Copper Deficiency

Copper is an essential mineral that works as a cofactor for enzymes (cuproenzymes) involved in energy production, iron metabolism, neuropeptide activation, connective tissue synthesis and neurotransmitter synthesis (NIH Office of Dietary Supplements). Ceruloplasmin, the main copper-carrying protein, carries more than 95% of the copper in healthy blood plasma and plays a role in iron metabolism. The adult body holds only 50-120 mg of copper, mostly in skeleton and muscle, and keeps its level steady by absorbing copper in the upper small intestine and releasing it into bile. Copper deficiency means that supply is too low for those jobs. The NIH describes it as uncommon in humans, because typical US diets meet or exceed the adult Recommended Dietary Allowance of 900 mcg a day. When deficiency does occur it usually has a reason: something that blocks absorption (gut surgery, celiac disease or a lot of zinc), feeding that supplies none, or an inherited defect such as Menkes disease. Its effects fall mainly on the blood and the nervous system. A review of the biology names hypochromic anemia and adult-onset peripheral neuropathy with ataxia (poor coordination) as the two most common clinical features (Prohaska, 2014). In the blood, deficiency causes anemia and neutropenia (low infection-fighting white cells), and sometimes low platelets. It can look like myelodysplastic syndrome (a group of bone marrow disorders): in a retrospective review of 40 patients with copper deficiency and blood abnormalities, anemia and neutropenia were the most common findings, and most also had nerve problems. In the nervous system, deficiency causes a spinal cord disease (myelopathy) with a stiff, unsteady gait and loss of position sense that closely resembles the damage from vitamin B12 deficiency. Less often it affects hair and skin color, cholesterol and resistance to infection, and bone defects are mainly described in infants and children. The two halves of the picture recover differently, which is why catching it early matters. Blood changes usually respond fully to copper replacement within 4-12 weeks (Myint, 2018), and in a Scottish national series 93% of cytopenias responded to copper replacement and treating the cause. Nerve damage often does not: the same series reported that 25% improved neurologically, 33% deteriorated and 42% were unchanged, and a systematic review of 198 published case reports of copper deficiency myelopathy found that only 24% improved and 5.1% returned to baseline despite copper treatment. Most acquired cases trace to impaired absorption. In 55 published case reports of copper deficiency myelopathy, the risk factors were previous upper gastrointestinal surgery, zinc overload and malabsorption syndromes, and no cause was found in 20%. Gastric bypass is now a common trigger. High-dose zinc supplements and heavy use of zinc-containing denture creams can also cause it, because zinc inhibits copper absorption. The condition is diagnosed with blood tests and treated by a clinician with copper replacement, by mouth or by vein, together with fixing the cause. It is not something to treat on your own, because copper itself is harmful in excess: the adult upper limit is 10 mg a day, based on liver damage.

• •Anemia, which can cause tiredness and pale skin
• •Neutropenia (low infection-fighting white cells) and more infections
• •Low platelets, or low counts of all blood cells (pancytopenia)
• •Stiff, unsteady, spastic walking (copper deficiency myelopathy)
• •Loss of position sense and poor balance (sensory ataxia)
• •Numbness and tingling from peripheral neuropathy
• •Optic nerve damage and vision changes
• •Osteoporosis and other bone defects, notably in infants
• •Loss of pigment (hypopigmentation) in skin or hair
• •Raised cholesterol (hypercholesterolemia)
• •Low muscle tone and slow growth in infants
• •Failure to thrive, seizures and kinky hair (Menkes disease)

• •Roux-en-Y gastric bypass and other bariatric surgery
• •Other upper gastrointestinal surgery, such as gastric resection
• •Malabsorption syndromes, including celiac disease
• •Regular high-dose zinc supplements
• •Excessive use of zinc-containing denture cream
• •Long-term parenteral (intravenous) nutrition without enough copper
• •Prolonged continuous renal replacement therapy
• •Prematurity
• •Infant diets of unmodified cow's milk
• •Recovery from childhood malnutrition
• •Menkes disease (ATP7A gene mutation)
• •No cause found (about 1 in 5 cases of myelopathy)

The common thread is that not enough copper gets absorbed, or none is supplied. Copper is taken up mainly in the upper small intestine, so surgery that removes or bypasses that region (Roux-en-Y gastric bypass, gastric resection and other bariatric operations), and diseases that damage its lining such as celiac disease, can starve the body of copper. In a retrospective review of 40 people with copper deficiency and blood abnormalities, 25% had bariatric surgery and a further 35% had other gastrointestinal surgery, usually gastric resection. At one US bariatric center, 9.6% of 136 gastric bypass patients had copper deficiency, and in 16 patients followed after surgery blood copper and ceruloplasmin activity fell over 6 and 24 months while blood zinc did not change. In a study of 200 people with celiac disease, 15% had copper deficiency. Zinc is the other major cause. The NIH explains that regular high doses of zinc from supplements, or excessive zinc-containing denture cream, can cause copper deficiency because zinc inhibits copper absorption; a copper-status marker fell with zinc intakes of about 60 mg a day for up to 10 weeks, and the adult upper limit for zinc (40 mg a day) was set partly for this reason. In the Scottish series of 16 patients, 12 had high blood zinc and nine used zinc-containing dental fixatives. In another review of 70 patients prescribed zinc, 62% were taking doses high enough to cause copper deficiency and plasma copper had been measured in only two. High zinc is not always found: blood zinc can be raised even without extra zinc intake, and no cause is found in roughly 20% to 30% of reported cases (20% of myelopathy case reports; 12 of 40 patients in the hematology review). Other routes are feeding without copper and a poor start in life. Long-term parenteral (intravenous) nutrition without added copper, and prolonged continuous renal replacement therapy, have caused deficiency. In infants, cases have followed prematurity, intravenous feeding, special diets and unmodified cow's milk, and recovery from malnutrition. Menkes disease is an inherited cause: mutations in the ATP7A gene sharply reduce copper absorption, causing failure to thrive, impaired development, seizures, aortic aneurysms and kinky hair. Most children with it die by age 3 if untreated, though copper injections started in the first weeks of life can reduce mortality and improve development.