Copper – The Forgotten Nutrient
The insidious rise of copper deficiency and its link to Heart disease, joint health, neurological disorders and aging. 8/1/20 Miles Price
When we think of supplements we need to take and potential deficiencies we may have, most of us tend to refer to either vitamin D3, Fish oils, Magnesium or Calcium. But hardly anyone mentions the word copper, as the body uses only a small amount / day, as we’re told by various researchers, up to 900mcg or more (RDA) in our daily intake. Most of believe we can get copper from our diet and thus its easy to obtain, and that deficiencies in copper are not so relevant today. Startlingly, we couldn’t be further from the truth.
In fact, copper deficiency is potentially more common than we think, and many factors contribute to this quandary. Copper is the master masquerader, the hidden deficiency behind many conditions which quite commonly go unnoticed by clinicians due to the lack of reliable clinical testing to determine a true deficiency, and the lack of understanding of the pathology of conditions related to copper deficiency. This lack of awareness inadvertently puts many people at risk of serious conditions which could quite easily be remedied by supplemental copper or eating more copper rich foods.
Dietary sources are lower than they were..
In addition, the dietary sources of copper are not easily available in typical diet, the best sources being liver and oysters are not readily consumed in a western diet. Other sources of nuts (cashews, almonds) seeds (sesame) and shitake mushrooms need to be consumed regularly if copper RDA levels are to be met on a consistent level. On top of this we have other issues which contribute to a copper deficiency, namely a reduction is soil bioavailability of copper, indicating a reduction of up to 81% of copper from 1940 to 2000 due to modern farming practices reducing copper in the soil1, showing depletions in actual foods like meats, cheese and dairy2. Thus our dietary patterns plus copper depletion in food supplies, is undoubtedly contributing to the problem of copper deficiency.
Are the RDA recommendations sufficient enough?
In the 1980’s before the RDA was set by the FDA it was suggested the adequate daily intake should be around 2-3 mg/ day, but this was lowered by the American administration when it was found that over 80% of the population was getting less than 900mcg from food3. Around 33% of our diets today contain less than 1mg of copper and in the EU and UK half the adult population consumes less than recommended amount of copper4 . Optimal copper intake recommended is 2.6mg / day4, with some authors like Prof Leslie Klevay recommending up to 8mg / day. Other dietary factors which can induce a copper deficiency include eating a Standard American Diet (high & processed carbs), high fructose intake5, having excess meat or high zinc supplementation as zinc competes for absorption with copper in the gut. As copper is absorbed mostly in the stomach and upper small intestine, any decrease in stomach acid secretion can impede copper absorption.
Measuring Copper Status: Ceruloplasmin is not the best method
Many reports of latent copper deficiencies in people in various population analyses identified that copper deficiencies were uncommon. However, when looking closely at the methods used to measure copper, clinicians were using ceruloplasmin or plasma copper levels to determine status. Its now been demonstrated that these methods are not sensitive enough to determine early signs of deficiency (which can go undetected for a long period of time), as copper in plasma and serum do not always change in depletion.6,7 Moreover the ceruloplasmin test which carries 95% of the copper in the blood, has a role of oxidizing the iron from ferrous Iron (Fe2+) to less damaging Ferric Iron (Fe3+), and therefore is indirectly influenced by the levels of iron the blood which can distort values. Ceruloplasmin acts as reactant that rises during infection and varies very little between sufficient and deficient copper status in subjects8
A more useful accurate measure of copper status is an intracellular white blood cell test(WBC), as demonstrated in a study comparing a sub-population in Japanese in japan and Japanese in Brazil which identified 33% lower WBC level of copper in population in brazil compared to those in japan, however the plasma copper levels didn’t differ.9 An additional study of 80 people with varying degrees of heart disease, from no disease to severe, WBC copper was significantly associated with the degree of coronary heart disease, the relationship between WBC copper and angiogram score was linear10 and was more representative than patients with high cholesterol.11
So why is copper getting the attention now?
In the Open Heart Journal in 2018 Dr Nicolantonio12 highlighted that copper deficiency could be the leading cause of heart disease, and presented a number of compelling threads to support his claim. Not only is copper related to heart disease but many other conditions which, being the true deceiver, may go undetected as symptoms are like other deficiencies. This is directly related to vitamin B12 deficiency which can mimic shared diagnoses as anemia, myelopathy but further investigations can reveal its true status.
In relation to copper deficiency and Cardio-vascular risk, Dr Nicolantonio highlights the following:
- Increased cholesterol and decreased glucose tolerance
- Increased LDL, triglycerides and decreased HDL
- Increased susceptibility of lipoproteins to oxidation
- Increased blood pressure
- Increased early and advance glycation end products (AGE’s)
- Increased atherosclerosis
- Hepatic iron overload (increasing oxidative stress)
- Increased inflammation
In relation to the heart, copper is one of the main elements affected by its deficiency, causing a reduction in metabolism and energy of the heart.13 In fact, insufficient copper can produce almost every risk factor for heart disease14, including glucose intolerance, high cholesterol, abnormal ECG and hypertension.
In relation to cholesterol, copper deficiency can increase the risk of LDL and HDL to oxidize which increases the risk of atherosclerosis,15 In a study with patients with high cholesterol who supplemented with 5mg/day of copper for 45 days had a decrease in total cholesterol LDL and triglycerides and an increase in HDL16 This research indicates that up to 40% of high cholesterol patients have copper deficiency which can be corrected by supplementation.
Copper deficiency exacerbates iron overload and oxidative stress which increases the risk of heart disease,17 moreover treating iron overload with copper supplementation reduces cardio-vascular risk.18 Think of it like copper making iron more useable, absorbable by cells by optimizing the oxygen carrying capacity thereby increasing energy output.
Aging, Mitochondria, oxidation.
Superoxide Dismutase (SOD) is one of the major endogenous antioxidants your body produces apart from Glutathione and Catalase. It is very much copper (and zinc) dependent, and it catalyzes the damaging superoxide radical to oxygen and less damaging hydrogen peroxide. Copper deficiency, by reducing SOD levels, can lead to reductions in Nitric Oxide (NO) which is an essential compound for regulating vascular integrity of blood vessels, so this increases the risk of heart disease.19 Aging is a key factor in Cardiovascular disease,20 a decrease in the ability of mitochondria to generate energy in the heart for example can contribute to an ‘aging’ heart and increased risk. This decrease is caused by free radicals21 and copper deficiency exacerbates this increased free radical production by having lower levels of SOD22, 23. If energy output is the key to antiaging then optimizing copper intake is important. Copper deficiency produces lower membrane potential inside cells and reduced rates of energy production.24
Copper deficiency and inflammation
Copper deficiency results in increasing levels of proinflammatory enzymes25 which increases levels of risk for cardio-vascular disease. Copper deficiency affects genetic expression of cells involved in inflammation and fibrin development in blood vessels.26 Increased Fibrin increases the ‘stickyness’ of blood, which in turn can increase cardiovascular risk.
Copper and blood vessels
Due to coppers’ direct influence on NO and blood flow, it is necessary for crucial mirco-vascular functions that affect the peripheral blood flow and blood vessel integrity. This has ramifications in areas of the body where peripheral micro-circulation is ctitical like fingers toes, eyes, ears, brain, keeping these areas optimal.
Collagen and elastin are integral components of blood vessels providing tensile strength and elasticity. Lysyl oxidases are enzymes which are copper dependent and are essential for providing the cross linking in collagen and elastin. Reduced Lysyl oxidases leads to cardio-vascular dysfunction, aneurysms and death,27 Copper deficiency severely depress the activity of lysyl oxidase, whereas copper supplementation rescues this activity by some 20-fold.
Copper And Joint Health.
Studies have shown lower levels of serum copper and ceruloplasmin in patients with Rheumatoid Arthritis (RA) and high levels of inflammatory markers (ESR), which indicates its potential correlation to the inflammatory process and copper.28 The anti-inflammatory role in joints could be directly correlated to the inhibitory effect of copper on histamine, which plays a role in the inflammatory cascade in the joint fluids of patients. We know that healthy collagen production requires copper (as well as Vitamin C), therefore a deficiency could hinder the maintenance of your joints.
Copper and mental health.
Studies have shown substantial deficiencies of copper in Alzheimer diseased patients,29 indicating its potential influence on protecting neurons in the brain. Further, copper deficiency has been shown to stunt brain development and affect the ability to learn and remember30 with its influence in particular on the synapses of neurons. It blocks glutamate receptors which in turn blocks excitatory neuro-transmission. Neurons require a high degree of protection from copper as a result of oxidative stresses in the brain and this protection comes from the protective enzymes of SOD and Cytochrome C oxidase, which copper is a key part of. However further research is needed to determine the interactions of copper with iron, manganese and glutathione in various protein reaction
Overall we can see a comprehensive role for copper in a variety of roles within the body affecting:
- The metabolism and energy levels.
- The health and mobility of joints.
- The mood and health of the brain
- The ability of the immune system to function properly.
- Protective affects on the cardiovascular system, keeping cholesterol well managed, and oxidation levels low.
Ensure that you test you copper levels by assessing your leucocyte (WBC) levels to obtain a more accurate picture of your status, and enjoy good health.
- New York Times, 2015: Magazine bread-is-broken.
- Thomas D The mineral depletion of foods available. Nutr Health 2007;19:21–55
- Georgopoulos PG , Wang SW , Georgopoulos IG , et al. Assessment of human exposure to copper: a case study using the NHEXAS database. J Expo Sci Environ Epidemiol 2006;16:397–409
- Klevay LM . Is the Western diet adequate in copper? J Trace Elem Med Biol 2011;25:204–12
- Song M , Schuschke DA , Zhou Z , et al High fructose feeding induces copper deficiency in Sprague–Dawley rats: a novel mechanism for obesity related fatty liver. J Hepatol 2012;56:433–40
- Klevay LM, Inman L, Johnson LK, et al. Increased cholesterol in plasma in a young man during experimental copper depletion. Metabolism 1984;33:1112-18
- Lukaski HC, Klevay LM, Milne DB. Effects of dietary copper on human autonomic cardiovascular function. Eur J Appl Physiol 1988;58:74-80.
- Mielcarz G, Howard AN ,Mielcarz B , et al Leucocyte copper, a marker of copper body status is low in coronary artery disease. J Trace Elem Med Biol 2001;15:31–5
- Mielcarz GW , Howard AN ,Williams NR . Copper and zinc status as a risk factor for ischemic heart disease: a comparison between japanese in brazil and Okinawa. The Journal of Trace Elements in Experimental Medicine 1997;10:29–35
- Mielcarz G,Howard AN ,Mielcarz B , et al . Leucocyte copper, a marker of copper body status is low in coronary artery disease. J Trace Elem Med Biol 2001;15:31–5
- Kinsman GD ,Howard AN , Stone DL , et al Studies in copper status and atherosclerosis. Biochem Soc Trans 1990;18:1186–8
- DiNicolantonio JJ, Mangan D, O’Keefe JH Copper deficiency may be a leading cause of ischaemic heart disease Open Heart 2018;5
- Nath R . Copper deficiency and heart disease: molecular basis, recent advances and current concepts. Int J Biochem Cell Biol 1997;29:1245–54
- Klevay LM Ischemic heart disease as deficiency disease. Cell Mol Biol 2004;50:877–84
- Rayssiguier Y, Gueux E, Bussiere L , et al. Copper deficiency increases the susceptibility of lipoproteins and tissues to peroxidation in rats. J Nutr 1993;123:1343–8
- Alarcon-Corredor OM , Guerrero Y Ramirez de Fernandez M , et al [Effect of copper supplementation on lipid profile of Venezuelan hyperlipemic patients]. Arch Latinoam Nutr 2004;54:413–8.
- Sullivan J . Iron and the sex difference in heart disease risk. The Lancet 1981;317:1293–4
- Videt-Gibou D , Belliard S , Bardou-Jacquet E , et alIron excess treatable by copper supplementation in acquired aceruloplasminemia: a new form of secondary human iron overload? Blood 2009;114:2360–1
- Al-Bayati MA , Jamil DA , Al-Aubaidy HA Cardiovascular effects of copper deficiency on activity of superoxide dismutase in diabetic nephropathy. N Am J Med Sci 2015;7:41–6.
- Lakatta EG , Levy D . Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: part I: aging arteries: a “set up” for vascular disease. Circulation 2003;107:139–46
- Ames BN . Delaying the mitochondrial decay of aging. Ann N Y Acad Sci 2004;1019:406–11
- Johnson WT ,Johnson LAK ,Lukaski HC Serum superoxide dismutase 3 (extracellular superoxide dismutase) activity is a sensitive indicator of Cu status in rats. J Nutr Biochem 2005;16:682–92.
- DiSilvestro RA Influence of copper intake and inflammation on rat serum superoxide dismutase activity levels. J Nutr 1988;118:474–9.
- Chen X , Jennings DB , Medeiros DMImpaired cardiac mitochondrial membrane potential and respiration in copper-deficient rats. J Bioenerg Biomembr 2002;34:397–406
- Schuschke DA , Adeagbo AS , Patibandla PK , et al. Cyclooxygenase-2 is upregulated in copper-deficient rats. Inflammation 2009;32:333–9
- Tallino S , Duffy M , Ralle M , et al. Nutrigenomics analysis reveals that copper deficiency and dietary sucrose up-regulate inflammation, fibrosis and lipogenic pathways in a mature rat model of nonalcoholic fatty liver disease. J Nutr Biochem 2015;26:996–1006
- Maki JM et alInactivation of the lysyl oxidase gene Lox leads to aortic aneurysms, cardiovascular dysfunction, and perinatal death in mice. Circulation 2002;106:2503–9
- Montosh Chakraborty, Happy Chutia, and Rita Changkakati Serum Copper as a Marker of Disease Activity in Rheumatoid Arthritis Jour of clinical diagnostic research 2015 Dec; 9(12).
- Xu J, Church SJ, Patassini S et al Evidence for widespread, severe brain copper deficiency in Alzheimer’s dementia Metallomics 2017 Aug 16;9(8):1106-1119
- Opazo PM, Greenough MA, Bush AI, Copper: from neurotransmission to neuroproteostasis. Front Aging NeuroSci 2014 Jul 3;6:143