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 low-
birth 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
http://www.merck.com/mmpe/sec01/ch005/ch005c.html
http://lpi.oregonstate.edu/infocenter/minerals/copper/
http://www.feinberg.northwestern.edu/nutrition/factsheets/copper.html