Vitamin E

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Summary

  • Naturally occurring tocochromanols include eight fat-soluble forms: α-, β-, γ-, and δ-tocopherol and α-, β-, γ-, and δ-tocotrienol. The body preferentially uses α-tocopherol, and only α-tocopherol supplementation can reverse vitamin E deficiency symptoms. Therefore, only α-tocopherol is defined as vitamin E. (More information) 
  • α-Tocopherol functions as a chain-breaking antioxidant, preventing the propagation of free radicals in membranes and plasma lipoproteins. α-Tocopherol is also likely involved in strengthening certain aspects of cell-mediated immunity. (More information)
  • Vitamin E deficiency can be caused by fat malabsorption disorders or by genetic abnormalities that affect vitamin E transport. Severe deficiency symptoms include vitamin E deficiency-induced ataxia, peripheral neuropathy, muscle weakness, and damage to the retina of the eye. (More information)
  • The current recommended dietary allowance (RDA) is 15 mg/day of α-tocopherol. Most Americans do not meet dietary intake recommendations for vitamin E. (More information)
  • Randomized controlled trials investigating primary and/or secondary prevention of chronic diseases, such as cardiovascular disease, cancer, and cataracts, do not currently support a preventative effect of supplemental α-tocopherol. (More information)
  • Limited clinical evidence suggests that vitamin E supplementation may be beneficial for managing age-related macular degeneration and fatty liver diseases secondary to obesity and/ or type 2 diabetes mellitus. (More information)
  • While observational studies have associated higher intakes of vitamin E with lower risks of dementia and Alzheimer’s disease, clinical studies have not shown a benefit of α-tocopherol supplementation in the primary prevention of dementia. (More information)
  • Plant seeds and nuts, especially sunflower seeds, almonds, and hazelnuts, are rich sources of α-tocopherol such that vegetable oils (e.g., olive oil and sunflower oil) are rich in α-tocopherol. Other sources include tomatoes, avocados, spinach, asparagus, Swiss chard, and broccoli. (More information)
  • High doses of supplemental α-tocopherol may interfere with the vitamin K absorption and thus increase the risk of bleeding. This interaction is especially important in individuals taking anticoagulant drugs. A tolerable upper intake level (UL) for α-tocopherol in adults is set at 1,000 mg/day and applies to both natural and synthetic α-tocopherol. (More information)


Vitamin E is defined as α-tocopherol, while tocochromanols describes a family of eight fat-soluble molecules with antioxidant activities: four tocopherol isoforms (α-, β-, γ-, and δ-tocopherol) and four tocotrienol isoforms (α-, β-, γ-, and δ-tocotrienol) (Figure 1). Only one form, α-tocopherol, meets human vitamin E requirements (see The RDA). In the human liver, α-tocopherol is the form of vitamin E that is preferentially bound to α-tocopherol transfer protein (α-TTP) and incorporated into lipoproteins that transport α-tocopherol in the blood for delivery to extrahepatic tissues. α-Tocopherol is the predominant fat-soluble antioxidant found in the blood and tissues (1). Moreover, α-tocopherol is the tocochromanol with the greatest nutritional significance and is therefore the primary topic of this article.

Vitamin E Figure 1. Natural alpha-tocopherol, as made by plants, has an RRR-configuration at the 2, 4', and 8'-position of the alpha-tocopherol molecule. Vitamin E is defined as 2R-alpha tocopherol. Chemically synthesized alpha-tocopherol, known as all-rac-alpha-tocopherol, contains a mixture of eight stereoisomers that arose from the three chiral carbons at the positions 2, 4', and 8': RRR, SRR, RSR, RRS, RSS, SSR, SRS, and SSS. Because only stereoisomers with an R-configuration in position 2 (aka 2-R-stereoisomers) of alpha-tocopherol meet human vitamin E requirements, half of the stereoisomers present in all-rac-alpha-tocopherol (RRR, RSR, RRS, and RSS) are considered to be biologically active forms of vitamin E.

Forms and Function

α-Tocopherol

Natural versus synthetic α-tocopherols

Natural α-tocopherol, as made by plants, has an RRR-configuration at the 2, 4’, and 8’-position of the α-tocopherol molecule (d-α-tocopherol on labels) (Figure 1). Chemically synthesized all-rac-α-tocopherol (all-racemic-α-tocopherol; dl-α-tocopherol on labels) is a mixture of eight stereoisomers of α-tocopherol, which arose from the three chiral carbons at the 2, 4’, and 8’-positions: RRR-, RSR-, RRS-, RSS-, SRR-, SSR-, SRS-, and SSS-α-tocopherol (Figure 1). While all stereoisomers have equal in vitro antioxidant activity, only the forms in the R-conformation at position 2 (noted 2R) meet the vitamin E requirements in humans (2). Supplementation with RRR-α-tocopherol or all-rac-α-tocopherol reverses human vitamin E deficiency, and the US FDA has ruled that vitamin E is defined as 2R-α-tocopherol (3).

Antioxidant activity

The main function of α-tocopherol in humans is that of a fat-soluble antioxidant that stops lipid peroxidation. Fats, which are an integral part of all cell membranes, are vulnerable to damage through lipid peroxidation by free radicals. α-Tocopherol is uniquely suited to intercept peroxyl radicals and thus prevent a chain reaction of lipid peroxidation (Figure 2). When a molecule of α-tocopherol intercepts a free radical, α-tocopherol is oxidized to the α-tocopheroxy radical and must be reduced. Other antioxidants, such as vitamin C, can regenerate the α-tocopheroxy radical to α-tocopherol (Figure 2) (reviewed in 1).

Aside from maintaining the integrity of cell membranes throughout the body, α-tocopherol protects the fats in low-density lipoproteins (LDLs) from oxidation. Lipoproteins are particles composed of lipids and proteins that transport fats through the bloodstream. LDLs specifically transport cholesterol from the liver to the tissues of the body. Oxidized LDLs have been implicated in the development of cardiovascular disease (4).

Vitamin E Figure 1. Natural alpha-tocopherol, as made by plants, has an RRR-configuration at the 2, 4', and 8'-position of the alpha-tocopherol molecule. Vitamin E is defined as 2R-alpha tocopherol. Chemically synthesized alpha-tocopherol, known as all-rac-alpha-tocopherol, contains a mixture of eight stereoisomers that arose from the three chiral carbons at the positions 2, 4', and 8': RRR, SRR, RSR, RRS, RSS, SSR, SRS, and SSS. Because only stereoisomers with an R-configuration in position 2 (aka 2-R-stereoisomers) of alpha-tocopherol meet human vitamin E requirements, half of the stereoisomers present in all-rac-alpha-tocopherol (RRR, RSR, RRS, and RSS) are considered to be biologically active forms of vitamin E.

Effects on cell-mediated immunity

Other functions of α-tocopherol are likely to be related to its antioxidant capacity (1). For instance, α-tocopherol can protect the physiological properties of lipid bilayer membranes and may influence the activity of membrane proteins and enzymes (5). In cell culture studies, α-tocopherol was found to improve the formation of an adhesive junction (known as immune synapse) between naïve T lymphocytes and antigen presenting cells (APC), which eventually prompted T cell activation and proliferation (see Disease Prevention) (6, 7).

γ-Tocopherol and tocotrienols — examples of other tocochromanols

In addition to α-tocopherol, some other tocochromanols are known to be potent fat-soluble antioxidants. In fact, tocotrienols and γ-tocopherol are thought to be better scavengers of peroxyl radicals and reactive nitrogen species, respectively, than α-tocopherol (8). Yet, in the body, (1) α-tocopherol is preferentially retained in the liver by the binding to α-tocopherol transfer protein (α-TTP), which incorporates α-tocopherol into lipoproteins for delivery to extrahepatic tissues; and (2) forms of vitamin E other than α-tocopherol are actively metabolized and excreted. Hence, while γ-tocopherol is the most common form of vitamin E in the American diet (9), its plasma and tissue concentrations are generally significantly lower than those of α-tocopherol. γ-Tocopherol is rapidly lost from the circulation, and more metabolites of γ-tocopherol are excreted in urine compared to α-tocopherol, suggesting less γ-tocopherol is needed for use by the body (1).

Studies conducted in vitro and in animals have indicated that γ-tocopherol and its major metabolite, γ-carboxyethyl hydroxychroman (γ-CEHC), may play a role in protecting the body from free radical-induced damage in various conditions of oxidative stress and inflammation (reviewed in 8). Limited intervention studies (highlighted in 8) have not convincingly demonstrated a potential anti-inflammatory effect of γ-tocopherol in humans. Yet, in two randomized, placebo-controlled studies, the supplementation of smokers with γ-tocopherol potentiated short-term benefits of smoking cessation (with or without nicotine replacement therapy) on vascular endothelial function (10, 11).

Numerous preclinical studies have also suggested that tocotrienols might be beneficial in the prevention of chronic diseases (12). For instance, tocotrienols (especially δ-tocotrienol) have shown greater anti-proliferative and pro-apoptotic effects than tocopherols in malignant cell lines (13). However, a number of factors, including dose, formulation, and type of study population, affect the bioavailability of tocotrienols and may undermine their putative efficacy in humans (14).

Metabolism

Intestinal absorption

Biliary and pancreatic secretions are needed in the small intestine for fat digestion. Tocochromanols, along with bile acids and products of fat digestion, are incorporated into micelles, and the contents are taken up by intestinal cells (enterocytes). α-Tocopheryl esters (e.g., α-tocopheryl acetate) from supplements or food fortificants must be hydrolyzed by pancreatic esterases to release α-tocopherol for incorporation into micelles. 

Tocochromanol uptake into enterocytes is facilitated by several transporters, including Niemann-Pick C1 like 1 (NPC1L1), scavenger receptor class B type I (SR BI), and cluster of differentiation 36 (CD36). Upon entry into enterocytes, tocochromanols and other fat-soluble compounds may accumulate in lipid droplets. 

The intestinal cell assembles nascent chylomicrons by synthesizing the major chylomicron protein, apolipoprotein B48 (apoB48). Chylomicron synthesis requires the microsomal triacylglyceride transfer protein (MTTP) to lipidate apoB48. Tocochromanols in lipid droplets in the enterocytes coalesce with newly synthesized chylomicrons. The assembled chylomicrons are then secreted into the lymph for subsequent delivery to the circulation. Tocochromanols take a prolonged time (9-12 hours) from being consumed to entering the circulation in chylomicrons, a process that is promoted by a subsequent meal (15). This multistep process allows additional fat and various fat-soluble compounds, including tocochromanols, to be incorporated into chylomicrons. 

Traber et al. (15) quantitated α-tocopherol absorption in healthy women using two different forms of deuterium-labelled α-tocopherol. One form was given intravenously as a fat emulsion resembling chylomicrons and the other was administered orally with a defined liquid meal. Both the quantitation of α-tocopherol absorption and the kinetics of plasma α-tocopherol disappearance were determined. On average, 55% of the oral dose of α-tocopherol was absorbed; the unabsorbed oral α-tocopherol dose was excreted in the feces (15)

Distribution—hepatic α-tocopherol secretion and lipoprotein transport 

All dietary tocochromanols are absorbed and delivered to the liver in chylomicrons, but only α-tocopherol is preferentially secreted from the liver. The hepatic α-tocopherol transfer protein (α-TTP) participates in a multistep process that results in plasma lipoprotein enrichment in α-tocopherol (16). α-TTP itself is not secreted from the hepatocyte but remains in the cytosol, while α-tocopherol is transferred to an external lipoprotein acceptor, such as nascent high-density or very low-density lipoproteins (HDL or VLDL). Defective or absent α-TTP causes rapid α-tocopherol excretion from the body, causing vitamin E deficiency in both humans and animals. In humans, this disorder is called "Ataxia with Vitamin E Deficiency" (AVED; see Deficiency below).

During the postprandial period, the plasma lipoproteins can contain a variety of tocochromanols that are absorbed and transported in chylomicrons. However, the liver-secreted VLDL preferentially contain α-tocopherol. These VLDL can also undergo lipolysis in the circulation, causing α-tocopherol to be distributed to circulating low-density lipoproteins (LDL) and HDL. This VLDL-enrichment process is repeated multiple times and enriches the plasma lipoproteins with α-tocopherol for delivery to tissues. Moreover, the entire plasma α-tocopherol pool is replaced daily because of the continued re-secretion from the liver of VLDL containing α-tocopherol (15).

Catabolism and excretion

Vitamin E is not accumulated in the body, suggesting that the xenobiotic mechanisms of catabolism and excretion are important. Cytochrome P450 4F2 (CYP4F2) initiates ω-oxidation of tocochromanols, a process that is followed by ß-oxidation to carboxyethyl hydroxychromanol (CEHC), which can be conjugated with glucuronide or sulfate and excreted in urine or bile. High α-tocopherol intakes, e.g., most vitamin E supplements, lead to increases in plasma α-tocopherol, decreases in plasma γ-tocopherol (17), and increases in excretion of both α-CEHC and γ-CEHC. 

Although the tissues involved in tocochromanol catabolism are not well identified, CYP4F2 is expressed in liver and kidney (18), as well as intestine (19). The potential functions of tocochromanol catabolites are under active investigation because they retain their antioxidant activity and are more water soluble than the parent compounds. Health benefits and anti-inflammatory activities have been attributed to the activity of tocochromanol catabolites, especially the 13'-COOH catabolite since it inhibits 5-lipoxygenase — a key enzyme in the biosynthesis of leukotrienes from arachidonic acid.

Nutrient interactions

Dietary and circulating fatty acids

In the circulation, all lipoproteins (i.e., VLDLs, LDLs, and HDLs) are involved in the transport and tissue distribution of α-tocopherol (1). Increased concentrations of lipids (cholesterol and triglycerides) in the blood have been correlated to higher serum α-tocopherol concentrations. However, if a high blood concentration of lipids is associated with a slower turnover of lipoproteins, then the distribution of α-tocopherol to tissues may be substantially altered (20).  

Vitamin C

A few human studies using conditions of oxidative stress have demonstrated the importance of vitamin C (ascorbic acid) in the recycling of oxidized α-tocopherol back to its reduced state (see Figure 2). Oxidative stress caused by cigarette smoking accelerates the depletion of plasma α-tocopherol in smokers compared to nonsmokers (21). In a double-blind, placebo-controlled trial in 11 smokers and 13 nonsmokers given α-tocopherol and γ-tocopherol that was labeled with deuterium, supplementation with vitamin C reduced the rate of vitamin E loss in plasma, likely by regenerating tocopheryl radicals back to nonoxidized forms (22).

Vitamin K

Both α-tocopherol and phylloquinone (vitamin K1) are fat-soluble vitamins and share similar side chains. These two vitamins undergo some common processes at the level of intestinal absorption, transport via chylomicrons to the liver, hepatic catabolism, and excretion (23). Large doses of vitamin E have been found to antagonize vitamin K. For more information, see the Safety section below.

Deficiency

Causes

In humans, severe vitamin E deficiency rarely occurs from inadequate α-tocopherol intake but has been observed as a result of malnutrition (24). Severe vitamin E deficiency has been associated with specific genetic defects affecting the hepatic trafficking of α-tocopherol by α-tocopherol transfer protein (α-TTP) and transport in lipoproteins (apolipoprotein B). Vitamin E deficiency has also been observed in individuals with fat malabsorption syndromes (including patients with cystic fibrosis25) that impair the absorption of dietary fats and therefore fat-soluble vitamins like vitamin E (see Nutrient interactions) (24).

Symptoms

Severe vitamin E deficiency results mainly in neurologic symptoms, including impaired balance and coordination (spinocerebellar ataxia), injury to the sensory nerves (peripheral neuropathy), muscle weakness (myopathy), and damage to the retina of the eye (retinopathy). For this reason, people who develop peripheral neuropathy, ataxia, or retinitis pigmentosa (RP) of unknown causes should be screened for vitamin E deficiency (24).

Inherited defects in α-TTP are associated with a characteristic syndrome called "Ataxia with Vitamin E Deficiency" (AVED). AVED is caused by an autosomal recessive mutation in the TTPA gene that encodes α-TTP. Symptoms of AVED usually manifest early in life (ages 5-15 years). Supplementation with high-dose vitamin E (800-1,500 mg/day) is used to prevent neurologic deterioration in AVED subjects; lifelong supplementation is required (26).

Moreover, the developing nervous system appears to be especially vulnerable to vitamin E deficiency. For instance, children with severe vitamin E deficiency at birth rapidly experience irreversible neurologic symptoms if not treated with vitamin E. In contrast, individuals who develop gastrointestinal disorders affecting vitamin E absorption in adulthood may not develop neurologic symptoms for 10 to 20 years (24). It should also be noted that neurologic symptoms caused by vitamin E deficiency have not been reported in healthy individuals who consume diets low in vitamin E.

Marginal deficiency

Although frank vitamin E deficiency is rare, marginal intake of vitamin E may be relatively common. Average daily intake of α-tocopherol from food (including enriched and fortified sources) for adults (≥20 years of age) in the US is 11.5 mg for men and 9.5 mg for women (27). These intake levels are well below the RDA of 15 mg/day (see the RDA).

Blood concentrations of α-tocopherol are often used to assess vitamin E status, although concentrations should be adjusted for plasma lipid concentrations when lipids are elevated (28). According to the US National Academy of Medicine, plasma α-tocopherol concentrations less than 12 μmol/L (516 μg/dL) in adults are indicative of vitamin E inadequacy (2). Using this cutoff, the prevalence of vitamin E inadequacy among US adults (≥20 years, excluding pregnant and lactating women) is extremely low (<1% of the population) (29). This contrasts with the data from dietary surveys that suggest vitamin E inadequacy in the US is widespread. Discrepancies may be due to a number of factors, including underreporting of fat and fat-soluble vitamin intake, inaccuracies in the food composition database that lists nutrient values of foods, and/or lack of correction of circulating vitamin E concentrations to lipid concentrations (29). Some have questioned whether the nutritional requirement of vitamin E needs to be reevaluated (28).

Cigarette smoking is thought to increase the utilization of a-tocopherol such that smokers might be at increased risk of deficiency compared with nonsmokers (21). Also, the 19-year follow-up analysis of the Alpha-Tocopherol, Beta-Carotene cancer (ATBC) trial in older, male smokers indicated that participants in the highest versus lowest quintile of serum α-tocopherol concentrations (>31 mmol/L vs. <23 mmol/L) at baseline had reduced risks of total and cause-specific mortality (30).

A nested case-control study in Bangladeshi women suggested that inadequate vitamin E status during early pregnancy may be associated with an increased risk of miscarriage (31). It is not yet known whether marginal vitamin E deficiency increases the risk of chronic disease (1).

The Recommended Dietary Allowance (RDA)

The RDA for vitamin E was last revised by the Food and Nutrition Board of the US National Academy of Medicine in 2000 (Table 1) (2). The RDA is based largely on the results of studies done in the 1950s in men fed vitamin E-deficient diets. In a test-tube analysis, vitamin E suppresses the breakdown of red blood cells (i.e., hemolysis) induced by hydrogen peroxide. Because hemolysis has also been reported in children with severe vitamin E deficiency, the preventive effect of vitamin E against oxidative damage-induced hemolysis was considered to be a clinically relevant in vitro analysis to assess vitamin E status. Importantly, this means that the latest RDA for vitamin E continues to be based on the prevention of deficiency symptoms rather than on health promotion and prevention of chronic disease.

Table 1 lists the RDA for α-tocopherol expressed in milligrams (mg).

Table 1. Recommended Dietary Allowance (RDA) for α-Tocopherol*
Life Stage Age Males Females
mg/day mg/day
Infants (AI) 0-6 months
4
4
Infants (AI) 7-12 months
5
5
Children 1-3 years
6
6
Children 4-8 years
7
7
Children     9-13 years
11
11
Adolescents 14-18 years
15
15
Adults 19 years and older
15
15
Pregnancy all ages
-
15
Breast-feeding all ages
-
19

*These recommended intakes are limited to 2R-stereoisomeric forms of α-tocopherol.

Disease Prevention

Age-related deterioration of immune function

The age-related decline of the immune function is accompanied by increased susceptibility to infections, a poorer response to immunization, and higher risks of developing cancers and autoimmune diseases. α-Tocopherol has been shown to enhance specifically the T cell-mediated immune response that declines with advancing age (reviewed in 32). T cell impaired response has been partly associated with a reduced capacity of naïve T cells to be activated during antigen presentation, and to produce interleukin-2 (IL-2) and proliferate as a result (7). However, very few studies have addressed the potential association between α-tocopherol and immune function in humans (32). In a small intervention study in older adults (mean age, 70 years), supplementation with 200 mg/day of all-rac-α-tocopherol (equivalent to 100 mg of RRR-α-tocopherol) for three months significantly improved natural killer (NK) cytotoxic activity, neutrophil chemotaxis, and phagocytic response, and enhanced mitogen-induced lymphocyte proliferation and interleukin-2 (IL-2) production compared to baseline (33). In an earlier trial, daily supplementation of healthy older adults (≥65 years of age) with 200 mg of all-rac-α-tocopherol for 235 days also improved T lymphocyte-mediated immunity — as measured with the delayed-type hypersensitivity (DTH) skin test — and increased the production of antibodies in response to hepatitis B and tetanus vaccines (34).

Lower α-tocopherol doses failed to improve the DTH response compared to a placebo in another study in healthy participants (ages, 65-80 years) (35). A randomized, placebo-controlled trial in 617 nursing home residents (≥65 years of age) reported that daily supplementation with 200 IU of synthetic α-tocopherol (90 mg of RRR-α-tocopherol) for one year significantly lowered the risk of contracting upper respiratory tract infections, especially the common cold, but had no effect on lower respiratory tract (lung) infections (36). More research is needed to examine whether supplemental vitamin E might enhance immune function and reduce risk of infection in older adults.

Cardiovascular disease

Primary prevention: in healthy adults

Observational studies: Results of several large observational studies in both men and women have suggested an inverse relationship between vitamin E consumption and risk of myocardial infarction or death from heart disease. Each study had a prospective design that measured vitamin E intake in generally healthy people who were followed over a period of time to determine the onset of cardiovascular events and analyze the association between the exposure and the outcome(s). In two of the studies, individuals who consumed more than 7 mg/day of dietary α-tocopherol were 35% less likely to die from heart disease than those who consumed less than 3-5 mg/day of α-tocopherol (37, 38). Two other large studies observed a significantly reduced risk of heart disease only in women and men who consumed at least 100 IU (67 mg)/day of supplemental RRR-α-tocopherol (39, 40). Moreover, in a large cohort study in Japan, higher dietary vitamin E intakes were associated with a lower risk of death from heart failure in women (n=35,597) but not in men (23,099) (41).

Intervention studies: A randomized, placebo-controlled, intervention trial in 39,876 women (aged ≥45 years) participating in the Women's Health Study (WHS) found that supplementation with 600 IU (400 mg) of RRR-α-tocopherol every other day for 10 years resulted in a 34% reduction in nonfatal myocardial infarction and a 49% reduction in cardiovascular-related deaths but only in women aged at least 65 years at baseline (representing 10% of study participants) (42). Further analyses of WHS data showed that women in the vitamin E arm of the study experienced a 21% reduction in risk of venous thromboembolism (VTE) compared to placebo: the reduction was of 12% in women younger than 55 years old, 26% in women aged 65 years and older, and 44% in women with a history of VTE (43, 44). Another large randomized controlled trial — the Physicians' Health Study II (PHSII) — conducted in healthy middle-aged men found no significant effect of 400 IU of synthetic α-tocopherol (180 mg of RRR-α-tocopherol), given every other day for eight years, on the risk of major cardiovascular events in the entire cohort and in subgroup analyses (45). Additionally, concerns were raised regarding a possible harmful effect of high-dose vitamin E supplementation on the risk of hemorrhagic stroke in this cohort (45). Yet a meta-analysis of seven trials did not find an increased risk of hemorrhagic stroke with vitamin E supplementation (46). In recent analyses, the US Preventive Services Task Force found no benefit of vitamin E supplementation in the prevention of cardiovascular disease and advises against its use (47, 48).

Secondary prevention: in individuals with or at risk of cardiovascular disease

Conventional risk factors for cardiovascular disease (CVD) include cigarette smoking, physical inactivity, hypertension, dyslipidemia, and being overweight or obese. Other factors such as oxidative stress and inflammation are also thought to contribute to increasing CVD risk, especially in patients with chronic conditions like type 2 diabetes mellitus and chronic kidney disease. Although trials do not appear to support any cardiovascular benefit in healthy middle-aged and older subjects, vitamin E supplementation might help improve cardiovascular health and/or lower the risk of CVD in specific, higher risk subjects.

Observational studies: The presence of atherosclerotic plaques in arterial walls is one of the hallmarks of cardiovascular disease. Plaque rupture that causes blood clot formation is the usual cause of myocardial and cerebrovascular infarctions. The cross-sectional Asymptomatic Carotid Atherosclerosis Disease In Manfredonia (ACADIM) study in 640 at-risk individuals reported an inverse association between carotid intima-media thickness (CIMT) — a marker of atherosclerosis — and circulating concentrations of antioxidants, including vitamin E (49). However, other observational studies found no association between plasma vitamin E concentrations and CIMT (reviewed in 50).

Intervention studies: A small randomized controlled study assessing the effect of lipid-lowering drugs in men who had previously undergone a coronary artery bypass surgery found that the use of at least 100 IU/day (compared to less than 100 IU/day) of supplemental α-tocopherol (45 mg of RRR-α-tocopherol) was associated with reduced CIMT progression over a two-year period but only among participants in the placebo arm of the study (i.e., those who did not receive lipid-lowering drugs) (51). However, a meta-analysis of seven small placebo-controlled trials found little evidence that vitamin E supplementation may improve flow-mediated vascular dilation (FMD) of the brachial artery, a marker of vascular endothelial health that is adversely affected by CVD risk factors (52). In the Cambridge Heart AntiOxidant Study (CHAOS), a randomized, placebo-controlled intervention trial in 2,002 patients with coronary heart disease, daily supplementation with either 400 IU or 800 IU of synthetic α-tocopherol (180 mg or 360 mg of RRR-α-tocopherol) for a median of 18 months dramatically reduced the occurrence of nonfatal myocardial infarctions by 77%. However, vitamin E supplementation did not significantly reduce total or cardiovascular-related deaths (53).

Another small trial in patients with renal failure — the Secondary Prevention with Antioxidants of cardiovascular disease in End-stage renal disease (SPACE) — found that supplementation with 800 IU (536 mg)/day of RRR-α-tocopherol for an average of 1.4 years significantly reduced the risk of myocardial infarction compared to placebo (54). Another randomized controlled study suggested that vitamin E supplementation may benefit a subgroup of patients with type 2 diabetes mellitus. The multicenter study by Milman et al. (55) was conducted in 1,434 patients with type 2 diabetes (≥55 years old) carrying a specific variant of the haptoglobin protein (Hp), Hp2-2, which has a lower efficacy to bind and remove pro-oxidant free hemoglobin from plasma, compared to Hp1-1 and Hp1-2 variants. The daily supplementation with 400 IU (268 mg) of RRR-α-tocopherol for 18 months resulted in a lower risk of myocardial infarction compared to placebo (55).

Other larger intervention trials conducted in cigarette smokers (the Alpha-Tocopherol, Beta-Carotene cancer prevention — ATBC study; 56), individuals at-risk of CVD (the Heart Outcomes Prevention Evaluation (HOPE)-The Ongoing Outcomes [HOPE-TOO study]; 57), or in patients who have suffered a myocardial infarction (Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico — GISSI-prevenzione trial; 58) failed to find significant CVD risk reductions with α-tocopherol supplementation. Additionally, potentially harmful effects of supplemental vitamin E were reported on the risk of hemorrhagic stroke in the ATBC trial and on the risk of heart failure in the HOPE and GISSI trials (see Safety) (56-58).

Cancer

Oxidative damage to DNA by free radicals can lead to mutations that may contribute to causing cancer (59). Because of its ability to neutralize free radicals, vitamin E has been suggested to possess anticancer activity by protecting cells against oxidative damage. Yet, several large prospective cohort studies have failed to find significant associations between vitamin E intake and the incidence of lung or breast cancer (2). The VITamins And Lifestyle (VITAL) study prospectively assessed the association between long-term use of supplemental vitamins (10-year intake) and the risk of lung cancer in a cohort of 77,126 men and women (60). No relationships were reported between intake of multivitamins, vitamin C, vitamin E, or folate and the risk of lung cancer. However, the use of supplemental vitamin E in current but not in former smokers was associated with an 11% increased risk of lung cancer for every 100 mg/day increase, and intakes greater than 215 mg/day were specifically linked to a 29% increase in risk for non-small cell lung cancer (60).

To date, most clinical trials have failed to find any beneficial effects of vitamin E supplementation on the risk of various cancers. A randomized, placebo-controlled trial in 39,876 women participating in the Women's Health Study found that supplementation with 600 IU (400 mg) of RRR-α-tocopherol every other day for 10 years had no effect on overall cancer incidence, tissue-specific cancer incidence, or cancer-related deaths (42). Yet, the results of a few large randomized controlled trials have suggested that vitamin E supplementation might affect the risk of prostate cancer. The Alpha-Tocopherol, Beta-Carotene cancer (ATBC) prevention study was a four-arm, randomized, double-blind, placebo-controlled trial designed to investigate the effect of α-tocopherol supplementation on lung cancer development in 29,133 male smokers. The study found a 32% reduction in the incidence of prostate cancer in participants given daily supplements of 50 mg of synthetic α-tocopherol (equivalent to 25 mg of RRR-α-tocopherol) alone or in combination with β-carotene compared to those given β-carotene alone or a placebo (61). However, no differences in the incidence of prostate cancer were found between α-tocopherol recipients and nonrecipients during the 18-year post-intervention period (62). In the Physicians' Health Study II (PHS II), which followed 14,641 healthy men aged 50 years and older, supplementation with 400 IU of synthetic vitamin E (equivalent to 180 mg of RRR-α-tocopherol) every other day for eight years had no effect on the risk of prostate cancer, other site-specific cancers, or total cancer (63). The supplementation of vitamin E (equivalent to 180 mg/day of RRR-α-tocopherol), alone or in combination with selenium, in the multicenter, randomized, placebo-controlled SELECT trial (SELenium and vitamin E Cancer prevention Trial) was halted because there was no evidence of benefit in preventing prostate cancer in 35,533 healthy men aged 50 years and older (64). After a median of seven years’ follow-up, the risk of prostate cancer was found to be significantly increased by 17% in participants supplemented with vitamin E alone during the trial period — but not when vitamin E was combined with selenium — compared to placebo (65). A study of cases versus subcohort individuals drawn from the SELECT study assessed the effect of vitamin E and/or selenium supplementation on prostate cancer risk in relation to the selenium status of participants at baseline (66). Supplemental selenium with or without vitamin E was associated with a significant increase in the risk of advanced prostate cancer in individuals with higher versus lower selenium status. In addition, the risks of total and advanced prostate cancer were significantly elevated with vitamin E supplementation in subjects with low versus high selenium status (66). Some investigations have suggested that sequence variations (polymorphisms) in vitamin E-related genes and genes coding for antioxidant enzymes, including selenoproteins, might modify the impact of high-dose vitamin E and selenium on the risk of prostate cancer (67-69).

In summary, most randomized controlled trials have not found a benefit of vitamin E supplementation in the prevention of cancer. A meta-analysis of five such trials found no effect of supplemental vitamin E on the incidence of cancer of any type (OR, 1.02; 95% CI, 0.98-1.08) (47). Accordingly, the US Preventive Services Task Force advises against the use of vitamin E supplements in the primary prevention of cancer (48).

Cataracts

Age-related cataracts appear to be the result of protein oxidation in the lens of the eye; antioxidants like α-tocopherol may protect the lens against oxidative damage from reactive oxygen species. In a cross-sectional study, vitamin E concentrations were found to be significantly lower in the lens and blood of subjects with age-related nuclear, but not cortical, cataracts when compared with an age-matched control group (70). However, earlier studies reported higher vitamin E concentrations in the lenses and blood of patients with cataracts (71, 72).

The results of several observational studies that examined the association between vitamin E consumption and the incidence or severity of cataracts are also mixed. Some reported that increased vitamin E intake protected against cataract development, while others found no association (73). Yet, a meta-analysis of eight studies, including 15,021 participants, found a 17% reduction in the risk of age-related cataract in subjects in the highest versus lowest quantile of dietary vitamin E intake (74). A prospective cohort study of 31,120 Swedish men followed for a mean of 8.4 years observed a greater risk of developing cataract in occasional and regular users of high-dose (about 100 mg/day) vitamin E supplements only, when compared with non-supplement users (75). However, the use of supplemental high-dose vitamin E with additional supplements or the use of low-dose vitamin E-containing multivitamin supplements was not found to be associated with an elevated cataract risk. A meta-analysis based on data from over 350,000 participants in 10 studies — including the above-cited study by Zheng Selin et al. (75) — found no association between supplemental vitamin E and risk of cataract (74).

In clinical settings, the supplementation of high-dose vitamin E — alone or in addition to other supplements — was found to be safe, yet the benefits regarding cataract risk or progression were limited. An early intervention trial found that a daily supplement of 50 mg of synthetic α-tocopherol (equivalent to 25 mg of RRR-α-tocopherol) did not alter the incidence of cataract surgery in male smokers (76). A randomized, placebo-controlled intervention trial in 4,629 men and women found that a daily antioxidant supplement containing 500 mg of vitamin C, 400 IU of all-rac-α-tocopheryl acetate (equivalent to 180 mg of RRR-α-tocopherol), and 15 mg of β-carotene did not affect development and progression of age-related cataracts over a seven-year period (77). Similarly, a four-armed, randomized, placebo-controlled study of 11,267 men from the Selenium and Vitamin E Cancer prevention trial (SELECT) failed to observe a reduction in cataract incidence with 400 IU/day of supplemental all-rac-α-tocopheryl acetate (180 mg/day of RRR-α-tocopherol), alone or in combination with selenium (200 μg/day), during a mean 5.6 years of follow-up (78). Daily antioxidant supplementation with 500 mg of vitamin C, 400 IU (268 mg) of RRR-α-tocopherol, and 15 mg of β-carotene did not limit the progression of cataract in a five-year intervention trial (79). Another four-year randomized, placebo-controlled trial reported that supplements containing 500 IU/day (335 mg/day) of RRR-α-tocopherol did not reduce the incidence or progression of cataract in older adults (80). Currently available data from clinical trials do not support a preventative effect of supplemental vitamin E on cataracts.

Disease Treatment

Age-related macular degeneration

A pooled analysis of four randomized controlled trials in 62,520 subjects found that supplemental vitamin E or β-carotene did not reduce the risk of developing age-related macular degeneration (AMD), a multifactorial disease affecting the central area of the retina (81). However, a review of currently available data suggested that supplements of antioxidants plus zinc may reduce the progression of AMD and vision loss in affected individuals (82). The main evidence came from the Age-Related Eye Disease Study (AREDS). In this clinical trial, participants with borderline to advanced age-related macular degeneration (AMD) were randomized to receive (1) placebo; (2) antioxidant vitamins (15 mg/day of β-carotene, 500 mg/day of ascorbic acid, and 400 IU/day of all-rac-α-tocopheryl acetate), (3) zinc (80 mg/day) and copper (2 mg/day); or (4) both antioxidant vitamins and zinc and copper (83). The five-year results indicated that the risk of developing advanced AMD was significantly reduced in those taking zinc with or without antioxidant vitamins. Antioxidant vitamins alone failed to prevent the progression to advanced AMD, even in individuals at higher risk. Similar results were found in a follow-up study, AREDS2, which examined the effect of a supplement containing vitamin E (400 IU/day of all-rac-α-tocopheryl acetate) — and several other nutrients and phytochemicals — in patients with intermediate or advanced AMD (84). It was concluded from both of these studies that a combination of antioxidant vitamins and minerals may benefit people with intermediate AMD or advanced AMD in one eye (82, 84, 85). Vitamin E is one of the ingredients in commercially available supplements based on AREDS and AREDS2 and marketed to those with AMD (86).

Type 2 diabetes mellitus

Oxidative stress contributes to the progression of type 2 diabetes mellitus and causes damage to many organs and tissues, including the pancreas, brain, eyes, peripheral nerves, and kidneys. Evidence from animal studies suggests that vitamin E supplementation could mitigate the role of oxidative damage in the occurrence of diabetes complications (reviewed in 87). In the Alpha-Tocopherol Beta-Carotene cancer prevention (ATBC) trial in male smokers, supplementation with 50 mg/day of synthetic α-tocopherol (25 mg/day of RRR-α-tocopherol) had no effect on the risk of incident type 2 diabetes mellitus during the 19-year post-intervention follow-up. Likewise, supplemental vitamin E intake during the trial made no difference on the incidence of macrovascular complications or mortality in participants with established type 2 diabetes (88). In addition, a meta-analysis of 14 heterogeneous randomized controlled trials, including 714 individuals with type 2 diabetes, found that supplementation with vitamin E (200-1,800 IU/day for 6-27 weeks) had no effect on markers of glycemic control, including glycated hemoglobin A1c (HbA1c) level and measures of fasting glucose and fasting insulin concentrations (89). Further subgroup analyses indicated that higher doses of vitamin E (>400 IU/day) supplemented for longer periods (>12 weeks) significantly reduced HbA1c level and fasting insulin concentration, suggesting that vitamin E could possibly enhance insulin action and glucose disposal in those with type 2 diabetes (89). Another meta-analysis of randomized controlled trials found that endothelial function in normal-weight and overweight — but not obese — patients with type 2 diabetes was significantly improved by supplementation with vitamin E and/or vitamin C (90). Although there is reason to suspect that vitamin E supplementation may have utility in the management of type 2 diabetes, evidence for benefit from large, well-controlled clinical trials is still lacking.

Fatty liver diseases

The increasing incidence of metabolic dysfunction-associated fatty liver disease (MAFLD; previously called nonalcoholic fatty liver disease [NAFLD]; this acronym is used below for studies published before this name change) in children and adults in industrialized countries is mainly attributed to the ongoing epidemics of obesity and type 2 diabetes mellitus (91). MAFLD is characterized by the abnormal accumulation of fat (steatosis) in the liver in the absence of heavy alcohol consumption and in the presence of obesity, type 2 diabetes mellitus, or metabolic dysregulation (92). Although the condition is considered to be largely benign, MAFLD can progress to a more severe disease called metabolic dysfunction-associated steatohepatitis (MASH; previously called nonalcoholic steatohepatitis [NASH]; 93) with increased risks of cirrhosis, hepatocellular carcinoma (liver cancer), and cardiovascular disease (94). Oxidative stress is thought to be one of the possible mechanisms responsible for prompting inflammatory processes that can lead to the progression of MAFLD to MASH.

There is currently no established treatment for MAFLD and MASH other than interventions that encourage lifestyle changes and the use of medicines to control or treat metabolic disorders (95, 96). In the multicenter PIVENS (PIoglitazone versus Vitamin E versus placebo for the treatment of Nonalcoholic Steatohepatitis) trial, 247 subjects with MASH but not diabetes mellitus were randomized to receive 30 mg/day of pioglitazone (an insulin-sensitizing drug), 800 IU/day (536 mg/day) of RRR-α-tocopherol, or a placebo for 96 weeks (97). Only vitamin E supplementation significantly increased the overall rate of improvement in histological abnormalities that characterize MASH on liver biopsies (i.e., hepatocellular ballooning, steatosis, and lobular inflammation) (98). Both active treatments improved some markers of liver function (i.e., alanine aminotransferase and aspartate aminotransferase) (98). Yet, results from another two-year, randomized controlled trial — the Treatment Of Nonalcoholic fatty liver disease In Children (TONIC) — in 173 children (ages, 8-17 years) with MAFLD failed to observe any significant reduction in blood concentrations of alanine and aspartate aminotransferases either with supplemental vitamin E (536 mg/day of RRR-α-tocopherol) or with metformin (an anti-diabetic drug; 1,000 mg/day) compared to placebo (99). However, vitamin E supplementation significantly improved the overall disease activity score — used to quantify the severity of the disease. In addition, a meta-analysis of another six trials found that vitamin E significantly lowered circulating aminotransferase concentrations in MAFLD and MASH patients, suggesting liver function improvements (100). Finally, in a small nonrandomized, unblinded, controlled study in 42 obese children (mean age, 8 years) with MAFLD, lifestyle recommendations combined with 600 mg/day of supplemental RRR-α-tocopheryl acetate for six months reduced markers of oxidative stress and liver dysfunction and improved insulin sensitivity and the profile of lipid in the blood, when compared to baseline. No such changes in markers of oxidative stress, liver function, and glucose utilization were reported in the lifestyle intervention only group (101). Further randomized and well-controlled studies are needed to confirm these preliminary findings.

Cognitive deterioration and Alzheimer's disease

Mitochondrial dysfunction and oxidative stress are thought to contribute to the onset and/or progression of several neurodegenerative diseases, especially Alzheimer's disease (AD) (102). The progressive degeneration of neuronal cells that accompanies the decline of memory and other cognitive functions in subjects with Alzheimer’s disease is associated with an intracellular aggregation of Tau fibrils, an extra-neuronal accumulation of b-amyloid peptides into senile plaques, and an oxidation-reduction (redox) imbalance of complex etiology. In the brain of patients with mild cognitive impairment (MCI) and those with AD, the level of markers of oxidative damage to DNA, proteins, and lipids is increased, while the expression and activities of glutathione and antioxidant enzymes are reduced (reviewed in 102). In a meta-analysis of prospective cohort studies, higher vitamin E intakes — from diet and supplements combined — were associated with lower risks of dementia (13 studies) and AD (8 studies) (103). Moreover, meta-analyses of observational studies have reported that circulating concentrations of vitamin E were significantly lower in AD patients than in cognitively healthy individuals (104, 105). Other studies have documented low concentrations of vitamin E in cerebrospinal fluid of cognitively impaired patients (reviewed in 106).

Because a reduction in oxidative stress may help maintain cognitive status and/or prevent deterioration, the effects of vitamin E supplementation have been assessed in a few intervention studies. An early multicenter, randomized, placebo-controlled study in individuals with AD of moderate severity found that supplementation with 2,000 IU/day of all-rac-α-tocopherol (equivalent to 900 mg/day of RRR-α-tocopherol) for two years significantly delayed cognitive decline, slowed disease progression, and increased median survival (107). However, a placebo-controlled trial in 769 patients with MCI found that the same dosage of vitamin E did not affect the probability of progression from MCI to AD over a three-year period (108). In a smaller, double-blind, placebo-controlled trial in 256 older adults, ages 60-75 years, co-supplementation with 300 mg/day of all-rac-α-tocopherol and 400 mg/day of vitamin C for one year reduced a biomarker of oxidative stress (malondialdehyde) but had no effect on cognitive performance — measured by the Mini Mental State Examination (MMSE) scoring system (109). In another double-blind, placebo-controlled trial, an improvement in cognitive performance (i.e., MMSE score) was reported in AD patients randomized to receive 800 IU/day of all-rac-α-tocopherol (360 mg/day of RRR-α-tocopherol) for six months only when the treatment effectively reduced oxidative stress (as assessed by the measure of total glutathione and markers of lipid peroxidation in the blood) (110). Conversely, a failure to reduce oxidative stress resulted in supplemental vitamin E being more detrimental to the cognitive function of AD patients than placebo. In a more recent multicenter, randomized, double-blind, placebo-controlled study, supplemental vitamin E (2,000 IU/day; form of vitamin E not mentioned in the publication) for over two years significantly delayed functional decline — determined by the (in)ability to perform basic activities of daily living — and reduced the annual mortality rate in mild and moderate AD patients (111). Yet, vitamin E failed to affect cognitive performance measured with MMSE scores and other cognitive ability tests.

There is currently little evidence to suggest that long-term supplementation of vitamin E provides any cognitive benefits in healthy older adults (112). In a primary prevention study among 3,629 cognitively healthy older adults, the Prevention of Alzheimer’s Disease by Vitamin E and Selenium (PREADViSE) trial, vitamin E supplementation (400 IU/day of supplemental all-rac-α-tocopheryl acetate [180 mg/day of RRR-α-tocopherol]) for a mean of 5.4 years had no benefit on prevention of dementia (113). Additional research is needed to examine whether vitamin E supplementation has utility in the management of patients with mild-to-moderate cognitive impairments. 

Sources

Food sources

Good sources of α-tocopherol include vegetable oils (olive, sunflower, and safflower oils), nuts, seeds, whole grains, avocados, tomatoes, and green leafy vegetables. All eight forms of tocochromanols (α-, β-, γ-, and δ-tocopherols and α-, β-, γ-, and δ-tocotrienols) occur naturally in mostly plant-based foods but in varying amounts. Table 2 lists the content of α-tocopherol and γ-tocopherol (in milligrams) in some rich sources of vitamin E. For more information on the vitamin E content of foods, search USDA's FoodData Central.

Table 2. Some Food Sources of Vitamin E and γ-Tocopherol
Food Serving α-Tocopherol (mg) γ-Tocopherol (mg)
Sunflower oil 1 tablespoon 9.6 <1.4
Sunflower seed kernels, dry roasted 1 ounce 7.4 0
Almonds 1 ounce 7.3 0.2
Safflower oil 1 tablespoon 6.4 0.5
Hazelnuts, dry roasted 1 ounce 4.3 0
Avocado 1 fruit 4.2 0.7
Grapeseed oil 1 tablespoon 3.9 -
Tomato sauce, canned 1 cup 3.5 0.2
Corn oil 1 tablespoon 3.2 8.5
Cranberry juice, unsweetened 1 cup (8 fl oz) 3.0 -
Peanut butter, smooth 2 tablespoons 2.9 2.4
Apricots, dried ½ cup (halves) 2.8 0.1
Canola oil 1 tablespoon 2.4 5.8
Olive oil 1 tablespoon 1.9 0.1
Spinach, boiled ½ cup 1.9 -
Soybean oil 1 tablespoon 1.7 9.9
Swiss chard, boiled ½ cup (chopped) 1.7 -
Peanuts, dry roasted 1 ounce 1.4 1.8
Asparagus, boiled ½ cup 1.4 0.2
Broccoli, boiled ½ cup (chopped) 1.1 -
Wheat germ 2 tablespoons 1.1 -
Blackberries, raw ½ cup 0.8 1.0
Salmon, sockeye, cooked, dry heat 3 ounces 0.8 0.2
Pecans 1 ounce 0.4 6.9
"-" means that the amount is not included in the USDA database

In the US, the average intake of α-tocopherol from food (including enriched and fortified sources) for adults (≥19 years of age) is 7.2 mg/day (25); this level is well below the RDA of 15 mg/day of α-tocopherol (see Table 1). While it appears feasible for individuals to meet the RDA from food only, Americans would have to depart from their current dietary practices and include greater intakes of nuts, seeds, fruit, and vegetables without increasing fat intake above recommended levels (96).

Supplements

RRR-α-tocopherol and all-rac-α-tocopherol

RRR-α-tocopherol is the only stereoisomeric form of α-tocopherol found in unfortified foods. The same is not always true for nutritional supplements. Supplements made from entirely natural sources contain only RRR-α-tocopherol (labeled d-α-tocopherol). RRR-α-tocopherol is the most bioavailable form of α-tocopherol in the body. Synthetic α-tocopherol, which is often found in fortified food and nutritional supplements and usually labeled all-rac-α-tocopherol or dl-α-tocopherol, include all eight possible stereoisomers of α-tocopherol (see Forms and Function). Because half of the isomers present as a mixture in synthetic α-tocopherol are not usable by the body, synthetic α-tocopherol is less bioavailable than natural α-tocopherol (see Figure 1).

The amount of vitamin E in a food or supplement should be listed in mg on the Nutrition Facts or Supplement Facts label (116). There is a wide range of α-tocopherol supplements on the market in varying dosages; thus, it is important to read the supplement label. In the past, labels listed vitamin E content in international units (IU), and several scientific studies have reported vitamin E dosage in IU. The unit conversions are as follows:

  • Natural vitamin E (RRR-α-tocopherol) containing supplements:
    IU of RRR-α-tocopherol x 0.67 = mg of RRR-α-tocopherol
    Example: 100 IU of natural vitamin E provides 67 mg of RRR-α-tocopherol
  • Synthetic vitamin E (all-rac-α-tocopherol) containing supplements: 
    IU of all-rac-α-tocopherol x 0.45 = mg of RRR-α-tocopherol
    Example: 100 IU of synthetic vitamin E provides 45 mg of RRR-α-tocopherol
α-Tocopheryl esters

α-Tocopheryl succinate and α-tocopheryl acetate are the main esterified forms of vitamin E in nutritional supplements. Tocopherol esters are more resistant to oxidation during storage than unesterified tocopherols (1). When taken orally, the succinate or acetate moieties are removed from α-tocopherol in the intestine. The bioavailability of α-tocopherol from α-tocopheryl succinate and α-tocopheryl acetate is equivalent to that of free α-tocopherol (117). Hence, the conversion factors used to determine the amount of bioavailable α-tocopherol provided by α-tocopheryl succinate and α-tocopheryl acetate are the same as those used for α-tocopherol (see above) (2). Cell culture studies indicated that the vitamin E ester, α-tocopheryl succinate, could inhibit proliferation and induce apoptosis in a number of cancer cell lines (13). Limited data from animal models of cancer found that α-tocopheryl succinate administered by injection inhibited tumor growth (118). There is currently no evidence in humans that taking oral α-tocopheryl succinate supplements delivers α-tocopheryl succinate to tissues. Of note, current research investigates nanomedicines to increase α-tocopheryl succinate bioavailability before exploring putative benefits in clinical settings (118).

α-Tocopheryl nicotinate is another α-tocopherol ester formed from synthetic α-tocopherol and nicotinic acid (niacin). While α-tocopheryl nicotinate can be prescribed as a lipid-lowering agent in Europe and Japan, it is marketed as a supplement only in the US (119).

α-Tocopheryl phosphates (Ester-E®)

There is currently no published evidence that supplements containing α-tocopheryl phosphates are more efficiently absorbed or have greater bioavailability in humans than those containing α-tocopherol (119).

Other supplemental forms

Supplements containing γ-tocopherol, mixed tocopherols, or tocotrienols are also commercially available; see the Dietary Supplement Label Database). The amounts of α- and γ-tocopherol in mixed tocopherol supplements vary, so it is important to read the label to determine the amount of each tocopherol form present in a capsule.

Safety

Toxicity

Few side effects have been noted in adults taking supplements of less than 2,000 mg of α-tocopherol daily (either natural or synthetic vitamin E). However, most studies assessing safety issues or toxicity of α-tocopherol supplementation have lasted only a few weeks to a few months, and side effects associated with long-term α-tocopherol supplementation have not been adequately studied. The most worrisome possibility is that of impaired blood clotting, which increases the likelihood of hemorrhage in some individuals. A meta-analysis of randomized controlled trials found that daily vitamin E supplementation — equivalent to 25 to 536 mg/day of RRR-α-tocopherol — for several years resulted in a significant, 10% reduction in the risk of ischemic stroke (five trials, 91,393 participants) and a nonsignificant trend towards an increased risk of hemorrhagic stroke (five trials, 100,748 participants) (120).

A tolerable upper intake level (UL) for any form of supplemental α-tocopherol (all possible stereoisomers) has been established by the Food and Nutrition Board of the US National Academy of Medicine to avoid the potential risk of bleeding (Table 3). Specifically, the UL of 1,000 mg/day of α-tocopherol in any supplemental form (equivalent to 1,500 IU/day of RRR-α-tocopherol or 1,100 IU/day of all-rac-α-tocopherol) corresponds to the highest dose unlikely to result in hemorrhage in almost all adults (2). Although only certain isomers of α-tocopherol are retained in the circulation, all forms are absorbed and metabolized by the liver. Hence, the rationale for a UL that refers to all stereoisomers of α-tocopherol is based on the fact that any form of α-tocopherol (natural or synthetic) can be absorbed and thus be potentially harmful.

Table 3. Tolerable Upper Intake Level (UL) for α-Tocopherol*
Age Group mg/day
Infants 0-12 months  Not possible to establish#
Children 1-3 years 200
Children 4-8 years 300
Children 9-13 years 600
Adolescents 14-18 years 800
Adults 19 years and older 1,000

*The UL for α-tocopherol applies to all stereoisomers of α-tocopherol (natural and synthetic) found in supplements and fortified food.

#Source of intake should be from foods or formula only.

In 2024, an EFSA (European Food Safety Authority) panel published a report on vitamin E safety (121). They concluded that the ULs previously set by the Scientific Committee on Food, which regard vitamin E from all sources (food, fortified food, and supplements combined), remain unchanged for various subpopulations: 50 mg/day for infants 4-6 months; 60 mg/day for infants 7-11 months; 100 mg/day for children 1-3 years; 120 mg/day for children 4-6 years; 160 mg/day for children 7-10 years; 220 mg/day for children 11-14 years; 260 mg/day for adolescents 15-17 years; and 300 mg/day for adults, including pregnant and lactating persons. These ULs regard all stereoisomeric forms of α-tocopherol. The panel further stated that these ULs don’t apply to people taking anticoagulant or antiplatelet medications (e.g., aspirin), to individuals with vitamin K malabsorption syndromes, or to patients with cardiovascular disease (121).

Some physicians recommend discontinuing high-dose vitamin E supplementation two to four weeks before elective surgery — including dental procedures — to decrease the risk of hemorrhage (119).  

Because dietary vitamin E is essential to prevent vitamin E deficiency in newborns, vitamin E must be supplied in parenteral nutrition solutions in infants who cannot be given enteral feeding, such as prematurely born infants. Yet, preterm infants appear to be especially vulnerable to adverse effects of α-tocopherol supplementation, and supplemental vitamin E should be administered only under controlled supervision by a pediatrician (122).

Finally, the results of one randomized controlled trial in 601 patients with common forms of retinitis pigmentosa indicated that supplementation with 400 IU/day of synthetic vitamin E (equivalent to 180 mg/day of RRR-α-tocopherol) modestly but significantly accelerated the loss of retinal function compared to placebo (123). Patients with common forms of retinitis pigmentosa should therefore avoid taking high-dose vitamin E supplements if they are not deficient in vitamin E (see Deficiency).

Does vitamin E supplementation increase the risk of all-cause mortality?

A prospective observational study in over 4,000 participants of the Framingham Heart Study and the Framingham Offspring Study — with or without preexisting cardiovascular disease — found no statistically significant association between vitamin E supplement intake and cardiovascular or all-cause mortality after a 10-year follow-up period (124). However, in addition to reports of increased risk of hemorrhage and heart failure with supplemental vitamin E in several randomized controlled studies (see Cardiovascular disease), a meta-analysis by Miller et al. (125) suggested an increased risk of death with the use of large doses of vitamin E, yet lower than the UL. Specifically, this meta-analysis combined the results of 19 clinical trials of vitamin E supplementation that mostly focused on secondary prevention and, as such, included subjects with pre-existing conditions, including heart disease, end-stage renal failure, and Alzheimer's disease. The study found that daily supplementation with at least 400 IU of synthetic vitamin E (equivalent to 180 mg of RRR-α-tocopherol) resulted in a 4% increase in risk of death from any cause compared to placebo (125). However, further dose-response analysis and adjustment for intake of other vitamin and mineral supplements indicated that all-cause mortality risk was significantly increased by 7% only at a dose of 2,000 IU/day, which is notably higher than the UL for adults (1,100 IU/day of synthetic tocopherol or 1,500 IU/day of natural tocopherol). Additionally, a meta-analysis of 46 randomized trials, including 171,244 participants, found that supplemental vitamin E, singly or in combination with other antioxidants, did not significantly alter the risk of all-cause mortality (126). At present, there is no convincing evidence that vitamin E supplementation below the UL increases the risk of death from cardiovascular disease or other causes, especially in generally healthy subjects. Yet, individuals with pre-existing conditions may be at increased risk of serious adverse effects (including death) if one considers the possibility that large doses of supplemental vitamin E might interfere with medications, and possibly lower their efficacy or increase their toxicity (1).

Nutrient interactions

Interactions with vitamin K  

Dating back to the 1940s, studies in animals found excessive dietary intake of vitamin E was associated with fatal hemorrhaging, which was prevented with vitamin K supplementation. In rat experiments, a decrease in phylloquinone (vitamin K1) and menaquinone-4 (a form of vitamin K2) concentrations in extra-hepatic tissues was found in animals administered excess α-tocopherol via the diet or by subcutaneous injection. One study in healthy adults with normal coagulation (blood clotting) status found that daily supplementation with 1,000 IU (670 mg) of RRR-α-tocopherol for 12 weeks decreased γ-carboxylation of prothrombin, a vitamin K-dependent factor in the coagulation cascade (127).

The use of vitamin E supplements may increase the risk of bleeding in individuals taking anticoagulant drugs (blood thinners), such as heparin and the vitamin K antagonist, warfarin (Coumadin); antiplatelet drugs, such as clopidogrel (Plavix), ticlopidine (Ticlid), tirofiban (Aggrastat), and dipyridamole (Aggrenox); and non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin, ibuprofen, and others. In addition, individuals who may be vitamin K deficient due to liver failure, those with a propensity to bleed (e.g., bleeding peptic ulcers), and those with inherited bleeding disorders (e.g., hemophilia) or a history of hemorrhagic stroke, should not take α-tocopherol supplements without close medical supervision because of the increased risk of hemorrhage (119, 128). Finally, it cannot be excluded that vitamin E would potentiate the antithrombotic activity of supplemental fish oils and herbal products, such as garlic, curcumin, or Ginkgo biloba (119).

Drug interactions

A number of cholesterol-lowering medications (like cholestyramine and colestipol), as well as orlistat, sucralfate, mineral oil, and the fat substitute olestra, which interfere with fat absorption, may theoretically decrease the absorption of fat-soluble vitamins, including vitamin E. The anticonvulsant drugs phenobarbital, phenytoin (Dilantin), and carbamazepine (Tegretol) may also lower plasma vitamin E concentrations in individuals with epilepsy (129).

Antioxidants and statins (3-hydroxy-3-methylglutary-coenzyme A reductase inhibitors)

A three-year randomized controlled trial in 160 patients with coronary heart disease (CHD) and low high-density-lipoprotein (HDL) levels found that a combination of simvastatin (Zocor) and niacin increased the HDL2 subfraction level (considered the most cardioprotective), inhibited the progression of coronary artery stenosis (narrowing), and decreased the frequency of cardiovascular events, such as myocardial infarction and stroke (130). Surprisingly, when an antioxidant combination of 1,000 mg of vitamin C, 800 IU (536 mg) of RRR-α-tocopherol, 100 μg of selenium, and 25 mg of β-carotene daily, was taken with the simvastatin-niacin combination, the protective effects were diminished. However, in a much larger randomized controlled trial of simvastatin and an antioxidant combination of 600 mg of all-rac-α-tocopherol (297 mg of RRR-α-tocopherol), 250 mg of vitamin C, and 20 mg of β-carotene daily) in more than 20,000 men and women with CHD or diabetes mellitus, the antioxidant combination did not adversely affect the cardioprotective effects of simvastatin therapy over a five-year period (131). These contradictory findings indicate that further research is needed on potential interactions between antioxidant supplementation and cholesterol-lowering agents like statins.

Linus Pauling Institute Recommendation

The Recommended Dietary Allowance (RDA) for vitamin E for adult men and women is 15 mg per day. According to dietary surveys, most US residents do not meet the daily requirement for vitamin E from food sources alone. Incorporating nuts, seeds, whole grains, green leafy vegetables, and vegetable oils in the diet will increase dietary vitamin E intake. LPI also recommends that generally healthy adults take a daily multivitamin/mineral supplement that contains 100% of the DV for vitamin E, i.e., 15 mg of RRR-α-tocopherol (d-α-tocopherol on labels) or 30 mg of all-rac-α-tocopherol (dl-α-tocopherol on labels).

Older adults (>50 years)

The Linus Pauling Institute’s recommendation to consume a vitamin E-rich diet and take a daily multivitamin/mineral supplement containing vitamin E is also appropriate for generally healthy older adults.


Authors and Reviewers

Originally written in 2000 by: 
Jane Higdon, Ph.D. 
Linus Pauling Institute
Oregon State University

Updated in November 2004 by: 
Jane Higdon, Ph.D. 
Linus Pauling Institute 
Oregon State University

Updated in June 2008 by: 
Victoria J. Drake, Ph.D. 
Linus Pauling Institute 
Oregon State University

Updated in May 2015 by: 
Barbara Delage, Ph.D. 
Linus Pauling Institute 
Oregon State University

Updated in May 2024 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in August 2024 by:
Maret G. Traber, Ph.D.
Ava Helen Pauling Professor Emeritus, Linus Pauling Institute
Professor Emeritus, College Health
Oregon State University

Copyright 2000-2024  Linus Pauling Institute


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