Infant copper deficiency

Blumenthal I, Lealman GT, Franklyn PP (1980) Fracture of the femur, fish odour and copper deficiency in a preterm infant. Arch Dis Child 55 229-231... 

In vivo tolerance to copper is quite high, however, deficiency and excess are serious problems. Infants are particularly vulnerable as they take time to assimilate the correct levels and it is known that trace copper from cooking utensils or water pipes can cause childhood cirrhosis. Copper deficiency leads to arterial weakness and heart enlargement. This is probably caused by a decrease in catecholamine neurotransmitters derived from the biosynthesis of adrenaline which requires the copper-containing enzymes phenylalanine hydroxylase, dopamine P-monooxygenase and tyrosinase. 

Castillo-Duran, C., and Uauy, R. (1983). Copper deficiency impairs growth of infants recovering from malnutrition. AjJi. /. C()>t. Nutt. 47, 710-714. 

Copper deficiency in human subjects recently has been reviewed by Graham and Cordano (9). Previously it has been widely accepted that copper deficiency in man does not occur (63), but recent evidence indicates that its presence is prevalent in untreated malnourished infants (64) and in infants fed low copper-milk diet (65,66). In addition, copper deficiency has been described in premature infants (67), in malnourished children during hyperalimentation (68,69), and in adults (70, 71,72),... 

During the first few days after birth, serum copper concentration in the baby rises from 50-150 /xg/100 mL, presumably because of increases in ceruloplasmin synthesis, and then it subsides again to normal level of 100 /xg/100 mL and is maintained throughout life (119), Thus, an infant needs at least 14 /xg Cu/kg to maintain his copper balance while in children, 60-100 /xg Cu/kg would be the minimal requirement. It also can be seen that low intake of copper by the mother during gestation can diminish copper stores in the embryo and thus can contribute to newborn copper deficiency. 

Cordano A. Clinical manifestations of nutritional copper deficiency in infants and children. Am J Clin Nutr 1998 67 1012S-6S. 

Copper was also shown to be essential in the early 1900s. Copper is needed for the absorption and mobilization of iron, so a deficiency of copper causes a type of anemia that is difficult to distinguish from iron deficiency anemia. Copper is also needed for the cardiovascular system, bone, brain, and nervous system. Premature and malnourished infants are particularly susceptible to developing copper deficiency, in part because milk is a poor source of copper. Whole grains, legumes, and nuts are the major dietary sources of copper. 

The average North American diet contains 3-5 mg copper per day. Because of the ubiquitous presence of copper in food constituents and even in drinking water, it is difficult to devise a balanced diet composed of natural foods that contains less than 1 mg copper per day. The daily minimal requirement of copper for the adult man is stated to be 2 mg per day (C5). Infants require 0.05 mg/kg body weight per day (Nl). These figures are only approximate and most probably far too high, since copper deficiency has not been produced with much lower intakes of copper (W3). 

Naturally occurring copper deficiency has not been proven to occur in man, most probably because of minimal requirements and plentiful supply in the diet. The copper deficiency, suspected on the basis of low serum copper levels in infants with various types of protein-losing enteropathy (S48, Z3), is of doubtful pathognomonic significance. 

The copper content of the tissues and blood of animals is markedly dependent on the dietary intake (U2). This has not yet been reported in man. Premature infants could not be made copper deficient by being put on a diet containing very little copper (W13). This, however, may be explained by the presence of large copper depots in this age group (see Section 5.1). The presence of increased amounts of copper in drinking water derived from copper pipes has been shown not to influence the copper content of the liver in man (M2). 

Sturgeon, P., and Brubacker, C., Copper deficiency in infants. A syndrome characterized by hypocupremia, iron deficiency anaemia and hypoproteinaemia.A.Af.A. J. Diseases Children 92, 254-265 (1956). 

Metal ions are required for many critical functions in humans. Scarcity of some metal ions can lead to disease. Well-known examples include pernicious anemia resulting from iron deficiency, growth retardation arising from insufficient dietary zinc, and heart disease in infants owing to copper deficiency. The ability to recognize, to understand at the molecular level, and to treat diseases caused by inadequate metal-ion function constitutes an important aspect of medicinal bioinorganic chemistry. 

More copper is found in the brain and heart than in any other tissue except for liver, where it is stored as copper thionein and released as ceruloplasmin or in the form of a complex with serum albumin. The high metabolic rate of the heart and brain requires relatively large amounts of copper metalloenzymes including tyrosinase, cytochrome c oxidase, dopamine-/3-hydroxylase, pyridoxal-requiring monamine oxidases, and Cu-Zn superoxide dismutase. Copper deficiency, which can occur for reasons analogous to those discussed above for Fe and Zn, leads to brain disease in infants, anemia (since cytochrome oxidase is required for blood formation), and heart disease. Few details are known about the molecular basis for copper uptake from foods. 

Both children and adults can develop symptomatic copper deficiency. Premature infants are the most susceptible since copper stores in the liver are laid down in the third trimester of pregnancy. In adults, deficiency is usually found following inicsiinul bypass surgery or in patients on parenteral nutrition. Symptoms range from bone disease to an iron-resistant microcytic hypochromic anaemia. 

Essentiality to Humans Copper deficiency in man is a rare exception, and would not occur if > 2 mg of copper is present in the daily diet. However, secondary copper deficiency can be caused by severe malabsorption, diarrhea accompanied by a copper-deficient diet in infants, or in the genetic disorder of copper transport and utilization that characterized Menkes disease. Except for Menkes disease (for which there is no effective treatment and which is invariably fatal), copper deficiency in man is simply treated by adding 5 mg copper (most conveniently as acetate) to the daily diet. In practical terms it is almost never necessary to supplement any but the most abnormal diets with copper to avoid its deficiency in man (Scheinberg... 

Copper deficiency is extremely rare, and there is no evidence that copper ever need be added to a normal diet. Even in chnical states associated with hypocupremia (sprue, celiac disease, and nephrotic syndrome), effects of copper deficiency usually are not demonstrable. Anemia due to copper deficiency has been described in individuals who have undergone intestinal bypass surgery, in those who are receiving parenteral nutrition, in malnourished infants, and in patients ingesting excessive amounts of zinc. While an inherited disorder affecting copper transport (Menkes disease) is associated with reduced activity of several copper-dependent enzymes, this disease is not associated with hematological abnormalities. 

Copper deficiency + + + + Unlikely in the absence of low birth weight, total parenteral nutrition, low-copper diet or in a term infant in the first 6 months of life... 

Copper deficiency occurs very rarely, but it is associated with mental aberrations. The normal diet contains one-third as much copper as iron, yet the metabolic demands are only one-fiftieth as great. Dietary copper deficiency develops in infants with diarrhea who are fed only milk. While lambs which are copper-deficient exhibit defective myelination, cerebral degeneration, and behavioral abnormalities, no such neurologic syndrome has been observed in humans. However, patients with Menkes Disease, caused by a defect in copper absorption and metabolism, are hypotonic, lethargic, and mentally retarded (Danks, 1983). 

Several recent reports document a symptomatic copper deficiency in premature infants and have included one subject receiving total parenteral alimentation. Premature infants have relatively small hepatic copper stores and probably require more than the term infant (Cordano aJ., 1964). Copper deficiency is generally seen in association with iron deficiency, but the anemia and weakness do not respond to iron therapy alone. 

Karpel and Peden (1972) have also reported an infant who developed symptomatic copper deficiency despite seven blood transfusions and four plasma transfusions. After 236 days of total parenteral nutrition the serum copper was 9 pg/lOO ml. Following 2.5 mg of oral copper per day there was prompt improvement but complete recovery required approximately 3 weeks. 

No definite evidence for the occurrence of copper deficiency in man has been presented, and human requirement is unknown. The diet usually furnishes 2 to 4 mg. of copper daily.Studies in man indicate that 2 mg. daily will maintain an adult in balance. The Food and Nutrition Board suggests a daily allowance of 1 to 2 mg. of copper for an adult, and 0.05 mg. per kilogram of body weight for infants and children. The copper content of whole blood is between 90 and 150 /xg- per 100 ml., equally divided between cells and plasma. There is little evidence that the administration of copper is of assistance in the therapy of hypochromic microcytic anemia. 

DEFICIENCY SYMPTOMS. Dietary copper deficiency is not known to occur in adults under normal circumstances, but it htis been diagnosed in Peru in malnourished children and in the United States in premature infants fed exclusively on modified cow s milk and in infants breast fed for an extended period of time. Fortunately, the liver of newborn babies contains 5 to 10 times as much copper as the liver of adults—a reserve which is drawn upon during the first year of life. 

The wool of copper-deficient sheep grows poorly and lacks the crimp characteristic of wool from normal, healthy animals (Underwood, 1971). In addition, the hair of human infants affected with Menkes syndrome, a genetic disease resulting in malabsorption of copper. 

With the exception of anemia, all the pathological abnormalities associated with copper deficiency in experimental animals have been observed in patients with Menkes syndrome (Banks, 1975). In fact, the similarity between wool from copper-deficient sheep and hair from Menkes patients prompted Banks et al. (1973a) to suggest that the term steely hair be used to describe the hair on these affected infants. 

Recognition of the symptoms of copper deficiency has been and will continue to be extremely important in maintaining the health and well-being of humans. Despite suggestions to the contrary, copper deficiency does occur in human beings. As early as 1931, Josephs (1931) detected copper deficiency in infants. More recently, the symptoms of copper deficiency have been observed in infants fed low-copper milk diets (Cordano et al, 1964), in premature infants (Al-Rashid and Spangler, 1971), in infants nourished by total parenteral alimentation (Karpel and Peden,... 

Reports of human copper deficiency are limited and suggest that severe nutrient deficiency coupled with malabsorption is required for this disease state to occur. Infants fed an exclusive cows milk diet are at risk for copper deficiency. Cows milk not only has substantially less copper than human milk but the bioavailability is also reduced. High oral intake of iron or zinc decrease copper absorption and may predispose an individual to copper deficiency. Other infants at risk include those with (1) prematurity secondary to a lack of hepatic copper stores (2) prolonged diarrhea and (3) intestinal malabsorption syndromes. Even the premature liver is capable of impressive copper storage. By 26 weeks gestational age the liver already has 3 mg of copper stored. By 40 weeks gestational age, the hepatic liver has 10-12 mg copper stored with the majority being deposited in the third trimester. Iron and zinc... 

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