Copper deficiency is quite rare as we need only trace amounts and most people get enough from a diet. However, it might be worth investigating in certain cases, such as hypothyroidism, anemia, poor immune function, and hair loss. Read this post to learn more about the harmful effects of copper deficiency, associated conditions, and ways to test copper levels.
Introduction & Risk Groups
Frank copper deficiency is rare in humans [1].
Most adults living in developed countries obtain proper amounts of copper through their diet, supplements, and drinking water [2].
Groups at risk of copper deficiency include:
- Infants (preterm, recovering from malnutrition, fed only cow’s milk formula, with prolonged diarrhea, with cholestasis) [3, 4, 5, 6]
- Individuals using zinc supplements or zinc-enriched dental creams [7, 8]
- Pregnant and breastfeeding women [9]
- Individuals with digestive problems that result in nutrient malabsorption, including Crohn’s disease, celiac disease, and short bowel syndrome [10, 11, 12]
- Individuals on prolonged parenteral nutrition lacking copper [13]
- Cystic fibrosis patients [14]
- Hypertensive individuals [15]
Causes of Copper Deficiency
1) Inadequate Copper Absorption
- Menkes’ disease [16]
- Weight reduction (gastric bypass) surgery [17, 18]
- Gastrectomy (stomach removal) and esophagectomy (esophagus removal) [16, 18, 19]
- Chronic antacid intake [20]
- Increased zinc consumption [21, 22, 8].
- Malabsorption syndromes (Crohn’s disease, celiac disease, short bowel syndrome) [10, 11]
2) Inadequate Copper Intake
- Low copper infant formula or cow’s milk only formula [3]
- Parenteral nutrition for long periods of time without copper supplementation [13]
- Protein-calorie malnutrition [23]
3) Excessive Copper Losses
- Malabsorptive states [10, 11]
- Copper chelating agents such as penicillamine [24]
- Burns [25]
- Nephrotic syndrome [26]
Signs & Symptoms
If you notice the following signs & symptoms of copper deficiency, immediately seek medical attention. Copper supplements are not meant to treat a diagnosed deficiency or any of the associated conditions.
- Anemia
- Neutropenia (low neutrophil levels)
- Connective tissue degeneration
- Growth retardation
- Bone abnormalities
- Pallor
- Poor temperature control
- Thinning, weak hair
- Poor skin quality
- Neurological problems (in severe cases)
- Seizures (in severe cases) [27]
Health Effects & Associated Conditions
Copper levels are a marker of general health and nutritional status. Low or high levels don’t necessarily indicate a problem if there are no symptoms or if your doctor tells you not to worry about it.
1) Anemia
Low copper is associated with anemia [28, 29, 30, 31].
Anemia is rapidly corrected within a few weeks with copper supplementation while oral iron may have no effect if the cause lies in copper deficiency [32].
Bone marrow dysplasia may be associated with copper deficiency so it is important to consider copper deficiency in the differential diagnosis of myelodysplastic syndrome (33, 34, 35).
2) Impaired Immunity
Copper deficiency is associated with low numbers of white blood cells known as neutrophils (neutropenia) [30].
Neutrophils can’t produce superoxides and kill microorganisms as effectively in people with a copper deficiency [36].
Low copper also promotes neutrophil activation and accumulation in the liver, which contributes to the development of inflammation [37, 38, 39, 7].
Copper deficiency is known to impair macrophage function, thus increasing susceptibility to bacterial infection [40, 41].
Studies also showed that T cell growth and IL-2 production is reduced in copper deficiency [42].
3) Bone Abnormalities
Copper deficiency reduces bone strength [43, 44].
Bone abnormalities are most common in copper-deficient, low-birth-weight infants and young children [45, 46].
Copper-deficient diet in infancy could lead to brittle bones resulting in fractures, forms of (osteogenesis imperfecta, and osteoporosis) [47, 48].
A study on elderly patients showed that low (blood copper levels are associated with an increased incidence of bone fractures [49].
4) Neurological Disorders
Neurologic deficits have been described in adults with copper deficiency. Neurological symptoms of copper deficiency include central nervous system demyelination, polyneuropathy (nerve damage), spasticity, muscle weakness, and inflammation of the optic nerve [50, 51].
Myelopathy (disease of the spinal cord) occurs in copper-deficient individuals and presents with walking difficulties [16, 52].
Neurologic manifestations are generally attributed to decreased levels of cytochrome C oxidase and may be similar to those observed with vitamin B12 deficiency [53, 54].
These symptoms can significantly improve after oral copper supplementation [53, 55].
5) Heart Disease
Severe copper deficiency in rats altered heart function and caused enlargement of the heart which may lead to congestive heart failure [56, 57, 58].
Also, reduced dilation of blood vessels and increased bleeding were associated with reduced copper intake in rats [59, 60].
Men fed with diets low in copper experienced irregular heart rhythms [61].
Low copper may also be associated with high blood pressure. People with essential hypertension had lower blood copper levels compared to people with normal blood pressure [15].
Studies show that copper deficiency increases plasma cholesterol and “bad” LDL-cholesterol while decreasing “good” HDL cholesterol, thus increasing the risk of cardiovascular disease [62].
6) Pale Skin
Copper is a cofactor of the enzyme tyrosinase, which is required for the formation of the pigment melanin. Melanin is the pigment that gives color to the hair, skin, and eyes [63, 64].
Decreased pigmentation of the skin and general pallor of copper-deficient infants can be attributed to decreased copper levels [54].
7) Hair Loss
Copper is important for hair growth [65].
Copper concentrations were reduced in men with hair loss comparing to those without hair loss [66].
8) Hypothyroidism
Severe copper deficiency is associated with impaired thyroid hormone metabolism [67, 68].
Copper deficiency reduced blood total T3 by 48%, blood total T4 by 21%, and whole-brain T3 by 10% in newborn rats [69].
Copper deficiency also reduces the conversion of T4 to T3, the latter of which is the more potent thyroid hormone [67].
Copper Status Tests
1) Blood Copper
Blood copper concentration is the most widely used laboratory test to evaluate copper status.
Total Blood Copper
This test measures the total amount of copper in the blood.
Normally 65 – 90% of copper in the blood is carried by a protein called ceruloplasmin [70].
Normal values for total copper range from 10-22 μmol/L or 65-140 mcg/dL.
High blood copper concentrations (hypercupremia) are seen in inflammation, infection, hematologic disease, pregnancy, liver disease, and diabetes [71, 72, 73, 74, 75, 76].
Low blood copper concentrations (hypocupremia) are seen in malabsorption syndromes, increased zinc consumption, patients following gastric bypass surgery, patients on prolonged parenteral nutrition without copper supplementation, and nephrotic syndrome [17, 13, 10, 26].
Free Blood Copper
This test measures the amount of copper unbound by ceruloplasmin, the copper that is “free” to accumulate in the liver and other organs.
Free serum copper ranges from 1.6 to 2.4 μmol/L.
2) Blood Ceruloplasmin
Ceruloplasmin is a protein that transports copper in the blood.
Normal serum ceruloplasmin levels: 2.83 – 5.50 μmol/L or 20 – 40 mg/dL
Ceruloplasmin is an acute-phase reactant and may be increased in stress, inflammation, hormonal changes, infection, and various chronic diseases, such as arthritis and cancer, thus its use as an indicator is limited [77, 78].
3) 24-Hour Urine Copper
The normal range for 24-hour urine copper is 20-50 μg [79].
High urine copper levels (hypercupriuria) is found in Menkes’ disease, hemochromatosis, cirrhosis, infections, malignant diseases, inflammation, patients taking contraceptives, and pregnancy [80].
Low urine copper levels (hypocupriuria) are seen in malnutrition, malabsorption, nephrotic syndrome, and increased zinc consumption [17, 13, 10, 26].
4) Liver Copper
Liver copper concentration is the best indicator of copper status.
However, this is an invasive procedure, and it is only justified when there is evidence of liver damage as a result of copper overload [81].
Normal liver copper concentrations range from 20-50 μg/g of tissue.
Liver copper is elevated in Wilson’s disease and other liver disorders.
5) Copper-Containing Enzymes in Blood Cells
The determination of copper-containing enzymes in red blood cells appears to be a promising technique for assessing copper status in humans.
The enzyme activities are sensitive to changes in copper stores and are not as sensitive to factors not related to copper status, such as inflammation and infection [82].
Superoxide dismutase (SOD) Activity
Red blood cell SOD is a good marker of copper nutrition in humans. SOD activity correlates well with blood copper [83, 84].
SOD activity changes in response to changes in copper status before any differences in blood copper or ceruloplasmin activity occur [61].
A decrease in the activity of SOD was found in patients deficient in copper and in subjects with low copper intakes.
Platelet Cytochrome-C Oxidase
Cytochrome-c activity is reduced in copper deficiency. This decrease occurs before the appearance of a change of SOD activity, suggesting this may be a more sensitive marker of copper status [81].
Sensitive indicators of copper may also include the activity of the enzyme glutathione peroxidase, and concentrations of platelet copper and clotting factor VIII [84].
Inherited Diseases of Copper Metabolism
1) Wilson’s Disease
Wilson’s disease (hepatolenticular degeneration) is an inherited disorder in which excessive amounts of copper accumulate in the body, particularly in the liver and brain [85, 86].
It is caused by mutations in the (ATP7B gene which results in defective excretion of copper into bile [87, 88].
Affected individuals usually present with liver disease including chronic (hepatitis, cirrhosis, or acute liver failure) [89].
Neurological and psychiatric symptoms are more common in adults and include clumsiness, tremors, difficulty walking, speech problems, impaired thinking ability, depression, anxiety, and mood swings [89].
In many individuals, copper deposits in the eye, and forms a green-to-brownish ring, called the Kayser-Fleischer ring [90].
Typical laboratory findings include decreased blood ceruloplasmin, increased urinary copper excretion, and elevated liver copper content [85].
Treatment with penicillamine is effective in most cases while trientine and zinc are useful alternatives. Liver transplantation is required for irreversible liver damage [91].
2) Menkes’ Disease
Menkes’ disease is a rare inherited disorder caused by the absence of the ATP7A gene [92].
This genetic mutation results in defective copper transport across the intestine, placenta, and brain. The disease, therefore, resembles a severe nutritional copper deficiency despite adequate ingestion of copper [93].
Children with Menkes’ disease typically begin to develop symptoms between 2 – 4 months of age, and most children die by age 3 [54].
Symptoms arise from the deficient activity of essential cuproenzymes. It is characterized by sparse, kinky hair, failure to thrive, mental retardation, inability to control body temperature, and bone defects [94].
Laboratory findings include decreased blood copper and ceruloplasmin [91].
Severe Menkes’ disease is fatal, and no therapy is currently available. Early treatment with copper histidine may be of value in less severe cases [92].
3) Occipital Horn Syndrome
Occipital horn syndrome, also called X-linked cutis laxa, is a less severe form of Menkes’ disease that begins in early to middle childhood [95].
It is characterized by calcium deposits in the skull bone, coarse hair, and loose skin and joints [96].
