conspectus of researchon copper metabolism and requirements

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2010 KARL E. MASON disease. This designation has since been largely replaced by the term "Wilson's dis ease." Not until 1953, through the more extensive studies of Beam (36), was the autosomal recessive nature of this inborn error of metabolism i.e., that both parents clearly established; of an affected sub ject must be hÃ©tÃ©rozygote carriers of the abnormal gene, and that their siblings have a one to four chance of receiving both genes; i.e., in being homozygous abnormal. For these reasons, the number of affected individuals is maintained at a relatively low level in the population, accentuated only by consanguinity. Other studies over the period (1912-1954) provided valid evidence that this disease represented a state of copper toxicosis characterized by 1) abnormally high levels of copper in the liver and brain (102, 134, 258, 316); 2) in creased urinary excretion of copper (163, 485, 499, 609, 731, 873); 3) aminoaciduria (123, serum 136, 163, 499, 608, 735); levels of ceruloplasmin 4) low (674); 5) decreased fecal excretion of copper (41, 80, 581, 753, 873) and 6) the occurrence of Kayser-Fleischer rings (134, 258) which had been shown as early as 1934 to repre sent excessive accumulations around the cornea (249). of copper Symptoms of the disease are decidedly variable in nature, time of onset and degree of severity. In the experience of some in vestigators the predominance of hepatic and neurological manifestations is about equally divided. In that of others, one or the other has been predominant. An excel lent discussion of laboratory findings and clinical manifestations Strickland and Lev has been given by (756), Sass-Kortsak and Beam (668) and Tu (791). How genetic determinants hold in check the metabolic and clinical expression of the disease for such variable periods of post natal life, and often for many decades, is unexplained. Wilson's disease Heterogeneity may be an of important the gene fac for tor. One may consider the fact that while hÃ©tÃ©rozygote carriers (parents of patients with Wilson's disease ) cannot be identified clinically, they do differ from normal indi viduals in showing a prolonged biological turnover of 67Cu (580, 753), reduced biliary excretion of copper (581), hyper- cupriuresis after penicillamine loading (792) and certain renal dysfunctions (448). Metabolic abnonnalities The classic form of this relatively rare inborn error of copper metabolism is char acterized by: 1) usual, but not universal, low serum levels of copper, primarily of ceruloplasmin, suggesting defective syn thesis of this cuproprotein by the liver; 2) abnormally high storage of copper in the liver, associated with decreased fecal excretion and chronic liver disease, reflect ing impaired biliary excretion of copper and/or abnormal copper protein binding by the liver; 3) progressive accumulation of copper in the brain, leading to a wide variety of neurological disorders; 4) ac cumulation of copper in the kidney, asso ciated with renal damage, cupruresis and aminoaciduria; 5) deposition of copper in the cornea, leading to the formation of Kayser-Fleischer rings and, occasionally, sunflower-type cataracts (87); and 6) epi sodes of hemolysis reflecting a rather sud den release of copper from a supersatu rated and cirrhotic liver. Since in normal man concentration of copper is higher in the liver, central nervous system and kid ney than in other organs and tissues (p. 1982) it might be expected that these levels would be significantly increased in a state of copper toxicosis. The report of a high concentration of copper in the skin of two patients with Wilson's disease (113) warrants verification. Of particular interest is recent evidence that in subjects with this disease there is in the liver an abnormal metallothionein having a binding constant for copper about 4-fold that in normal liver (197). It is felt that the increased binding affinity of this protein alters normal homeostasis such that decreased biliary copper excretion and decreased ceruloplasmin synthesis result, and with saturation of binding sites in hepatocytes non-ceruloplasmin copper is released to the serum. Whether this pro tein, or the presence of an abnormal pro tein of similar nature, may explain copper accumulation in non-hepatic organs and tissues is an unresolved question. In view of the fact that low serum ceru loplasmin levels are characteristic of young Downloaded from jn.nutrition.org by guest on February 27, 2013
COPPER METABOLISM AND REQUIREMENTS OF MAN 2011 infants and subjects with Wilson's disease, it is not possible to diagnose this disease (other than perhaps by liver biopsy) and to institute therapeutic measures, prior to the 3rd month of life (638). Largely for this reason little has been learned about the presymptomatic manifestations of the disease during early and late infancy. However, the report of Scheinberg and Sternlieb (682) that copper concentrations in the liver of a 3M-year old child with Wilson's disease were at least 40-fold nor mal adult levels, does indicate progressive liver storage prior to clinical manifestation of the disease and supports the concept that the liver is the primary site of the dis order. The latter is characterized by a dis ruption of the normal homeostatic mech anisms for utilization and excretion of copper. Possibly at fault is the presence of either an abnormal protein with high avidity for copper, as proposed by Uzman et al. in 1956 (801), a similar protein un usually rich in sulfhydryl groups and given the designation L-6D (536) or a metallothionein-like protein with a protein-binding constant about 4-fold that of normal man (197). The concept that the metabolic defect in Wilson's disease is liver-based is supported by observations that in two teen-age boys with Wilson's disease treated with orthoptic liver transplantation the extrahepatic manifestations of the disease were significantly reduced (281 ). A similar response to the same procedure is reported in a 11-year old boy in whom there was strong but not incontrovertible evidence of Wilson's disease (172). In the normal infant liver stores of cop per are gradually decreased and serum copper levels increased during the first 3 or more months of life, until a close to zero copper balance is maintained. According to a recent evaluation of Wilson's disease (672), there may be an early arrest of these postnatal processes, especially abili ties to synthesize normal amounts of ceruloplasmin and to excrete the normal frac tion of dietary copper through hepatic lysosomes (normally an important func tion of lysosomes) into the biliary system. As a result, copper progressively accumu lates in the liver, leading to inflammatory reactions, hepatic cell necrosis and post- necrotic cirrhosis. Meanwhile, excessive amounts of non-ceruloplasmin copper cause, in an unpredictable manner, ac cumulation and injury to different regions of the brain, the kidney and the cornea. It is somewhat academic to ask whether administered estrogens or those of preg nancy can significantly influence the low serum ceruloplasmin levels in Wilson's disease. Beam (37) finds that synthetic estrogens may have a significant effect in some patients but not in others, with no influence on urinary copper excretion. With somewhat larger oral doses of a different estrogen, German (250) reports improve ment in some cases and accentuation of symptoms in others, and also notes a cupriuresis in some cases correlated with in creased serum levels of direct reacting cop per but not with ceruloplasmin. Subjects with Wilson's disease have been able to complete gestation with delivery of normal infants (14, 33, 47, 104, 155, 680). There is a report of one untreated case in which there was an appreciable increase in ceru loplasmin, reaching a maximum at delivery ( 104). Effects of pregnancy upon the clini cal status of the mothers have been equivocal. In instances where penicillamine treatment was discontinued prior to gesta tion (155) and after the first trimester (680), neither ceruloplasmin levels nor clinical symptoms were improved. In fact, in one case occurrence of hemolytic anemia during the 5th month required restoration of therapy (155). In three other instances, where therapy was maintained throughout pregnancy, Aere is reported definite ameli oration of clinical manifestations which continued postpartum for periods of a few weeks (14), 3 months (47) and 6 months (706). Data on serum ceruloplasmin are fragmentary. The ocurrence of several spontaneous abortions during therapy, both prior to (47) and following (14) preg nancies, raises questions concerning pos sible deleterious effects of penicillamine upon the fetus. Although the copper-binding capacity of bile is not altered in Wilson's disease (233), there is increasing evidence that decreased biliary excretion of copper repre sents a major metabolic defect (234, 235, 581, 752, 753), and also that this defect 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 31: 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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COPPER METABOLISM AND REQUIREMENTS
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