Copper Deficiency Anemia Copper is required for the function of over 30 proteins.

It is a component of prolyl and lysyl hydoxylases, enzymes involved in collagen synthesis. Because of this, connective tissue-rich tissues such as capillaries, scar tissue, and bone matrix are most sensitive to copper status. Copper also functions at the catalytic site of the antioxidant enzyme superoxide dismutase. Additionally, the copper-containing plasma protein ceruloplasmin is integral to iron metabolism since it catalyzes oxidation of the mineral, which is required for its binding to proteins involved in absorption, transport, and storage. The redox potential of copper ions gives it a key role in energy metabolism as a component of the cytochromes that participate in electron transport. Copper also works with vitamin C to make elastin. In addition, copper containing enzymes such as superoxide dismutase, copper protects against oxidants and free radicals and promotes the synthesis of melanin and cathecholamines. Copper is also needed in minute amounts for the formation of hemoglobin. The metabolism of copper and iron are closely related; systemic copper deficiency generates cellular iron deficiency, which results in diminished work capacity, diminished growth, alterations in bone mineralization, and diminished bone response. Copper deficiency also results in reduced activity of white blood cells and reduced thymus hormone production, thus resulting in increased infection rates. Marginal deficits of this element can contribute to the development and progression of a number of disease states including cardiovascular disease and diabetes. Homocysteine thiolactone accumulates when homocysteine is high and inhibits lysyl oxidase which depends on copper to catalyze cross linking of collegen and elastin in arteries and bone. Overall supplementation of 3–6 mg of copper per day can improve copper status in otherwise healthy individuals. Increased intake could reduce the risk of arterosclerosis by promoting improved fibrinolytic capacity. Copper along with zinc and iron are essential metals for normal central nervous system development and function. If there were to be imbalances death could result (apoptosis). Neuronal death may be contributing factors in Alzheimers and Parkinson’s Disease.

About 90% of the copper in serum is incorporated into ceruloplasmin; the rest is loosely bound to albumin, transcuprein, and other proteins, free amino acids, and possibly histidine. Copper is transported in the blood to other tissues, primarily bound to albumin. Copper is usually not directly incorporated into ceruloplasmin. It requires an intermediate carrier protein (albumin) in order to establish a more stable binding with ceruloplasmin. It also exists in the blood as ceruloplasmin, a functional protein that acts as an enzyme at the erythrocyte forming cells of the bone marrow. Serum copper and immunoreactive ceruloplasmin levels tend to be higher in women than in men. The serum copper concentration is greatest in the neonate and decreases gradually in the first year of life. Approximately one third of the total body pool of copper is localized in skeletal muscle. Another third is found in brain and liver. The remaining amount of total body copper is found in bone and other tissues. Since copper is excreted primarily in the bile, diseases of the liver and gall bladder may affect copper balance. Copper absorption is regulated by changes in the total body pool. The increase in absorptive efficiency observed when total body copper decreases is mediated by an intestinal copper-binding protein that is also involved with mucosal storage of zinc. Consequently, high dose zinc supplements (150 mg/day) can dramatically contribute to copper deficiency by decreasing the amount of protein available to bind copper. High dose vitamin C supplements (1500 mg/day) may also decrease copper absorption because the reduced form of the mineral, which is increased in the presence of vitamin C, is less well-absorbed than the oxidized form. Although severe copper deficiency is rarely observed, marginal copper status is not uncommon. High dose supplements of zinc, vitamin C, and iron are contributing causes of marginal copper deficiency. Microcytic hypochromic anemia in the presence of normal serum ferritin is the primary clinical feature of marginal copper deficiency. This microcytic anemia is unresponsive to iron therapy. Copper deficiency is also characterized by hypoferremia, neutropenia, and usually the presence of vacuolated erythroid precursors in the marrow. This anemia, which is hematologically identical to iron-deficiency anemia, develops as a result of abnormalities in iron utilization. Skeletal abnormalities, reproductive difficulties, impaired nervous tissue function, fatigue, edema, skin sores, irregular heart rhythms, reduced thyroid functions, and changes in hair and skin pigmentation have

been observed in severe copper deficiency. A role for copper in the maintenance of bone mass has been determined from observations of osteoporosis in preterm infants born with inadequate copper reserves. Hospitalized patients should also be evaluated carefully. Although enteral feedings have trace elements problems with bioavailability may occur. Cow's milk is relatively low in copper, and cases of copper deficiency have been reported in high-risk infants and children fed only cow's milk formula. High-risk individuals include: premature infants (especially those with lowbirth weight), infants with prolonged diarrhea, infants and children recovering from malnutrition, and individuals with malabsorption syndrome including celiac disease, sprue, and short bowel syndrome due to surgical removal of a large portion of the intestine. Individuals receiving intravenous total parenteral nutrition or other restricted diets may also require supplementation with copper and other trace elements. Recent research indicates that cystic fibrosis patients may also be at increased risk of copper insufficiency. Diagnosis is based on low copper and ceruloplasmin levels in serum, although these tests are not always reliable. Because early diagnosis and treatment seem to result in a better prognosis, the disorder is ideally detected before age 2 wk. However, diagnostic accuracy of these tests is limited. Thus, infants at risk (eg, those with a family history) can be screened by measuring dopamine, norepinephrine, dihydroxyphenylacetic acid, and dihydroxyphenylglycol in plasma. A dihydroxyphenylacitic acid: dihydroxyphenylglycol ratio of > 4 appears to indicate deficiency, and a dopamine: norepinephrine ratio of > 0.2 appears to confirm it. Other lab work may include CBC, Homocysteine, Alb, transthyretin, CRP, RBP, Serum Zinc (often elevated), and EPO (elevated). Inteventions • Correct copper deficiency and documented anemias. • Instruct patient on good sources of protein, iron, and copper to prevent recurrences. • Monitor use of zinc supplements (Since zinc reduces copper absorption).

• Protein should be at least 1g/kg for adults; iron intake should be adequate for age and sex.

Monitor use of multivitamin-mineral supplements to avoid large doses of zinc. Ascorbic acid can act as a prooxidant in the presence of metals such as iron or copper, large doses are not recommended. Monitor tube fed patients to ensure they are receiving sufficient amounts of copper. Avoid taking copper with NSAID’s, birth control pills, allopurinol, estrogen hormones, or cimetidine. Herbs and botanicals and supplements should not be used unless consulting with a physician.

References Sylvia Escott-Stump: Nutrition Diagnosis Related Care, 6th Edition, Lippincott-Williams & Wilkins, 2007 ES West, et al., Textbook of Biochemistry. 4th ed. Oxford Lichtmann et al., William’s Hematology. 10th ed. Mahan, Escott-Stump: Krause’s Food, Nutrition & Diet Therapy, 12th Ed., WB Saunders 2008

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