conspectus of researchon copper metabolism and requirements

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2038 KARL E. MASON and other organs of the fetus and infant. An intrauterine defect could explain why even in infants with early postnatal diag nosis, therapeutic measures of varied types have done little more than improve serum copper and ceruloplasmin levels, while the disease process continues unabated. The recent discovery and study of two genetic animal models in mice with striking simi larities to Menkes' disease, combined with continued study of dietary copper defi ciency in the rat and guinea pig, offer challenging opportunities for further inves tigation of the metabolic defect(s) under lying this disease and some remote possi bility of more effective therapeutic mea sures than currently exist, even though intervention in utero may be the only recourse. Mystery also still surrounds the primary defect in Wilson's disease (hepatolenticu- lar degeneration), an autosomal recessive inborn error of metabolism first described in 1912 and characterized by the accumu lation of excessive and often toxic amounts of copper in the liver, central nervous sys tem, kidney and other tissues. Accumulat ing evidence points to the liver as the site of metabolic derangement, and decreased biliary excretion of copper the basic reason for the progressive increase of liver copper to toxic levels. Hypotheses proposed sug gest: 1) the presence in the liver, and possibly in other affected tissues, of an intracellular protein having greatly in creased affinity for the binding of copper; 2) defects in a liver protein or peptide serving in a specific "carrier mechanism" for copper or, 3) defective intracellular transport of copper secondary to dysfunc tion of hepatocyte lysosomes. The further pursuit of these concepts should open new vistas concerning the metabolic defect in Wilson's disease. As an example, recent evidence of dramatic improvement in extrahepatic manifestations of Wilson's dis ease following orthoptic liver transplanta tion also supports the concept that the metabolic defect in Wilson's disease is liver-based. For more than 20 years the therapeutic use of D-penicillamine, a cop per chelator, has led to slow clinical im provement, especially when instituted in early states of the disease. A real need exists for an improved method for diag nosis of asymptomatic cases of the disease, replacing liver biopsy and radiocopper studies, to permit earlier establishment of therapeutic measures. The possible exist ence of a more effective therapeutic agent seems not to have been given the attention deserved. There is recent evidence that at least two liver diseases, primary biliary cirrhosis and chronic active liver disease, resemble Wilson's disease with respect to elevated levels of liver copper. Whether in these disorders benefits may be derived from penicillamine therapy has not been established. In the development and practical appli cation of total parenteral nutrition over the past 10 years, isolated instances of states of copper deficiency occurring in children and adult man have emphasized the need for more serious attention to the content of copper and other trace elements in parenteral solutions. Information gained from experiences with parenteral nutrition have given strong support to conclusions reached by balance studies concerning the minimal requirements of copper for infants and adults. A much greater hazard has been created by copper-contaminated tap water or copper-containing valves and stopcocks in conduits employed in hemodialysis, due to the high toxicity of intra venous copper. There are sporadic reports of accidental and suicidal poisoning from oral intake of copper salts. There is little or no evidence of toxicity from industrial sources. Extensive evidence based upon the cop per content of human milk (approximately three times that of cow's milk ), copper bal ance studies and experiences with total parenteral nutrition indicate that copper requirements for young full-term infants are 0.025 to 0.05 mg/kg/day, and that those for premature infants are somewhat greater. Rather limited data, based largely on balance studies, suggest requirements in the range of 0.05 to 0.10 mg/kg/day for young and adolescent children. There is a serious lack of information concerning copper requirements of teenagers, and especially pregnant teenagers. It has long been felt that an adult man requires 2.0 to 2.5 mg copper daily. Balance studies of Downloaded from jn.nutrition.org by guest on February 27, 2013
COPPER METABOLISM AND REQUIREMENTS OF MAN 2039 the past 12 years suggest that a copper in take not much in excess of 1 mg/day may represent the minimal requirement. There is recent evidence that interactions between zinc and copper, and between molybdenum and copper can seriously in terfere with absorption and/or utilization of copper in man, as is well known to be true of domestic and laboratory animals. ACKNOWLEDGMENTS Preparation of this conspectus was car ried out under Contract No. E-13357-ARS- 76 with the Nutrition Institute, United States Department of Agriculture. This is the last of a series of conspectuses by the Nutrition Institute, USDA, Beltsville, MD on the nutritional requirements of man for protein, amino acids, vitamin A, calcium, zinc, vitamin C, iron and folacin. All have been published in previous issues of The Journal of Nutrition. The Nutrition Insti tute wishes to acknowledge the great as sistance and cooperation of the Editors and reviewers of The Journal of Nutrition in making the publication of these conspec tuses possible. The writer wishes to thank Drs. Walter Mertz, Robert D. Reynolds and G. Thomas Strickland for their valued judgments and constructive criticism of the manuscript, and Mrs. Shirley Cress for her patience and painstaking preparation of the same. Trib ute is also paid to the late Dr. Isabel Irwin who, prior to her death March 25, 1975, had collected an extensive literature on the subject of this conspectus. LITERATURE CITED 1. Abderhalden, E. (1900) Die Beziehungen des Eisens zur Blutbildung. Ztschr. ÃŸiol. 39, 482-523. 2. Abood, L. G., Gibbs, F. A. & Gibbs, E. ( 1957 ) Comparative study of blood ceruloplasmin in schizophrenia and other dis orders. A.M.A. Arch. Neurol. Psychiat. 77, 643-645. 3. Abraham, P. A. & Evans, J. L. (1972) Cytochrome oxidase activity and cardiac hypertrophy during copper depletion and repletion. In: Trace Substances and Envi ronmental Health (Hemphill, D. D., ed. J, vol. V, pp. 335-347, Univ. Missouri, Colum bia. 4. Adams, P. C., Strand, R. D., Bresnan, M. J. & Lucky, A. W. (1974) Kinky hair syn drome: serial study of radiological findings with emphasis on the similarity to the bat tered child syndrome. Radiol. 112, 401-407. 5. Adelstein, S. J., Coombs, T. L. & Vallee, B. L. ( 1956 ) Metalloenzymes and myocardial infarction. I. The relation between serum copper and ceruloplasmin and its catalytic activity. New Engl. J. Med. 255, 105-109. 6. Adelstein, S. J. & Vallee, B. L. (1961) Copper metabolism, in man. New Engl. I. Med. 265, 892-897; 941-946. 7. Adelstein, S. J. & Vallee, B. L. (1962) Copper. In: Mineral Metabolism (Comar, C. L. & Bronner, F., eds.), vol. 2, part B, pp. 371-401, Academic Press, New York. 8. Adolph, W. H. & Chou, T. (1933) Cop per in Chinese food materials. Chinese J. Physiol. 7, 185-188. 9. Agarwal, A. K. (1975) Crippling cost of India's big dam. New Scientist 65, 260-261. 10. Agarwal, B. N., Bray, S. H., Bercz, P., Plotzker, R. & Labovitz, E. (1975) Inef fectiveness of hemodialysis in copper sul phate poisoning. Nephron 15, 74-77. 11. Aguilar, M. J., Chadwick, D. L., Okuyama, K. & Kamoshita, S. (1966) Kinky hair disease. 1. Clinical and pathological features. J. Neuropath. & Exper. Neurol. 25, 507- 522. 12. Ahlgren, Menkes' kinky P. & hair Vestermark, disease. Neuroradiol. S. (1977) 13, 159-163. 13. Akerfeldt, S. (1957) Oxidation of N.Ndimethyl-p-phenylenediamine by serum from patients with mental disease. Science 125, 117-119. 14. Albukerk, J. N. (1973) Wilson's disease and pregnancy. A case report. FÃ©rtil.Steril. 24, 494-497. 15. Alexander, F. W., Clayton, B. E. & Delves, H. T. (1974) Mineral and trace metal balances on children receiving normal and synthetic diets. Quart. J. Med. 43, 89-111. 16. Allen, K. G. D. & Klevay, L. M. (1978) Cholesterolemia and cardiovascular abnor malities in rats caused by copper deficiency. Atheroscler. 29, 81-93. 17. Al-Rashid, R. A. & Spangler, J. (1971) Neonatal copper deficiency. New Engl. J. Med. 285, 841-843. 18. American Academy of Pediatrics, Committee on Nutrition ( 1976 ) Commentary on breast feeding and infant formulas, includ ing proposed standards for formulas. Pedi atrics 57, 278-285. 19. American Academy of Pediatrics, Committee on Nutrition ( 1977 ) Nutritional needs of low-birth-weight infants. Pediatrics 60, 519- 530. 20. Angel, C., Leach, B. E., Martens, S., Cohen, M. & Heath, R. G. (1957) Serum oxida tion tests in schizophrenic and normal sub jects. A.M.A. Arch. Neurol. Psychiat. 78, 500-504. 21. screening Aoki, T. & method Nakahashi, for Wilson's M. J1977) disease New and Menkes' kinky-hair disease. Lancet 2, 1140. 22. Arachi, H., Tornii, S. & Mega, T. (1974) Studies on the copper in the human serum and organs. J. Nara. Med. Assn. 25, 171- 179. Downloaded from jn.nutrition.org by guest on February 27, 2013
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A CONSPECTUS OF RESEARCH ON COPPER
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INTRODUCTION The discovery of coppe
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COPPER METABOLISM AND REQUIREMENTS
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COPPER METABOLISM AND REQUIREMENTS
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