conspectus of researchon copper metabolism and requirements

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2012 KARL E. MASON may reside in the hepatic cell lysosomes (260, 261, 749, 755) whose catabolic func tions and importance in transfer of copper to the bile canaliculi are well recognized. It appears that early in the disease copper is diffusely distributed in hepatocytes, later as more discrete granules, and that when hepatic damage is more widespread it be comes more localized in the lysosomes, where it may be less toxic ( 261 ). Delay in this uptake by lysosomes could be a key factor in the defective liver transport of copper in Wilson's disease (721). Ques tions still remain as to whether abnormal copper-binding proteins or lack of un known cell enzymes involved in transfer of copper to, or in release of copper from, the lysosomes are responsible. The inter esting observations of Goldfisher and Sternlieb (161) have raised the hypothesis that Wilson's disease may prove to be a "lysosomal disease," as discussed in some detail by Sternlieb et al. (749) and Strickland et al. (755). f Major results of reduced biliary excre tion are increased copper accumulation in hepatocytes, varying degrees of pathology, jaundice and episodes of hemolytic anemia, the latter being secondary to release of copper from an overloaded and damaged liver into the blood stream. If this release is sudden, there can be severe damage to circulating erythrocytes, resulting in repet itive or fatal episodes of hemolytic anemia. A recent report (516) tabulates pertinent data on 18 reports involving 28 subjects. Of these, six presented hemolysis prior to any diagnosis of Wilson's disease and 20 showed evidence of hemolysis at the time of diagnosis. Evidence of hepatic dysfunc tion was noted in at least 22, whereas neurological dysfunction was recognized in only three or four. A more recent report of two cases of fulminating hemolysis in Wilson's disease calls attention to acute renal failure as well as hepatic failure (302). Hence, this hemolytic manifestation of Wilson's disease has become a more common phenomenon than previously rec ognized. In view of the fact that there is an associated marked increase in the cop per content of erythrocytes and in the number of Heinz bodies during periods of crisis, hemolysis is attributed to increased oxidative stress due to an excessive ac cumulation of copper in the cells (155, 508). Whether this is primarily a mem brane defect is still an open question (516). It has been considered (102, 155, 508) a counterpart of the well known "enzootic jaundice" in sheep, the history and nature of which has been presented by Underwood (798). This concept is strongly supported by a recent study of controlled, experimental copper poisoning in sheep demonstrating extensive forma tion of Heinz bodies, predominantly mem brane-attached, as the first morphological alteration observed (725). Hepatocellular and renal tubular necrosis were also noted. Therapy The chance observation of Mandelbrote et al. (485), in a study of copper mobiliza tion in multiple sclerosis, that one of the control subjects who was later found to have Wilson's disease was greatly benefited by treatment with BAL (/3,/3-dimercaptopropanol), known to have properties of a chelator, provided the first therapeutic measure, introduced by Cumings in 1948 ( 135). While daily intramuscular injections proved effective in increasing the urinary output of copper (39, 46, 135, 163), there was no effect upon the aminoaciduria or other clinical manifestations. The same was true when BAL treatment was combined with intravenous casein hydrolysate and oral potassium sulfide, the latter forming an insoluble copper compound in the di gestive tract (102); and also when EDTA ( ethylenediamine-tetra-acetic acid, or "ver sene") was extensively tested (46). Nine weeks of estrogen treatment of an adult male with Wilson's disease failed to im prove serum copper or ceruloplasmin levels (652). Intravenous use of a purified concentrate of human ceruloplasmin also proved ineffective (681). These discourag ing results, together with the adverse side effects of BAL therapy, stimulated search for better measures. In 1956 Walshe (820) described the re markable effectiveness of oral DL-penicillamine as a chelating agent capable of mark edly increasing the urinary output of copper. A few years later die less toxic D-penicillamine (ÃŸ,/3-dimethylcysteine) be- Downloaded from jn.nutrition.org by guest on February 27, 2013
COPPER METABOLISM AND REQUIREMENTS OF MAN 2013 came available and has since been ex tensively used, often in combination with low-copper diets, in the treatment of Wil son's disease. If instituted during early phases of the disease, especially in asymp tomatic patients, it can gradually reduce excessive tissue levels to reasonably nor mal levels and provide assurance of a nor mal life expectancy provided no adverse reactions occur (24, 156, 745, 746, 821). In such instances, which are rare, Walshe (823) proposes the use of tetraethylene tetramine dihydrochloride. This compound, which is cheap and easy to prepare, has not been found to be associated with toxic reactions. It is very effective as a chelating agent, and its mobilization of copper may differ from the action of penicillamine (823). It has not been produced commer cially, but would seem to justify more thorough testing as an inexpensive thera peutic agent. Beneficial effects of L-dopa as an adjunct to a copper-deficient diet and oral penicillamine are reported (246) but not verified. Despite disappearance of disease symp toms and remarkable improvement in liver function following penicillamine therapy for 2 to 7 years (277) and 9 to 13 years (156), hypocupremia, hypoceruloplasminenia and hypercupruria have persisted ( 156) and no more than limited improve ment in liver morphology has been ob served in most cases (277). One exception is that of a 10-year old girl in whom 27 months of penicillamine treatment not only abolished clinical symptoms but greatly improved liver morphology (204). Mitochondrial abnormalities of hepatocytes characteristic of Wilson's disease are less pronounced or absent after 3 to 5 years of therapy, which may have relevance to im proved liver function, but liver structure is not significantly influenced (738). Penicillamine has the properties of a lathyrogen, with ability to not only chelate copper but also to inhibit cross-linking in collagen (381, 560). Grand and Vawter (277) suggest that penicillamine may re tard the formation of permanent scars if begun prior to the onset of the cirrhotic process, as it appears to do in the case of chronic active hepatitis (440). Once cir rhosis is established one might expect some thinning of fibrous scars with prolonged therapy (277). It is disappointing that morphological and ultrastructural studies on biopsies of liver exposed to many years of penicillamine therapy make no com ment on changes observed in liver col lagen (204, 738 ). Another feature of peni cillamine action that justifies further ex ploration is the generalized loss of taste acuity in a variable number of subjects with scleroderma, rheumatoid arthritis, cystinuria and idiopathic pulmonary fibrosis given penicillamine treatment, and the restoration to normal after oral admin istration of copper (323). That only 4% of Wilson's disease subjects under the same treatment show hypogeusia is attributed to the fact that only rarely are their tissue stores of copper sufficiently reduced (323 ). A further complexity is presented by a case of hypogeusia in a patient with mul tiple myeloma which responded effectively to either oral copper or oral zinc (322). The role of copper in taste acuity is still questionable. Low-copper diets often used in addition to penicillamine treatment of patients with Wilson's disease, usually providing 1.0 to 1.5 mg copper, not only exclude a number of generally consumed foods but also are monotonous and of low nutritional value (90). In predominantly rice-eating coun tries, such as Taiwan, preparation and acceptance of such diets present no great problem (754, 755, 793). A vegetarian diet is said to be highly effective in decreasing positive copper balance and in increasing fecal output, due perhaps to copper bind ing to some unabsorbed component of the diet (90). There appears to be no confir mation of these observations. Related disorders Two other abnormalities of copper me tabolism, both associated with low serum levels of ceruloplasmin justify brief men tion. Gahlot et al. (240) describe 15 cases of primary retinitis pigmentosa unrespon sive to conventional treatment. Serum ceruloplasmin levels were very low and urinary copper excretion very high, al though serum copper levels were normal or nearly normal. The investigators sug gest that this retinal pigmentary distur- 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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Page 55 and 56: Ã®1co 1stW Â»aÂ«a3 COPPER MET
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COPPER METABOLISM AND REQUIREMENTS
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COPPER METABOLISM AND REQUIREMENTS
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