Copper for Optimal Health

Dr. Weeks Comment:  Has your doctor ever measured your copper level or your ceruloplasmin level? She or he has probably measured your iron or ferritin level but without measuring copper, the whole picture is not visible.  Copper and iron are two sides of one coin in that their actions – both beneficial and toxic – are interrelated. But I want you to focus on copper today and appreciate only 3 of its many unique benefits: 1) it is part of your body’s most powerful anti-oxidant and anti-inflammatory molecules 2) it detoxifies iron stored in tissues by bringing iron back in circulation and 3) it is critical in optimizing energy production in your mitochondria.  Also, if you are anemic and your doctor is giving you iron, think again: you need copper.

Tests for your doctor to order are:  CBC and differential, serum copper, ceruloplasmin, serum zinc, serum retinol, serum 1,25 OH-vit D, serum iron, Total iron binding capacity(TIBC), serum ferritin, serum transferrin, plasma zinc, red blood cell (RBC) magnesium.

Best book on Copper is    CU-re: your fatigue. how balancing 3 minerals and 1 protein is the solution that you’re looking for. By  Morley M. Robbins

Here are two powerful and detailed articles on the dance of copper and iron for you to learn more.

A brilliant SHORT article on Copper

(Bold italics are added by Dr Brad.)



James F. Collins, Leslie M. Klevay

Advances in Nutrition, Volume 2, Issue 6, November 2011, Pages 520–522,

Copper is the 26th element in abundance in the crust of the earth and is the 29th element in the periodic table with 2 stable and 9 radioactive isotopes. Copper deficiency is the leading deficiency worldwide among nutritional diseases of agricultural animals. The essentiality of copper for animals and humans has been known for nearly a century. Needed in only trace amounts, the human body contains slightly >100 mg, although measurements are scarce. Only kidney and liver exceed the concentration of copper in brain (∼5 μg/g), with heart being close behind. These high concentrations are probably related to metabolic activity, because copper is a cofactor for cytochrome c oxidase, the terminal enzyme in the electron transport chain. Because of their size, skeleton and muscle contain more than one-half of the copper in the body.


Adequate copper intake permits normal utilization of dietary iron in that intestinal iron absorption, iron release from stores (e.g. in macrophages of liver and spleen), and iron incorporation into hemoglobin are copper-dependent processes. In addition to preventing anemia, copper assists in blood coagulation and blood pressure control; cross-linking of connective tissues in arteries, bones, and heart; defense against oxidative damage; energy transformation; myelination of brain and spinal cord; reproduction; and synthesis of hormones. Inadequate copper produces adverse effects on the metabolism of cholesterol and glucose, blood pressure control and heart function, mineralization of bones, and immunity. Isoprostanes are also known to increase during copper deficiency (1). Moreover, it is now an accepted medical fact that copper-deficient humans also suffer from osteoporosis, which can be cured with extra copper. Although it is unknown whether copper deficiency contributes to osteoporosis in Western populations, 2 double-blind, placebo-controlled trials have shown that trace element supplements, including copper, improved bone mineral density in postmenopausal women (1). Further, as much as 1.03 mg copper/d has been proven insufficient for adult males (2).

Diet recommendations:

Dietary reference intakes for copper were established almost a decade ago (3). Based on a lack of experimental data, Adequate Intake levels for copper have been established for infants 0–6 mo of age (200 μg/d) and for those between 7 and 12 mo (220 μg/d). The RDA increases throughout childhood and adolescence (all in μg/d: 1–3 y old, 340; 4–8 y, 440; 9–13 y, 700; 19–50+ y, 900). Copper needs increase in pregnancy (1000 μg/d) and lactation (1300 μg/d). Upper tolerable intake levels have also been established for copper, varying from 1000 μg/d at 1–3 y old to 10,000 μg/d in adults. Interestingly, copper recommendations for adults in the UK, the European Community, and Australia/New Zealand range from 1.1 to 1.2 mg/d, suggesting that the U.S. and Canadian RDA values for adults may be low.

The relative amount of copper in the diet seems to be the major predictor of intestinal absorption, although percent absorption increases during states of deficiency. Dietary factors, including iron, vitamin C, and zinc, have been reported to exert adverse effects on the bioavailability of copper. Lead poisoning, hemochromatosis, and excessive ingestion of soft drinks produce more subtle effects. Bariatric surgery and excessive use of denture creams high in zinc are the most recently identified ways of inducing deficiency (1). The impact of dietary components on copper absorption may be more pronounced in neonates, as digestive function and homeostatic regulation of biliary copper excretion are immature.

Deficiency occurs when requirements exceed intakes; little is known about the variability of adult copper requirements. Recent reviews of deficiency (4–6) reveal that 20–40% of cases are of unknown origin. Whether these individuals have low intakes or unusually high requirements is unknown.

Food sources:

Copper absorption, at 55–75%, is considerably higher than for that of other trace elements; absorption occurs mainly in the upper small intestine. The copper concentration of foods is an important characteristic determining nutritional usefulness. In order of increasing concentration on a weight basis, fats and oils, dairy products, sugar, tuna, and lettuce are low in copper (all <0.4 μg/g); legumes, mushrooms, chocolate, nuts and seeds, and liver are high in copper (all >2.4 μg/g). Although not high in copper, bread, potatoes, and tomatoes are consumed in sufficiently large amounts by U.S. adults to substantially contribute to copper intake. Copper and magnesium are highly correlated in U.S. diets and food groups high in folate tend to be high in copper (1).

Clinical uses:

Copper gluconate is the only copper supplement listed by the United States Pharmacopeial Convention for oral use. A recent study supplemented adults with 10 mg cupric gluconate/d for 12 wk without evidence of liver damage or gastrointestinal distress (7). Cupric oxide is contained in some vitamin-mineral supplements but is poorly utilized. Deficient people should be supplemented with several times the EAR or RDA, because these recommendations are only for healthy people. Adults have tolerated daily supplements of 3–7 mg for long periods (1).

No single indicator provides an adequate assessment of copper nutriture. Reductions in plasma copper and ceruloplasmin (CP) activity are noted in severely copper-deficient humans; CP carries the predominance of copper in the blood, so alterations in blood copper likely reflect the amount of circulating CP. Observed reductions in serum Cu and CP activity are, however, complicated by the fact that several physiological alterations can increase copper content and CP activity in blood, including the acute phase response to infection and inflammation, pregnancy and other hormonal perturbations, some carcinogenic phenotypes, and smoking. Circulating copper may thus be unexpectedly high during inflammation and may not reflect the actions of copper-dependent enzymes in cells. Furthermore, numerous experiments with animals reveal that plasma copper can be normal or increased even though copper in liver and other organs is low. Low plasma copper indicates physiological impairment (1). Better indices, particularly for the detection of moderate deficiency, are clearly needed (8–10).


Copper toxicity is rather rare in humans and animals, because mammals have evolved precise homeostatic control of copper due to the high reactivity of the free metal. Free copper in cells and in the body is extremely low; copper almost always exists in biological systems bound to proteins. Ingestion of high copper levels may, however, override the innate checkpoints designed to regulate overall body copper levels, including, but not limited to, enhanced intestinal absorption in the absence of a physiological demand for copper. Due to possible adverse consequences of high copper ingestion, an upper tolerable intake level of 10 mg/d has been established (3). Copper toxicity risks are higher for neonates and infants given an immature biliary excretion system and enhanced intestinal absorption. Copper loading is observed clinically today in the setting of Wilson’s disease and other disorders in which biliary copper excretion is impaired, such as biliary cirrhosis and biliary atresia.

Recent research:

Traditional approaches to copper nutrition have emphasized either anemia or the nutrition of infants. Descriptions of anemia with hypochromic, microcytic erythrocytes can be found in many textbooks.

Two new adult syndromes are being identified along with the new ways of becoming deficient (above). Leukocytes also can be affected by deficiency; some cases of myelodysplastic syndrome respond to copper supplementation (1).

Neuromuscular defects resembling those of pernicious anemia and responding to copper instead of vitamin B12 are being increasingly reported and have been referred to as “human swayback” in reference to well-known copper deficiency in ruminants (4–6,11). The similarity of these syndromes might not be as mysterious as it may seem. Nitrous oxide anesthesia can induce vitamin B12 deficiency very rapidly by inactivating methionine synthase (12), which requires vitamin B12 for activity (13). Activity of this enzyme is decreased in copper-deficient rats, suggesting it may be a copper enzyme (14).

An extensive body of recent literature has explored the interaction between copper and iron (15); certain aspects of these interactions have in fact been recognized for >150 y (16). Described points of interaction include 2 multicopper ferroxidases, which are important for intestinal copper absorption (hephaestin) and release of iron from body stores (CP). The expression and activity of both ferroxidases is decreased in copper-deficient rodents. Moreover, CP expression and activity increases during iron deficiency anemia in humans (17) and rodents (18), suggesting that it may play a compensatory role in the response to low body iron levels. Further studies have revealed alterations in the expression of copper homeostasis-related genes in the intestines of iron-deficient rodents, including the Menkes copper ATPase (Atp7a, a copper exporter) and metallothionein, an intracellular copper storage protein, again suggesting that copper is important for the proper response to decreased body iron stores (19,20).

 For references, see



a brilliant LONG and DETAILED article on copper and iron


Intersection of Iron and Copper Metabolism in the Mammalian Intestine and Liver

Caglar Doguer,#1,2 Jung-Heun Ha,#1,3 and James F. Collins*,1


Major teaching points

  • Iron and copper are essential nutrients for humans since they mediate numerous important physiologic functions; deficiency of either is associated with significant pathophysiologic outcomes.
  • Iron and copper exist in two oxidation states in biological systems, and high redox potentials lead to toxicity in cells and tissues when in excess.
  • Iron and copper atoms have similar physiochemical properties, and as such, interactions between them are predictable.
  • Both minerals are absorbed by duodenal enterocytes, after first being reduced in the gut lumen from their predominant dietary forms.
  • Intestinal and hepatic ferrireductases, such as duodenal cytochrome B or STEAP proteins, may promote iron and copper reduction, which is required for absorption into enterocytes and subsequent uptake into hepatocytes.
  • Two multicopper ferroxidases perhaps best exemplify iron-copper interactions: hephaestin (HEPH) in duodenal enterocytes and ceruloplasmin (CP) circulating in the plasma. HEPH is required for optimal intestinal iron absorption during physiologic conditions and during pregnancy, while CP is required for iron release from stores and other tissues (e.g., brain).
  • During iron deficiency, copper transport into duodenal enterocytes increases, possibly promoting iron absorption. This may be mediated by the principal intestinal iron transporter, divalent metal-ion transporter 1 (DMT1), which can also transport copper.
  • Hepatic copper accumulation during iron deficiency may enhance biosynthesis of CP.
  • Intestinal genes encoding iron transporters are regulated by a hypoxia-inducible transcription factor, HIF2α. Copper enhances the DNA-binding activity of the HIFs, exemplifying another way in which copper may influence iron homeostasis.
  • Iron overload, as seen in the genetic disease hereditary hemochromatosis, may impair copper utilization. Moreover, high-dose iron supplementation may increase risk for copper depletion in humans, and as such, it has been suggested that iron supplements should also contain copper.


Iron and copper have similar physiochemical properties; thus, physiologically relevant interactions seem likely. Indeed, points of intersection between these two essential trace minerals have been recognized for many decades, but mechanistic details have been lacking. Investigations in recent years have revealed that copper may positively influence iron homeostasis, and also that iron may antagonize copper metabolism. For example, when body iron stores are low, copper is apparently redistributed to tissues important for regulating iron balance, including enterocytes of upper small bowel, the liver, and blood. Copper in enterocytes may positively influence iron transport, and hepatic copper may enhance biosynthesis of a circulating ferroxidase, ceruloplasmin, which potentiates iron release from stores. Moreover, many intestinal genes related to iron absorption are transactivated by a hypoxia-inducible transcription factor, hypoxia-inducible factor-2α (HlF2α), during iron deficiency. Interestingly, copper influences the DNA-binding activity of the HIF factors, thus further exemplifying how copper may modulate intestinal iron homeostasis. Copper may also alter the activity of the iron-regulatory hormone hepcidin. Furthermore, copper depletion has been noted in iron-loading disorders, such as hereditary hemochromatosis. Copper depletion may also be caused by high-dose iron supplementation, raising concerns particularly in pregnancy when iron supplementation is widely recommended. This review will cover the basic physiology of intestinal iron and copper absorption as well as the metabolism of these minerals in the liver. Also considered in detail will be current experimental work in this field, with a focus on molecular aspects of intestinal and hepatic iron-copper interplay and how this relates to various disease states.

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Among the essential trace minerals, iron and copper are unique as they exist in two oxidation states in biological systems and can potentiate the formation of damaging oxygen free radicals when in excess. Deficiencies of both nutrients are also associated with significant physiological perturbations. Given the potential adverse effects of too much or too little iron or copper, their homeostasis is tightly controlled at the cellular and organismal levels by local and systemic mediators. The reactive nature of these metal ions underlies important biological functions related to electron transfer (i.e., redox) reactions, in which both metals function as enzyme cofactors. Moreover, given their similar physiochemical properties, including comparable atomic radii and electrical charges, it is not surprising that biologically-relevant interactions between iron and copper have been frequently noted in mammals (5487105).

Iron extraction from the diet in the proximal small intestine is tightly controlled since no active, regulated mechanisms exist in humans to excrete excess iron (although rodents do have a limited capacity to excrete iron in bile). Iron homeostasis is regulated at the whole-body level by the hepatic, peptide hormone hepcidin (HEPC). HEPC is released when body iron stores increase and during infection and inflammation, and it functions to reduce serum iron concentrations. It accomplishes this by binding to the iron exporter, ferroportin 1 (FPN1), which is expressed on the surface of cells that absorb and store iron, causing its internalization and degradation (208). Additional transcriptional and posttranscriptional mechanisms also exist at the cellular level to locally regulate iron homeostasis. Collectively, these homeostatic loops modulate the expression of genes encoding iron metabolism-related proteins, including iron transporters and an iron reductase (i.e., a “ferrireductase”). One such mechanism involves the transactivation of genes in enterocytes by a hypoxia-inducible factor-2α (HIF2α) during iron deprivation (with concurrent hypoxia). Another regulatory mechanism acts posttranscriptionally to control mRNA levels within many cells via interaction of a stem-loop structure within the transcripts [i.e., iron-responsive elements (IREs)] with cytosolic, iron-sensing proteins [called iron-regulatory proteins (IRPs)]. These interactions can either inhibit translation of a message or increase its stability, leading to the production of more protein. Intracellular modulation of “free,” or unbound, iron levels also occurs via interaction with ferritin, which sequesters excess iron, thus rendering it unreactive.

Copper metabolism is also regulated according to physiologic demand, but the mechanisms involved have not been elucidated to date. Modulation of copper homeostasis by a copper-regulatory hormone was proposed in mice (145), but more recent, confirmatory studies have not been reported. The purported factor was released from the heart in response to low copper levels, and it supposedly increased intestinal copper absorption and hepatic copper release by upregulating expression of a copper exporter [copper-transporting ATPase 1 (ATP7A)]. Furthermore, cellular copper metabolism is modulated within cells by a host of cytosolic chaperones, which control copper trafficking. Copper may also be sequestered within cells by metallothionein (MT), which is a copper- and zinc-binding protein (but it has a higher affinity for copper) (144). Whole-body copper concentrations are controlled by excretion into the bile; biliary copper is complexed with bile salts and thus cannot be reabsorbed in the gut.

Adequate iron and copper intake is critical for humans and other mammals, especially during the rapid postnatal growth period. This fact is exemplified by the pathophysiological consequences of deficiency of iron or copper in humans. Iron deficiency (ID) is the most common nutrient deficiency worldwide, according to the World Health Organization ( Infants and children that lack adequate dietary iron during critical developmental periods develop irreversible cognitive deficits (54). ID is also common in developed countries like the United States (171), occurring in individuals that are unable to assimilate necessary amounts of dietary iron to meet demands. This occurs frequently in children and adolescents (who are rapidly growing), women of child-bearing age (who lose menstrual blood), and during pregnancy and lactation (when iron demands are elevated). ID may also occur in individuals that have malab-sorptive disorders (e.g., inflammatory bowel diseases, IBDs) or as a consequence of gastric bypass surgery for morbid obesity, which effectively increase dietary iron requirements. Dietary studies have shown that average iron intake is below the RDA for many Americans, particularly amongst infants, young children, teenaged girls, pregnant women, and premenopausal women ( (2122115). ID is most commonly treated with either oral or intravenous iron supplementation. Furthermore, iron excess is also a common condition in humans, most commonly associated with a group of genetic disorders, collectively referred to as hereditary hemochromatosis (HH). Individuals with HH hyperabsorb dietary iron, and over time, excess iron accumulates in various tissues and eventually causes damage due to oxidative stress. HH is caused by mutations in genes that encode proteins that regulate HAMP (the gene encoding HEPC) transcription in hepatocytes, which effectively causes HEPC insufficiency. HH can be treated by iron chelators or by phlebotomy, which may decrease body iron burden over time.

Copper deficiency, conversely, occurs less frequently. It is most often occurs in patients with Menkes disease (MD), a genetic disorder of impaired copper homeostasis. MD results from mutations in the gene encoding ATP7A, which leads to a defective protein, resulting in impaired intestinal copper absorption and consequent severe systemic copper deficiency. The pathophysiologic outcomes of such are devastating, particularly with regard to brain development. If detected early enough, affected individuals can be treated with supplemental copper, which may lessen the severity of the disease. Excess copper has also been reported in humans, most often being associated with another, rare genetic disorder, Wilson’s disease (WD). This disorder is caused by impaired biliary copper excretion, due to mutations in the gene encoding copper-transporting ATPase 2 (ATP7B). As a result, copper accumulates in the liver and other tissues that require ATP7B for copper export, eventually resulting in pathologies related to copper accumulation (i.e., oxidative stress and consequent tissue damage). WD can be treated with copper chelators or by high zinc intake, which blocks intestinal copper absorption.

This review will focus on synergistic and antagonistic interactions between iron and copper at the level of the intestinal mucosa. This is an important, active area of research, as accumulating evidence supports the postulate that copper promotes iron absorption, especially during ID. Moreover, recent evidence suggests that high dietary and body iron levels can perturb copper homeostasis. A detailed description of mechanisms of intestinal iron absorption will be provided, and how this process is influenced by copper will be considered. Mechanisms of intestinal copper absorption will also be considered in detail, although less is known about this process (at least in comparison to what is known about intestinal iron absorption). How iron may influence copper absorption will also be covered. Also pertinent to this topic is the metabolism of iron and copper in the liver, given that the liver plays an important role in regulating intestinal iron transport (by producing and releasing HEPC), and this process may be influenced by copper. Therefore, this review will not only outline how these metals interact in the gut, but will also consider hepatic metabolism as well. The overall goal of this review is thus to provide updated information on mechanisms of iron and copper absorption and then to discuss in detail how these essential trace minerals intersect at the subcellular, cellular, and tissue levels in humans and other mammals…

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