Muriel Bost

Dietary copper and human health: Current evidence and unresolved issues.

Although copper (Cu) is recognized as an essential trace element, uncertainties remain regarding Cu reference values for humans, as illustrated by discrepancies between recommendations issued by different national authorities. This review examines human studies published since 1990 on relationships between Cu intake, Cu balance, biomarkers of Cu status, and health. It points out several gaps and unresolved issues which make it difficult to assess Cu requirements. Results from balance studies suggest that daily intakes below 0.8 mg/day lead to net Cu losses, while net gains are consistently observed above 2.4 mg/day. However, because of an incomplete collection of losses in all studies, a precise estimation of Cu requirements cannot be derived from available data. Data regarding the relationship between Cu intake and potential biomarkers are either too preliminary or inconclusive because of low specificity or low sensitivity to change in dietary Cu over a wide range of intakes. Results from observation and intervention studies do not support a link between Cu and a risk of cardiovascular disease, cognitive decline, arthritis or cancer for intakes ranging from 0.6 to 3mg/day, and limited evidence exists for impaired immune function in healthy subjects with a very low (0.38 mg/day) Cu intake. However, data from observation studies should be regarded with caution because of uncertainties regarding Cu concentration in various foods and water. Further studies that accurately evaluate Cu exposure based on reliable biomarkers of Cu status are needed.

A Selenium Supplement Associated or Not with Vitamin E Delays Early Renal Lesions in Experimental Diabetes in Rats

Abstract Seventy rats were separated into five groups: one group of 12 was used as a control and received a purified diet, and four groups of streptozotocin-induced diabetic rats, totalling 58, were fed the same diet without or with selenium (Se) supplementation. Of the noncontrol rats, 14 were without supplementation (Group D), 14 were fed a Se-rich yeast diet (i.e., selenion) (Group DSel), 14 received selenomethionine (Group DSm), and 16 received selenomethionine + tocopherol acetate (Group DSmE). Supplementation with Se in all groups was 0.99 μmole/100 g of diet and with tocopherol acetate was 0.145 μmole/100 g. All diabetic rats were mildly balanced by insulin. After 24 weeks of diet, plasma glucose tended to decrease in diabetic Sesupplemented groups DSmE>DSm>DSel versus Group D. In DSm and DSmE groups, plasma lipid peroxides also decreased compared with Group D, but this decrease reached significance only for DSmE (P<0.01 for both TBARS and conjugated dienes). Plasma triglycerides also decreased in DSm and DSmE groups versus Group D (P<0.01; P<0.05, respectively). At the same time, Se increased significantly in kidneys of Groups DSel and DSm versus D and more weakly in Group DSmE, but in this case was associated with a large increase of vitamin E. These beneficial effects of selenium supplement and more so of selenium combined with vitamin E were associated with a protection of kidneys in diabetic rats which found expression in a significant correction of renal hyperfiltration (P<0.05) and in a diminution of the number and severity of glomerular lesions (P<0.0005). [P.S.E.B.M. 1996, Vol 211]

Effect of selenium and vitamin E supplementation on lipid abnormalities in plasma, aorta, and adipose tissue of Zucker rats

Twenty-nine obese female Zucker rats (fa / fa) were fed with a laboratory chow supplemented or not with a selenium-rich yeast (Selenion), or Selenion + vitamin E, or vitamin E alone. Twelve lean female Zucker rats (Fa / Fa) of the same littermates fed with the same diet were used as control. After 32 wk of diet, obesity induced a large increase in plasma insulin and lipid levels. A significant decrease in the plasma vitamin E/triglycerides ratio (p < 0.005) and an increase in plasma thiobarbituric reactive substances (TBARS) (p < 0.005) were also observed. Plasma selenium and vitamin E increased in all supplemented rats. The plasma insulin level was decreased by selenion supplementation and the vitamin E/triglycerides ratio was completely corrected by double supplementation with Selenion + vitamin E. TBARS were also efficiently decreased in two obese groups receiving vitamin E.In plasma, adipose tissue and aorta, obesity induced an increase in palmitic acid (C16:0), a very large increase in monounsaturated fatty acids (palmitoleic acid C16:l, stearic acid C18:l) associated with a decrease in polyunsaturated n-6 fatty acids (linoleic acid C18:2 n - 6, arachidonic C20:4 n - 6). These alterations in fatty acid distribution were only partly modulated by Se and vitamin E supplements. However, in the aorta, antioxidant treatment in obese rats significantly reduced the increase in C16:0 and C16:l (p < 0.05 andp < 0.01, respectively) and the decrease in arachidonic acid (p < 0.05). These changes could be beneficial in the reduction of insulin resistance and help to protect the vascular endothelium.

Selenium in diabetes: Effects of selenium on nephropathy in type I streptozotocin‐induced diabetic rats

Oxidative stress is involved in diabetes mellitus and its complications. Selenium is a nutritional antioxidant, especially because it is required for the activity of selenium-dependent glutathione peroxidase. Selenium also may have insulin-like properties and improve insulin sensitivity. However, its effects are not sufficiently documented in diabetes and its complications. Thus we supplemented type I diabetic rats with a selenium-rich yeast, selenomethionine and selenomethionine + vitamin E for 24 weeks. Selenium supplementations increased selenium levels in plasma. Selenium and more efficiently Sm + vitamin E decreased plasma glucose level and glycated hemoglobin. Supplementations increased selenium levels in kidney and double supplementation increased renal vitamin E level. However, no differences were observed in thiobarbituric acid-reactive substances in kidneys in the different groups. Selenium decreased or normalized the increased arachidonic acid content observed in diabetic kidneys and so may reduce the level of thromboxane involved in nephropathy. Glomerular hyperfiltration is common in early stages of diabetic nephropathy. We observed an increased renal creatinine clearance in diabetic rats, indicating renal hyperfiltration. Nevertheless, this hyperfiltration was corrected by selenium supplementations. Renal lesions were markedly increased in diabetic rats, but very significantly reduced or corrected by supplementations. Thus we concluded that selenium supplementation could be a useful additive therapeutic to delay diabetic nephropathy. J. Trace Elem. Exp. Med. 12:379–392, 1999.

Effect of molecular adsorbents recirculating system treatment in children with acute liver failure caused by Wilson disease.

Objectives: Because fulminant Wilson disease (WD) has an extremely poor prognosis, the use of liver support that can bridge patients to liver transplantation is lifesaving. We report the experience of albumin dialysis in acute liver failure (ALF) caused by WD in children. Methods: Chart review of children admitted for ALF secondary to acute WD and treated by the molecular adsorbents and recirculating system. Measures of copper level in blood and within the circuit during molecular adsorbents recirculating system (MARS) sessions were performed. Clinical and biological assessments after MARS session were reported. Results: Four children, with a median age of 12.3 years, were treated from 2004 to 2009 for a severe ALF associated with acute renal failure, haemolysis, and severe cholestasis. All of the children had a new Wilson index >12. A total of 14 MARS sessions were performed, for a median duration of 7.5 hours. Tolerance was good, except for 1 child who experienced haemorrhage because of vascular injury following insertion of the dialysis catheter. A neurological improvement or stabilisation was noted in all of the children along with an improvement in the Fisher index and ammonia level after MARS treatment. MARS was able to remove copper, to decrease the serum copper level of 28% in mean, and to decrease the bilirubin and creatinin levels >25%. All of the children were subsequently underwent liver transplants with a good outcome without disability. Conclusions: MARS is able to remove copper and to stabilise children with ALF secondary to WD, allowing bridging to LT.

Wilson disease in offspring of affected patients: Report of four French families

BACKGROUND Wilson disease (WD) is an autosomal recessive genetic disorder caused by mutations in the ATP7B gene resulting in toxic accumulation of copper mainly in the liver and brain. Early treatment may prevent irreversible tissue damage. AIM We report on four families with an occurrence of WD in two consecutive generations in order to highlight the need for screening offspring of affected parents. RESULTS In all families, one parent was known to be affected with WD. Screening for the disease was not performed in children from two families until occurrence of liver disease in one and of neurological symptoms in the other. In two other families, screening of children as soon as diagnosis was performed in the affected parent allowed a timely rescue of advanced liver disease in one while two affected children were asymptomatic. In three children, diagnosis required direct sequencing of the ATP7B gene. Two novel disease-causing mutations are reported. CONCLUSION Patients with WD should be offered genetic counselling when considering pregnancy and offspring should always be screened for the disease. Diagnostic difficulties based on copper disturbances in asymptomatic children that are obligate carriers of the Wilson gene and the usefulness of molecular diagnosis are discussed.

In vitro and in vivo effects of selenium and selenium with vitamin E on platelet functions in diabetic rats relationship to platelet sorbitol and fatty acid distribution

In vitro 30 min of incubation with selenomethionine (Sm)+vitamin E multiplied by about five platelet selenium (Se) decreased significantly platelet thrombin and ADP-induced aggregation decrease. Four groups of streptozotocin-induced diabetic rats were fed with a supplemented purified diet with an Se-rich yeast (Selenion): DSel, Sm: DSm, Sm α-tocopherol: DSmE or unsupplemented diet: D. After 24 wk of supplementation, only a decrease in thrombin-induced aggregation in group DSel compared to DSm and DSmE and D was observed. However, after 24 wk of diet compared to 14 wk, in group D and DSm, a significant increase in thrombin-induced aggregation occurred (p<0.0001), whereas a significant decrease in groups DSel and DSmE (p<0.0001,p<0.03) was noted. After 21 wk of diet, in DSmE, platelet adhesion to fibronectin was significantly decreased compared to group D (p<0.05). These changes in DSmE were associated with a significant decrease in platelet sorbitol (p<0.02) and a very significant increase in platelet Se (p<0.0005). Sm associated with vitamin E would appear more efficient to prevent oxidative damage of diabetic platelet membrane and thus to modulate its hyperactivity.

Intellectual and Visuo-spatial Assessment in Long-Term Pediatric Liver Transplantation for Biliary Atresia

Biliary atresia affects children in the first few months after birth. Therefore, the need for liver transplantation (LT) is early. Studies examining the cognitive and neuropsychological outcomes of patients who underwent LT identified deficits in global intellectual assessment (1), language performance (2), attention, and memory (3). In contrast, visuo-motor tests were normal after the LT (4). In these studies, a variety of pretransplant diagnoses and ages at transplantation were included. Thus, we assessed intellectual and visuo-spatial status in the late postoperative phase (average 9.2 years postoperatively) of children who had undergone LT with a diagnosis of biliary atresia. The sample consisted of 13 children (nine females and four males) who obtained postoperative follow-up for at least 4 years. The mean age at testing time was 10.5 years. Intellectual performances were assessed with the five subscales of Wechsler Intellectual Scale for Children, fourth edition (WISC-IV) (5): total intellectual quotient and the four composite indices: verbal comprehension index (VCI), perceptual reasoning index (PRI), processing speed index (PSI), and working memory index. The visuospatial status was assessed by the REY figure copy test (6). The children scored in the normal range on the total intellectual quotient, VCI, PRI, and PSI, see Table 1. The Wilcoxon rank sum test shows that the children scored significantly below the norm in the working memory index (P 0.003) and the REY figure copy test (P 0.001). In contrast to Adebäck et al. (1), the current study shows no difference between LT children performances and normal values in total intelligence score, verbal and nonverbal (i.e., performance reasoning) parts. Furthermore, no difference is observed between LT children performances and normal values in PSI. The difference between the two studies can be explained by the two versions of the WISC test. First, the WISC-IV is composed of four composite scores instead of two in the WISC-III. Second, the verbal part of the WISC-III was composed of arithmetic subtest, which is considered as a sensitive task to the working memory and attention components. Third, the performance part was made of object assembly and image completion very sensitive subtests to the visuo-spatial performances. In the visuo-spatial domain, contrary to LT adults who performed normally 2 years postoperatively (4), LT children demonstrate weak performances several years after the transplantation. The current study cannot provide definitive evidence concerning effects of LT on intellectual functions because of the lack of baseline testing before the LT attributed to the age limits of the tests and the relatively small group size. Nevertheless, it seems that the early age at LT and the long period after the LT are positive factors, which allow the children who underwent LT to perform normally in total intellectual, VCI, PRI, and PSI scores. However, the domains of working memory and visuo-spatial functions are deficient even after a 9.2 year average postoperative period in LT children. Thus, we suggest that the liver failure these children experienced caused cerebral dysfunction, which led to the longterm damage in these two cognitive components.

Restriction polymorphisms of the ceruloplasmin gene on chromosome 3.

Using a probe isolated from a human liver cDNA library, polymorphisms were observed in the human ceruloplasmin gene with the enzymes PstI and MspI. The PstI polymorphism was frequent (allele frequencies, 0.46 and 0.54) whereas the polymorphisms found with MspI were rare.

Relative exchangeable copper: a valuable tool for the diagnosis of Wilson disease

Measuring of the relative exchangeable copper seems to be a promising tool for the diagnosis of Wilson disease. The aim of our study is to determine the performance of REC for the diagnosis of Wilson disease in a population of patients with chronic liver diseases.