Nutritional Anemias, edited by S. J. Fomon and S. Zlotkin, Nestle Nutrition Workshop Series, Vol. 30, Nestec Ltd., Vevey/Raven Press. Ltd., New York © 1992.
Copper Deficiency in Term and Preterm Infants
Jonathan C. L. Shaw
Department of Paediatrics, Faculty of Clinical Sciences, University College London, The Rayne Institute, London, England, United Kingdom
In 1928 Hart et al. (1) demonstrated that copper was essential for erythropoiesis in the rat. They showed that rats fed a milk diet developed an anemia that could not be corrected by iron alone. It was cured, however, by the addition of ash of liver, lettuce, or corn. By precipitating copper from acid extracts of the ash with hydrogen sulfide, they were able to show that it was the copper in the ash that was essential for the full reversal of the anemia. As a result of this work, copper deficiency has been recognized as a cause of anemia in man, although the full syndrome has a number of other features. It is now known that copper is a component of several enzymes, some of which are listed in Table 1. These enzymes generally bind between 1 and 8 gram-atoms of copper per mole, and the presence of copper is essential for their activity. Many of them engage in oxidation-reduction reactions. Some, but not all, of the features of copper deficiency can be explained by the functions of these enzymes.
THE ANEMIA OF COPPER DEFICIENCY
The anemia of copper deficiency has been dealt with in a number of reviews which should be referred to as a source of references (2-6). Most of the investigations on the etiology of the anemia in copper deficiency have been carried out in experimental animals, and the difference between species means that their results must be inter- preted with caution. Nevertheless, it seems probable that the anemia results from defects in at least two points where copper enzymes interact with iron metabolism.
Release of Iron from Iron Stores
In copper-deficient swine, ceruloplasmin levels fall to less than 1% of normal and there is an associated fall in the serum iron. Iron absorption is diminished and iron accumulation is observed in the intestinal mucosal cells, in the adjacent macro- 105 106 COPPER DEFICIENCY IN INFANTS
TABLE 1. Some copper enzymes in humans
Cytochrome c oxidase Ceruloplasmin Superoxide dismutase Tyrosinase Dopamine p hydroxylase Lysyl oxidase
phages, and in the parenchymal cells of the liver, suggesting a difficulty in the release of iron from iron stores. Injection of iron in the form of colloidal iron or storage- damaged erythrocytes results in trapping of the iron in the iron stores and reticu- loendothelial cells of the copper-deficient animals. Injection of ceruloplasmin causes a prompt rise in the plasma iron concentration, indicating a release of iron from iron stores. These data are consistent with the hypothesis that ceruloplasmin acts as a ferroxidase oxidizing ferrous (Fe2+) iron to ferric (Fe3+) iron prior to its incorpo- ration into plasma transferrin (2,5). The data do not, however, account entirely for the anemia of copper deficiency for a number of reasons. In the first place, parenteral iron does not fully correct the anemia of copper deficiency (7) and perfusion with ceruloplasmin does not augment the transfer of iron from the serosal surface of isolated perfused intestine of copper- deficient rats (8). Also in Menkes' disease and Wilson's disease, where the ceru- loplasmin is low, anemia is not a feature (6). Finally there is considerable variability of ceruloplasmin oxidase activity amongst different species, and it is said to be vir- tually absent in the plasma of the turkey, the peacock, and certain crocodiles (4). Clearly much remains to be explained.
Synthesis of Heme
The final stage of heme synthesis involves the insertion of iron into protoporphyrin IX, and this takes place within the inner mitochrondrial membrane. It requires the participation of ferrochelatase and a supply of electrons to reduce ferric (Fe3+) to ferrous (Fe2+). Though there has been some evidence that ferrochelatase activity may be reduced in copper deficiency (9), there has been no recent confirmation of this. The anemia of copper deficiency is a sideroblastic, microcytic, hypochromic ane- mia. The bone marrow shows vacuolated erythroid and myeloid precursors with ringed sideroblasts which accumulate iron in the cytosol. Such anemias are char- acteristic of ineffective erythropoiesis, implying a defect in iron metabolism, heme synthesis, or globin chain synthesis. In copper deficiency there is no defect in pro- phyrin synthesis, and because both iron and protoporphyrin accumulate in the er- ythroid cells of copper-deficient animals the precursors of heme synthesis are not lacking. Iron uptake by copper-deficient reticulocytes from transferrin has been COPPER DEFICIENC Y IN INFANTS 107 shown to be 52% of normal, whereas heme synthesis was reduced by 33% (10). Synthesis of heme from protoporphyrin IX and Fe2+ is not impaired in tissues from copper-deficient animals, but synthesis from protoporphyrin IX and Fe3+ is. Syn- thesis of heme from protoporphyrin IX and ferric iron is dependent on a supply of substrate for electron transport. Inhibitors of the citric acid cycle and electron trans- port chain such as malonate, rotenone, antimycin A, and cyanide profoundly inhibit heme synthesis (10), whereas inhibitors of ATP synthesis such as 2,4-dinitrophenol do not. This has been interpreted as indicating that intact electron transport rather than ATP synthesis is the essential function. Reduction in the activity of cytochrome c oxidase is a regular finding in copper deficiency, and it is probable that the defect of heme synthesis contributes both to the reduced activity of cytochrome c oxidase and to the sideroblastic anemia.
COPPER DEFICIENCY IN TERM AND PRETERM INFANTS
The features of copper deficiency in infants given below are based on 51 cases reported in the pediatric literature since 1956 (11-32). Of the 51 cases, 49 were 18 months or less at the time of diagnosis (11,12,13-15,17-32). Those regarded as full term include seven infants who are presumed to be full term but whose birth weight or gestation are not given. The low-birth-weight infants are infants whose birth weight is given or who are stated to be of low birth weight (<2.5 kg). Their median birth weight was 1.040 kg (range 0.68-2.3 kg). The features of the syndrome of copper deficiency in infants are as follows: • Psychomotor retardation • Hypotonia • Hypopigmentation • Prominent scalp veins in palpable periosteal depressions • Pallor • Sideroblastic anemia, resistant to iron therapy. Bone marrow shows vacuolated erythroid and myeloid cells with iron deposition in the vacuoles • Hepatosplenomegaly (a feature of sideroblastic anemia) • Neutropenia, usually <1.0 x 109/l • X-ray changes of osteoporosis, blurring and cupping of the metaphyses, sickle- shaped metaphyseal spur formation, subperiosteal new bone formation and fractures • Plasma copper level usually <6.3 (imol/1 (<40 jJLg/dl), and ceruloplasmin <130 mg/1 The etiology of the sideroblastic anemia has been discussed above. The prominent scalp veins and bone changes are thought to result from impaired collagen and elastin cross-linking due to depressed lysyl oxidase activity. The consequent reduction in strength of the bone collagen causes fragile bones that fracture easily. The hypo- pigmentation is probably due to depressed tyrosinase activity and impaired melanin synthesis. The cause of the neutropenia is not understood. 108 COPPER DEFICIENC Y IN INFANTS
PREDISPOSING FACTORS
In the published reports, one or more of a number of predisposing factors have been present in every case. These are discussed below.
Low Birth Weight
Forty percent of reported cases were less than 2.5 kg at birth (11,12,14,15,18,26, 27,29,30,32). Low-birth-weight infants have lower body stores of copper at birth than do full-term infants [55 (imol (3.5 mg) per kilogram fat-free body weight at 20 weeks' gestation rising to 76 |imol (4.8 mg) at term (33)]. During the last 3 months of gestation they accumulate copper at a daily rate of about 0.8 nmol (51 |xg) per kilogram (4). If, however, they are born prematurely they may be in negative copper balance for up to 6 weeks after birth (34). Full-term infants also have a period of negative balance following birth (35). Though this will cause a transient decline in the total body copper, it is not thought to cause copper deficiency if the subsequent dietary copper intake and absorption are sufficient. The full-term infant at least has a high concentration of copper in the liver (36), and the current evidence suggests that full-term infants have stores sufficient for at least 5 months and that low-birth- weight infants have them for at least 2 months.
Dietary Deficiency of Copper
Total Parenteral Nutrition
Twenty-three percent of the infants received total parenteral nutrition (12,13,20- 22,24,29,31). In eight of the cases the solutions were deficient in copper. In the three other cases (29) copper had been added to the solutions, but other predisposing causes, namely prematurity and copper-deficient milk, were present.
Copper-Deficient Milk
Fifty-four percent of infants were fed exclusively or predominantly on cow's milk with very short periods of breast-feeding (12,15,16,19,23,26,28). A further 12% were fed formulas (11,14,17,18,32) of which at least one was copper-deficient (11). The changes in the concentration of copper in breast milk are given in Tables 2 and 3. Cow's milk contains a much lower concentration of copper than does breast milk. The copper content of cow milk is stated to be 3.1 jtmol /I, range 1.6-4.7 (20 jxg/dl, range 10-30) (39), and in one report values as low as 0.9 jimol/l (5.7 jjug/dl) were found (26). Copper deficiency has never been described in an infant fed exclusively on breast milk, nor has it ever been described in a full-term infant fed a formula known to contain adequate amounts of copper [i.e., >6.3 n.mol/1 (>40 (ig/dl)]. COPPER DEFICIENC Y IN INFANTS 109
TABLE 2. Changes in concentration of copper in human milk during lactation (37)
Post partum Copper (days) (fimol/l) SD
7 9.7 2.0 14 7.6 1.2 21 6.7 1.3 28 6.1 0.7 35 5.8 1.0 42 5.6 1.0 49 5.1 0.9 60 4.7 0.7 90 4.2 0.8 120 3.5 1.0 150 3.5 0.8 180 2.8 0.9 210 2.6 1.0 240 3.0 0.8 270 2.8 0.92
Antecedent Malnutrition
Twenty-five percent of the cases suffered from severe antecedent malnutrition. This was due to a starvation diet (15) or malabsorption and diarrhea (13,30), giardiasis (15), a probable disaccharidase deficiency (16), short bowel (21,24,31), or celiac disease (17).
CLINICAL FEATURES
Age at Presentation (Infants Younger than 18 Months at Diagnosis)
The median age at presentation for full-term infants was 8.3 (range 5-18) months (13,15-17,19-26,28,31) and for the low-birth-weight infants it was 3.0 (range
TABLE 3. Comparison of changes in copper concentration in milk from mothers of full-term and preterm infants (38)
_ Full-term copper Preterm copper (days) (j.mol/1 SD p.mol/1 SD
3-5 11.3 2.0 13.1 3.3 8-10 11.5 3.3 12.3 2.8 12-17 9.0 1.3 11.8 3.8 28-30 9.1 1.4 9.9 2.2 110 COPPER DEFICIENC Y IN INFANTS
2.2-15) months (11,12,14,15,18,26-30,32). This difference presumably reflects the difference in the body stores of copper present at birth and the higher specific growth rate of the preterm infants.
History and Physical Examination
Details of physical examination were reported in only 14 of the 52 cases (11,12,15,17,19,23,25,29,30). In these 14 infants, hypotonia was reported in 43%, hypopigmentation in 29%, psychomotor retardation in 21%, skin rash in 21%, dilated veins in 15%, and hepatosplenomegaly in 15%.
Infection
Specific infections are mentioned in six cases. They include two cases of congenital syphilis and tuberculosis (15), one case of bronchopneumonia (32), one case of in- fected central venous catheter used for total parenteral nutrition (21), one of otitis media (23), and the case of giardiasis mentioned above (15). Others are described as "mild and nonspecific" (26). These cannot easily be construed as being a con- sequence of copper deficiency, and the giardiasis probably contributed to it.
Plasma Copper and Ceruloplasmin
In the full-term infants the median plasma copper was 5.8 (imol/l, range 1.1-14 (37 (ig/dl, range 7-89), and the median ceruloplasmin was 30 mg/1"1 (range 4-130). In the low-birth-weight infants the median plasma copper was 4.4 (imol/l, range 0.08- 10.2 (28 |xg/dl, range 0.5-65), and the median ceruloplasmin was 30 mg/1 (range 0- 40). During the last 30 years the analytical methods for copper have improved, and most of the higher values in the literature date from the earlier period 1956-1970. In the more recent reports, where modern methods (i.e., atomic absorption spec- trophotometry) were used, no case of copper deficiency has been reported in a full- term infant with a plasma copper of more than 6.8 (imol/l (43 (xg/dl) or in a low- birth-weight infant with a plasma copper of more than 5.2 p,molA (33 (xg/dl).
Plasma Copper and Fractures
The median plasma copper in those infants who had fractures was 2.3 p,mol/l, range 0.7-11 (14.5 |xg/dl, range 4.5-68). Only one value was over 5.3 |imol/l (33 \xgl dl), and this dated from 1964 when analytical methods were not so reliable.
Normal Plasma Copper
The changes in plasma copper in full-term infants and preterm infants are given in Tables 4 and 5. In evaluating the plasma copper it is important to take into account COPPER DEFICIENC Y IN INFANTS 111
TABLE 4. Changes in serum copper with age in full-term infants (4)
Plasma copper Postnatal age ixmol/l SD
Cord blood 4.6 1.7 5 days 7.4 1.4 1 month 9.9 2.7 3 months 12.8 2.7 5 months 16.4 3.9 6-12 months 17.5 3.0 6-12 years 17.2 2.7
the birth weight and the age of the baby because the plasma copper and ceruloplasmin both vary with postnatal age and gestation. In the newborn, about 85% of the plasma copper is bound to ceruloplasmin and the remainder is probably bound to the serum albumin and complexed with amino acids. The plasma copper and ceruloplasmin are both low at birth and rise to adult values at about 6 months of age (Table 4). The plasma concentrations in preterm and small-for-gestation infants are about the same as in full-term normal-weight infants at birth but rise more slowly (Table 5). The values shown in Table 5 were the same whether the infants were fed a formula containing 6.3 jtmol/1 (40 (Jtg/dl) of copper or one containing 26.3 |j,mol/l (167 |ig/dl) (41). It therefore seems likely that these values are representative of plasma copper levels to be found in low-birth-weight infants who are not copper-deficient. The normal range would therefore be the mean ± 2 SD. From these data it can be seen that a small preterm infant of 2-3 months may have a very much lower plasma copper than a full-term infant of same postnatal age and yet not have copper deficiency.
TABLE 5. Changes in plasma copper in preterm infants (40)
Plasma copper Postconceptional age (weeks) (i.mol/1 SD
25-28 4.6 2.7 29-30 4.3 2.4 31-32 5.0 2.8 33-34 5.7 2.4 35-36 6.1 2.2 37-38 7.4 3.8 39-40 8.3 1.9 41-42 9.4 1.9 43-44 11.0 4.4 45-46 10.2 2.5 47-48 12.9 2.8 112 COPPER DEFICIENC Y IN INFANTS
Hematological Changes
Anemia
Ninety-two percent of the full-term infants and 85% of the low-birth-weight infants had a hemoglobin concentration of less than 10 g/dl. The median hemoglobin of the full-term infants was 4.9 g/dl (range 2.6-13.6), and that of the low-birth-weight infants was 7.0 g/dl (range 2.7-11.9). Examination of the bone marrow typically showed maturation arrest with marked vacuolization in the erythroid and myeloid cells and numerous ringed sideroblasts (12). The picture is not therefore one of iron deficiency, though in some cases, (notably those fed cow's milk) the reticulocyte response to iron therapy showed that iron deficiency did coexist with the copper deficiency. The median plasma iron concentration in the full-term infants was 3.6 jtmol/l, range 0.7- 20 (20 (j-g/dl, range 4-114), and in the low-birth-weight infants it was 2.9 p.mol/1, range 1.8-14 (16 \ig/dl, range 10-78). The higher median hemoglobin concentration in the low-birth-weight infants was probably attributable to the fact that they were transfused.
Neutropenia
A neutropenia of less than 1.0 x 109 per liter was found in 84% of the infants in whom the results of a white blood cell count were reported (n = 25) (11,12,14— 21,23,25,29-32), and all these infants had a neutrophil count less than 2.0 x 109 per liter. There were no differences between the low-birth-weight infants and the full- term infants. The median neutrophil count was 0.376 x 109 per liter (range 0.049- 1.9).
Bone Disease
The results of x-ray examination of the bones of infants with copper deficiency are summarized in Table 6. Fractures were found in 11 cases (11,14- 16,18,19,22,24,30,32). The percentage incidence of fractures is based on the whole group of infants (n = 51), on the supposition that a fracture is unlikely to be missed clinically. The percentage incidence of the other changes is based only on the cases where bone x-ray changes are reported (n = 27) (11,12-16,18-25,19-32) because many of the findings are not evident clinically and might not be detected if an x-ray had not been taken. The subperiosteal new bone formation can be very extensive and reflect organizing subperiosteal hemorrhage (22,24,30); in other cases it can be quite inconspicuous and may simply reflect normal bone growth, particularly in pre- mature infants. The higher incidence of bone changes in the premature infants prob- ably reflects the multifactorial etiology of their bone disease. COPPER DEFICIENCY IN INFANTS 113
TABLE 6. Bone changes reported in copper deficiency*
Full term Low birth weight (n = 31) (n = 20) Fractures n % n %
Fracture of long bone(s) 3 10 5 25 Fracture of epiphyseal plate(s) 2 6 2 10 Fracture of ribs — 0 3 15 Metaphyseal chip fracture 1 3 — 0 Fracture of the skull — 0 — 0
Other changes Full term Low birth weight (n = 14) (n = 13) n % n %
Osteoporosis 8 57 11 85 Fraying and cupping of the metaphyses 9 64 11 85 Spurs 8 57 — 0 Subperiosteal new bone formation 6 43 7 54
a The incidence of fractures is for the whole group, and the incidence of other changes is for the group in whom the results of x-rays were reported. Note that some infants had more than one fracture.
RESPONSE TO TREATMENT
In the reported cases the daily median copper intake used in treatment was 4.6 (jimol/kg, range 1.0-12.6 (290 p,g/kg, range 63-800); in one case on total parenteral nutrition, intravenous treatment was given in a dose of 0.79 |i,mol/kg day (50 n-g/kg/ day). Treatment resulted in a reticulocyte response within 1-2 weeks, median 4.6% (range 2-14%), and the neutrophils rose above 1.0 x 109 per liter within about 5 days. Healing of the fractures and resolution of the other bone changes were well advanced after 30 days. Because some of the infants recovered without any special treatment other than introducing a more varied diet with a higher copper content, it is possible that the occasional infant may pass through a period of transient de- ficiency and recover spontaneously as his repertoire of food increases, without ever being diagnosed.
THE COPPER CONTENT OF MILKS
There is some uncertainty about the copper content of formulas sold for infant feeding in different parts of the world. Table 7 gives the mean values and range of copper found in formulas in different countries. The data are mainly from Lonnerdal et al. (42), but the data on English milks are my own unpublished data from 1982. It can be seen that at that time some formulas had a very low copper content and 114 COPPER DEFICIENC Y IN INFANTS
TABLE 7. Copper concentration of different infant formulas (42)
Copper ((imol/l) Country of origin Number of samples Mean Range
USA 14 7.6 4.9-10.2 Sweden 12 2.8 0.5-11.0 West Germany 12 3.1 0.2-21.3 Japan 8 0.9 0.3-2.4 The Netherlands 2 4.4 2.2-6.8 United Kingdom 2 2.2 0.8-3.6 Full-term formula3 9 2.8 0.2-7.4 Preterm" 3 10.7 9.8-11.5 Soy formula8 1 8.0 France 2 1.9 0.8-3.1 Norway 1 3.9
"Chemical analyses performed by the author in 1982. at 150 ml/kg/day would supply much less than the amount supplied by breast milk (Tables 2 and 3) or the recommended requirements for full-term infants (see summary below). Since 1984, copper has been added to infant formulas in Japan, with a con- sequent reduction in the incidence of copper deficiency (43).
SUMMARY OF RECOMMENDED COPPER INTAKES FOR FULL-TERM AND PRETERM INFANTS (44)
1. ESPGAN Committee on Nutrition (1977) (full-term infants): Minimum value 0.47 ixmol (30 (ig)/100 kcal [0.31 (imol (20 |xg)/100 ml]. 2. Department of Health and Social Security (1980) (full-term infants): "It seems likely that the amount of copper in infant feeds should be not more and not less than the amounts present on average in mature human and cow's milk, that is to say not less than 0.16 u-mol (10 (ig) and not more than 0.94 u-mol (60 u-g)/100 ml, but at present sufficient information is not available for a recommendation to be made." 3. American Academy of Pediatrics (1976) (full-term infants): Minimum intake 1.42 (jimol (90 M-gVlOO kcal. 4. American Academy of Pediatrics (1977) (low-birth-weight infants): "Recent data suggests that an intake of 1.42 u-mol (90 (ig)/100 kcal is desirable." 5. Canadian Paediatric Society (1981): "It has been suggested that low-birth- weight infants require 1.42 u-mol (90 u-g)/100 kcal to avoid copper depletion." 6. American Academy of Pediatrics (1985) (low-birth-weight infants): "1.42 (xmol (90 u,g)/100 kcal continues to be appropriate." 7. ESPGAN Committee on Nutrition (1987) (preterm infants): "There seems to be no case for routinely supplementing breast-fed infants with copper. . . . Formulas . . . should provide at least 90 u.g/100 kcal (i.e., 117 u-g/kg per day at 130 kcal/kg per day). . . . there seems no reason to exceed 120 u,g/100 kcal." COPPER DEFICIENC Y IN INFANTS 115
Unfortunately in the United Kingdom the recommendations (see 2 above) were framed in such a way that the manufacturers felt that they did not necessarily have to fortify formulas with copper. As a result, the copper content of some infant for- mulas sold in the United Kingdom in the past was less than 1.6 (xmol/1 (10 jig/dl), and in some samples copper was almost undetectable. However, at the present time all contain enough copper (~6.3 nmol/1,40 ng/dl), and have done since at least 1983. It is therefore evident that while milks used for infant feeding in the United King- dom contain what is believed to be sufficient copper this may not be the case worldwide.
CONCLUSION
Anemia due to copper deficiency, though rare, continues to be reported sporad- ically throughout the world. Its incidence in areas where malnutrition is endemic is probably underestimated. There is generally a predisposing cause such as antecedent malnutrition, malabsorption, prematurity, or dietary insufficiency, often due to cop- per-deficient total parenteral nutrition solutions. The anemia seems to be mediated by a specific defect in the synthesis of heme and compounded by inability to mobilize iron from iron stores. Subclinical deficiency may be more common than supposed, but there are few data bearing on its incidence.
REFERENCES
1. Hart EB, Steenbock H, Waddell J, Elvehjem CA. Iron in nutrition. VII. Copper as a supplement to iron for hemoglobin building in the rat. J Bid Chem 1928; 77: 797-812. 2. Lee GE, Williams DM, Cartwright GE. Role of copper in iron metabolism and heme biosynthesis. In: Prasad AS, Oberleas D, eds. Trace elements in human health and disease, vol 1. New York: Academic Press, 1976: 373-90. 3. O'Dell B. Biochemistry and physiology of copper in vertebrates. In: Prasad AS, Oberleas D, eds. Trace elements in human health and disease, vol. 1. New York: Academic Press, 1976: 391-413. 4. Shaw JCL. Trace elements in the fetus and young infant. II. Copper, manganese, selenium and chromium. Am J Dis Child 1980; 134: 74-81. 5. Frieden E, Hsieh HS. Ceruloplasmin: the copper transport protein with essential oxidase activity. Adv Enzymol 1976; 44: 187-235. 6. Danks DM. Copper deficiency in humans. Annu Rev Nutr 1988; 8: 235-57. 7. Prohaska JR, Bailey WR, Cox DA. Failure of iron injection to reverse copper dependent anaemia in mice. In: Mills CF, Bremner I, Chesters JK, eds. Trace elements in man and animals—TEMA5. Slough, Bucks, United Kingdom, Commonwealth Agricultural Bureau, 1985: 27-32. 8. Coppen DE, Davies NT. Studies on the roles of apotransferrin and caeruloplasmin on iron absorption in copper-deficient rats using an isolated vascularly- and luminalry-perfused intestinal preparation. BrJ Nutr 1988; 60: 361-73. 9. Tephly TR, Wagner G, Sedman R, Piper W. Effects of metals on heme biosynthesis and metabolism. FedProc 1978; 37: 35-9. 10. Williams DM, Loukopoulos D, Lee GR, Cartwright GE. Role of copper in mitochondria! iron me- tabolism. Blood 1976; 48: 77-85. 11. Al-Rashid RA, Spangler J. Neonatal copper deficiency. N Engl J Med 1971; 285: 841-3. 12. Ashkenazi A, Levine S, Dialjetti M, Fishel E, Benvenisti O. The syndrome of neonatal copper deficiency. Pediatrics 1973; 52: 525-33. 13. Bennani-Smires C, Medina J, Young LW. Radiological case of the month. Infantile nutritional copper deficiency. Am J Dis Child 1980; 134: 155-6. 116 COPPER DEFICIENCY IN INFANTS
14. Blumenthal I, Lealman GT, Franklyn PP. Fracture of the femur, fish odour, and copper deficiency in a preterm infant. Arch Dis Child 1980; 55: 229-31. 15. Cordano A, Baertl JM, Graham GG. Copper deficiency in infancy. Pediatrics 1964; 34: 324-36. 16. Cordano A, Graham GG. Copper deficiency complicating severe chronic intestinal malabsorption. Pediatrics 1966; 38: 596-604. 17. Goyens P, Brasseur D, Cadranel S. Copper deficiency in infants with active coeliac disease. J Pediatr Gastroenterol Nutr 1985; 4: 677-80. 18. Griscom NT, Haigh JN, Neuhauser EBD. Systemic bone disease developing in small premature infants. Pediatrics 1971; 48: 883-95. 19. Grunebaum M, Horodniceanu C, Neuhauser EBD. The radiographic manifestations of bone changes in copper deficiency. Pediatr Radiol 1980; 9: 101-4. 20. Heller RM, Kirchner SG, O'Neill JA Jr, Hough AJ Jr, Howard KM, Kramer SS, Green HL. Skeletal changes of copper deficiency in infants receiving prolonged total parenteral nutrition. J Pediatr 1978; 92: 947-9. 21. Karpel JT, Peden V. Copper deficiency in long term parenteral nutrition. J Pediatr \
44. European Society of Paediatric Gastroenterology and Nutrition. Committee on Nutrition of the Pre- term Infant. Nutrition andfeeding ofpreterm infants. Oxford: Blackwell Scientific Publications, 1987.
DISCUSSION
Dr. Viteri: You stated that there were no cases of copper deficiency recorded among breast- fed babies. Is this also true of preterm breast-fed babies? Dr. Shaw: The 50 or 60 reports in the literature were written for many different reasons. They don't all report every clinical detail, so it is difficult to be absolutely sure what any particular baby has been fed on during the development of the copper deficiency. I can only say there has been no report in which it is stated that a baby with copper deficiency has been fed exclusively on breast milk, preterm or full term. Dr. Viteri: Are small newborns with copper deficiency primarily preterm, or are small-for- gestational age babies also at risk? The majority of small babies in the developing world are SGA. Dr. Shaw: Unfortunately in the published reports birth weight is usually given but gestation only rarely. When I did the analyses of these cases it was impossible to determine whether there were any SGA babies or not. There are certainly some cases of copper deficiency in preterm infants—the ones most people know about have resulted from the use of copper- deficient parenteral nutrition solutions. There is one that was certainly fed copper-deficient milk, and there are some in whom I doubt the diagnosis of copper deficiency. I would not say that this is predominantly a disease of preterm babies—it is predominantly a disease of babies suffering malnutrition (perhaps with chronic intestinal malabsorption possibly aug- mented by parasites) and fed on copper-deficient diets, of which the classical one is cow's milk, which really has quite inadequate amounts of copper in it. Dr. Viteri: It is generally accepted, though I think mistakenly, that copper contamination of iron preparations used in therapy of iron deficiency is sufficient to take care of copper needs. Could you comment on this? Dr. Shaw: You would have to tell me how much copper there was in the preparation. It is certainly possible that iron salts may supply the manganese requirement. In the ferrous sulfate that I used in my copper balance studies there was only a trivial amount of copper, but this was high-grade analytical ferrous sulfate. I could not say this was true for all com- mercial preparations—it depends on how they are prepared. Dr. Viteri: You said that the mechanism of the neutropenia is not known. I think cell replication must be affected in copper deficiency. Is this something that could serve as a lead in exploring possible mechanisms for the neutropenia? Dr. Shaw: I feel that the neutropenia must be related to the defect of cytochrome function, which probably affects every cell in the body. Brain cytochrome is known to be depleted in copper deficiency, and this may be an important cause of the psychomotor retardation. What interests me is that it takes 10 days for the white cells to recover, whereas the red cells recover much more quickly. I know little about hematology, but it suggests that the mech- anisms might be different. Dr. Valyasevi: What would make you suspicious of copper deficiency in a child in the developing world? I have seen no reports of the condition in developing countries. Dr. Shaw: In growing infants the first thing that would make me suspicious would be neutropenia and metabolic bone disease affecting the growing ends of the long bones, possibly with some periosteal hemorrhages and elevation of the periosteal membrane. Though the 118 COPPER DEFICIENC Y IN INFANTS picture may resemble rickets, the calcium, phosphorus, and alkaline phosphatase are normal. In any child with unexplained neutropenia or any child with anemia resistant to iron therapy you need to think of copper deficiency. The only practical way to diagnose it is to measure plasma copper or ceruloplasmin. I don't think you need both, though it is probably better to measure both if you can. Dr. Viteri: We have measured plasma and urinary copper in children in Guatemala, in both highland and lowland areas, and have found only very occasional values that would be compatible with copper deficiency. Neutropenia hardly ever occurs. Dr. Shaw: I don't think copper deficiency is going to be a problem on a worldwide scale, unlike thalassemia or iron deficiency. For individual patients it matters a great deal, however, because you have a cause of anemia and bone disease that can easily be treated. People doing relief aid in famine areas such as Ethiopia may well find that severely malnourished children would do better if they were given copper supplements with their food, particularly if their rehabilitation diet is based on cow's milk. Dr. Brabin: Are there any copper chelators in the diet? Dr. Shaw: Although I have read about chelators and chelating treatments that have induced zinc deficiency, I have never heard of a case of copper deficiency produced in this way. Dr. Walter: Several years ago infants with malnutrition (mainly marasmus) admitted to recovery centers in Santiago and other parts of Chile were mostly refed with powdered cow's milk alone. We started to see cases of anemia and neutropenia and on further study found that 20% of the infants had low copper and ceruloplasmin levels. Of these infants, however, only about 60-70% had iron-unresponsive anemia and only 5% had neutropenia. Thus I think that subclinical copper deficiency is much more prevalent than florid cases with anemia, neutropenia, and bone changes. I don't think we identified a single case with bone changes. Of course these infants are all given copper sulfate now, as well as zinc sulfate. Dr. Shaw: In order to develop bone changes you have to be growing. I assume that the cases you are talking about had arrested growth. Dr. Walter: Yes, but we looked for these changes after prolonged cow's milk feeding. We found that children admitted because of diarrheal disease were more likely to develop copper deficiency than children without diarrhea. Dr. Gibson: I recall a study which suggested the presence of an iron-copper interaction. Absorption of copper apparently increased when infants were changed from an iron-fortified formula to an unsupplemented one. If such an interaction does occur, is it possible that iron- fortified formulas could exacerbate secondary copper deficiency? Dr. Shaw: I have no evidence that the amounts of iron in formulas, which are relatively small, could possibly impair copper absorption. Dr. Cooper: Ceruloplasmin is homologous to factor 5 and factor 8 of the blood coagulation factors. Factor 5 has been shown to contain copper. Has anyone found any coagulation disorders in copper-deficient patients? Dr. Shaw: There is no report of a coagulation defect in copper deficiency. Dr. Hallberg: Is there any relationship between the copper content of drinking water, copper piping in houses, and copper in breast milk? Dr. Shaw: Breast milk copper is amazingly constant. I think if there was a relationship of the sort you imply in your question, one would see much more variation in the copper concentration in breast milk samples. Dr. Viteri: I think we must look at micronutrient deficiencies both in the short term and in the long term. Obviously in the long term we all want to ensure better diets, better lifestyles, better environmental sanitation, etc., for as many people as possible. In the short term we COPPER DEFICIENC Y IN INFANTS 119 must try to do something about the highly prevalent micronutrient deficiencies. We must try to use the systems that are already in place for short-term control of the most common deficiencies—and ideally for the control of other less common deficiencies—rather than substitute one micronutrient deficiency for another. Given our present knowledge, control measures should in the short term be directed towards specific micronutrients with the aim of a combined approach and avoiding duplication of effort. For example, in the case of iron supplementation for pregnant women, could iodine and small doses of vitamin A be incor- porated into some of the iron preparations used in the supplemental programs for women and children? Dr. Dallman: I agree with this but am also concerned that there are likely to be more nutrient interactions than we recognize at present. Might not multivitamin-multimineral sup- plements for pregnant women be a safer way of preventing deficiencies than giving relatively large doses of one or a few micronutrients? Dr. Fomon: It is important that our recommendations take into account the circumstances that exist in a country or region. We must avoid making global recommendations. Iodine is a good example. In many countries and regions, iodine supplementation is an important public health measure, but in a country such as the USA the use of iodized salt or the inclusion of iodine in prenatal capsules for pregnant women should be discouraged since there is no longer endemic iodine deficiency anywhere in the USA. The population is at greater risk of iodine intoxication than iodine deficiency. Dr. Gibson: I should like to make a comment relating to zinc. Zinc deficiency is a problem in some developing countries, but zinc as a nutrient is often overlooked because the signs and symptoms of deficiency are not very dramatic or specific. Malawi is a country where one could probably improve the zinc status of the children by manipulating methods of food preparation. The zinc intakes of Malawian children are comparable to those of Canadian children, but the molar ratios of phytate to zinc are very high in Malawian diets so the zinc is less available. If a fermentation step was introduced during the preparation of the unrefined maize staple, the zinc status of Malawian children could be significantly improved. This shows how an intervention program might be tailored to the specific dietary patterns of a country. Dr. Viteri: I think we should address the deficiencies that we are aware of, and we should also address well-established interactions. I don't think we should give micronutrients that are not in short supply in the population we are dealing with. An overall multivitamin- multimineral supplementation for pregnant women and for children at risk is probably not feasible. However, I do agree with Dr. Dallman that supplementing with vitamin A, iron, and iodine alone may not be the best solution in areas where deficiencies of riboflavin, copper, or zinc are also prevalent. We must become better informed about the predominant micro- nutrient deficiencies in different regions. Then at least we shall be able to address the most pressing problems. Dr. Dallman: With respect to zinc, we are handicapped by not having good diagnostic indicators of deficiency. Thus zinc deficiency will be difficult to recognize if it develops, for example, after administration of large doses of iron with meals. Bo Lonnerdal emphasizes the importance of maintaining physiological ratios of iron, zinc, and copper in fortified foods. Dr. Cooper: I recall a presentation by Medawar in 1960, when he was trying to explain the physiological basis for renal transplantation—the only human organ transplantation going on at the time. He indicated that it was clear that no one knew enough to transplant kidneys in people but fortunately the surgeons didn't know this and so it worked! As a non-nutritionist I should think that if you as nutritionists don't get around to treating deficiencies you know to be present, you will never get anything done.