conspectus of researchon copper metabolism and requirements

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2008 KARL E. MASON time and excretory loss is reduced, thus in creasing the biological half-life in the body by two to three times, as compared to nor mal controls (159, 160). Under similar circumstances subjects with Wilson's dis ease show normal absorption of copper but, because of reduced biliary excretion, the half-life is increased to about the same degree as in Menkes' disease ( 160 ). Hence, these two diseases have dissimilarities re lating to intestinal absorption but similari ties in inability to release copper acquired by the liver. Although a defect in the intestinal trans port of copper undoubtedly plays an im portant role in postnatal life, it does not provide an adequate explanation for the diverse manifestations of Menkes' disease. With impressive evidence that this disease begins in utero, it would appear that vary ing degrees of genetic expression may ex plain differences in postnatal age when manifestations, such as frequent seizures, make their appearance. There remain many important questions the answers to which will be difficult to obtain. For example, is there defective placental transfer of cop per comparable to that proposed in the in testine? Is placental transfer normal, but the types of fetal protein to which copper becomes bound abnormal? For this or for other reasons, is the concentration of nor mally or abnormally bound copper in cer tain tissues and organs significantly de ranged? Are there abnormalities in the production of copper-containing enzymes or in membrane receptors in certain cells and tissues? Obviously, knowledge of the underlying metabolic disturbances in Men kes' disease is in a state of immaturity, but offers many challenges for future research. For further details the reader is referred to some recent reviews (75, 143, 144, 272, 301, 351, 818). Therapy Oral administration of copper salts to infants with Menkes' disease has been reported to cause slight clinical improve ment, such as reduced hypothermia and improved hair color, and slight increase in serum copper levels (148, 467, 468), but other investigators find no beneficial effect (72, 243, 566, 833, 849). Intramuscular injections of copper complexed with EDTA can cause a significant increase in serum copper and serum ceruloplasmin (146, 817, 838), as also can a slow subcutaneous drip of copper sulphate over a period of 2 hours every 3 to 4 days (161). In one case so treated for 5 months a moderately encouraging clinical response was obtained ( 161). However, Wheeler and Roberts (838) report that while intramuscular in jections of a copper-EDTA complex main tained reasonably normal serum copper and ceruloplasmin levels for 8 months in one infant, no clinical improvement was apparent. Intravenously administered copper in various forms (copper sulphate, copper acetate, copper-albumin, copper-EDTA complexes and human ceruloplasmin) has produced increases in serum copper and ceruloplasmin to values approaching nor mal (72) or essentially normal (146, 161, 282, 283, 833, 849), or no significant change (243, 244). Usually the period of treat ment has been short (7-10 days) or inter mittent over somewhat longer periods. In one instance normal serum copper levels and subnormal ceruloplasmin levels were maintained for more than 9 months by weekly intravenous infusions (833). A similar experience with 427 days of subcutaneously administered copper as a CuClo + L-histidine complex, has also been reported (849). However, in all cases the disease has pursued its relentless course. But a faint gleam of hope comes from a report of Grover and Scrutton (282, 283) who, employing repeated infusions of cop per sulphate once or twice weekly in an infant diagnosed as having Menkes' disease at 3 days of age, obtained mental func tional levels equivalent to 4 months at 6 months of age. However, similar treatment of another infant beginning at 4 months of age and continued for 9 months provided no improvement. Hence, the answer is equivocal. Excessive urinary excretion of copper observed after parenteral therapy (242, 243, 849) is attributed to decreased hepatic uptake of copper, reflecting an ab normality of transport comparable to that in the intestinal mucosa. These observa tions suggest that a defect in membrane transport could explain both the in utero and postnatal deprivation of copper at Downloaded from jn.nutrition.org by guest on February 27, 2013
COPPER METABOLISM AND REQUIREMENTS OF MAN 2009 multiple organ levels including placenta, intestine and liver; however, a favored alternative is that of a defect in intracellular transport in intestine, liver and kidney due to abnormalities in the trans port and storage protein, metallothionein (242, 244). From the information currently available, it seems questionable whether institution of any type of therapeutic measure during the period of gestation, if such were pos sible, would significantly alter the course of this genetically determined abnormality of copper metabolism. Animal models It seems obvious that there is still much to be learned regarding the metabolic de fect in Menkes' disease. Challenging op portunities for future research are pro vided by several genetic animal models of this disease. One model is a recessive gene mutation (crinkled, CR) in mice. Such mice have a smooth coat with thin skin, delayed pigmentation, early mortality, and hair changes closely resembling those of Menkes' disease (374). In fact, all three types of hair abnormalities found in Menkes' disease are demonstrable (373). The observation that increased dietary in take of copper during pregnancy and lacta tion favorably altered the expression of the mutant gene (374) is certainly worthy of further exploration. Another model, a sexlinked "brindled" or "mottled" (MO"r) mutant in the mouse, is characterized by subnormal levels of lysyl oxidase (648), plasma ceruloplasmin, decreased copper levels in brain and liver, increased copper in the intestinal wall and virtual absence of hair pigmentation (371). Moreover, a recent study (200) indicates that in the affected homozygous male both intestinal absorption and hepatic uptake are im paired, and that in the heterozygous fe male they are intermediate between the affected male and normal mice. Danks (143, 144) and Holtzman (351) present excellent reviews of the literature and in teresting comparisons of altered copper metabolism in the mottled mutant mouse and infants with Menkes' disease. A third mouse mutant called "quaking" manifests some of the neurological signs of copper- deficient animals. Dietary copper decreases their tremors, indicating that copper me tabolism is involved in expression of the gene (396). Furthermore, Prohaska and Wells (621) describe striking similarities between bio chemical abnormalities in the brain of suck ling young of copper-deficient rats and those observed in Menkes' disease. These involve slow growth, abnormal behavior, decrease in myelin, reduction in cerebellar cytochrome c oxidase and Superoxide dismutase and a 5-fold reduction in brain copper. Extensive lesions of the cerebral cortex and mid-brain have also been de scribed in copper-deficient rats (92). In the guinea pig, which undergoes consid erable myelination in utero, copper de ficiency causes gross brain abnormalities, aneurisms, agenesis of the cerebellum, ataxia, wiry nature and depigmentation of hair, abnormal behavior patterns, and de creased liver copper (201). Morphologi cally, there is underdevelopment of myelin and cellular derangement and loss of neural elements in the cerebellum (202). Further study of the copper-deficient rat and guinea pig might well shed further light on the nature of Menkes' disease. WILSON'S DISEASE A vast literature has dealt with the na ture, diagnosis and treatment of Wilson's disease. The findings have been well re corded in a number of reports and reviews (37, 38, 46, 137, 262, 267, 555, 666-668, 672, 678, 679, 683, 684, 737, 740, 744, 747, 756, 791, 821, 822). What follows is largely a summation of early observations concern ing the nature of the disease, current con cepts concerning the metabolic abnormali ties involved and therapeutic measures. Nature of the disease The history of this disease, as well out lined by Goldstein and Owen (262), goes back to 1912 when Wilson (855) de scribed a familial disease associated with cirrhosis of the liver and neurological mani festations, occurring predominantly during the first few decades of life. The term "hepatolenticular degeneration" was coined in 1921 by Hall (296), who also recognized the recessive mode of inheritance of the 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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