conspectus of researchon copper metabolism and requirements

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2016 KARL E. MASON pernicious anemia, aplastic anemia and thalassemia major ( 103). It should be kept in mind that in view of decreased blood iron levels in anemia, the increased copper levels may be more apparent than real. In iron deficiency anemia, pernicious anemia and leukemia, as well as in chronic infec tions, there is an increased copper level in whole blood, red blood cells and plasma, and only in iron deficiency anemia is there an increase in the ratio of erythrocyte to plasma copper (100, 592). Aside from states of copper toxicity, blood cell copper remains quite constant. Since direct react ing copper of serum is only about 1% of the total, both hypo- and hypercupremic states reflect changes primarily in ceruloplasmin copper. To the present there have been proposed no acceptable explanations of the basic mechanisms involved, of the tissues from which the copper is mobilized, or the function(s) that hypercupremia serves. An extensive literature on this sub ject has been well reviewed elsewhere (7, 44, 100, 211, 319, 666). Neoplasms. Hypercupremia is a common feature of acute and chronic leukemia (100, 162, 630, 773), lymphatic leukemia (255), Hodgkin's disease (100, 328, 363, 364, 386, 774, 775), malignant tumors (255) and of multiple and acute myeloma (255, 268, 456, 457). In leukemia of chil dren plasma zinc levels are low, and the ratio of zinc to copper may prove useful in monitoring the response to treatment ( 162 ). In Hodgkin's disease blood cop per levels are valuable in evaluating the disorder itself and the effects of therapy (363, 364, 774, 775, 778, 829). Cases of multiple myeloma appear to present special abnormalities of copper metabolism. Goodman et al. (268) report a case in a 69-year old woman whose serum copper levels ranged from 20- to 40fold normal, due entirely to a phenomenal increase in nonceruloplasmin copper. Evi dence indicated its association with an abnormal monoclonal immunoglobulin. More recently, Lewis et al. (457 ) recorded a quite similar hypercupremia, with blood copper levels as much as 14-fold normal, in a 41-year old woman manifesting an early, clinically asymptomatic stage of mul tiple myeloma. Liver (biopsy) was normal in structure and copper concentration. In both cases there was extensive copper in filtration of the cornea and of the anterior and posterior surface of the lens, not un like that seen in the Kayser-Fleischer ring of Wilson's disease. These observations raise questions regarding the pathognomonic value of the latter and also the pos sible recognition of a unique variety of multpile myeloma, both of which justify further exploration. Largely in the hope of finding an addi tional diagnostic criterion of value, atten tion has been given to serum levels of cop per, and in some studies to zinc and iron, in subjects with varied types of neoplasia. In osteosarcoma, serum copper and copperzinc ratios are increased in the primary phase, further increased following metasta sis, and approach normal levels in patients whose tumor is amputated and show no clinical sign of the disease (212). Also, copper in the bone of osteogenic carcinoma is significantly greater than in normal bone (384). In lung and breast carcinoma the serum copper/iron ratio is high (602, 769 ). In gastric and pulmonary carcinoma serum copper levels are significantly increased, but not in cases of tumors of the large in testine (670). Only one study reports no differences between the serum copper con tent of healthy humans and those suffering from malignant tumors (22 ). Other reports indicate increased serum copper in lymphomas and certain other malignancies (539), and no change in prostatic carci noma prior to or during radiation therapy (363). In Hodgkin's disease, leukemia and lymphomas, there is general agreement that serum copper levels have merit in diagnosis and in evaluation of therapy (162, 375, 386, 421, 539, 592, 773), as is also true of osteosarcomas (212). How ever, in none of the studies referred to above has a clear explanation, or even a challenging hypothesis, been provided toward explaining the possible mechanisms involved. 'Neurological diseases. Recognition of low serum ceruloplasmin and copper levels as one criterion of Wilson's disease led to nu merous studies on a wide variety of neuro logical diseases and disorders, many directed toward hopes of finding other conditions Downloaded from jn.nutrition.org by guest on February 27, 2013
COPPER METABOLISM AND REQUIREMENTS OF MAN 2017 wherein increased or decreased levels of copper might provide a useful diagnostic measure of the disease state. On the whole, these efforts have proved rather unfruit ful. Considerable controversy has arisen regarding schizophrenia and other psy chotic states, following an early report of high serum copper levels in the majority of 27 cases of schizophrenia and in cases of manic depression and epilepsy (319). Subsequent studies have indicated a tend ency toward significant increases in ceruloplasmin serum levels in schizophrenia (2, 675, 677), in manic depression and senile psychosis (13), but values obtained over lap with those of normal subjects to vari able degrees. Since the activity of copper oxidase is reduced as serum ascorbic acid increases, it is felt that the increased levels observed in many states of mental illness may reflect low ascorbate intake in sub jects institutionalized for prolonged pe riods ( 13, 20 ). Other investigators find no significant changes in serum copper in schizophrenia (30, 31, 360, 575), or in brain tissue (279 ). These differences might relate to the fact that schizophrenics are very heterogeneous biochemically, such as in serum levels of histamine, in serum levels of zinc and manganese, and in re actions to penicillamine and to contracep tive estrogens in particular (596, 597). In any case, serum copper levels have no diagnostic value (677). In epilepsy there is said to be an increase in serum copper (70, 89) involving whole blood, serum and blood cell levels (800). Cerebrospinal fluid copper is reported to be decreased (89) and increased (800), and urinary and fecal copper increased (800). These unverified and somewhat variant observations probably have little relevance. Cardiovascular diseases. More than 25 years ago Vallee (803) reported a pro nounced hypercupremia during the acute phase of myocardial infarction, which sub sided during recovery, and later Adelstein et al. (5) demonstrated a linear relation ship between the serum copper, ceruloplasmin and copper oxidase activity. These findings have been well confirmed (405, 806, 831), and a reciprocal decrease in serum zinc has been noted (806, 831). In myocardial infarction, but not in angina, coronary insufficiency or myocardial ischemia, there is also a marked elevation in serum of the zinc-dependent enzymes, malic and lactic dehydrogenase (811), and in benzidine oxidase (760). Such findings naturally raise questions as to whether in creases in serum ceruloplasmin represent anything other than a reaction to acute stress. There are but a few unconfirmed reports indicating hypercupremia in atherosclerosis (53, 659), arteriosclerosis (81, 82) and hypertension (287); also, decreased levels of copper in the wall of larger arteries (404) and coronary arteries (836) of sub jects with atherosclerosis. There is also described a linear decrease in the copper content of the wall of larger arteries with increase in degree of atherosclerosis (404), and a questionably significant lower level of copper in the coronary artery of sub jects with atherosclerosis and myocardial infarction (836), which may reflect de creased metabolic activity of the altered arterial tissue. Hemolysis associated with hypercu premia, usually transient and self-limiting, is a well recognized manifestation of Wil son's disease (see p. 2014). It may occur also as a fulminating event secondary to acute liver failure (643), sometimes combined with acute renal failure (302). It can be attributed to sudden release of nonceruloplasmic copper from a damaged liver and excessive accumulation in erythrocytes, resulting in acute oxidative stress upon the cells and cell membranes (155, 302, 643). Liver diseases. Considering the key role of the liver in initial storage of absorbed copper, in the synthesis and release of ceruloplasmin, and in excretion of copper via the biliary system, it is to be expected that metabolic and pathologic dysfunctions of this organ might well be reflected in atypical levels of copper in the serum, and also perhaps in erythrocytes of the circu lating blood. This has been well demon strated. Serum copper levels are signifi cantly elevated in portal cirrhosis, biliary tract disease and hepatitis (62, 245, 255, 271, 285, 600), possibly reflecting inter ference with the normal excretion of cop- 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 37: 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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