conspectus of researchon copper metabolism and requirements

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2004 KARL E. MASON number of informative reviews (461, 533, 666, 843). DIETARY COPPER DEFICIENCY There appear repeated statements in the literature that in view of the ubiquitous occurrence of copper in foods of every type, and lack of evidence of any recog nized manifestations of copper deficiency such as commonly observed after dietary depletion of copper in experimental ani mals or under natural conditions in farm animals, man appears to be free of hazards of a state of copper deficiency. However, there has developed convincing evidence that a copper deficiency state can occur in man, even though it may be of rare oc currence and as the result of rather special types of situations. A syndrome characterized by hypocupremia, hypoferremia, hypoproteinemia, edema and hypochromic anemia, respon sive to oral copper but not to iron, has been observed in infants fed diets limited largely to milk (432, 437, 758, 796, 797, 874). In certain cases, especially those of Ulstrom et al. (796, 797), a fundamental defect in protein metabolism at the cellular level may have been a primary factor, rather than exhaustion of neonatal copper stores (874). The fact that infants 6 to 18 months of age usually have been involved suggests a relation to periods of life when initial liver storage of copper has been depleted, combined with prolonged main tenance on milk diets and increased de mands for copper during a period of rapid growth. However, the possibility of de grees of protein depletion sufficient to im pair retention of dietary copper deserved consideration. Maintenance of two infants (one 8 days old with multiple congenital anomalies, and the other 10 months old) for 4 to 5 months on a milk diet identical to one which produced copper deficiency in pig lets, caused neither anemia nor hypocupremia (101). Comparable results were obtained in the studies of Wilson and Lahey (854) involving seven premature infants with mean body weight of 1.24 kg fed a similar milk diet for 7 to 10 weeks. It was concluded that small premature in fants fed a diet providing approximately 15 /xg/kg/day of elemental copper over a 2 to 3-month period do not differ, by any of the criteria used, from prematures fed five or more times this amount. However, it should be recognized that at this period such infants could be utilizing liver stores of copper, and that the depletion period was much shorter than that required for production of a deficiency state in piglets with a relatively more rapid rate of growth. Not until 1964 was a state of dietary copper deficiency documented in humans when Cordano et al. (126, 128) reported finding in infants, recovering from maras mus on exclusive milk diets, deficiency manifestations (anemia, decreased plasma copper and ceruloplasmin levels, intermit tent neutropenia, severe osteoporosis and pathological fractures) quite comparable to those observed after experimental cop per deficiency in pigs (436). Similar find ings were observed in a 6-year old child with severe chronic intestinal malabsorption, who gave a dramatic response to cop per therapy (127). In a later report, Graham and Cordano (276) state that in a series of 173 infants suffering from severe malnutrition and chronic diarrhea, admit ted to the British American Hospital, Lima, Peru, over a period of 6 years, 62 instances of copper deficiency were identified, of which 44 were judged to have been de pleted of copper prior to admission. The peak incidence was at 7 to 9 months of age. Responses to oral copper therapy in dicated that repletion of total serum cop per was more important than restoration of ceruloplasmin in correction of the defi ciency state (352). Instances of copper de pletion have also been observed in infants with chronic diarrhea in the United States (354). There have also appeared more recent reports of neonatal copper deficiency in a premature infant 3 months old (17), in three very small premature infants during their third month of life (280), in a pre mature infant 3 months of age (700), and in a premature infant at 6 months of age (25). Neutropenia, low plasma ceruloplas min and osteoporosis have been among the manifestations regularly observed. Favor able response to oral copper has usually been reported. Although none of the in- Downloaded from jn.nutrition.org by guest on February 27, 2013
COPPER METABOLISM AND REQUIREMENTS OF MAN 2005 vestigators make reference to it, the clini cal and pathological findings reported bear striking resemblance to many of those characteristic of Menkes' steely-hair syn drome (p. 2007). A comparable picture has been observed in an infant maintained for some months on total parenteral nutri tion following surgery for ileal atresia (394) and in others treated likewise for protracted diarrhea (463). Also, a state of copper deficiency has been described in a 12-year old child and an adult after prolonged total parenteral therapy follow ing extensive bowel resection ( 177). In all cases there was a good response to cop per therapy. It is worthy of note that in all instances where a naturally occurring copper de ficiency has been observed, as described above, only premature infants have been involved. This is in accord with the fact that premature infants do not benefit from the additional copper storage in the liver and other tissues acquired by the fullterm infant, and are customarily main tained for longer periods on natural milk or milk formulae before having access to cereals and other foods. Furthermore, pre matures have much lower copper reserves in the liver and spleen than do full-term infants, and show a negative copper bal ance during the first month of life which tends to become positive only after the second month of life (761). Suggestions that consideration should be given to special supplementation of the premature infant formula with copper (843) appears to be well justified. The major manifestations of copper de ficiency in infancy, and their relationship to decreased activity of copper-containing proteins, justify brief summarization. 1) Neutropenia and hypochromic anemia responsive to oral copper but not to oral iron are early manifestations of deficiency, in large part the result of lowered levels of ceruloplasmin and impaired release and transport of iron from body stores. 2) Osteoporosis, with enlargement of costochondral cartilages, is also an early phenomenon, followed by cupping and flaring of metaphyses of long bones with spur formation and submetaphyseal frac ture, periosteal reactions and spontaneous fractures, especially of the ribs. These are usually referred to as "scurvy-like" changes, and may also suggest the "battered child syndrome." Deficiency of copper-contain ing oxidases, essential for the cross-linking of bone collagen, adequately explains these manifestations. 3) Decreased pigmentation of the skin and general pallor of copper-deficient in fants, can be attributed to decreased activ ity of tyrosinase, necessary for the produc tion of melanin. 4) In later stages of deficiency there may be neurological abnormalities such as hypotonia, episodes of apnea and pos sible psychomotor retardation, generally attributed to decreased levels of cytochrome c oxidase. MENKES' DISEASE This progressive brain disease inherited as a sex-linked recessive trait was first recognized in five young boys (siblings), and its major clinical and pathological manifestations described in 1962 by Menkes et al. (513). Other cases were soon re ported by Bray (59) and Aguilar et al. (11). While subsequently referred to as "kinky-hair" disease and "trichopoliodystrophy" (225), the currently accepted des ignation is "steely-hair" disease (or syn drome) proposed by Danks et al. who ( 145) in 1972, first recognized the disease as an inherited defect in copper absorp tion; in fact, a congenital copper deficiency. Since the term "kinky-hair" implied crimped hair like that of the black races, whereas that of affected infants more closely resembled depigmentation and loss of crimp in wool observed in copperdeficient sheep (252), "steely-hair" appears to be more appropriate ( 146). It is said to occur in 1 of 35,000 live births (145). As of 1977, Ahlgren and Vestermark (12) list 42 cases reported in the literature. Manifestations Symptoms of Menkes' disease usually ap pear between birth and 3 months of age, followed by death prior to the 4th or 5th year of life. The age of onset is somewhat earlier in prematures than in full-term in fants. Occurrence as late as the 6th year has been reported (28). Characteristics of 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
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COPPER METABOLISM AND REQUIREMENTS
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