Friday, January 24, 2014

Copper: The Forgotten Essential Nutrient

1. Background

My interest in the dietary copper began after I read Stephan Guyenet's article Copper and Cardiovascular Disease, in which he showed that copper restriction has been able to cause heart disease to cows, pigs and humans.

Later, Paul Jaminet published his article Micronutrient Deficiencies: An Underappreciated Cause of Hypothyroidism, in which he mentioned that copper deficiency can also cause low thyroid hormone levels. Because I knew about the association between thyroid hormones and heart disease, I found the article interesting.

I while ago, I also happened to find two epidemiological studies, in which higher intake of copper was associated with five-fold lower risk (RR 0.19) of metabolic syndrome[1] and three-fold lower risk of lung cancer[2].

And when I recently wrote my essay on near-infrared light, I had noticed that both thyroid hormone and near-infrared light have one common factor in the mechanism how they improve health. They both increase the function of the copper-containing mitochondrial enzyme cytochrome c oxidase.

2. Dietary copper intake

Stephan Guyenet's article Copper in Food, gives some information about the copper content of foods.

The amount of copper in the soil has decreased, and therefore foods contain quite low amounts of copper nowadays. According to a British study, the copper content of food supply has decreased by 76 per cent since the 40's.[3]

According to one report, more than 80% of Eaton County citizens get less than 0.9mg copper per day.[4] In Finland the intake is 1.2mg in women and 1.5mg men. 60% of this copper is coming from grains, fruits and vegetables, while meat provides 20% of the daily intake.

Plant-based "whole food diet" might provide more copper than an usual diet[5], but the overwhelmingly best source of copper is beef liver (14mg/100g).

3. Clinical studies

"Copper deficiency is the only nutritional insult that has been shown to produce abnormal electrocardiograms, glucose intolerance, hypercholesterolemia, hypertension, hyperuricemia, injury by free radicals, and thrombosis in animals, and to which male individuals respond differently than female individuals. More than 31 men and women have responded to diets low in copper with potentially harmful changes in lipids, glucose tolerance, blood pressure, and electrocardiograms. Copper in these daily diets ranged from 0.65 to 1.02 mg, amounts readily available to the general population." - Gary E. Fraser[7]

Even modest copper reductions have been able to cause problematic changes in subjects' cholesterol levels, EKG, blood pressure[6] and glucose tolerance.[7]

Similar effects have been shown in rats (heart, lipids, sugar tolerance, liver function, antioxidant systems).[8-13] In one study, lard and sugar caused heart disease and anemia to mice, but a copper supplement prevented these harmful effects.[14]

In rats, a meat diet led to increased cholesterol levels and the bones 23% weaker bones (femur), when compared to a liver-supplemented diet.[15] This seems to be consistent with the study result shown with postmenopausal women, in which a copper supplement (amino acid chelate) seemed to reduce age-related bone loss.[16]

4. Copper paradoxes: Serum levels and inflammation

While higher dietary intake of copper appears healthy, higher serum copper levels are associated with increased total mortality.[17] The reason seems to be that inflammation causes high blood copper levels.[18,19]

Cholesterol feeding can cause atherosclerosis to rats, while simultaneously increasing their serum copper but decreasing heart copper.[20] Inflammation seems to be able to move copper from the tissues into the circulation.

It has also been shown, that dietary copper restriction doesn't seem to decrease serum copper during the first months.[21] Because of this, serum levels of copper doesn't seem to be a very useful marker of copper status in most cases. Tissue levels seem more useful. In fatty liver patients, the liver has 40% less copper than the healthy subjects.[11] However, Alzheimer patients seem to also have lower serum level of copper.[22]

5. Copper paradoxes: Cancer

It was recently demonstrated that while copper isn't a carcinogen, copper restriction could be used to "fight" against cancer. Copper deficiency limits the growth of tumor, and one of the important mechanisms is the increased anaerobic glycolysis.[23]

If this treatment decreases aerobic metabolism of tumors, I suppose that it can also cause energy problems in other tissues as well, likely increasing total mortality in the long term. The idea of restricting the intake of essential nutrients to battle cancer reminds me of T. Colin Campbell's infamous rat experiment. The rats didn't die because of the cancer, because their (protein-)deficient diet killed them very prematurely.

6. Copper paradoxes: Alzheimer's disease

In some animal studies copper(sulfate) seems to decrease Alzheimer-related amyloid problems[24], while in other studies, increased harmful effects have been reported.[25,26]

In a human study, 8mg of copper orotate appeared helpful for the markers of Alzheimer, but didn't affect the symptoms. Brewer has criticized this study, claiming that the orotate form isn't very bioavailable.[27-29]

Because of mixed results, some authors have claimed that copper deficiency could be the main reason of Alzheimer's disease[30], while others seem to think that copper is causing the problems. George J. Brewer has also argued that the dietary organic copper is healthy, while inorganic copper can bypass liver and gets into the bloodstream in the free form. He has noted that the serum levels of free copper are associated with Alzheimer's disease.[31,32,33]

"Normally food copper is metabolized by the liver and channeled into safe pathways such as being incorporated in to ceruloplasmin. [...] When we administer inorganic copper orally labeled with 64Cu, we see a fraction of the label appear in the blood in 1-2 hours, too soon to be processed by the liver. [...] We believe this fraction of 64Cu-labeled inorganic copper is bypassing the liver, is therefore not incorporated safely into ceruloplasmin, contributes directly to the nonceruloplasmin free copper pool, and represents what is happening to at least a portion of the inorganic copper ingested in drinking water or copper supplements."[32]

These views are supported by the epidemiological results showing that the copper in dietary supplements is associated with higher total mortality[34] and faster rate of cognitive decline[35], but dietary copper is associated with better health[1,2] and slower rate of cognitive decline in some subjects[35].

7. Biological associations (cytochrome c oxidase, etc.)

I've been writing about the important health effects of near-infrared light and thyroid hormones. Both of these work by affecting the same copper-containing enzyme, cytochrome c oxidase. Lack of dietary copper can lead to lower concentrations of this enzyme.[36,37] I think that lack of cytochrome oxidase could be an important reason why copper restriction causes so many kinds of problems.

When Klevay argued that copper deficiency is the main cause of Alzheimer's disease, he cited approximately ten scientific articles showing that people with Alzheimer's disease have decreased function of cytochrome c oxidase.[30]

8. Conclusion

Once again, it seems that we should aim to eat a versatile diet to avoid nutritional deficiencies. When talking about diverse diets, we often focus on plants, but it should be noted that some nutrients such as collagen, choline, vitamin K2 and copper are best obtained from some animal-based foods such as bones, skin, eggs, cheese and organ meats (especially liver).

It seems that the food is the safest source of copper. The main reason is probably the fact that the copper comes in the organic form, but some other dietary factors might also be important for copper mechanism. For example, carnitine protects hens from too much copper, and if you eat liver, you are getting some carnitine as well.[38]


[1] Nutrition & Dietetics. 2007 70: 218–226. doi: 10.1111/1747-0080.12026 (2013), Dietary intakes of zinc and copper and cardiovascular risk factors in Tehranian adults: Tehran Lipid and Glucose Study. Shab-Bidar S, Hosseini-Esfahani F, Mirmiran P, Mehran M, Azizi F. [found this paper via SuppVersity]

[2] Int J Cancer. 2007 Mar 1;120(5):1108-15. Dietary zinc, copper and selenium, and risk of lung cancer. Mahabir S, Spitz MR, Barrera SL, Beaver SH, Etzel C, Forman MR.

[3A study on the mineral depletion of the foods available to us as a nation over the period 1940 to 1991. TRACE MINERALS (UK) LTD

[4] J Expo Sci Environ Epidemiol. 2006 Sep;16(5):397-409. Epub 2005 Oct 26. Assessment of human exposure to copper: a case study using the NHEXAS database. Georgopoulos PG, Wang SW, Georgopoulos IG, Yonone-Lioy MJ, Lioy PJ.

[5] Am J Clin Nutr. 2001 Dec;74(6):803-7. Apparent copper absorption from a vegetarian diet. Hunt JR, Vanderpool RA.

[6] Eur J Appl Physiol Occup Physiol. 1988;58(1-2):74-80. Effects of dietary copper on human autonomic cardiovascular function. Lukaski HC, Klevay LM, Milne DB.

[7] Arch Intern Med. 1993;153(3):402. Copper in Nuts May Lower Heart Disease Risk-Reply. Fraser GE, Sabaté J, Beeson WL

[8] Biol Trace Elem Res. 2000 Winter;78(1-3):179-89. Marginal copper deficiency and atherosclerosis. Hamilton IM, Gilmore WS, Strain JJ.

[9] Am J Physiol Endocrinol Metab. 2013 May 15;304(10):E1023-34. Dietary copper supplementation restores β-cell function of Cohen diabetic rats: a link between mitochondrial function and glucose-stimulated insulin secretion. Weksler-Zangen S, Jörns A, Tarsi-Chen L, Vernea F, Aharon-Hananel G, Saada A, Lenzen S, Raz I.

[10] Ann Nutr Metab. 2005 Sep-Oct;49(5):283-8. Epub 2005 Aug 2. Beneficial effects of dietary copper supplementation on serum lipids and antioxidant defenses in rats. Galhardi CM, Diniz YS, Rodrigues HG, Faine LA, Burneiko RC, Ribas BO, Novelli EL.

[11] Am J Gastroenterol. 2010 Sep;105(9):1978-85. doi: 10.1038/ajg.2010.170. Epub 2010 Apr 20. A role for low hepatic copper concentrations in nonalcoholic Fatty liver disease. Aigner E, Strasser M, Haufe H, Sonnweber T, Hohla F, Stadlmayr A, Solioz M, Tilg H, Patsch W, Weiss G, Stickel F, Datz C.

[12] Int J Exp Pathol. 2004 Oct;85(5):265-75. The effects of coadministration of dietary copper and zinc supplements on atherosclerosis, antioxidant enzymes and indices of lipid peroxidation in the cholesterol-fed rabbit. Alissa EM, Bahijri SM, Lamb DJ, Ferns GA.

[13] Atherosclerosis. 2002 Oct;164(2):229-36. Effect of dietary copper supplementation on cell composition and apoptosis in atherosclerotic lesions of cholesterol-fed rabbits. Lamb DJ, Avades TY, Allen MD, Anwar K, Kass GE, Ferns GA.

[14] Atherosclerosis. 1985 Feb;54(2):213-24. Atrial thrombosis, abnormal electrocardiograms and sudden death in mice due to copper deficiency. Klevay LM.

[15] J Trace Elem Med Biol. 2002;16(3):149-54. Meat diets and fragile bones: inferences about osteoporosis. Klevay LM, Wildman RE.

[16] J. Trace Elem. Exp. Med., 9: 87–94. Copper supplementation and the maintenance of bone mineral density in middle-aged women. Eaton-Evans J, Mcllrath EM, Jackson WE, McCartney H, Strain JJ

[17] Age (Dordr). 2012 Jun;34(3):539-52. Cu to Zn ratio, physical function, disability, and mortality risk in older elderly (ilSIRENTE study). Mocchegiani E, Malavolta M, Lattanzio F, Piacenza F, Basso A, Abbatecola AM, Russo A, Giovannini S, Capoluongo E, Bustacchini S, Guffanti EE, Bernabei R, Landi F.

[18] Biol Trace Elem Res. 2003 Summer;93(1-3):95-104. Effects of inflammation and antiinflammatory treatment on serum trace elements concentrations. Akçil E, Yavuz G, Koçak M.

[19] Br J Pharmacol. 1983 May; 79(1): 45–52. Copper metabolism during acute inflammation: studies on liver and serum copper concentrations in normal and inflamed rats. Conforti A, Franco F, Milanino R, Totorizzo A, Velo GP

[20] Nutrition. 1995 Sep-Oct;11(5 Suppl):588-91. Free radicals, ceruloplasmin, and copper concentration in serum and aortic tissue in experimental atherosclerosis. Vlad M, Uza G, Zirbo M, Olteanu D.

[21] Am J Clin Nutr. 1996 Mar;63(3):358-64. Effects of a diet low in copper on copper-status indicators in postmenopausal women. Milne DB, Nielsen FH.

[22] J Alzheimers Dis. 2005 Sep;8(1):23-7. Cognitive decline correlates with low plasma concentrations of copper in patients with mild to moderate Alzheimer's disease. Pajonk FG, Kessler H, Supprian T, Hamzei P, Bach D, Schweickhardt J, Herrmann W, Obeid R, Simons A, Falkai P, Multhaup G, Bayer TA.

[23] Proceedings of the National Academy of Sciences, (2013). 110(48), 19507-19512. Bioavailable copper modulates oxidative phosphorylation and growth of tumors. Ishida S, Andreux P, Poitry-Yamate C, Auwerx J, Hanahan D.

[24] Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14187-92. Dietary Cu stabilizes brain superoxide dismutase 1 activity and reduces amyloid Abeta production in APP23 transgenic mice. Bayer TA, Schäfer S, Simons A, Kemmling A, Kamer T, Tepest R, Eckert A, Schüssel K, Eikenberg O, Sturchler-Pierrat C, Abramowski D, Staufenbiel M, Multhaup G.

[25] Proceedings of the National Academy of Sciences, 110(36), 14771-14776 (2013) Low levels of copper disrupt brain amyloid-β homeostasis by altering its production and clearance. Singh I, Sagare AP, Coma M, Perlmutter D, Gelein R, Bell RD, Deane R.

[26] Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):11065-9. Epub 2003 Aug 14. Trace amounts of copper in water induce beta-amyloid plaques and learning deficits in a rabbit model of Alzheimer's disease. Sparks DL, Schreurs BG.

[27] J Neural Transm. 2008 Dec;115(12):1651-9. Effect of copper intake on CSF parameters in patients with mild Alzheimer's disease: a pilot phase 2 clinical trial. Kessler H, Pajonk FG, Bach D, Schneider-Axmann T, Falkai P, Herrmann W, Multhaup G, Wiltfang J, Schäfer S, Wirths O, Bayer TA.

[28] J Neural Transm. 2008 Aug;115(8):1181-7. Intake of copper has no effect on cognition in patients with mild Alzheimer's disease: a pilot phase 2 clinical trial. Kessler H, Bayer TA, Bach D, Schneider-Axmann T, Supprian T, Herrmann W, Haber M, Multhaup G, Falkai P, Pajonk FG.

[29] Int J Alzheimers Dis. 2011;2011:537528. Issues raised involving the copper hypotheses in the causation of Alzheimer's disease. Brewer GJ.

[30] Med Hypotheses. 2008;70(4):802-7. Epub 2007 Oct 24. Alzheimer's disease as copper deficiency. Klevay LM.

[31] J Trace Elem Med Biol. 2012 Jun;26(2-3):89-92. Copper toxicity in Alzheimer's disease: cognitive loss from ingestion of inorganic copper. Brewer GJ.

[32] Int J Alzheimers Dis. 2011;2011:537528. Issues raised involving the copper hypotheses in the causation of Alzheimer's disease. Brewer GJ.

[33] Am J Alzheimers Dis Other Demen. 2010 Sep;25(6):490-7. Copper and ceruloplasmin abnormalities in Alzheimer's disease. Brewer GJ, Kanzer SH, Zimmerman EA, Celmins DF, Heckman SM, Dick R.

[34] Arch Intern Med. 2011 Oct 10;171(18):1625-33. Dietary supplements and mortality rate in older women: the Iowa Women's Health Study. Mursu J, Robien K, Harnack LJ, Park K, Jacobs DR Jr.

[35] Arch Neurol. 2006 Aug;63(8):1085-8. Dietary copper and high saturated and trans fat intakes associated with cognitive decline. Morris MC, Evans DA, Tangney CC, Bienias JL, Schneider JA, Wilson RS, Scherr PA.

[36] Am J Clin Nutr. 1998 May;67(5 Suppl):1041S-1045S. Copper intake and assessment of copper status. Milne DB.

[37] J Nutr. 2007 Jan;137(1):14-8. Copper deficiency decreases complex IV but not complex I, II, III, or V in the mitochondrial respiratory chain in rat heart. Zeng H, Saari JT, Johnson WT.

[38] Biol Trace Elem Res. 2011 Dec;144(1-3):725-35. Carnitine supplementation modulates high dietary copper-induced oxidative toxicity and reduced performance in laying hens. Güçlü BK, Kara K, Çakır L, Çetin E, Kanbur M.

[extra] J Trace Elem Med Biol. 2014 Mar 18. pii: S0946-672X(14)00020-0. doi: 10.1016/j.jtemb.2014.03.002. [Epub ahead of print] Copper and public health: Dietary intakes vs. clinical data. Klevay LM. "Correction of copper intake data for the 77% error in large surveys of the United States [6] reveals that roughly half the people do not meet the recommendations; even with uncorrected data, nearly 25% of people do not meet the higher standards for Europe, Australia and New Zealand [2]."

[extra] Proc Soc Exp Biol Med. 1996 Apr;211(4):381-6. Copper intestinal absorption in the rat: effect of free fatty acids and triglycerides. Wapnir RA1, Sia MC.