Mineral Biomarkers: Serum Copper

Optimal Takeaways

Copper is an essential trace mineral with important roles in iron metabolism, red blood cell health, energy generation, antioxidant systems, hormone metabolism, and immunity. Low levels are associated with anemia, oxidative stress, and decreased cognitive performance. High levels are associated with low serum zinc, obesity, diabetes, heart disease, and nephrotic syndrome. High copper levels are also associated with decreased cognition and compromised antioxidant status. It is important to evaluate other metabolic parameters when assessing copper status.

Standard Range: 70.00 – 175.00 ug/dL (10.99 – 27.48 umol/L)

The ODX Range: 90– 150 ug/dL (14.16 – 23.60 umol/L)              

Low copper levels are associated with excess zinc intake above 40 mg/day, anemia (hypochromic, microcytic, macrocytic, and normocytic), decreased erythropoiesis, neutropenia, thrombocytopenia, leukopenia, hypopigmentation of hair and skin, malabsorption, celiac disease, inflammatory bowel disease, neurologic dysfunction, oxidative stress, decreased ceruloplasmin, Menkes disease, and proton pump inhibitor use (Gropper 2021).

Copper insufficiency can cause iron overload, cirrhosis, platelet aggregation, inflammation, and increased glycation end-products and may be the leading cause of ischemic heart disease (DiNicolantonio 2018).

Insufficiency may also contribute to impaired energy generation, altered glucose and cholesterol metabolism, immune cell dysfunction, disrupted cardiac electrophysiology and contractility, compromised neuropeptide production and processing (Hordyjewska 2014), myeloneuropathy, pseudotabes (Marotta 2021), ataxia, and increased LDL/HDL cholesterol ratio (Burkhead 2022).

High copper levels may be associated with inflammation, rheumatoid arthritis (Raymond 2021), cognitive deficits (Lam 2008), diabetes (Olaniyan 2012), obesity (Gu 2020), nephrotic syndrome (Dwivedi 2009), cardiovascular disorders, and heart failure (Huang 2019).

Overview

Copper, an essential trace mineral, is found in several secretions, such as saliva, gastric juices, bile, and pancreatic secretions. The reabsorption and recycling of this copper are essential to maintain adequate levels in the body. Procurement of copper from foods depends on hydrochloric acid, pepsin, and small intestine proteolytic enzyme activity. Copper is an essential metabolic cofactor and participates in iron metabolism, superoxide dismutase antioxidant activity, ATP production, oxidation of biogenic amines (e.g., dopamine, serotonin, norepinephrine, tyramine, and histamine), collagen production, catecholamine synthesis, melanin production, hormone activation, blood clotting, and immunity. Approximately 60-70% of copper in the blood is incorporated into ceruloplasmin (ferroxidase) which contains six atoms of copper. The remainder of circulating copper is bound to albumin and other proteins, while the kidney, liver, brain, and skeleton contain the most copper at the tissue level (Gropper 2021).

Dietary copper comes from food sources such as whole grains, fruit, nuts, and offal, as well as drinking water which can provide 0.02-5 mg per liter. A copper intake between 0.6 and 3 mg/day should maintain copper homeostasis and decrease the risk of CVD, arthritis, cognitive decline, and cancer. However, a decrease in copper intake from a marginal intake of 0.66 to 0.38 mg/day can significantly decrease copper activity and compromise metabolism with an associated decline in serum levels (Bost 2016).

Overt copper deficiency has long been recognized as a cause of anemia, neutropenia, depigmentation of hair and skin, bone changes, and physical and mental retardation (Hatano 1982). However, both low and high copper levels may be associated with complications.

Low copper contributes to decreased antioxidant capacity and increased oxidative stress, a phenomenon observed in nephrotic syndrome. A study of 150 subjects found significantly increased lipid peroxidation (malondialdehyde) and homocysteine and decreased total antioxidant capacity, copper, zinc, and vitamin C in patients versus controls. Nutrition supplementation significantly reduced these parameters. Serum copper in patients before supplementation was significantly lower, with a mean of 70.69 ug/dL (11.1 mmol/L) in patients versus 123.6 ug/dL (19.41 mmol/L) in healthy controls (Dwivedi 2009). Both human and animal studies suggest an association between copper deficiency and ischemic heart disease, noting increased susceptibility of LDL-cholesterol when sufficient copper is unavailable. Copper insufficiency also contributes to hypercholesterolemia, increased platelet aggregation, iron overload, hepatic cirrhosis, and endothelial dysfunction due to reduced superoxide dismutase and nitric oxide (DiNicolantonio 2018).

Researchers observed a complex relationship between copper and cognitive performance in a cross-sectional study of 1,451 individuals without clinical dementia. In men, copper levels above 215 ug/dL (33.9 umol/L) and below 90 ug/L (14.2 umol/L) were associated with poorer cognitive performance involving memory, calculations, and visuomotor attention. Very high and very low serum iron was also associated with these deficits. In women, serum copper above 215 ug/dL (33.9 umol/L) was associated with poor long-term and short-term recall, a pattern also seen with very high iron but not with lower copper (Lam 2008).

In a cross-sectional case-control study, significantly higher serum copper was found in diabetics, with a mean of 148.4 ug/dL (23.3 umol/L) versus 127 ug/dL (19.9 umol/L) in healthy controls. Researchers observed significantly lower zinc in diabetics at a mean of 77.8 ug/dL (11.9 umol/L) versus 95.4 ug/dL (14.6 umol/L) in controls as well (Olaniyan 2012).

Meta-analysis reveals a significant association between increased serum copper and obesity, although researchers suggest the association may be related to lower serum zinc and higher leptin seen with obesity. Researchers note that high serum copper may promote oxidative stress by reducing serum zinc which can occur due to the antagonistic relationship between copper and zinc (Gu 2020).

The antioxidant function of copper-zinc superoxide dismutase depends on both elements and disrupting their balance can jeopardize endogenous antioxidant systems. Researchers suggest that an increase in copper and a decrease in zinc may contribute to the association between elevated copper and increased risk of heart failure seen in a meta-analysis of 13 studies comprising 1,504 subjects (Huang 2019).

It should be noted that serum copper in Wilson’s disease may be low, high, or normal. Though it is a genetic disorder of copper metabolism, toxicity occurs at the tissue level and may not correlate with serum copper (Aliasgharpour 2015).

References

Aliasgharpour, Mehri. "Mini Review Article A review on copper, ceruloplasmin and wilson's disease." Int J Med Invest 4.4 (2015): 344-347.

Bost, Muriel et al. “Dietary copper and human health: Current evidence and unresolved issues.” Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS) vol. 35 (2016): 107-15. doi:10.1016/j.jtemb.2016.02.006

Burkhead, Jason L, and James F Collins. “Nutrition Information Brief-Copper.” Advances in nutrition (Bethesda, Md.) vol. 13,2 (2022): 681-683. doi:10.1093/advances/nmab157

DiNicolantonio, James J et al. “Copper deficiency may be a leading cause of ischaemic heart disease.” Open heart vol. 5,2 e000784. 8 Oct. 2018, doi:10.1136/openhrt-2018-000784

Dwivedi, Jyoti, and Purnima Dey Sarkar. "Study of oxidative stress, homocysteine, copper & zinc in nephrotic syndrome: therapy with antioxidants, minerals and B-complex vitamins." Journal of Biochemical Technology 1.4 (2009): 104-107.

Gropper, Sareen S.; Smith, Jack L.; Carr, Timothy P. Advanced Nutrition and Human Metabolism. 8^th edition. Wadsworth Publishing Co Inc. 2021.

Gu, Kunfang et al. “The Relationship Between Serum Copper and Overweight/Obesity: a Meta-analysis.” Biological trace element research vol. 194,2 (2020): 336-347. doi:10.1007/s12011-019-01803-6

Hatano, S et al. “Copper levels in plasma and erythrocytes in healthy Japanese children and adults.” The American journal of clinical nutrition vol. 35,1 (1982): 120-6. doi:10.1093/ajcn/35.1.120

Hordyjewska, Anna et al. “The many "faces" of copper in medicine and treatment.” Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine vol. 27,4 (2014): 611-21. doi:10.1007/s10534-014-9736-5

Huang, Lei et al. “Association between serum copper and heart failure: a meta-analysis.” Asia Pacific journal of clinical nutrition vol. 28,4 (2019): 761-769. doi:10.6133/apjcn.201912_28(4).0013

Lam, P K et al. “Plasma trace elements and cognitive function in older men and women: the Rancho Bernardo study.” The journal of nutrition, health & aging vol. 12,1 (2008): 22-7. doi:10.1007/BF02982160

Olaniyan, O. O., et al. "Serum copper and zinc levels in Nigerian type 2 diabetic patients." African Journal of Diabetes Medicine Vol 20.2 (2012).

Marotta, Dario A et al. “Myeloneuropathy in the Setting of Hypocupremia: An Overview of Copper-Related Pathophysiology.” Cureus vol. 13,7 e16254. 8 Jul. 2021, doi:10.7759/cureus.16254