Mineral Biomarkers: Copper to Zinc Ratio

Optimal Takeaways

Evaluating the plasma ratio of copper to zinc (CZr) provides information about both copper and zinc status and may be superior to evaluating each biomarker alone. An increasing CZr suggests an insufficiency of zinc or an excess of copper and is associated with inflammation, oxidative stress, infection, metabolic dysfunction, and decreased educational achievement. A CZr below optimal suggests copper deficiency or zinc excess.

Standard Range: 0.8 - 2.0 Ratio      

The ODX Range: 0.7 - 1.5 Ratio  

Low copper-to-zinc ratio may be associated with a copper deficiency or zinc toxicity.

High copper-to-zinc ratio may be associated with increased inflammation, infection, aging, diabetes, glucocorticoids, stress, decreased growth hormone, decreased albumin (Malavolta 2015), oxidative stress, chronic degenerative disease (Mezzetti 1998), and severe infection (Bahi 2017). An increased CZr is also associated with decreased educational achievement (Bockerman 2016).

Overview

The balance between copper and zinc is essential, as an excess of one can cause a deficiency of the other, disrupting many critical metabolic functions. Calculating the ratio between copper and zinc (the CZr) provides information about inflammation, immune competence, oxidative stress, and antioxidant capacity. An increasing value suggests an increase in inflammation and oxidative stress. A balance close to 1:1 will promote optimal enzyme function, while a progressively increasing value suggests increased inflammation and oxidative stress (Bockerman 2016).

One prospective study of 498 free-living Italian elders found that an increased CZr was associated with increased markers of inflammation, including decreased albumin and increased CRP, ESR, and IL-6 and increased risk of all-cause mortality. The CZr value in the highest tertile was above 1.78 for males and 2.06 for females, while the lowest tertile CZr values were below 1.41 for males and below 1.53 for females. The CZr increased with age and was higher in those with stable CVD and those who had died by the end of the 3.5-year follow-up period (Malavolta 2010).

A CZr above 2.0 is associated with an increased inflammatory response, especially in older adults. The increase in CZr seen with inflammation and infection appears partly due to the immune system reducing serum zinc to reduce its availability to pathogens. The immune response may also be associated with increased serum copper as it is transferred to the site of injury or infection. The increase in CZr with aging may also reflect a mobilization of resources from a state of growth and proliferation to one of maintenance and repair (Malavolta 2015). In one study of 143 elderly subjects, elevated CZr was associated with significantly elevated systemic oxidative stress and higher plasma lipid peroxides, which increased as CZr increased. The CZr was significantly higher in those with chronic degenerative diseases versus those who were healthier (Mezzetti 1998).

A study of multidrug-resistant tuberculosis found a significantly decreased zinc and significantly increased CZr in patients versus controls free of disease. Initial pretreatment CZr in patients was 5.71 in males and 4.13 in females, versus controls with a CZr of 1.29 in males and 1.21 in females. Researchers note that the CZr ratio reflects zinc status in these patients and that a CZr above 2 indicates severe infection (Bahi 2017).

A cross-sectional study of copper to zinc ratio in 191 healthy women of child-bearing age was conducted in China. The inclusion criteria strictly defined healthy ranges for BMI, total cholesterol, triglycerides, LDL, HDL, glucose, HbA1C, hemoglobin, uric acid, blood pressure, and heart rate. The study yielded a reference interval for plasma CZr of 0.54-1.68, while the geometric mean for plasma CZr was 0.81-0.96. Plasma copper ranged from 74.30 to 170.68 µg/dL (11.67-26.8 umol/L), and plasma zinc ranged from 70.46 to 177.53 µg/dL (10.78-27.16 umol/L). Researchers note that the immune response to infection is most effective with a balanced CZr closest to 1:1 (Zhang 2021).

The CZr may help evaluate lung cancer's presence and degree of malignancy. In one study of 184 subjects, those with a malignant lesion had a significantly higher mean CZr at 2.24 compared to 1.63 with a benign lesion and 1.43 in controls. The CZr was significantly higher at 2.65 in those with advanced stage 3 disease versus 1.9 in those at stages 1 and 3. Researchers suggest a cut-off of 1.72 to help identify the malignant disease (Diez 1989).

The CZr may help evaluate neurobehavioral function AS WELL. Autistic children had a higher CZr (and lower zinc-to-copper ratio) as the severity of autism increased. Those with autism had a mean CZr of 1.65 versus 1.38 in controls (Viktorinova 2016). The copper-to-zinc ratio may also help evaluate violent behavior. Compared to controls, an elevated CZr was observed in assaultive young males 3-20 years old. The median CZr in violent subjects was significantly higher at 1.4 compared to 1.02 in controls (Walsh 1997).

Targeted supplementation can help restore a healthy CZr, as demonstrated in a randomized study of hemodialysis (HD) patients with plasma zinc below 80 mg/dL (12.24 umol/L), with a mean value of 40 mg/dL (6.1 umol/L). The mean CZr was 2.4-2.5 in HD patients and 0.7 in healthy controls. The group of HD patients receiving 11 mg of elemental zinc for eight weeks experienced an increase in plasma zinc and a decrease in CZr; a reduction in inflammatory markers and oxidative stress; and significantly higher CD4 and CD19 lymphocyte counts as well as an increase in CD4/CD8 ratios. Zinc supplementation also increased beta-carotene, vitamin C, and vitamin E levels (Guo 2013). A CZr above 1.5 may indicate a zinc deficiency which should be further investigated and supplemented with additional zinc as needed (Yanagisawa 2004).

An elevated CZr, representative of increased copper and decreased zinc, is considered one of the most common trace mineral imbalances, and researchers recommend its evaluation even in childhood. Research suggests that a higher CZr is associated with lower educational achievement, with a 30% decrease in years of education related to each standard deviation increase of CZr above the mean of 1.26 (Bockerman 2016).

References

Bockerman, Petri et al. “The serum copper/zinc ratio in childhood and educational attainment: a population-based study.” Journal of public health (Oxford, England) vol. 38,4 (2016): 696-703. doi:10.1093/pubmed/fdv187

Bahi, Gnogbo Alexis et al. “Assessments of serum copper and zinc concentration, and the Cu/Zn ratio determination in patients with multidrug resistant pulmonary tuberculosis (MDR-TB) in Côte d'Ivoire.” BMC infectious diseases vol. 17,1 257. 11 Apr. 2017, doi:10.1186/s12879-017-2343-7

Dìez, M et al. “Use of the copper/zinc ratio in the diagnosis of lung cancer.” Cancer vol. 63,4 (1989): 726-30. doi:10.1002/1097-0142(19890215)63:4<726::aid-cncr2820630421>3.0.co;2-p

Guo, Chih-Hung, and Chia-Liang Wang. “Effects of zinc supplementation on plasma copper/zinc ratios, oxidative stress, and immunological status in hemodialysis patients.” International journal of medical sciences vol. 10,1 (2013): 79-89. doi:10.7150/ijms.5291

Malavolta, Marco et al. “Plasma copper/zinc ratio: an inflammatory/nutritional biomarker as predictor of all-cause mortality in elderly population.” Biogerontology vol. 11,3 (2010): 309-19. doi:10.1007/s10522-009-9251-1

Malavolta, Marco et al. “Serum copper to zinc ratio: Relationship with aging and health status.” Mechanisms of ageing and development vol. 151 (2015): 93-100. doi:10.1016/j.mad.2015.01.004

Mezzetti, A et al. “Copper/zinc ratio and systemic oxidant load: effect of aging and aging-related degenerative diseases.” Free radical biology & medicine vol. 25,6 (1998): 676-81. doi:10.1016/s0891-5849(98)00109-9

Viktorinova, Alena et al. “Changed Plasma Levels of Zinc and Copper to Zinc Ratio and Their Possible Associations with Parent- and Teacher-Rated Symptoms in Children with Attention-Deficit Hyperactivity Disorder.” Biological trace element research vol. 169,1 (2016): 1-7. doi:10.1007/s12011-015-0395-3

Walsh, W J et al. “Elevated blood copper/zinc ratios in assaultive young males.” Physiology & behavior vol. 62,2 (1997): 327-9. doi:10.1016/s0031-9384(97)88988-3

Yanagisawa, Hiroyuki. "Zinc deficiency and clinical practice." Japan Medical Association Journal 47.8 (2004): 359-364.

Zhang, Huidi et al. “Study on Reference Range of Zinc, Copper and Copper/Zinc Ratio in Childbearing Women of China.” Nutrients vol. 13,3 946. 15 Mar. 2021, doi:10.3390/nu13030946