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A 58-year-old patient, without any notable medical history, except for alcoholism and treated hypertension, developed anemia and leukopenia with macrocytosis. Folate deficiency was diagnosed and subsequently treated. Despite folate supplementation, the hematological parameters did not normalize. Further diagnosis investigations were led to search for uncommon etiologies of anemia and leukoneutropenia. We diagnosed severe copper deficiency on the basis of decreased plasma levels of copper and ceruloplasmin. Copper supplementation improved blood counts within three months. This case illustrates hematological disorders due to copper deficiency, initially masked by an associated folate deficiency. The copper deficiency etiology was not identified in this case.

In order to evaluate the status of zinc and copper in pregnant women and in preeclampsia, we conducted a prospective case-control study. It involved 56 pregnant women compared with 30 non-pregnant women selected as controls. For pregnant women, serum levels of zinc, copper and ceruloplasmin were determined quarterly. These same measurements were performed once in controls. The comparison of various parameters in normal pregnancy and in control women revealed a statistically significant decrease in serum levels of zinc from 1st to 3rd quarter. The serum levels of copper were normal both in controls and in parturients. However, a significant increase of copper levels from 1st to 3rd quarter of pregnancy was found. The serum levels of ceruloplasmin appear to be invariable during pregnancy. Moreover, we noted a disturbance of these parameters in preeclampsia (hypozincemia, hypocupremia and a significant increase of ceruloplasmin). Zinc and copper are essential for the development and fetal growth. Their involvement in several maternal-fetal complications is not currently in any doubt.

Copper is essential for many enzymatic reactions and in neurotransmitter biosynthesis. Its deficiency or its excess has consequences on many organs, especially the liver and the brain. The biochemical tests performed in case of suspicion of copper metabolism disorder are difficult to analyse. They include the measurement of serum ceruloplasmin, serum copper and 24h urinary copper excretion. The interpretation must take into account the clinical features. We distinguish mainly: (1) copper deficiency, acquired in malabsorption or in copper diet deficiency, or related to a genetic disease (Menkes disease); (2) copper overload, acquired or from a genetic origin (Wilson disease); (3) aceruloplasminemia, reducing ferroxidase activity leading to iron overload. It is important to diagnose these diseases as some of them have an effective treatment if it is started early enough., (Copyright © 2010 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.)

Background: Menkes disease is a rare X-linked disorder due to a defect in intracellular copper transport. Clinical symptoms appear during the first months of life, with a progressive developmental delay leading to death within a few years. Diagnosis is confirmed by the demonstration of copper retention in fibroblasts and/or DNA testing. However, these investigations are complexes and time consuming., Case Report: We report 1 case of Menkes disease with neonatal onset, diagnosed on multiple organ failure, hypothermia, and major central nervous system damage, leading to death in a few weeks. The diagnosis, suggested by the clinical features, was rapidly supported by the microscopic examination of the hairs, showing pili torti, and the demonstration of severely decreased levels of plasma copper and ceruloplasmin. Diagnosis was further confirmed by the demonstration of an increased copper uptake and retention in fibroblasts., Conclusion: This report highlights the clinical variability of Menkes disease with the possibility of a neonatal onset. Microscopic examination of the hairs and the determination of copper and ceruloplasmin plasma levels are simple and inexpensive investigations, which can provide rapidly valuable information to support this diagnosis.

We assessed oxidative stress in 35 chronic renal failure under conservative treatment (CRF), 50 hemodialysed (HD) and 30 renal transplant (RT) patients, and 31 age- and sex-matched healthy subjects. Compared to controls, CRF patients exhibited significantly higher conjugated dienes (139 +/- 37 versus 121 +/- 22 micromol/l) and LDL oxidation (126 +/- 65 versus 99 +/- 46 micromol/l). Glutathione peroxidase activity was decreased in CRF and HD (5.31 +/- 2.46 and 5.39 +/- 2.32 versus 7.42 +/- 2.72 U/ml in healthy subjects). Superoxide dismutase activity was lower in HD (91 +/- 38 U/ml) and higher in RT patients (132 +/- 33 U/ml) than controls (116 +/- 30 U/ml). Plasma zinc concentrations were significantly decreased in CRF and HD patients and copper concentrations were significantly decreased in TPR. Plasma selenium levels were normal in the three groups of patients. Vitamin A was significantly increased, whereas vitamin E was normal in the 3 groups of patients compared to healthy controls. Total antioxidant status was increased in CRF and HD, but not in RT patients. Patients with cardiovascular disease showed increased serum copper, and significantly decreased glutathione peroxidase activity. This study revealed an oxidative stress in CRF and HD patients that may favour the development of cardiovascular diseases.

Abnormalities of copper distribution in tissues and serum has been described in obese subjects. In this prospective study, we evaluated the seric level of copper by atomic absorption in a group of 32 obese (BMI > or = 30 kg/m2) compared to a group of 32 healthy subjects. We have noted an elevation of serum copper in obese with a middle level of 133 mg/dl significantly superior to the middle level of serum copper of healthy subjects, 108 mg/dl (p < 0.001). In another hand, we have noticed that the levels of serum cooper rise with the BMI. In fact, 58.3% of the obese that have a BMI > or = 40 kg/m2 show a high concentration of serum copper although only 5% of obese with BMI < 40 kg/m2 show this high concentration. This work must be completed by the determination of ceruloplasmin levels in a larger group of obese in order to establish correlations between the serum ceruloplasmin levels, the serum copper levels and the obesity.

In Morocco, malnutrition is a public health problem. Indeed, 25% of 6- to 60-month-old children suffer from malnutrition. Imbalance between antioxidant protection and prooxidant stress has been reported to accurately predict the survival of malnourished children. Therefore, we determined blood antioxidant vitamins (retinol, alpha-tocopherol and carotenoids), trace elements (serum zinc, copper and selenium) and enzymes (erythrocyte Se glutathione peroxydase and Cu-Zn superoxide dismutase) as well as blood oxidative stress index [ferritine, thiobarbituric-acid reactants (TBARS)] in 21 children suffering from severe malnutrition, 15 children suffering from mild malnutrition and in 20 healthy control children. Selenium, retionol, alpha-tocopherol and carotenoids were significantly decreased in malnourished children. These decreases were related to the severity of malnutrition. Moreover, the percentage of vitamin and trace element concentrations under deficient cutoff were high in malnourished children. On the contrary, TBARS, ferritin and prognostic inflammatory and nutritional index (PINI) were significantly increased in malnourished children. Except for TBARS, these increases were related to the severity of malnutrition. On the other hand, blood retional, alpha-tocopherol, beta-carotene and selenium were negatively related to alpha 1-acid glycoprotein. Blood beta-cryptoxanthin, lycopene, carotenes and copper were positively related to weight. Finally, blood lutein/zeaxanthin and copper were positively related to height. These results confirm the imbalance between antioxidant protective factors and oxidative stress index in malnourished children. Moreover, the decrease in antioxidant protective factors is related to inflammation or stature. These results suggest that antioxidant micronutrient supplementation of the refeeding diet could be required in the nutritional rehabilitation of malnourished children.

Background: Serum copper and zinc levels are decreased in malnourished and infected children. The role of either malnutrition or infection remains undetermined., Population and Methods: Serum zinc and copper concentrations were measured by atomic absorption spectrophotometry in 31 malnourished infants aged 1 to 26 months and 28 eutrophic infants aged 3 to 22 months. Fourteen infants of the first group and 10 of the second were infected at the time of study., Results: Serum zinc and copper levels were significantly decreased in infants with malnutrition (zinc: 66 +/- 32 micrograms/dl and copper: 81 +/- 51 micrograms/dl versus 108 +/- 26 and 185 +/- 21, respectively, in eutrophic infants) (p < 0.001). These levels were still lower in those malnourished infants who were infected (zinc: 49.5 +/- 18 micrograms/dl and copper: 63.5 +/- 37 micrograms/dl versus 81.56 +/- 35 and 94 +/- 56 in non infected patients) (p < 0.02)., Conclusions: Infection increases the risk of low serum zinc and copper concentrations seen in malnourished children. This factor must be taken in account when treating malnutrition.

Thiopronin is a second line drug for rheumatoid arthritis with proven efficacy in controlled trials versus a placebo, D-penicillamine, or gold salts. This 4-month study was aimed mainly at comparing the efficacy and safety of two thiopronin regimens, i.e., 1 g/d for 2 weeks followed by 1.5 g/d (regimen A) versus 0.5 g/d for 1 month, 0.750 g/d during the second month, then 1 g/d (regimen B). Because earlier investigations have suggested a role for copper in the activity of D-penicillamine, a secondary goal of this study was to evaluate whether the clinical effects of thiopronin were related to changes in serum copper and ceruloplasmin levels. Among the 61 included patients, 32 received regimen A and 29 regimen B. The primary efficacy criterion was the physician's overall efficacy assessment. Efficacy was rated good or excellent in 65.5% of regimen A patients and 55.6% of regimen B patients. Eighteen of the 32 regimen A patients and 23 of the 29 regimen B patients experienced at least one adverse event (p = 0.055). Failure to tolerate the drug required withdrawal in 12 of the 32 regimen A patients (37.5%) versus 11 of the 29 regimen B patients (37.9%). Declines in serum copper and ceruloplasmin levels were not correlated with treatment efficacy or tolerance. These findings, together with previously reported data, suggest that treatment should be initiated in a dosage of 1 g/day and that thiopronin-related adverse events are not dose-dependent.

Zinc treatment of Wilson's disease was introduced by Schouwink en 1961 and is still uncommon in France. We evaluated the effectiveness and safety of zinc in 5 patients with Wilson's disease aged from 19 to 40 years. There were three neurological, one hepatic and one asymptomatic cases. Zinc was administered in doses of 120 to 272 mg/day, alone in 3 cases and combined with D-penicillamine in 2 cases. After 1 to 7 years of zinc therapy, our experience is consistent with data from recent literature and provides further evidence of zinc effectiveness. Zinc may be prescribed as first treatment in most patients, including asymptomatic cases. The only exception concerns patients with severe symptoms in whom it is recommended to combine zinc with D-penicillamine during the early phase of treatment for more rapid effectiveness. Because of its safety, zinc is particularly indicated in cases of intolerance to D-penicillamine and trien.

This article deals with the evaluation of the three year results of the French interlaboratory control for serum copper and zinc analysis. We pointed out some results interpreted on the basis of the existence of differences between the notions of quality control and total quality assurance. The main finding was a surprising change in the annual range in the final results of the laboratories. All 'good' laboratories in the first year showed a significant fall in their individual performance the second year. We can interpret that as a falling off of vigilance in relation with the self satisfaction after the publication of the first results. We concluded that good laboratory practices must be accompanied by a quality program not limited to an analytical control.

The possible alterations of zinc and copper serum levels in dyslipemies were studied. The population were classified taking into account total cholesterol HDL and triglycerides levels and the serum test at 4 degrees C in 4 groups: 1) Hypercholesterolemia (type II A), 2) Endogenous hyperlipemia (types II B and IV), 3) Mixed hyperlipemia (type V), 4) Exogenous hyperlipemia (Type I), and also the presence of over weight ("15% ideal weight body, according to Bray), that occurred in the 29.5% of the sample. Zinc and copper were determined by AAS (Smith & Butrimovitz method). Total cholesterol, HDL, LDL and triglycerides by enzymatic methods. The main results and conclusions obtained were the following: A significative increase in zinc serum level was observed; Hyperglycemia, present in nearly half of the studied population could be the responsible for it. Obesity was associated with an increase of zinc values, and this could be related to an insulinic dysfunction. A direct correlation between glycemia and triglyceridemia, and between glycemia and zincemia was found. Cardiovascular alterations seemed to decrease zinc serum levels; on the opposite however hypertension increased them. Neither lipidic metabolism alterations, nor obesity did modify copper serum level.

A brief analysis of copper metabolism demonstrates that coeruleoplasmine, an enzyme synthesized by the liver, contains approximately 90 p. cent of the serum copper. There are major alterations of copper metabolism during pregnancy. Copper and coeruleoplasmine concentrations increase from the sixth week, reaching particularly high levels during the third trimester before returning to normal six weeks after delivery. The copper concentration in the cord serum is much lower than that of the maternal plasma. The mechanism of this placenteal transfer is unknown. There is a reserve form of copper which is specific to the fetus and the newborn, represented by the neonatal mitochondrocupreine of the liver. Elevated levels of maternal serum copper would be the result of the mobilisation of copper stocked in the liver an other tissues. The copper needs would then be increased in order to restore the reserves. Since diabetes mellitus is a major cause of maternal and perinatal complications, the first results of the serum copper obtained, in Nantes, in diabetic insulin-dependent pregnant women, in the cord blood and in newborns, are presented. A review of the current knowledge of copper in the maternal milk concludes this study.

In 1988 the Trace Elements Commission of the French Society for Clinical Biology operated an interlaboratory comparison program for copper and zinc determination in serum. The main objective is to enable participants to maintain or improve the accuracy of their analytical performance by comparing their results periodically, on the basis of three criteria: comparison of the results with the mean value, accuracy (recovery of copper and zinc additions), between-run reproducibility for identical samples. The statistical methods for evaluation are reported in detail. After one year, the results show a regular improvement in their homogeneity, especially for copper, indicating that the participants have taken into account their results to improve their analytical performance. The recovery of the copper and zinc additions shown a considerable improvement of their homogeneity. The coefficients of variation improved from 30 to 21 p. cent for copper and from 29 to 15 p. cent for zinc. The between-run reproducibility for identical samples was also evaluated. A performance score for each participant was calculated for each evaluation criteria, and a global score was attributed. The procedure for individual and global evaluation was reported in detail. The best scores were obtained for accuracy and the worst for the comparison with the mean value. The participants were considered "good", "acceptable" or "inadequate" in view of their global scores. The global performance was compared to other international interlaboratory comparison programs for copper and zinc in serum.

The authors describes a case of Menkes' disease, sex-linked recessive hereditary disease characterized by early progressive psychomotor deterioration, failure to gain weight, seizures, hypothermie and characteristic Kinky hair (Pilitorti). This boy is a blind child, unable to fix and follow light. Fundus examination shows optic nerve atrophy with tortuosity of the retinal blood vessels. The case is discussed in the light of similar and others reports in the literature. The disease is believed to be cause by a generalized copper deficiency in the body by defect in copper intestinal absorbtion. The pathologic changes in the retina are similar to those seen in the brain which shows diffuse neuronal degeneration lose of nerve filers and optic atrophy. Retinal changes should be reversible by short term systemic copper administration.

The authors report trace elements concentrations (zinc, nickel, selenium, copper, manganese and chromium) during myocardial infarction described in some publication. Serum zinc decreases during the first two days after acute myocardial infarction and returns to normal level in two weeks. Serum nickel increases during the first 36 hours and copper during the first four days. The different explanations of these disturbances are also exposed.

In this report, the authors have studied the plasma and red blood cell concentrations of both zinc and copper in 90 uremic patients treated by intermittent hemodialysis. They found that plasmatic and erythrocytic levels of zinc together with the copper red blood cell concentrations determined before and after the hemodialysis are not significantly different from these recorded on normal subjects. However, the plasmatic copper concentrations are markedly increased, although no relevant correlation between the determined values and those measured in the dialysis bath can be drawn. Plasmatic copper levels fluctuations have been followed on 5 patients during an hemodialysis period ranging from 4 to 36 months, and did not reveal any relevant increase of copper levels. The etiology of the plasmatic copper concentration still be remain to be determined.

Increasing interest and demand in determinations of copper, zinc and aluminium in clinical biochemistry, led us to pay particular attention to problems of blood collection. We tested several blood collecting tubes for contamination by these metals. Evacuated tubes must be avoided; polystyrene and polypropylene tubes are apparently the least polluting. However, strict rules cannot be made, and each biochemist should test the blood collecting devices he wants to use for trace elements analysis.

Serum biochemistry was monitored in 50 patients with otosclerosis confirmed surgically. Age distribution was 25 to 50 years (mean:30 years), and the group included 8 men. Constants determined were serum sodium, potassium, chlorine, iron, phosphorus, aluminium, magnesium, copper and alkaline phosphatase. All patients were free from systemic or metabolic disease. Results failed to demonstrate variations in sodium, potassium, iron, and chlorine concentrations when compared with controls, with non-significant differences in copper, magnesium, phosphorus, aluminium and alkaline phosphatases. These findings were observed both in young patients in whom the otosclerotic process is in the active phase, and in older patients, this excluding correlations between duration of the disease and variations in concentrations of specific ions. The presence of aluminium in the active otosclerotic process is therefore due to local factors of which the mechanism is unknown at the present time.

The authors studied the variations in levels of copper and ceruloplasmin in the mother and in products of conception during the first trimester of pregnancy, during the 4th month of pregnancy and near term, having a series of 12 pregnancies with the copper I.U.D. in position. No change was observed between the levels of copper and ceruloplasmin in comparison with a control series.

The authors have studied a direct automated colorimetric determination of iron serum on Centrifichem. Accuracy and linearity are the same than these obtained by the SFBC recommended method. Precision is poor: the coefficient of variation is about 15% for low values. No alteration in the absorbance is recognized by bilirubin, even in the serum which contains 342 mumol.l-1 of bilirubin. The value of serum iron increases significantly as hemoglobin and copper are added to the serum.

For some authors, absolute or relative copper deficiency, with an elevated plasmatic zinc/copper ratio, could be a risk factor in the etiology of cardiovascular diseases by altering lipid metabolism. Animal or human studies carried out with zinc and/or copper supplemented or deficient diets on biochemical lipid parameters, led to inconsistent results. Nevertheless, no study was already done in hypercholesterolemic patients, concerning possible correlation between serum levels of these trace elements and cholesterol, HDL cholesterol and apolipoprotein B blood levels. 67 patients were distributed in three groups according to their hypercholesterolemia. The serum copper concentration was elevated, serum zinc concentration and zinc/copper ratio were decreased in the hypercholesterolemic group (cholesterol greater than 7.7 mmol/l). Serum zinc, copper and zinc/copper ratio were significantly correlated with HDL cholesterol (respectively r = + 0.56 p less than 0.05, r = - 0.68 p less than 0.01, r = + 0.76 p less than 0.001).

The notion of risk indicator depends on the background of its application. The search for a better understanding of pathological processes implies a rigorous methodology in order to establish a link between the indicator and the risk. Today, the clinician often resorts the Bayes' theorem without taking in account the etiological role of each diagnostic indicator. In the field of public health, the risk indicator is often useful for descriptive or evaluative purposes. Its predictive use implies that it has been built on experimental epidemiological data. In most instances, the use of a multivariate model does not properly solve the problem of the interactions between variables.

The blood levels of zinc, lead, copper and albumin and the activity of erythrocyte delta-aminolevulinic acid dehydratase (ALA D), with and without addition of zinc in vitro, were measured in healthy subjects and in patients with cirrhosis. In cirrhosis there was a decrease, of zinc (-40%) albumin (-38%) and of activity of ALA D (-48%) and an increase in blood lead (+80%). Correlation between these results has been studied. The increase of blood lead is probably the result of zinc decrease. Moreover, as the urinary excretion of zinc is enhanced by chelation therapy, the prescription of zinc in lead intoxication is to be recommended. The activity of ALA D in patients with cirrhosis is less enhanced by addition of zinc in vitro than is the activity in patients intoxicated with lead. Probably in cirrhosis there is especially a decrease in the synthesis of ALA D, and lead intoxication the enzyme is inhibited.

The authors describe the principle of inductively coupled argon plasma emission spectrometry (ICP) to determine inorganic compounds in biological samples. This method is compared with more classical electrothermal flame atomisation absorption spectrometry. The association of ICP with different instruments is reminded (HPLC, mass spectrometry, graphite furnace, hybride generation). Finally, the review ends with some applications in biological fluids.

One group of 20 adult female rats was fed ad libitum for four months with a synthetic regime containing less than 1 p.p.m. Cu. A second group received the same regime, supplemented with Cu and containing 87 p.p.m. on the 1st month, 109 p.p.m. in the 2nd and 3rd and 158 p.p.m. in the 4th month. Hairs were not clipped at the beginning of the experiment. Five rats of both groups were killed at the end of each month and Cu was determined in blood, liver, femur, and hair. Hair was washed with a water-ethanol (I/I/I) solution for 30 minutes under mechanical shaking, and Cu was determined in the washing solution (leachable copper) and in hair (stable copper). No clinical symptoms of Cu deficiency were observed. However there was an early and important drop (p less than 0.001) in blood and liver copper as early as the first month, which continued until the end of the experiment. Stable hair Cu dropped slightly on the first month (p less than 0.005) and continued to do so on the following three months (p less than 0.001). Hair leachable Cu and bone Cu were unaffected by the deficiency. Liver Cu increased at the 158 p.p.m. level of intake on the fourth month.

Copper deficiency anemia occurs in some specific situations if supplemental copper is not given: low birth-weight premature infants fed milk only, protracted total parenteral nutrition, chronic diarrhea with severe malnutrition. Severe neutropenia precedes the onset of sideroblastic anemia. Iron therapy is ineffective. Diagnosis is established by the low serum copper concentrations, the delayed osseous anomalies, and the dramatic response to copper therapy. Low serum vitamin E concentrations may be found in low birth-weight premature infants aged six to ten weeks with hemolytic anemia. In such cases, vitamin E therapy is effective. This condition occurs more often in infants fed milk formulas without supplemental copper and in infants given high doses of iron. Whether vitamin E deficiency causes anemia is still an open question. Preventive vitamin E supplementation is only partly effective.

The influence of glycaemic control and diabetes characteristics on plasma concentrations of magnesium, zinc, copper, selenium, rubidium and bromine has been evaluated in 44 diabetics (30 insulin-dependent, 14 non insulin-dependent), and the results obtained were compared to those of 309 control subjects of the same mean age. Diabetics had reduced plasma magnesium concentrations (P less than 0.01) but normal erythrocyte magnesium levels. Plasma zinc and selenium concentrations were reduced, whereas those of copper were increased and those of bromine and rubidium were normal. Correlation between glycaemic control, evaluated by measurement of glycosylated haemoglobin levels, and each of the parameters studied was only demonstrated with magnesium in insulin-dependent diabetics (r = -0.561; P less than 0.02). No correlation was found with the other clinical or anthropometric characteristics of the diabetic patients studied. Diabetes seems to be associated with numerous abnormalities of plasma trace elements and magnesium, but the mechanism of these abnormalities has not yet been elucidated. A decrease in zinc and selenium concentrations and an increase in copper concentrations might be additional factors of atherogenicity.

Copper is an essential dietary component, being the coenzyme of many enzymes with oxidase activity, e.g. ceruloplasmin, superoxide dismutase, monoamine oxidase, etc. The metabolism of copper is complex and imperfectly known. Active transport of copper through the intestinal epithelial cells involves metallothionein, a protein rich in sulfhydryl groups which also binds the copper in excess and probably prevents absorption in toxic amounts. In hepatocytes a metallothionein facilitates absorption by a similar mechanism and regulates copper distribution in the liver: incorporation in an apoceruloplasmin, storage and synthesis of copper-dependent enzymes. Metallothioneins and ceruloplasmin are essential to adequate copper homeostasis. Apart from genetic disorders, diseases involving copper usually result from hypercupraemia of varied origin. Wilson's disease and Menkes' disease, although clinically and pathogenetically different, are both marked by low ceruloplasmin and copper serum levels. The excessive liver retention of copper in Wilson's disease might be due to increased avidity of hepatic metallothioneins for copper and decreased biliary excretion through lysosomal dysfunction. Menkes' disease might be due to low avidity of intestinal and hepatic metallothioneins for copper. The basic biochemical defect responsible for these two hereditary conditions has not yet been fully elucidated.

We report a case of Wilson's disease, with a rapidly progressive course, in which peritoneal dialysis was performed. The physiopathology of acute features occurring during the course of the disease is reviewed. The different methods for eliminating copper, particularly peritoneal dialysis, are discussed. The authors recall the precautions which are necessary when initiating D-penicillamine therapy.

The study of copper and zinc in 35 patients, over periods of up to 21 days following thermal injury, is marked by an important and early fall in serum copper and zinc levels. The maximum intensity of the biological disturbance appears about two days after the injury. Reversion to near normal values coincides with recovery from the large part of the lesions. The comparison of the evolution of serum levels does not permit any definite relationship to be established between copper and zinc metabolism.