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Increased oxidative damage to cell membrane constituents causes profound changes in the membrane cytoarchitecture and modifications of the membrane physiological properties, e.g., the ability to respond to hormonal stimuli. In uremic patients receiving intermittent hemodialysis, a metabolic block of the phosphate pentose shunt has been described. This leads to insufficient detoxication of the hydroxyl radicals formed within the cells and therefore to increased oxidative damage to the polyunsaturated fatty acid constituents of the cell membranes. Vitamin E is known to reduce this oxidative damage and its harmful effects. We studied vitamin E (alpha-tocopherol acetate) administration in 10 chronically uremic patients receiving intermittent hemodialysis for positive effects on cell membrane-receptor response. The patients were studied before and after treatment for the extent of oxidative damage in peripheral mononuclear cells and for response to monoclonal antibodies to specific markers of T-lymphocyte subsets. After vitamin E treatment, oxidative damage decreased, and the membranes of peripheral mononuclear cells contained greater amounts of some unsaturated fatty acids. This is in agreement with a modification of the membrane phenotype markers of T-lymphocyte subsets and seems to confirm in vivo that changes in membrane structure first induced by increased oxidative damage due to the blockage of the phosphate pentose shunt can be reduced by the antioxidant action of vitamin E, which significantly influences the expression of membrane determinants.

The intestinal absorption of vitamin E is often thought to be closely correlated to that of fatty acids, but the biochemical mechanisms involved in the process are still not clear. For this reason, the present study aimed to assess the absorption of triglycerides and vitamin E, following oral administration, in 11 children with suspected malabsorption syndromes. Intestinal biopsy in 9 children showed the presence of a flat mucosa, whereas no changes were present in 2 patients. The results confirm the inverse correlation between the absorption of triglycerides and vitamin E, as if tocopherols used an independent system of transport. These findings contrast with those reported in the literature perhaps due to the low level of precision of colorimetric techniques previously used to assay vitamin E.

The result of vitamin E treatment in 19 uremic patients in chronic hemodialysis is evaluated. In particular, the levels of erythrocyte malonyldialdehyde (MDA) and vitamin E were determined, and the fatty acid composition of red blood cell (RBC) membrane before and after treatment with parenterally administered vitamin E. A decrease of RBC MDA levels, an increase of RBC vitamin E concentrations, and a decreased saturated fatty acid to unsaturated fatty acid ratio were found after treatment with vitamin E. There was a statistically significant increase of the packed RBC volume.

It has been reported that increased peroxidation of the polyunsaturated fatty acids in the erythrocyte membranes is one of the causes of chronic hemolysis in uremic patients on hemodialysis and that therapeutic doses of vitamin E are effective in reducing peroxidation, improving the hematocrit. The present study shows how the reduced peroxidation, induced by a course with therapeutic doses of vitamin E, is paralleled by a significant reduction of plasma hemoglobin concentrations at the end of the dialysis and by a significant improvement of erythrocyte osmotic resistance. The findings lead to the suggestion that the administration of tocopherol to patients on chronic hemodialysis for end-stage renal disease may be beneficial in improving anemia, acting via a reduction of lipid peroxidation of the red blood cell membranes. Whether this can reduce the need for the transfusions can be assessed only with a longitudinal long-term study, which is also necessary to determine whether the preliminary findings of this report have important clinical applications.

In haemodialysis patients, increased concentrations of malonyldialdehyde and decreased vitamin E content indicate lipid peroxidation in the platelets from oxidative damage. The same process has been described in red blood cells and in mononuclear cells in peripheral blood. However, platelet aggregation is within normal limits and does not change after treatment with vitamin E. On the other hand vitamin E supplementation reverts completely the biochemical abnormality of the platelets.

We described previously that in the erythrocytes and mononuclear blood cells from uremic patients on chronic hemodialysis, the membrane concentrations of malonyldialdehyde (MDA), resulting from peroxidation of polyunsaturated fatty acids (PUFA) in the membrane itself increased, and the concentrations of vitamin E (VIT E), the major antioxidizing agent, were lower. In the present study we analysed whether similar oxidative damage is seen in the serum from hemodialysis patients and whether the serum fatty acid pattern is affected. No evidence was found of oxidative damage in the serum during hemodialysis, serum concentrations of MDA and VIT E remaining constant before and after dialysis. No change was observed in serum pattern of PUFA, particularly linoleic acid. We therefore assume that the oxidative damage described in uremic patients is mainly intracellular.

In 10 children with chronic cholestasis and without neurologic signs, we evaluated lipid peroxidation and vitamin E levels in serum and in the erythrocytes before and after a therapeutic trial with alpha-tocopherol. We also studied the effects of vitamin E administration on hematocrit and hemoglobin values and on reticulocyte and erythrocyte counts. Plasma and erythrocyte malonyldialdehyde (MDA) values were significantly higher compared with normal control values, whereas plasma and erythrocyte tocopherol measurements were lower. Oral administration of high doses of vitamin E (300 mg/day for 15 days) resulted in lower serum MDA levels, whereas serum vitamin levels did not change significantly. In erythrocytes, the MDA decreased but not to control levels, and vitamin E increased but to lower values than normal. Hematologic values also improved. We conclude that longer treatment might be necessary to completely reverse the oxidative damage associated with vitamin E deficiency in children with cholestasis.

The tocopherol and malonyldialdeyde levels in the erythrocytes of 15 children affected by chronic renal failure, free of therapy, have been studied. Decreased levels of the former and increased of the latter were found. These data indicate red blood cell lipids peroxidation, responsible, at least in part, of the reduced red blood cell survival and of chronic anemia.

Recently, we have demonstrated that hemodialysis (HD) patients have higher serum and lower erythrocyte concentrations of vitamin E than controls. It is known that transfer of vitamin E from serum to erythrocyte is mostly due to high-density lipoproteins (HDL). For a better definition of the pattern of distribution of vitamin E in HD patients, we have dosed the amount of vitamin bound to serum HDL fraction. In 8 patients and in 8 healthy controls, we have determined the concentration of serum erythrocyte and HDL-bound vitamin E. The latest was obtained on an ultracentrifuged HDL fraction. HDL fractions from HD patients have been found to contain larger amounts of vitamin E than controls. The previously described higher serum and lower erythrocyte concentrations of vitamin E in HD patients have been confirmed in the study. The deficit of vitamin E in the membranes of erythrocytes from HD patients has been shown to be the result of increased consumption of the vitamin in the erythrocyte membranes, where it represents the major antioxidant agent. However, the finding of increased amounts of vitamin bound to HDL in HD patients suggests that the transfer of the vitamin to the erythrocyte membranes may also be defective.

Lipid peroxidation and vitamin E levels in peripheral blood mononuclear cells (PBMC) were studied in 10 patients on maintenance hemodialysis. Significant increases of PBMC malonyldialdehyde (MDA) were detected, together with low vitamin E levels. After a fifteen-day-course of parenteral vitamin E supplementation, PBMC MDA reverted to normal values, while PBMC vitamin E levels remained lower than controls. In a parallel study an immunological monitoring was performed in the same patients before and after vitamin E supplementation. NK activity and PHA blastogenesis were not influenced by treatment, while a reduction of the number of OKT8+ lymphocytes were observed after vitamin E therapy. It is tempting to speculate that peroxidative damage of PBMC cell membranes in hemodialysis patients could, by impairing their functionality, influence immune responses and expression of functionally relevant membrane determinants.

Human blood platelet activation elicited by latex particles is associated to a 30% decrease in the cellular content of vitamin E. The vitamin E consumption is inhibited by the addition of catalase (500 U/ml) and azide (1 mM), but it is not affected by potassium cyanide (1 mM). It may be proposed that the challenge of platelets with particulate stimuli causes generation of oxygen reduction products, which leads to vitamin E depletion.

In beta-thalassemic homozygotes, low plasma levels of tocopherols may induce a red blood cell (RBC) lipid peroxidation and consequent hemolysis. This is an indication to treat these patients with vitamin E. In this study 26 beta-thalassemic homozygotes aged 2-14 years, were given vitamin E, 10 orally and 16 parenterally, 300 mg per day for 15 days. Prior to administration and blood transfusion, as compared to normal subjects of the same age, plasma and RBC tocopherols were significantly lower, whereas RBC malonyldialdehyde (MDA) was significantly increased. In both groups, after tocopherol administration, an increase in plasma and RBC tocopherols and a decrease in RBC MDA were found. The significance of these variations was greater in the parenterally treated group than in orally treated group. The treatment with vitamin E, appears to be effective to reduce the RBC oxidative damage in homozygous beta-thalassemia, principally when administered parenterally perhaps because of its poor intestinal absorption in these subjects.