conspectus of researchon copper metabolism and requirements

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2026 KARL E. MASON times that of later milk (437, 449, 541, 647, 877). Moreover, the somewhat lower ratio of zinc to copper (about 4:1) in human milk may significantly enhance cop per absorption in breast-fed infants (843). Cow's milk has a very low content of copper. Values recorded by different in vestigators have varied widely, and their documentation would serve no useful pur pose. Suffice it to say that three of the more recent reports (546, 598, 843) give values within a range of 0.04 to 0.30 mg/ liter. Difference in forage and in season of the year are largely responsible for varia tions in values obtained. Special attention may be called to analyses of commercial milk samples from 65 cities throughout the USA giving a national mean of 0.086 (range 0.04-0.19) mg/liter (547). The first serious study of the copper content of human milk, by Zondek and Bandmann (877), indicated levels of 0.5 to 0.6 mg/liter in 85 samples obtained during the first 2 months of lactation. Munch- Peterson (541), who carried out 74 analy ses of milk from 10 mothers during the first 8 days of lactation, recorded a mean content of 0.48 mg/liter. He also found that intravenous administration of a watersoluble compound containing 19% of cop per given to seven other mothers had no influence on the copper content of the milk, even though serum copper levels were greatly increased. This confirmed the early report of Elvehjem et al. (189) that a 5 to 10-fold increase in dietary intake of copper had no demonstrable effect on its level in the milk of the cow or goat. This restriction in mammary transfer of copper might reflect a homeostatic mechanism for protection of the neonate. Rottger (647) reported a mean value of 0.44 ( range 0.27- 0.84) mg/liter for 15 samples of human milk during early phases of lactation. Munch-Peterson (541) and Rottger (647) independently estimated a daily intake of about 0.25 mg/Cu by young infants. In comparison, other investigators have re ported higher values for early milk (107, 437, 449) and others give values approxi mately one-half or less than those recorded above, for mature human milk not identi fied as early milk (275, 546, 598, 843). A striking decrease in copper content of milk at successive months of lactation (11.2, 7.3, 5.4, 4.6 and 1.5 /Â¿g/100ml) is reported by Kleinbaum (410). Similar data are given by Hambidge (299). Noteworthy is the recent and extensive study of Picciano and Guthrie (598), based on analyses of 350 milk samples from 50 lactating, healthy women (seven samples each). Copper content varied considerably among women and with the same woman. Several samples taken over periods of days or weeks were necessary to provide a re liable estimate of the copper content of milk from any individual. Their mean value of 0.24 (range 0.09-0.63) mg/liter is essen tially the same as that reported by Murthy and Rhea (546); namely, about 0.24 Â± 0.03 mg/kg, on analyses of 22 milk sam ples from lactating women. Picciano and Guthrie (598) calculated that breastfed infants less than 3 months of age, with a body weight of 4 kg and a daily milk intake of 850 ml, would ingest approximately 0.2 mg/day ( or 0.05 mg/kg/ day). These estimates are in good agree ment with the values of 0.25 mg/day of Munch-Peterson (541) and Rottger (647), also based upon human milk. They are also slightly less than estimates of 0.05 to 0.10 mg/kg/day based on balance studies with young children 3 to 6 years of age (142, 695), the estimate of 0.08 mg/kg/day by Cartwright ( 100), and the statement of the Committee on Recommended Dietary Al lowances of the National Research Council (549) that "The requirements of infants and children have been estimated at be tween 0.05 and 0.1 mg/kg of body weight per day; an intake of 0.08 mg/kg/day ap pears to be adequate." The World Health Organization in its 1973 report (861) recommends 0.08 mg/kg per day for in fants and young children and 0.04 mg/kg per day for older children. It would seem that under normal circumstances the cop per provided by nature in human milk is, when supplemented by storage in the new born liver, a reasonably good measure of optimal requirements during early life. The premature infant presents special problems. According to Widdowson et al. (843) about % of fetal copper is trans ferred during the last 10 to 12 weeks of gestation. As a consequence, premature in- Downloaded from jn.nutrition.org by guest on February 27, 2013
COPPER METABOLISM AND REQUIREMENTS OF MAN 2027 fants of 28 to 30 weeks gestation, weighing about 1 kg, have much smaller reserves of copper in the liver, spleen and other tissues to be called upon postnatally than do fullterm infants. Sultanova (761) has carried out copper analyses of livers and spleens from groups of premature infants with birth weights of 1.0 to 1.5, 1.5 to 2.0 and 2.0 to 2.5 kg, and term infants dying soon after birth. In successive groups there were definite increases in the copper levels per gram of tissue in both organs. Hence, the smaller the premature the lower the copper concentration in its tissues. As an other handicap, the premature is usually obliged to subsist on an exclusive milk diet for much longer periods than the fullterm infant. Although in newborn prema tures copper deficiency is unknown, their status does place them in a more pre carious situation than full-term infants when states of malnutrition intervene. To compensate for this, Widdowson et al. (843) have suggested that premature in fants be provided a special milk formula which might assure a retention of at least 0.085 mg of copper per day. Cordano ( 124) feels that for prematures the recom mended 0.06 mg/100 kcal for infants (18) should be increased to 0.09 mg/100 kcal (i.e., 0.1 mg/kg/day). This is the current recommendation of the American Academy of Pediatrics ( 19) for low-birth-rate in fants. Balance studies. A pioneer balance study of copper in infancy, to which relatively little has since been added, is that of Kleinbaum (409), who studied six breast fed full-term infants over the 13th to 23rd days of life. Birth weights averaged 3.4 kg, but later weights are not given. Total copper intake and output for the 10-day period averaged 4.74 and 4.72 mg, respec tively. Three infants showed a negative and three a positive copper balance. Hence, these data might be interpreted as indicating that healthy full-term infants during the first month of life require an intake of approximately 0.5 mg/Cu/day to keep in positive balance. The 10-day bal ance study of Priev (619) on two infants 8 and 3 months of age indicates require ments of 0.30 and 0.42 mg/day, respec tively. Similar 10-day balance studies of Kleinbaum (409) on 31 premature infants initiated at ages of 2 to 82 days, and with average intakes of 0.28 mg reveal a slightly negative balance in all instances. Hence in the balance studies described there is reasonably good accord with a requirement of approximately 0.05 mg/kg/day for maintaining a positive copper balance in young infants of the six infants weighing in the range of 6 to 10 kg. States of copper deficiency. In studies with experimental animals, while the daily intake necessary to prevent development of a deficiency of a nutrient provides the most reliable estimate of basic requirements, a determination of the smallest intake neces sary to effect cure of an early stage of deficiency also provides the next best esti mate of minimal requirements. Such pro cedures are, for many reasons, not applica ble to man at any age. Even though an arbitrary level of therapy might prove to be marginal in effect, deficiencies or even excesses of other nutrients, together with malabsorption and diarrhea, are usually present and a simple deficiency state such as obtainable in experimental animals does not exist. Such a situation characterizes the pio neer studies of Cordano et al. ( 126) on four malnourished infants manifesting anemia, neutropenia, scurvy-like bone changes and hypocupremia. Rehabilitation on high caloric diets supplemented with iron, ascorbic acid, folie acid and other vitamins was incomplete without the addi tion of elemental copper. In fact, it was later recognized that the increased growth rate resulting from the improved diet greatly decreased the protective effect of the low levels of copper provided by the milk diet (28-42 ,ug/kg body weight). On the basis of varied levels of copper supple mentation it was estimated that for rapidly growing infants 6 to 9 months of age, with inadequate stores of copper and main tained exclusively on milk diets, the daily requirement for copper was greater than 0.042 mg but less than 0.135 mg/kg body weight. Since each of the children weighed approximately 10 kg at the beginning of supplementation, these values are slightly higher than those derived from balance studies but approximate the estimated re- Downloaded from jn.nutrition.org by guest on February 27, 2013
Page 1 and 2: A CONSPECTUS OF RESEARCH ON COPPER
Page 3 and 4: INTRODUCTION The discovery of coppe
Page 5 and 6: COPPER METABOLISM AND REQUIREMENTS
Page 47: COPPER METABOLISM AND REQUIREMENTS
Page 53 and 54: s &5Â°.S0 0lÃ¬Â»"oPH o^â€
Page 55 and 56: Ã®1co 1stW Â»aÂ«a3 COPPER MET

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