Copper

Contents

Copper

Copper

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 ¹. 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) ², ³, ⁴, ⁵, ⁶. Furthermore, defense against oxidative damage depends mainly on the copper-containing superoxide dismutases ⁷, ⁸. 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, ⁵, ⁶. 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 ¹⁰. 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 ¹¹, ¹². 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).

In the human body, most of the copper (Cu) is present as cuprous (Cu⁺) and oxidized cupric (Cu²⁺) compounds ¹⁰. Copper is therefore an intermediary for electron transfer in redox reactions (oxidation-reduction reactions and in scavenging free radicals) ¹³. The oxidation states, Cu³⁺ and Cu⁴⁺, are uncommon ¹⁴. 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 ¹⁵. The human copper transport protein 1 (hCTR1), located at the level of enterocytes, transfers the copper ion (Cu⁺) following the reduction of dietary cupric (Cu²⁺) into cuprous (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 ¹⁶.

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 ¹⁷, ⁴, ¹⁸, ¹⁹, ²⁰, ²¹. The current recommended dietary intake of copper in the USA is 900 mcg/day ²², ²³.

Copper is absorbed mainly from the duodenum and proximal jejunum, and partly from the stomach ²⁴. Low dietary copper intake reduces immune response, which is not restored to normal levels even after several weeks of a high copper intake ²⁵. 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 ⁴, ¹⁸. Almost two-thirds of the body’s copper is located in the bone and muscle ⁴, ²².

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 ⁴, ¹⁸. 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 ²².

Copper status is not routinely assessed in clinical practice, and no biomarkers that accurately and reliably assess copper status have been identified ¹⁸. 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) ¹⁸. Serum copper and ceruloplasmin (CP) levels may fall to 30% of normal in cases of severe copper deficiency ⁵. However, plasma ceruloplasmin (CP) and copper levels can be influenced by other factors, such as estrogen status, pregnancy, infection, inflammation, and some cancers ¹⁸. 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 ⁵.

Normal serum concentrations are 10–25 micromol/L (63.5–158.9 mcg/dL) for copper and 180–400 mg/L for ceruloplasmin (CP) ²⁶.

Figure 1. Copper metabolism in the brain

Copper metabolism in the central nervous system

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 ¹⁰ ]

Free Copper

The fact that cells contain one free copper ion (Cu⁺) or less highlights the tight regulation ²⁷. The redox (oxidation-reduction reactions) 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 (H₂O₂) is transformed into the very reactive hydroxyl (OH^–) 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 ²⁸. Ceruloplasmin plays important functions, acting as an iron oxidase, an amine oxidase, an antioxidant and a glutathione peroxidase ²⁹. 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 ³⁰. 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 ³¹. 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) ³². 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.

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 ³³, ³⁴, ³⁵, ³⁶. 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 ³⁷. 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 ³⁸.

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 ³⁹, ⁴⁰. Ceruloplasmin (CP) knockout (Cp-/-) mice accumulate excess iron in their liver but have normal copper status ⁴¹, ⁴². 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 ⁴³. 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 ⁴⁴.

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 ⁴⁵. Also, cytochrome C oxidase (CCO) is required for the biosynthesis of phospholipids, which are critical structural components of the myelin sheath ³⁸.

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 ³⁸. 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 ⁴⁶. 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 ³⁸. 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 ⁴⁶.

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 ⁴⁷. Cytosolic copper may also influence mRNA expression levels of specific genes, in a dose-dependent manner, implicating possible transcriptional regulation ⁴⁸, ⁴⁹, ⁵⁰. 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 ⁵¹.

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 ⁵². 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 ⁵³, ⁵⁴. 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 ⁵⁵. 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 ²⁵. Mechanistic studies also support a role for copper in the innate immune response to bacterial and viral infections ⁵⁶, ⁵⁷. Severe copper deficiency thus has adverse effects on immune system function; however, whether marginal copper insufficiency impairs immunity in humans has not been established.

Copper health benefits

Cardiovascular disease

Copper deficiency leads to changes in blood lipid levels, a risk factor for atherosclerotic cardiovascular disease ⁴. Animal studies have shown that copper deficiency is associated with cardiac abnormalities, possibly because of the resulting decreases in the activity of several cardiac cuproenzymes ⁴, ¹⁸.

Observational studies have linked elevated serum copper levels to an increased risk for developing cardiovascular disease. For example, a prospective cohort study examined serum copper levels in more than 4,500 men and women 30 years of age and older in the United States ⁵⁸. During the subsequent 16 years, 151 participants died from coronary heart disease (coronary artery disease). After adjusting for other risk factors, those with serum copper levels in the two highest quartiles had a significantly greater risk of dying from coronary artery disease. Case-control studies conducted in Europe also had similar outcomes. For example, a case-cohort study of 2,087 adults in Germany reported an association between higher serum copper concentrations and increased risk of incident cardiovascular disease, including myocardial infarction and stroke ⁵⁹. Another study in 60 patients with chronic heart failure or ischemic heart disease reported that serum copper was a predictor of short-term outcomes ⁶⁰. Higher serum copper was also linked to an increased risk of heart failure in a prospective cohort study of 1,866 middle-aged and older men in Finland ⁶¹. Another prospective cohort study in 4,035 middle-aged men in France reported that high serum copper levels were significantly related to a 50% increase in all-cause mortality; however, serum copper was not significantly associated with cardiovascular disease mortality in this study ⁶². Serum copper was also elevated in patients with rheumatic heart disease ⁶³. In summary, these studies may indicate that high serum copper reflects elevated body copper content, which increases oxidative stress and accelerates tissue/organ damage and disease development. Importantly, however, most copper in the serum is contained within ceruloplasmin (CP), up to 90% depending upon the species, with the remaining, smaller proportion of serum copper bound to albumin or α2-macroglobulin ⁶⁴, ⁶⁵. Serum ceruloplasmin (CP) is an acute-phase reactant protein, with levels increasing by up to 50% as a result of trauma or infection and during chronic inflammatory states. Changes in circulating ceruloplasmin (CP) are associated with proportional changes in serum copper levels, independent of body copper status. Therefore, elevated serum copper in coronary heart disease patients may simply reflect increased ceruloplasmin (CP) production due to the inflammation that typifies atherosclerosis. Collectively, these observations raise concerns about linking elevated serum copper to increased tissue copper content and chronic disease development in humans ⁶⁶.

In contrast to the observational findings discussed above linking high serum copper levels to heart disease, two autopsy studies found copper levels in cardiac muscle were actually lower in patients who died of coronary heart disease than in those who died of other causes ⁶⁷. Additionally, the copper content of white blood cells has been positively correlated with the degree of patency of coronary arteries in coronary heart disease patients ⁶⁸, ⁶⁹. Furthermore, patients with a history of heart attack (myocardial infarction) had lower concentrations of copper-dependent, extracellular superoxide dismutase than those without a history of heart attack (myocardial infarction) ⁷⁰. Thus, due to the lack of specific, reliable biomarkers of copper nutritional status, it is not clear whether copper is related to cardiovascular disease. It is also important to note that altered copper metabolism may be symptomatic of a cardiovascular condition, rather than a factor that primarily influences its development.

Studies examining dietary intake of copper are scarce. In a prospective cohort study in Japan, which included 58,646 participants followed for a median of 19 years, dietary copper intake — measured by a food frequency questionnaire — was not associated with coronary heart disease mortality ⁷¹. Yet, this study associated higher copper intakes with an increased risk of mortality from stroke and other cardiovascular diseases ⁷¹. Notably, it was suggested that elevated plasma copper concentrations could be linked to high circulating homocysteine levels in individuals with cardiovascular disease ⁷², ⁷³, ⁷⁴. Increased blood homocysteine may precipitate development of arterial wall lesions and increase risk of cardiovascular disease ⁷⁵; however, this matter is currently open to debate ⁷⁶. In animal models, copper-homocysteine interactions were linked to impaired vascular endothelial function ⁷⁶, ⁷⁷. Copper restriction in experimental animals decreased homocysteine levels and reduced incidence of atherogenic lesions ⁷⁸, ⁷⁹, but it is not known whether copper imbalance contributes to a possible atherogenic effect of homocysteine in humans ⁸⁰.

Although free copper and ceruloplasmin (CP) can promote low-density lipoprotein (LDL) cholesterol oxidation in the laboratory, there is little evidence that high dietary copper increases oxidative stress in the human body ⁵. Increased serum copper levels have been associated with increased cardiovascular disease risk, as outlined above, but the significance of these findings is unclear due to the complex association among serum copper, ceruloplasmin (CP), and inflammatory mediators. Clarification of the relationships of copper intake, copper nutritional status, ceruloplasmin (CP) levels, and cardiovascular disease risk thus requires further research.

A few small studies that assessed the impact of copper supplementation in healthy adults have found little evidence that copper supplementation affects cardiovascular disease risk factors ⁶. For example, daily supplementation with 2 mg copper as copper glycinate for 8 weeks in 70 healthy adults aged 45 to 60 years increased the activity of two cuproenzymes, erythrocyte superoxide dismutase 1 (SOD1) and plasma ceruloplasmin (CP), but had no effect on five other cardiovascular disease-related plasma markers (CRP; homocysteine; and total, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) cholesterol) ⁸¹. In 16 healthy women (mean age 24 years), daily supplementation with 3 mg or 6 mg elemental copper as copper sulfate had no significant effect on cardiovascular disease risk factors, including total plasma cholesterol or triacylglycerol concentrations ⁸². However, the concentration of fibrinolytic factor PAI-1 decreased by about 30% (indicating reduced cardiovascular disease risk) with 6 mg/day copper supplementation compared with placebo. No clinical trials of copper supplementation have been conducted in people with increased cardiovascular disease risk.

Overall, the evidence to date is insufficient to support any conclusions about the association between copper concentrations and cardiovascular disease risk or the impact of copper supplementation on cardiovascular disease ⁶.

Alzheimer’s disease

Cognitive deterioration in individuals with Alzheimer’s disease is linked to the presence of beta-amyloid plaques and abnormal Tau protein-forming aggregates. The possibility that copper imbalance is involved in the onset of Alzheimer’s disease is under investigation. Some experts believe that dietary copper deficiency plays a role in the cause and pathophysiology of Alzheimer’s disease, the leading cause of dementia, because of several reports of low copper levels and low activity of copper-dependent enzymes in the brains of people with the disease ¹⁹, ⁸³. Limited evidence shows that people with higher copper levels have a lower risk of Alzheimer’s disease ⁸⁴. However, high levels of copper have also been found in the brains of people with Alzheimer’s disease, and some researchers argue that excess amounts of dietary copper are involved in the development of Alzheimer’s disease ⁸⁵. Furthermore, copper accumulation in damaged brain regions in Alzheimer’s disease might not directly reflect overall body copper status or copper intakes ⁸⁶.

One study assessed cognitive function using four cognitive tests during home visits every 3 years for 6 years and intakes of copper and saturated and trans fats using a food frequency questionnaire in 3,718 community-dwelling (noninstitutionalized) adults aged 65 and older ⁸⁷. In the overall study population, dietary and total copper intakes were not associated with cognitive decline. However, in 604 participants (16.2%) who consumed a diet higher in saturated and trans fat, total copper intake in the highest quintile (median 2.75 mg/day) was associated with a significantly faster rate of cognitive decline compared with the lowest intake quintile (median 0.88 mg/day) ⁸⁷. In contrast, an analysis of data on 1,112 adults older than 60 years found no differences in serum copper or ceruloplasmin (CP) levels between patients with Alzheimer’s disease (n=211) and healthy controls (n=695) ⁸⁶. This study did reveal, however, a significant decline in serum copper not bound to ceruloplasmin (CP) in patients with mild cognitive impairment or Alzheimer’s disease compared with the healthy control group 18 months after baseline ⁸⁶.

A few observational studies have assessed the relationship between dietary copper levels and Alzheimer’s disease, with mixed results. Meta-analyses have found that people with Alzheimer’s disease tend to have higher serum copper levels than adults without the disease. In an earlier meta-analysis of 26 studies in a total of 1,058 patients with Alzheimer’s disease and 932 controls, those with Alzheimer’s disease had significantly higher levels of serum copper than the healthy controls ⁸⁸. In a 2014 meta-analysis of 10 studies in 867 healthy individuals and 599 with Alzheimer’s disease (mean age greater than 70 years in both groups), patients with Alzheimer’s disease had significantly higher serum levels of copper not bound to ceruloplasmin (CP) and total serum copper than healthy controls ⁸⁹. A recent 2021 meta-analysis of case-control studies described higher blood concentrations of copper in Alzheimer’s disease patients (N=2,929) as compared to healthy subjects (N=3,547), from a total of 46 studies reviewed ⁹⁰. Also, ‘free’ serum copper (i.e., not bound to ceruloplasmin [CP]) was higher in Alzheimer’s disease patients (N=1,595) than in healthy control subjects (N=2,399), representing 18 total studies. These observations were confirmed in another recent review of published studies ⁹¹. An additional meta-analysis of 12 case-control studies revealed Alzheimer’s disease patients had lower copper concentrations in various brain regions compared to healthy controls, further exemplifying dysregulation of copper homeostasis in Alzheimer’s disease ⁹².

Very little clinical evidence is available on the impact of copper supplementation in patients with Alzheimer’s disease. One clinical trial that randomly assigned 68 patients aged 50 to 80 years with mild Alzheimer’s disease to supplementation with 8 mg copper daily or placebo for 12 months found no significant differences in cognition between groups ⁹³.

Experts participating in the 2013 International Conference on Nutrition and the Brain suggested that individuals at increased risk of Alzheimer’s disease using multivitamin-mineral supplements choose those that have no copper (or iron) because excessive intakes of these minerals could contribute to cognitive issues in some patients ⁹⁴. However, much more research is needed to determine whether high or low levels of serum or plasma copper are associated with Alzheimer’s disease risk and whether supplements containing copper could affect Alzheimer’s disease risk or symptoms.

Additional research is required to determine whether genetic variation could influence individual susceptibility to environmental exposure of high copper levels. Copper administered in drinking water was associated with development of enhanced pathological features in animal models of Alzheimer’s disease ⁹⁵, ⁹⁶. One study in a rabbit model reported that combining a high-cholesterol diet and copper (120 mcg/L in drinking water) impaired cognition ⁹⁵. A prospective cohort study in 3,718 elderly participants in the Chicago Health and Aging Project, followed for 5.5 years, evaluated the impact of fat and copper intakes using food frequency questionnaires on cognitive function. For individuals with high intakes of saturated and trans fat, cognitive decline was greater for those in the highest quintile of total copper intake compared to the lowest quintile (median intake of 2.75 vs. 0.88 mg copper per day) ⁸⁷.

Although dysfunctional copper metabolism is suggested as a risk factor for Alzheimer’s disease, it could also be symptomatic of the disease, rather than causative. Moreover, it is still unclear whether copper supplementation or restriction could delay the progression of Alzheimer’s disease. A small, double-blind, placebo-controlled trial in 68 individuals with mild Alzheimer’s disease found that supplementation of 8 mg/day of copper for one year delayed the decrease of the beta-amyloid peptide Aβ42 in cerebrospinal fluid; a decrease in Aβ42 has been linked to cognitive deterioration ⁹⁷. This delay, however, was not associated with improved cognitive performance ⁹³. Relating to the use of zinc supplementation to block copper absorption in Wilson disease, slow-release zinc acetate administration (150 mg/day for six months) in a randomized, placebo-controlled study of 60 patients with mild-to-moderate Alzheimer’s disease resulted in a decrease in serum ‘free’ copper and stabilization of cognition deficits ⁹⁸. A specific role for copper was not, however, determined in these notable outcomes. In summary, additional human studies are needed to clarify the role of copper in Alzheimer’s disease prevention, development, and progression.

Parkinson’s disease

Neurologically presenting Wilson disease and inherited aceruloplasminemia are characterized by copper accumulation in the brain and development of neurological symptoms, including dystonia and cognitive impairment, that resemble Parkinson’s disease ⁹⁹. Disruption of copper homeostasis has been documented in Parkinson’s disease ¹⁰⁰. Copper depletion occurs in brain regions with loss of neurons in Parkinson’s disease patients ¹⁰¹, ¹⁰². Furthermore, some studies have documented lower serum copper and/or ceruloplasmin (CP) concentrations in Parkinson’s disease patients compared to healthy controls ¹⁰³, ¹⁰⁴, ¹⁰⁵. Dietary copper intake did not, however, relate to the risk of developing Parkinson’s disease in two small case-control studies ¹⁰⁶, ¹⁰⁷. As in Alzheimer’s disease, further research is required to elucidate whether copper imbalance contributes to the pathogenesis of Parkinson’s disease.

Osteoporosis

Progressive decrease of bone mineral density (BMD) is commonly observed in the elderly, frequently leading to development of osteopenia (pre-osteoporosis) and osteoporosis ⁵. Women are more often affected by osteoporosis than men, (e.g., prevalence ratio is 5:1 in non-Hispanic whites) ¹⁰⁸, primarily due to the postmenopausal reduction in the production of estrogen, which is essential for maintaining strength of muscle, bone, and connective tissue ¹⁰⁹. Osteoporosis is associated with an increased risk of falls, bone fracture, and mortality in individuals over 65 years of age ¹¹⁰.

Osteoporosis has been reported in infants with severe copper deficiency, but how copper depletion affects bone and connective tissue health in adults is less certain ¹¹¹, ¹¹². One recent investigation documented bone resorption (breakdown) in 11 healthy adult males consuming marginal copper for six weeks (700 mcg/day) ¹¹³. Also, supplementation of 3 to 6 mg/day of copper for six weeks had no effect on biochemical markers of bone resorption or bone formation in two studies of healthy adult men and women ¹¹⁴, ¹¹⁵. An effect of copper deficiency on bone integrity seems likely, since a copper-dependent enzyme, lysyl oxidase (LOX), is required for the maturation (cross-linking) of collagen, a key element in the organic matrix of bone. In individuals with marginal copper intake and less efficient copper absorption, such as the elderly, it seems plausible that lysyl oxidase (LOX) activity is decreased, possibly increasing risk for bone and connective tissue effects.

Limited studies of copper supplementation and bone health outcomes have been undertaken. A small study in perimenopausal women, who consumed ~1 mg of dietary copper daily, reported decreased loss of bone mineral density (BMD) from the lumbar spine after copper supplementation of 3 mg/day for two years ¹¹⁶. Additionally, a two-year, double-blind, placebo-controlled trial in 59 postmenopausal women found that daily intake of supplemental calcium plus trace minerals, including 2.5 mg of copper, resulted in maintenance of spinal bone mineral density (BMD) ¹¹⁷. Supplemental calcium or trace minerals, alone, were not as effective at preventing loss of bone density ¹¹⁷. Another randomized, double-blind, placebo-controlled study in 224 healthy, postmenopausal women ages 51 to 80 years, found daily supplementation with 600 mg of calcium, 2 mg of copper, and 12 mg of zinc for two years decreased whole-body BMD compared to supplemental calcium alone. Another trial showed that bone mineral density (BMD) was reduced in subjects with dietary copper intakes below the RDA (900 mcg/day), but copper supplementation did not prevent the progressive loss of BMD as well as a calcium regimen alone ¹¹⁸. Finally, several studies have suggested that tooth loss might be related to defects in the maintenance of bone mineral density (BMD) ¹¹⁹, ¹²⁰. When compared with 20 healthy-matched controls, 50 patients (mean age, 47.5 years) with low spinal bone mineral density (BMD) and advanced tooth wear were found to have significantly lower copper content in tooth enamel. However, despite evidence of bone demineralization, serum copper levels in this population were similar to those of the healthy group ¹²¹. In summary, additional research is required to draw meaningful conclusions regarding the effects of marginal copper depletion and copper supplementation on bone metabolism and risk for developing age-related osteoporosis.

Nonalcoholic fatty liver disease (NAFLD)

Similar to findings from animal models ¹²², human studies have documented low circulating copper ¹²³, ¹²⁴ or low hepatic copper content in adults and children with nonalcoholic fatty liver disease (NAFLD) ¹²⁵, ¹²⁶. An inverse association between hepatic copper content and liver disease severity has also been observed ¹²⁵, ¹²⁶. However, it is not known whether low dietary intake of copper might be a contributor to disease pathogenesis or whether dysregulated copper metabolism is only a manifestation of liver disease.

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 ²². 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) ¹²⁷.

Table 1 lists the current Recommended Dietary Allowance (RDA) for copper ²². 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 ⁶ ]

Food Sources of Copper

Many foods contain copper. You can get recommended amounts of copper by eating a variety of foods, including the following ¹²⁸:

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 ¹⁷. 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 ¹²⁹. 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 ⁶ ]

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 ¹³⁰. 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) ⁶.

Supplementation of adults with 10 mg/day of cupric gluconate for 12 weeks did not cause copper toxicity ¹³¹. 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) ¹³². 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% ¹³².

Copper IUDs versus long-acting hormone injections and implants for contraception

Reversible, long-term contraception is relied on by millions of women to prevent unwanted pregnancy. Two very common methods of pregnancy prevention are the use of a copper-containing intrauterine device (IUD) or an injection of a progestogen hormone.

According to this (source ¹³³) the effectiveness of copper-containing intra-uterine devices (coil) specifically the T-shaped IUDs with copper on the arms are the most effective, have the longest duration of action and are the IUDs of choice. TCu380A or TCu380S appear to be more effective than other IUDs. No IUD showed consistently lower removal rates for bleeding and pain in comparison to other IUDs. There is no evidence that any particular framed copper device is better suited to women who have not had children.

In the populations studied (studies that compared these two highly effective methods and found the IUD to be better at preventing pregnancy than depot medroxyprogesterone acetate) (source ¹³⁴), the IUD was more effective than hormonal contraception with respect to pregnancy prevention.

The copper intrauterine device (copper IUD) is a highly-effective non-hormonal type of birth control, and is the most commonly used method in the world. However, use of the copper IUD is low in countries with relatively high rates of unintended pregnancy, such as the United Kingdom and United States. Since the copper IUD is one of the most effective reversible contraceptive methods, primary care and family planning and practitioners could consider adopting these interventions ¹³⁵.

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 ²⁶. More serious signs of acute copper toxicity include severe liver damage, kidney failure, coma, and death ⁵. 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 ¹³⁶. People with Wilson’s disease can develop neurologic and liver damage that can result in cirrhosis ⁴. 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 ²⁶, ¹³⁷. The Environmental Protection Agency has established a recommended upper limit for copper in public water systems of 1.3 mg/L ¹³⁷, ¹³⁸ and by the World Health Organization (2 mg/liter) ¹³⁹.

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 ²⁶. 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 ⁶ ]

Copper Toxicosis

The symptoms of acute copper intoxication include nausea, vomiting, diarrhea, abdominal pain, tachycardia and hemolytic anemia. The intoxication usually follows the ingestion of contaminated water or food ¹⁴⁰.

The daily intake of copper determines the occurrence of copper toxicosis. High levels of copper in drinking water and food can cause a subacute to chronic syndrome of copper toxicosis ¹⁴¹. The current tolerable upper intake level is 10 mg/day ¹⁴². An oral supplement of copper 10 mg/day (supplementation with plain tap water between meals, consisting of two 5-mg copper gelatin capsules as copper sulfate) during two months induces a transient, but significant, elevation of aminotransferases ¹⁴³. Drinking water from wells via copper pipes has been incriminated in copper toxicosis ¹⁴⁴. The syndrome affects mainly young children. Their parents may be clinically healthy ¹⁴⁴. The disorder can lead to death. In India, a micronodular cirrhosis has been reported ¹⁴⁵. Copper toxicosis may be idiopathic, but these cases are very rare.

Rats exposed to copper in drinking water develop liver damage due to increased hepatocellular stores, with a significant increase of concentrations of the metal in the CNS and biochemical evidence of oxidative stress ¹⁴⁶. The activity of superoxide dismutase (SOD) decreases, and the concentrations of malondialdehyde rise.

Copper and Drug interactions

Relatively little is known about the interaction of copper with drugs. Penicillamine is used to bind copper and enhance its elimination in Wilson disease, a genetic disorder resulting in hepatic copper overload. Because penicillamine dramatically increases the urinary excretion of copper, individuals taking the medication for reasons other than copper overload may have an increased dietary copper requirement. Additionally, antacids may interfere with copper absorption when used in very high amounts ³⁸. Also, the anti-tuberculosis drug ethambutol may chelate copper in mitochondria and reduce cytochrome c oxidase activity specifically in optic nerve axons, possibly contributing to optic neuropathy which is a documented side-effect of this drug ¹⁴⁷.

Am I getting enough copper?

Most people get enough copper from the foods they eat. However, certain groups of people are more likely than others to have trouble getting enough copper:

People with celiac disease
People with Menkes disease, a rare genetic disorder
People taking high doses of zinc supplements, which can interfere with the ability to absorb copper and could lead to copper deficiency

What happens if I don’t get enough copper?

Copper deficiency is rare in the United States. Copper deficiency can cause extreme tiredness, lightened patches of skin, high levels of cholesterol in the blood, and connective tissue disorders affecting the ligaments and skin. Other effects of copper deficiency are weak and brittle bones, loss of balance and coordination, and increased risk of infection.

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 ¹⁴⁸, ¹⁴⁹, ¹⁸. Copper deficiency in the United States is believed to be relatively rare but has been described in the setting of zinc supplementation ¹⁵⁰, myelodysplastic syndrome ¹⁵¹, use of total parenteral nutrition (TPN) ¹⁵² and chronic tube feeding ¹⁵³ especially via jejunostomy ¹⁵⁴ 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 ¹⁵⁵, ¹⁵⁶. 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 ¹⁵⁶.

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 ⁴, ¹⁵⁷, ¹⁵⁸. 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 ¹⁵⁹, ¹⁴⁹, 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 ⁵. 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 ¹⁶⁰. Ceruloplasmin (CP) plays a role in iron metabolism and carries more than 95% of the total copper in healthy human plasma ¹⁶¹. In copper-deficient pig, intestinal iron absorption is impaired but iron distribution among tissues or organs is normal ¹⁶², ¹⁶³, ¹⁶⁴. Low serum iron from reduced absorption is an unlikely cause of this anemia since intravenous provision of iron did not correct it ⁵. 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 ¹⁶⁵, ¹⁶⁶. More research is clearly needed to further define the mechanisms underlying copper deficiency-induced anemia and neutropenia ¹⁶⁵, ³³. 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 ³⁸, ³⁷.

Normal serum concentrations are 10–25 micromol/L (63.5–158.9 mcg/dL) for copper and 180–400 mg/L for ceruloplasmin (CP) ²⁶.

The treatment for copper deficiency is not yet developed and depends on the underlying cause of the copper deficiency ¹⁵⁹. 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 ¹⁶⁷. 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 ¹⁶⁸.

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 ¹⁶⁹, 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 ¹⁷⁰. The association between a remote history of upper gastrointestinal surgery, copper deficiency and myelopathy was first described in 2001 ¹⁷¹, and has since been increasingly reported following both non-bariatric ¹⁷² and bariatric intervention ¹⁷³.

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 ¹⁷⁴, copper deficiency may manifest over 40 years after the operation ¹⁷⁵ 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 ¹⁷⁰. 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 ¹⁷⁶.

Drug-induced copper deficiency

Rosa ¹⁷⁷ 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 ¹⁷⁸, and the teratogenicity of the drug can be modulated by maternal dietary copper intake ¹⁷⁹. 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 ¹⁸⁰. 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 ¹⁸¹. 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 ¹⁸². 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 ¹⁸³. 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 ¹⁸⁴. Mothers with diabetes are reported to have low concentrations of copper in erythrocytes ¹⁸⁵. In addition, maternal hypocupremia is often noted in cases of spontaneous abortion or rupture of the fetal and placental membranes ¹⁸⁶.

Copper-diet interactions

Zinc

Zinc intakes, well in excess of the amount normally found in the diet, can decrease copper absorption in adults ¹⁸⁷. In one case report, an infant who was given 16 to 24 mg/day of zinc developed copper deficiency ¹⁸⁸. 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 ¹⁸⁹. 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 ¹⁹⁰. 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 ¹⁹¹.

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 ¹⁹². Such an interaction has been reported to produce reduced copper status in infants ¹⁹³.

Fructose

Studies in rats demonstrated that diets very high in fructose were associated with increased severity of copper deficiency in rats ¹⁹⁴, but a similar effect was not observed in pigs ¹⁹⁵, which have cardiovascular systems and gastrointestinal tracts more similar to those of humans. The effects were inconsistent in humans ¹⁹⁶ 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 ¹⁸³. 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 ¹⁹⁷. The aberrant pattern of the plasma and cerebrospinal fluid of Menkes patients has been attributed to low activity of dopamine-B-monoxygenase ¹⁹⁸. Moreover, individuals with Menkes disease are characterized by low activity of ceruloplasmin and peptidylglycine a-amidating monooxygenase ¹⁹⁹. 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 ²⁰⁰. 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 ²⁰¹.

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 ⁴. In these individuals, intestinal absorption of dietary copper drops sharply, leading to signs of copper deficiency, including low serum copper and ceruloplasmin (CP) levels ⁴, ²⁰². The typical manifestations of Menkes disease include failure to thrive, impaired cognitive development, aortic aneurysms, seizures, and unusually kinky hair ¹⁵. 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 ²⁰³.

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 ²². 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 ²².

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 ²⁰⁴. Copper deficiency leads to functional disorders of hematopoiesis such as anemia and neutropenia, as well as neurological disorders such as myelopathy ²⁰⁵. Symptoms accompanying the copper deficiency included normocytic, hypochromic anemia, leukopenia, and neutropenia. Osteoporosis was observed in copper-deficient infants and growing children ²⁰⁶.

Acquired copper deficiency has long been recognised as a cause of anemia and, less commonly, other cytopenias ²⁰⁷. It was only in 2001 that an association with myelopathy was reported ¹⁷¹. The neurologic manifestations of copper deficiency may be similar to the myeloneuropathy observed with vitamin B12 deficiency ²⁰⁸. The clinical and radiological picture is usually indistinguishable from subacute combined degeneration due to vitamin B12 (cobalamin) deficiency ²⁰⁹ and the syndrome is thought to represent the human counterpart of swayback or enzootic ataxia, a copper deficiency myelopathy occurring in ruminants ²¹⁰. Other, less frequently reported and less clearly causally related neurological associations of acquired copper deficiency include isolated peripheral neuropathy ²¹¹, motor neuron disease ²¹², myopathy ²¹³, cerebral demyelination ²¹⁴, cognitive dysfunction ²¹⁵ and optic neuropathy ²¹⁶.

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 ²¹⁷.

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 ²¹⁸. 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 ²¹⁹.

Copper deficiency treatment dose

Typical daily doses were equivalent to 2–4 mg of elemental copper ²²⁰. 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 ²²¹. 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 ¹⁷².

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Copper

Copper

Free Copper

Ceruloplasmin

What is the function of copper?

Energy production

Connective tissue formation

Iron metabolism

Central nervous system function

Melanin biosynthesis

Antioxidation

Regulation of gene expression

Immune system function

Copper health benefits

Cardiovascular disease

Alzheimer’s disease

Parkinson’s disease

Osteoporosis

Nonalcoholic fatty liver disease (NAFLD)

How much copper do I need?

Table 1. Recommended Dietary Allowances (RDAs) for Copper

Food Sources of Copper

Table 2. Selected Foods Copper Content

Copper supplements

Copper IUDs versus long-acting hormone injections and implants for contraception

Can copper be harmful?

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

Copper Toxicosis

Copper and Drug interactions

Am I getting enough copper?

What happens if I don’t get enough copper?

Copper deficiency

Copper deficiency causes

Upper gastrointestinal surgery

Malabsorption

Drug-induced copper deficiency

Disease-induced copper deficiency

Copper-diet interactions

Zinc

Iron

Fructose

Gene-induced copper deficiency

Groups at Risk of Copper Inadequacy

People with Celiac disease

People with Menkes disease

People taking high doses of Zinc supplements

Copper deficiency signs and symptoms

Copper deficiency test

Normal copper reference values

When is copper test ordered?

What does abnormal copper test result mean?

Table 4. Copper test results interpretation

Should everyone’s copper metabolism be evaluated?

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

Copper deficiency treatment

Copper deficiency treatment dose

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