is reduced. This response has been used as a therapy to diminish copper absorption in patients with Wilson’s disease ¹⁴⁰. The interaction could also be responsible for reducing copper absorption during consumption of zinc supplements. When zinc-to-copper ratios of 2:1, 5:1, and 15:1 were fed to humans, there were limited effects on copper absorption ¹⁴¹.

Iron

High iron intakes may interfere with copper absorption in infants. Infants fed a formula containing low concentrations of iron absorbed more copper than infants consuming the same formula with a higher iron concentration ¹⁴². Such an interaction has been reported to produce reduced copper status in infants ¹⁴³.

Fructose

Studies in rats demonstrated that diets very high in fructose were associated with increased severity of copper deficiency in rats ¹⁴⁴, but a similar effect was not observed in pigs ¹⁴⁵, which have cardiovascular systems and gastrointestinal tracts more similar to those of humans. The effects were inconsistent in humans ¹⁴⁶ but did not result in copper depletion, and the extremely high levels of fructose fed (20 percent of energy intake) suggest the effect would not be relevant to normal diets.

Gene-induced copper deficiency

There are at least two genetic defects that are expressed as copper-deficiency syndromes (Menkes disease and occipital horn syndrome). Both disorders are due to defects in a copper-transporting P-type ATPase. Infants with Menkes disease are characterized by progressive degeneration of the brain and spinal cord, hypothermia, connective-tissue abnormalities, and failure to thrive. Menkes disease has been recognized as a disorder of copper metabolism for over 20 years. The prognosis for infants with the disorder is poor and death typically occurs before 3 years of age ¹³³. Similar to the blotchy mouse, the developmental abnormalities associated with Menkes disease are thought to be the consequence of low activity of numerous cuproenzymes during embryonic and fetal development. Those cuproenzymes include dopamine-B-monoxygenase, peptidylglycine a-amidating monooxygenase, cytochrome c oxidase, lysyl oxidase, and CuZnSOD ¹⁴⁷. The aberrant pattern of the plasma and cerebrospinal fluid of Menkes patients has been attributed to low activity of dopamine-B-monoxygenase ¹⁴⁸. Moreover, individuals with Menkes disease are characterized by low activity of ceruloplasmin and peptidylglycine a-amidating monooxygenase ¹⁴⁹. Thus, low activity of numerous enzymes that rely on the amidation of peptides for their activity might occur as a secondary effect of low peptidylglycine a-amidating monooxygenase activity.

Groups at Risk of Copper Inadequacy

The following groups are most likely to have inadequate copper status.

People with Celiac disease

In a study of 200 adults and children with celiac disease, of which 69.9% claimed to maintain a gluten-free diet, 15% had copper deficiency (less than 70 mcg/dL in serum in men and girls younger than 12 years and less than 80 mcg/dL in women older than 12 years and/or ceruloplasmin (CP) less than 170 mg/L) as a result of intestinal malabsorption resulting from the intestinal lining alterations associated with celiac disease ¹⁵⁰. In its 2009 clinical guidelines for celiac disease, the American College of Gastroenterology notes that people with celiac disease appear to have an increased risk of copper deficiency and that copper levels normalize within a month of adequate copper supplementation while eating a gluten-free diet ¹⁵¹.

People with Menkes disease

Menkes disease is a rare, X-linked, recessive disorder of copper homeostasis caused by ATP7A gene mutations, which encode a copper-transporting ATPase ¹². In these individuals, intestinal absorption of dietary copper drops sharply, leading to signs of copper deficiency, including low serum copper and ceruloplasmin (CP) levels ¹², ¹⁵². The typical manifestations of Menkes disease include failure to thrive, impaired cognitive development, aortic aneurysms, seizures, and unusually kinky hair ¹⁵³. Most individuals with Menkes disease die by age 3 years if untreated, but subcutaneous injections of copper starting in the first few weeks after birth can reduce mortality risk and improve development ¹⁵⁴.

People taking high doses of Zinc supplements

High dietary intakes of zinc can interfere with copper absorption, and excessive use of zinc supplements can lead to copper deficiency. Reductions in red blood cell copper-zinc superoxide dismutase, a marker of copper status, have been reported with even moderately high zinc intakes of approximately 60 mg/day for up to 10 weeks ⁴⁰. People who regularly consume high doses of zinc from supplements or use excessive amounts of zinc-containing denture creams can develop copper deficiency because zinc can inhibit copper absorption. This is one reason the Food and Nutrition Board established the Tolerable Upper Intake Level (maximum daily intake unlikely to cause adverse health effects) for zinc at 40 mg/day for adults ⁴⁰.

Copper deficiency signs and symptoms

Copper plays a role as a cofactor for various enzymes in the human body, and is indispensable for myeloid and neurological structure and function ¹⁵⁵. Copper deficiency leads to functional disorders of hematopoiesis such as anemia and neutropenia, as well as neurological disorders such as myelopathy ¹⁵⁶. Symptoms accompanying the copper deficiency included normocytic, hypochromic anemia, leukopenia, and neutropenia. Osteoporosis was observed in copper-deficient infants and growing children ¹⁵⁷.

Acquired copper deficiency has long been recognised as a cause of anemia and, less commonly, other cytopenias ¹⁵⁸. It was only in 2001 that an association with myelopathy was reported ¹²¹. The neurologic manifestations of copper deficiency may be similar to the myeloneuropathy observed with vitamin B12 deficiency ¹⁵⁹. The clinical and radiological picture is usually indistinguishable from subacute combined degeneration due to vitamin B12 (cobalamin) deficiency ¹⁶⁰ and the syndrome is thought to represent the human counterpart of swayback or enzootic ataxia, a copper deficiency myelopathy occurring in ruminants ¹⁶¹. Other, less frequently reported and less clearly causally related neurological associations of acquired copper deficiency include isolated peripheral neuropathy ¹¹⁰, motor neuron disease ¹⁶², myopathy ¹⁶³, cerebral demyelination ¹⁶⁴, cognitive dysfunction ¹⁶⁵ and optic neuropathy ¹⁶⁶.

Though copper deficiency is thought to be rare in developed countries, the neurologic symptoms can be profound and are frequently irreversible, making awareness and early diagnosis essential ¹⁶⁷.

Copper deficiency test

Copper testing may be ordered when a person has signs and symptoms that may be due to a copper deficiency, such as:

• Abnormally low numbers of neutrophils, a type of white blood cell (neutropenia)
• Osteoporosis
• Anemia
• Less commonly, neurologic symptoms and delayed growth in children

One or more of the copper tests may be ordered periodically when monitoring is recommended.

A hepatic (liver) copper test may be ordered to further investigate copper storage when copper and ceruloplasmin results are abnormal or equivocal.

Copper testing is primarily used to help diagnose Wilson disease, a rare inherited disorder that can lead to excess storage of copper in the liver, brain, and other organs. Less commonly, a copper test may be used to detect copper excess due to another condition, to detect a copper deficiency, or to monitor treatment for one of these conditions.

Rarely, a copper test may be used to help diagnose Menkes kinky hair syndrome (Menkes disease), a rare inherited disorder of copper transport dysfunction.

Copper is an essential mineral but in excess, it can be toxic. In the blood from normal, healthy humans, more than 95% of the copper is incorporated into the enzyme ceruloplasmin and only a small amount is in a “free” or unbound state (loosely bound to albumin).

Typically, a total blood copper test is ordered along with a ceruloplasmin level. If the results from these tests are abnormal or unclear, then they may be followed by a 24-hour urine copper test to measure copper elimination and/or a copper test performed on a liver biopsy to evaluate copper storage in the liver.

Sometimes a free (unbound) blood copper test is also ordered. If Wilson disease is suspected, genetic testing may be performed to detect mutations in the ATP7B gene. However, these tests have limited availability and are usually performed in special reference or research laboratories.

Normal copper reference values

• 0-2 months: 0.40-1.40 mcg/mL
• 3-6 months: 0.40-1.60 mcg/mL
• 7-9 months: 0.40-1.70 mcg/mL
• 10-12 months: 0.80-1.70 mcg/mL
• 13 months-10 years: 0.80-1.80 mcg/mL
• > or =11 years: 0.75-1.45 mcg/mL

When is copper test ordered?

One or more copper tests are ordered along with ceruloplasmin when someone has signs and symptoms that a health practitioner suspects may be due to Wilson disease, excess copper storage, or copper poisoning. These signs and symptoms may include:

• Anemia
• Nausea, abdominal pain
• Jaundice
• Fatigue
• Behavioral changes
• Tremors
• Difficulty walking and/or swallowing
• Dystonia

Copper tests may also be ordered to aid in the diagnosis of:

• Primary biliary cirrhosis
• Primary sclerosing cholangitis

What does abnormal copper test result mean?

Copper test results must be evaluated in context and are usually compared to ceruloplasmin levels. Abnormal copper results are not diagnostic of a specific condition; they indicate the need for further investigation. Interpretation can be complicated by the fact that ceruloplasmin is an acute phase reactant – ceruloplasmin may be elevated whenever inflammation or severe infections are present. Both ceruloplasmin and copper are also increased during pregnancy and with estrogen and oral contraceptive use.

• Serum copper below the normal range is associated with Wilson disease, as well as a variety of other clinical situations (see below). Excess use of denture cream containing zinc can cause hypocupremia.
  • Low blood copper concentrations along with increased urine copper levels, low ceruloplasmin levels, and increased hepatic copper are typically seen with Wilson disease.
• Serum concentrations above the normal range are seen in primary biliary cirrhosis and primary sclerosing cholangitis, as well as a variety of other clinical situations (see below).
• Increased blood and urine copper concentrations and normal or increased ceruloplasmin levels may indicate exposure to excess copper or may be associated with conditions that decrease copper excretion, such as chronic liver disease, or that release copper from tissues, such as acute hepatitis.
• Increased hepatic copper may be present with chronic conditions.
• Decreased blood and urine copper concentrations and decreased ceruloplasmin may indicate a copper deficiency.
• A normal hepatic copper test may indicate that copper metabolism is functioning properly or that the distribution of copper in the liver is uneven and the sample is not representative of the person’s condition.
• If a person is being treated for Wilson disease or copper toxicity with drugs that bind copper (chelators), then that person’s 24-hour urine copper levels may be high until body copper stores decrease. Eventually, blood copper and 24-hour urine copper concentrations should normalize.
• If someone is being treated for a condition related to copper deficiency and the person’s ceruloplasmin and total copper concentrations begin to rise, then the condition is likely responding to the treatment.
• Medications such as carbamazepine and phenobarbital can increase blood copper levels. They may also be elevated with rheumatoid arthritis and with some cancers and decreased with a variety of conditions associated with malabsorption, such as cystic fibrosis.
• Total serum copper concentrations are normally low at birth, rise over the next few years, peak, and then decline slightly to a relatively stable level.

Low serum copper, most often due to excess iron or zinc ingestion and infrequently due to dietary copper deficit, results in severe derangement in growth and impaired erythropoiesis. Low serum copper is also observed in hepatolenticular degeneration (Wilson disease) due to a decrease in the synthesis of ceruloplasmin and allelic variances in cellular metal ion transporters. In Wilson disease, the albumin-bound copper may actually be increased, but ceruloplasmin copper is low, resulting in low serum copper. However, during the acute phase of Wilson disease (fulminant hepatic failure), ceruloplasmin and copper may be normal; in this circumstance, hepatic inflammation causes increased release of ceruloplasmin. It is useful to relate the degree of liver inflammation to the ceruloplasmin and copper-see discussion on hypercupremia below. Significant hepatic inflammation with normal ceruloplasmin and copper suggest acute Wilson disease.

Other disorders associated with decreased serum copper concentrations include malnutrition, hypoproteinemia, malabsorption, nephrotic syndrome, Menkes disease, copper toxicity, and megadosing of zinc-containing vitamins (zinc interferes with normal copper absorption from the gastrointestinal tract).

Hypercupremia is found in primary biliary cirrhosis, primary sclerosing cholangitis, hemochromatosis, malignant diseases (including leukemia), thyrotoxicosis, and various infections. Serum copper concentrations are also elevated in patients taking contraceptives or estrogens and during pregnancy.

Since the gastrointestinal (GI) tract effectively excludes excess copper, it is the gastrointestinal tract that is most affected by copper ingestion. Increased serum concentration does not, by itself, indicate copper toxicity.

Table 4. Copper test results interpretation

Test	Wilson Disease	Copper Toxicity	Menkes Disease (Kinky Hair Syndrome)	Copper Deficiency
Copper, blood	Low but may be normal	High	Low	Low
Copper, serum free	High	High	Low	Low
Ceruloplasmin	Low but may be normal	High	Low	Low
Copper, urine	Very high	High	Low	Low
Copper, liver/hepatic*	Positive but, depending on the site sampled, may be negative	High or normal	Low	Low

Footnote: *Excess copper in the liver is often unevenly distributed and may not be detected in a sample. Care must be taken, especially with a 24-hour urine sample, not to contaminate the sample with an external source of copper. Talk to the health practitioner and/or the laboratory that will perform the test about necessary precautions. If a urine or blood copper test result is higher than expected, the health practitioner may have the test repeated with a new sample to confirm the findings.

Should everyone’s copper metabolism be evaluated?

General screening for copper concentrations is not recommended or necessary. Many people with conditions not associated with copper, such as people with infections or inflammation, may have temporarily increased concentrations.

Can I choose either a blood (total or free) or urine copper test?

These tests provide complementary information and your healthcare provider will determine which tests are necessary to evaluate your condition.

Copper deficiency treatment

Treatment of copper deficiency consists of parenteral (IV) and oral copper replacement until normal copper levels in blood are achieved. The response to copper replacement is variable and likely depends on the degree and duration of copper depletion. The hematologic abnormalities have been reported to correct within four to six weeks; however, improvements in neurologic symptoms are modest and often difficult to demonstrate objectively. Paresthesias may resolve, but significant gait abnormalities may remain, consistent with clinical observations in reported cases ¹⁶⁸. Despite malabsorption being the likely mechanism underlying some copper deficiency after roux-en-Y gastric bypass surgery, oral supplementation has been found to correct copper deficiency, suggesting that super-saturation of intestinal copper transport systems is a reliable way to maintain adequate serum levels ¹⁶⁹.

Copper deficiency treatment dose

Typical daily doses were equivalent to 2–4 mg of elemental copper ¹⁷⁰. In one case attributed to non-bariatric gastrointestinal surgery, administration of 2 mg of oral copper per day normalized blood parameters and improved neurological symptoms. However, a subsequent symptomatic and biochemical relapse necessitated that the dose be incremented to 4 mg and then 6 mg, which achieved sustained remission ¹⁷¹. Another patient with idiopathic zinc overload was poorly compliant with oral copper supplementation at 2 mg/day. His serum copper levels remained low and the neurological deficit progressed, though serum ceruloplasmin increased to a value at the low end of the normal range and the anaemia resolved. The copper dose was gradually escalated to 8 mg/day but compliance remained poor and he continued to deteriorate neurologically. Subsequently, the patient reported better compliance and his neurological status improved. However, his highest recorded serum copper level remained below the normal range, and it was unclear whether this reflected insufficient dosage, poor compliance or other factors. Copper doses of up to 9 mg per day have been reported ¹²².

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