conspectus of researchon copper metabolism and requirements

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2018 KARL E. MASON per via thÃ¨bile and consequent release of an excess into the circulation. Although states of hypocupremia are rare in liver disease, low serum copper levels are re ported in hemolytic jaundice, hemochromatosis and some types of liver cirrhosis (255, 824), presumably the result of reduced capacity of the damaged liver to synthesize ceruloplasmin (824). Liver biopsies from subjects of long standing hepatic diseases due to biliary obstruction regularly show in periportal hepatocytes accumulations of coarse gran ules staining with the rubeanic acid method and the Mallory-Parker hematoxlin method for copper, and reacting positively to orcein, which indicates the presence of sulfhydryl groups, all of which suggest the binding of copper to a metallothionein type of protein (661, 719, 720). Rubeanic acid-staining granules of similar type have been described in the livers of vineyard sprayers exposed for many years to copper sulfate sprays (599), but this staining pro cedure is not a particularly reliable test for liver copper. In view of the role of copper as a hepatoxin in sheep (784), it is pos sible that copper may contribute to the de velopment of liver cirrhosis in long-stand ing liver cholestasis (661). It should be of interest to explore the possible relation of these granules to hepatic lysosomes, and also to learn what effect penicillamine may have upon their histochemical picture. Liver copper levels are not altered in extrahepatic biliary obstruction (862) or in acute hepatitis, steatosis of the liver, he patic amyloidosis or hemochromatosis (640). In viral hepatitis, serum copper levels are said to be significantly increased during the acute phase according to one report (270) and during improvement of the clinical state according to another (326 ), but no change in liver copper levels has been reported. Patients with chronic active hepatitis respond favorably to 5 months or more of penicillamine therapy (440). Rheumatic diseases. For many centuries copper amulets have been worn, hopefully, for relief from arthritis, rheumatism and many other afflictions of man, and copper has been a common component of folk remedies for arthritis in particular. There is reported (815) a recent correspondence and questionnaire type of study, involving 240 sufferers of arthritis/rheumatism, half of whom were previous wearers of copper bracelets and the other half not, randomly allocated to three treatment groups wear ing copper bracelets or placebo (anodised aluminum) bracelets, or neither. Prelimi nary results of psychological analyses of the questionnaire responses indicate that "previous users seem to be significantly worse when not wearing their copper bracelets." However, convincing evidence of beneficial effects of copper bracelets does not yet exist. These studies did reveal that surprisingly large amounts of copper (average of 13 mg/month from a 14-g bracelet) can be absorbed through the dermis, which would give in 12 months more than the total amount estimated to be present in the human body. The rationale for copper therapy in rheumatic diseases is not at all clear, and little or no infor mation exists concerning copper metab olism in such states other than in rheuma toid arthritis, and that is somewhat con flicting. In rheumatoid arthritis, serum copper levels are said to be appreciably increased (133, 423, 559, 604, 622, 623) and in the synovial fluid there is an increased level of ceruloplasmin copper, as well as of iron and zinc (558, 559). On the other hand, mean values for the copper levels and Superoxide dismutase activity of erythrocytes of male and female subjects with rheumatoid arthritis do not differ signifi cantly from normal controls (696). A marked elevation of nonceruloplasmin serum copper reported by Lorber et al. (466) has not been substantiated (743), which may be due to differences in meth odology (465). However, the more recent studies of Bajpayee (29) in which serum ceruloplasmin levels were significantly in creased in rheumatoid arthritis patients on estrogens, but were normal in female patients not on estrogens and in male patients, raise serious questions concern ing the validity of data previously reported. Bajpayee points out that in prior investi gations no effort was made to segregate, from the populations studied, those females who were on estrogen treatment. Downloaded from jn.nutrition.org by guest on February 27, 2013
COPPER METABOLISM AND REQUIREMENTS OF MAN 2019 Nevertheless, copper has received much attention in the treatment of rheumatoid and other forms of arthritis. The claimed efficacy of intravenous administration of an organic salt of copper (221) is not substantiated (795). Penicillamine has been used with some response in about 80% of cases after 6 months or more of treatment (88, 380). Efforts have been made to enhance the effectiveness of aspirin, salicylates and penicillamine by forming with them copper coordination compounds. As tested only by the rat model for evaluating inflammatory and antiulcer potentials, these have given somewhat equivocal results (626, 728, 729 ) depending upon the route of adminis tration and the degree of tissue irritation produced. The hypothesis of Sorenson (728, 729) that anti-inflammatory drugs might react in vivo with available copper to generate more effective complexes for regulation of inflammatory or non-inflam matory states certainly justifies further exploration. So also does the question of whether the higher serum copper levels in females as compared to males bears any relation to the high female to male ratio seen in rheumatoid arthritis. Spontaneous remissions of rheumatoid arthritis are associated with obstructive biliary/liver disease and with pregnancy, characterized by increased serum ceruloplasmin levels. These questions are raised by Whitehouse (841) in his review and critical discussion of the topics referred to above. Obviously, there are fertile fields for new explorations of the possible role of copper in arthritis and related diseases. Pellagra. Krishnamachari (427) de scribes in pellagrins in India a hypercupremia uniquely due to increase in nonceruloplasmin copper and associated with wide variation in urinary copper excretion, both of which return to normal levels after oral administrations of nicotinic acid. On the basis of evidence that the high leucine content of the millet Sorghum vulgÃ¤re,a staple food of populations in India, is causally related to pellagra, healthy adult volunteers were given 5-g L-leucine for 6 consecutive days. They showed compar able degrees of hypercupremia and urinary loss both of which disappeared after leucine withdrawal. This investigator sug gests that leucine enhances the absorption of dietary copper in normal subjects. From the same area of India is the report of Deosthale and Gopalan (164) that certain varieties of sorghum also greatly increase serum copper levels and urinary copper excretion, attributable to the high molyb denum content of the sorghum samples. Unfortunately, serum levels of direct react ing copper and ceruloplasmin were not determined. Hence, there is need for more critical study of the possible role of leucine and, or molybdenum excesses in producing the hypercupremia and hypercupriuria de scribed in pellagrins, and for confirmation that the hypercupremia is due primarily to increased nonceruloplasmin copper. Bantu pellagrins in South Africa are said to manifest a hypercupremia which is re duced rapidly after an intramuscular in jection of pantothenic acid, but not after oral nicotinamide (210). The latter obser vations carried out 20 years ago, seem not to have been denied or confirmed. Skin disorders. Elevated serum copper levels occur in psoriasis (400, 430, 531, 751, 859, 872, 875) but not in other derma toses (872). Although these levels have been generally attributed to increased ceruloplasmin, as a reaction to disturbed keratinization (751, 876), several reports state that ceruloplasmin levels are normal (400, 438) unless associated with condi tions of arthritis (423). The tissue copper levels of psoriatic lesions are no different from those of uninvolved skin, although zinc levels are increased (529, 531). After beneficial response to heliotherapy or thalassotherapy most patients show clini cal improvement, with return of serum copper ceruloplasmin levels toward nor mal (875). The mechanisms involved are unknown. With regard to vitÃligo,informa tion is both limited and contradictory. This disorder is said to be characterized by hypercupremia, which is reduced in subjects responding favorably to helio therapy (247, 876), whereas others find that in about 39% of subjects both albu min-bound and ceruloplasmin serum cop per levels are below the normal range (372). Again the question of methodology arises. 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 39: 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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