Vitamin E: Not only a single stereoisomer.

The recent publication by Azzi and colleagues puts forth the argument that only RRR-α-tocopherol should be considered as vitamin E from a physiological point of view. They base their argument primarily on the assertion that only this form has been used to treat stark vitamin E deficiency in humans (known as AVED, or Ataxia with Vitamin E Deficiency). Azzi et al. also argue that other chemically similar molecules, such as tocopherols other than α-tocopherol and tocotrienols do not provide vitamin E activity. Azzi and colleagues are correct on this second point. An investigation into the biological activities of vitamin E, and the mechanisms behind these activities, confirms that physiological vitamin E activity is limited to certain α-tocopherol forms. However, it is also clear that these activities are not restricted only to the RRR-form but include other 2R-forms as well. Indeed, the α-tocopherol transfer protein (α-TTP), which is critical to mediate vitamin E trafficking and biological activity, and genetic defects of which lead to vitamin E deficiency, binds well to all 2R-forms of α-tocopherol. Furthermore, both RRR-α-tocopherol and the other 2R-forms are maintained in human plasma and distributed to tissues and organs, whereas the 2S-stereoisomers are excreted quickly. As such, in recent years the definition of vitamin E including both 2R- and RRR-α-tocopherol has gained both broad scientific and regulatory acceptance. Consistent with this understanding, we provide evidence that AVED has indeed been treated successfully with forms in addition to RRR-α-tocopherol, again arguing against the restriction of the definition to RRR-α-tocopherol only. Finally, we provide evidence against any safety concerns utilizing the currently accepted definition of vitamin E.

Atypical retinopathy in ataxia with vitamin E deficiency: report of a sibship.

Typical retinitis pigmentosa (RP) may not be the only retinal phenotype encountered in ataxia with vitamin E deficiency (AVED). The following short case series describes a novel form of retinopathy in AVED. We describe two patients with AVED belonging to the same consanguineous sibship. Both presented an unusual retinopathy consisting of scattered, multifocal, nummular, hyperautofluorescent atrophic retinal patches. The retinopathy remained stable under vitamin E supplementation. We hypothesize these changes to be the result of arrested AVED-related RP following early supplementation with α-tocopherol acetate.

Genetic heterogeneity within a consanguineous family involving TTPA and SETX genes.

Autosomal recessive cerebellar ataxias (ARCA) constitute a highly heterogeneous group of progressive neurodegenerative disorders that typically occur prior to adulthood. Despite some clinical resemblance between these disorders, different genes are involved. We report in this study four Tunisian patients belonging to the same large consanguineous family, sharing autosomal recessive cerebellar ataxia phenotypes but with clinical, biological, electrophysiological, and radiological differences leading to the diagnosis of two distinct ARCA caused by two distinct gene defects. Two of our patients presented ataxia with the vitamin E deficiency (AVED) phenotype, and the other two presented ataxia with oculo-motor apraxia 2 (AOA2). Genetic testing confirmed the clinical diagnosis by the detection of a frameshift c.744delA pathogenic variant in the TTPA gene, which is the most frequent in Tunisia, and a new variant c.1075dupT in the SETX gene. In Tunisia, data suggest that genetic disorders are common. The combined effects of the founder effect and inbreeding, added to genetic drift, may increase the frequency of detrimental rare disorders. The genetic heterogeneity observed in this family highlights the difficulty of genetic counseling in an inbred population. The examination and genetic testing of all affected patients, not just the index patient, is essential to not miss a treatable ataxia such as AVED, as in the case of this family.

The low prevalence rate of vitamin E deficiency in urban adults of Wuhan from central China: findings from a single-center, cross-sectional study.

BACKGROUND: Vitamin E is an essential nutrient in human body famous for its antioxidant and non-antioxidant functions. However, little is known about vitamin E deficiency status in urban adults of Wuhan from central China. Our aim is to describe the distribution of both circulating and lipid-adjusted serum vitamin E concentration in urban adults of Wuhan. METHODS: We hypothesized that the prevalence rate of vitamin E deficiency would be low in Wuhan in consideration of the Chinese food composition. A cross-sectional study with 846 adults was performed in a single-center. Concentrations of vitamin E were measured by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). RESULTS: The median (interquartile range, IQR) of serum vitamin E concentration was 27.40 (22.89-33.20) µmol/L while that of serum vitamin E concentration adjusted by total cholesterol or the sum of cholesterol (TC) and triglyceride (TG) (the sum of cholesterol and triglyceride, TLs) were 6.20 (5.30-7.48) and 4.86 (4.10-5.65) mmol/mol, respectively. No significant difference of the circulating and TC-adjusted vitamin E concentration was found between male and female except for vitamin E/TLs. However, concentrations of vitamin E increased significantly (r = 0.137, P < 0.001) with age, but lipid-adjusted concentrations of vitamin E did not. On analysis of risk factors, the subjects characterized by hypercholesterolemia are more likely to exhibit higher circulating but lower lipid-adjusted vitamin E level due to adequacy of the serum carriers for delivery of vitamin E. Only 0.47% of the population were below 12 µmol/L of vitamin E defined as functional deficiency. CONCLUSION: The prevalence rate of vitamin E deficiency in urban adults of Wuhan is low, which is important and useful to clinicians for clinical decision-making in public health practice.

Vitamin E deficiency in childhood: a narrative review.

Vitamin E is an important nutrient from the earliest stages of life. It plays key roles as an antioxidant and in the maintenance of the immune system, among others. Vitamin E deficiency (VED), which occurs more frequently in children, is rarely addressed in the literature. This narrative review aims to summarise the chemistry, biology, serum indicators and clinical trials that have evaluated the impact of fortification and other relevant aspects of vitamin E, in addition to the prevalence of its deficiency, in children worldwide. Vitamin E intake in recommended amounts is essential for this nutrient to perform its functions in the body. Serum α-tocopherol is the most widely used biochemical indicator to assess the prevalence of VED. VED has been associated with symptoms secondary to fat malabsorption and may lead to peripheral neuropathy and increased erythrocyte haemolysis. Reduced concentrations of α-tocopherol may be caused by the combination of diets with low amounts of vitamin E and inadequate consumption of fats, proteins and calories. The lowest prevalence of VED was found in Asia and the highest in North America and Brazil. High proportions of VED provide evidence that this nutritional deficiency is a public health problem in children and still little addressed in the international scientific literature. The planning, evaluation and implementation of health policies aimed at combatting VED in the paediatric population are extremely important.

Vitamin E Levels in Preterm and Full-Term Infants: A Systematic Review.

Vitamin E deficiency (VED) is associated with clinical repercussions in preterm newborns (PTN), but low levels are also found in full-term newborns (TN). As this inadequacy can compromise neurogenesis in childhood, studies are needed to assess whether there is a difference in vitamin E status among newborns according to gestational age to provide support for neonatal monitoring protocols. This systematic review presents a synthesis of the available information on the vitamin E status among PTN and TN. The review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Observational studies that evaluated alpha-tocopherol levels were searched in the databases reported in the protocol registered in PROSPERO (CRD42021165152). The Newcastle-Ottawa Scale was used to assess the methodological quality. Overall, 1809 articles were retrieved; 10 were included in the systematic review. In the PTN, the alpha-tocopherol levels ranged from 3.9 to 8.5 mmol/L, while in TN, they were 4.9 to 14.9 mmol/L, and VED ranged from 19% to 100% in newborns. Despite substantial heterogeneity in research methodology and VED classification, the results suggest that the alpha-tocopherol levels among preterm and full-term newborns is below the recommended levels. Our findings demonstrate that further investigations are needed to standardize this classification and to monitor vitamin E status in birth and postnatal with adequate bias control.

The Role of Vitamin Deficiency in Liver Disease: To Supplement or Not Supplement?

Over the past few years, growing interest has been shown for the impact of dietary requirements and nutritional factors on chronic diseases. As a result, nutritional programs have been reinforced by public health policies. The precise role of micronutrients in chronic liver disease is currently receiving particular attention since abnormalities in vitamin levels are often detected. At present, treatment programs are focused on correcting vitamin deficiencies, which are frequently correlated to higher rates of comorbidities with poor outcomes. The literature reviewed here indicates that liver diseases are often related to vitamin disorders, due to both liver impairment and abnormal intake. More specific knowledge about the role of vitamins in liver disease is currently emerging from various results and recent evidence. The most significant benefits in this area may be observed when improved vitamin intake is combined with a pharmacological treatment that may also affect the progression of the liver disease, especially in the case of liver tumors. However, further studies are needed.

Ataxia with vitamin E deficiency in the Philippines†: A case report of two siblings.

Here we report two siblings with ataxia and peripheral neuropathy. One patient showed head tremors. Genetic analysis revealed a mutation in the hepatic α-tocopherol transfer protein (α-TTP) gene (TTPA) on chromosome 8q13. They were diagnosed with ataxia with vitamin E deficiency which is firstly reported in the Philippines. As the symptoms of ataxia with vitamin E deficiency can be alleviated with lifelong vitamin E administration, differential diagnosis from similar syndromes is important. In addition, ataxia with vitamin E deficiency causes movement disorders. Therefore, a common hereditary disease in the Philippines, X-linked dystonia-parkinsonism, could be another differential diagnosis. The Philippines is an archipelago comprising 7,107 islands, and the prevalence of rare hereditary diseases among the populations of small islands is still unclear. For neurologists, establishing a system of genetic diagnosis and counseling in rural areas remains challenging. These unresolved problems should be addressed in the near future. J. Med. Invest. 68 : 400-403, August, 2021.

Vitamin E: How much is enough, too much and why!

α-Tocopherol (α-T) is a required dietary nutrient for humans and thus is a vitamin. This narrative review focuses on vitamin E structures, functions, biological determinants and its deficiency symptoms in humans. The mechanisms for the preferential α-T tissue enrichment in the human body include the α-T transfer protein (TTPA) and the preferential metabolism of non-α-T forms. Potential new α-T biomarkers, pharmacokinetic data, and whether there are better approaches to evaluate and set the α-T dietary requirement are discussed. Finally, the possible role of α-T supplements in delay of chronic diseases and the evaluation of vitamin E safety are considered.

Reflections on a century of vitamin E research: Looking at the past with an eye on the future.

The name vitamin E, was given by Barnett and Sure who suggested that the factor proposed by Evans and Bishop as substance "X," be termed vitamin "E" as the next vitamin after the A, B, C and D vitamins had been already described. The identification of vitamin E with a-tocopherol was made in 1936 by Evans' group. One year later ß-tocopherol and 11 years later δ-tocopherol were isolated. Tocotrienol (named zetatocopherol) was first described in 1957 and later isolated in 1961. The antioxidant property of tocopherols was reported by Olcott and Emerson in 1937. Inherited vitamin E deficiency, AVED, characterized by a form of neuromyopathy was first described in 1981. The disease, was localized to chromosome 8q and found to be caused by a mutation of the a-TTP gene. The subsequent paragraphs are not a comprehensive review but only critical reflections on some important aspects of vitamin E research.

α-Tocopherol transfer protein (α-TTP).

α-Tocopherol transfer protein (α-TTP) is so far the only known protein that specifically recognizes α-tocopherol (α-Toc), the most abundant and most biologically active form of vitamin E, in higher animals. α-TTP is highly expressed in the liver where α-TTP selects α-Toc among vitamin E forms taken up via plasma lipoproteins and promotes its secretion to circulating lipoproteins. Thus, α-TTP is a major determinant of plasma α-Toc concentrations. Familial vitamin E deficiency, also called Ataxia with vitamin E deficiency, is caused by mutations in the α-TTP gene. More than 20 different mutations have been found in the α-TTP gene worldwide, among which some missense mutations provided valuable clues to elucidate the molecular mechanisms underlying intracellular α-Toc transport. In hepatocytes, α-TTP catalyzes the vectorial transport of α-Toc from the endocytotic compartment to the plasma membrane (PM) by targeting phosphatidylinositol phosphates (PIPs) such as PI(4,5)P2. By binding PIPs at the PM, α-TTP opens the lid covering the hydrophobic pocket, thus facilitating the release of bound α-Toc to the PM.

GPX4 and vitamin E cooperatively protect hematopoietic stem and progenitor cells from lipid peroxidation and ferroptosis.

Ferroptosis, a newly defined mode of regulated cell death caused by unbalanced lipid redox metabolism, is implicated in various tissue injuries and tumorigenesis. However, the role of ferroptosis in stem cells has not yet been investigated. Glutathione peroxidase 4 (GPX4) is a critical suppressor of lipid peroxidation and ferroptosis. Here, we study the function of GPX4 and ferroptosis in hematopoietic stem and progenitor cells (HSPCs) in mice with Gpx4 deficiency in the hematopoietic system. We find that Gpx4 deletion solely in the hematopoietic system has no significant effect on the number and function of HSPCs in mice. Notably, hematopoietic stem cells (HSCs) and hematopoietic progenitor cells lacking Gpx4 accumulated lipid peroxidation and underwent ferroptosis in vitro. α-Tocopherol, the main component of vitamin E, was shown to rescue the Gpx4-deficient HSPCs from ferroptosis in vitro. When Gpx4 knockout mice were fed a vitamin E-depleted diet, a reduced number of HSPCs and impaired function of HSCs were found. Furthermore, increased levels of lipid peroxidation and cell death indicated that HSPCs undergo ferroptosis. Collectively, we demonstrate that GPX4 and vitamin E cooperatively maintain lipid redox balance and prevent ferroptosis in HSPCs.

Gene Expression of CRAL_TRIO Family Proteins modulated by Vitamin E Deficiency in Zebrafish (Danio Rerio).

An evaluation of the impact of vitamin E deficiency on expression of the alpha-tocopherol transfer protein (α-TTP) and related CRAL_TRIO genes was undertaken using livers from adult zebrafish based on the hypothesis that increased lipid peroxidation would modulate gene expression. Zebrafish were fed either a vitamin E sufficient (E+) or deficient (E-) diet for 9 months, then fish were euthanized, and livers were harvested. Livers from the E+ relative to E- fish contained 40-times more α-tocopherol (P <0.0001) and one fourth the malondialdehyde (P = 0.0153). RNA was extracted from E+ and E- livers, then subject to evaluation of gene expression of ttpa and other genes of the CRAL_TRIO family, genes of antioxidant markers, and genes related to lipid metabolism. Ttpa expression was not altered by vitamin E status. However, one member of the CRAL_TRIO family, tyrosine-protein phosphatase non-receptor type 9 gene (ptpn9a), showed a 2.4-fold increase (P = 0.029) in E- relative to E+ livers. Further, we identified that the gene for choline kinase alpha (chka) showed a 3.0-fold increase (P = 0.010) in E- livers. These outcomes are consistent with our previous findings that show vitamin E deficiency increased lipid peroxidation causing increases in phospholipid turnover.

Low Serum Vitamin E Level Associated with Low Hand Grip Strength in Community-Dwelling Adults: Korean National Health and Nutrition Examination Survey (KNHANES VII) 2016-2018.

This study assessed the association between serum vitamin E levels and hand grip strength (HGS) in community-dwelling adults data of 1011 men aged 50 years and older and 1144 postmenopausal women were analyzed. Low HGS was defined as HGS below the sex-stratified median value. Proportion of low HGS was the greatest in the lowest quintile of serum vitamin E level (<10.51 mg/L, 57.1%), with a decreasing trend toward the highest vitamin E quintile (>17.81 mg/L, 43.6%; p < 0.001). A one-unit (mg/L) decrease in vitamin E levels was associated with lower HGS in men (adjusted beta coefficient -0.10, 95% confidence interval [CI] -0.18 to -0.02, p = 0.019), but not in women (-0.01, 95% CI -0.06 to 0.03, p = 0.550). Compared with the middle quintile (Q3; 12.59-14.69 mg/L), the lowest vitamin E quintile (Q1) was associated with elevated odds of low HGS (adjusted odds ratio [aOR]: 1.38, p = 0.045), independent of sociodemographic factors, health-related lifestyles, comorbidities, dietary intake, and cholesterol level. However, the odds of low HGS did not differ significantly in other vitamin E quintiles (Q2, aOR 1.12; Q4, aOR 1.38; Q5, aOR 1.12; p > 0.05). Individuals with the lowest quintile vitamin E level had elevated odds of low HGS independent of covariates, findings which merit further validation.

[A cachectic man with a severe vitamin deficiency]. / Een cachectische man met een ernstig vitaminetekort.

A 57-year-old man, known with severe malnutrition, vitamin E deficiency and peripheral neuropathies, presented with vomiting and abdominal tenderness. There was a suspicion of ileus and small bowel obstruction. During the exploratory laparotomy a complete brown colored bowel without peristalsis was seen.

Vitamin E Deficiency Disrupts Gene Expression Networks during Zebrafish Development.

Vitamin E (VitE) is essential for vertebrate embryogenesis, but the mechanisms involved remain unknown. To study embryonic development, we fed zebrafish adults (>55 days) either VitE sufficient (E+) or deficient (E-) diets for >80 days, then the fish were spawned to generate E+ and E- embryos. To evaluate the transcriptional basis of the metabolic and phenotypic outcomes, E+ and E- embryos at 12, 18 and 24 h post-fertilization (hpf) were subjected to gene expression profiling by RNASeq. Hierarchical clustering, over-representation analyses and gene set enrichment analyses were performed with differentially expressed genes. E- embryos experienced overall disruption to gene expression associated with gene transcription, carbohydrate and energy metabolism, intracellular signaling and the formation of embryonic structures. mTOR was apparently a major controller of these changes. Thus, embryonic VitE deficiency results in genetic and transcriptional dysregulation as early as 12 hpf, leading to metabolic dysfunction and ultimately lethal outcomes.

Hidden Hunger of Vitamin E among Healthy College Students: A Cross- Sectional Study.

BACKGROUND: College students may have a risk of fat-soluble vitamin deficiencies due to unhealthy dietary habits, especially for vitamin A and E. They are important members of the human antioxidant network; deficiencies of these vitamins may increase the risk of many critical diseases. OBJECTIVE: The current study was undertaken to determine the status of vitamin A and E in college students. METHODS: Healthy college students were recruited, and fasting blood samples of them were collected and used for determining serum levels of retinol and α-tocopherol by the HPLC method. RESULTS: We found that there was no vitamin A deficiency in college students. However, vitamin E deficiency existed in 34.5% of college students, especially in males. All the students had no vitamin E adequacy. In addition, our findings showed that BMI was inversely associated with serum α-- tocopherol, but not serum retinol. CONCLUSION: These results suggest that vitamin E deficiency in college students should be given more attention, and it is necessary to consider using vitamin E supplements.