Vitamin E

Vitamin E is a fat-soluble nutrient found in many foods, added to others, and available as a dietary supplement. “Vitamin E” is the collective name for a group of fat-soluble compounds with distinctive antioxidant activities ¹⁾. Naturally occurring vitamin E exists in eight chemical forms: four tocopherol isoforms (alpha-, beta-, gamma-, and delta-tocopherol OR α-, β-, γ-, and δ-tocopherol) and four tocotrienol isoforms (alpha-, beta-, gamma-, and delta-tocotrienol OR α-, β-, γ-, and δ-tocotrienol) that have varying levels of biological activity (see Figure 2) ²⁾, ³⁾. Alpha- (or α-) tocopherol is the only form that is recognized to meet human requirements and the body preferentially uses alpha-tocopherol, and only α-tocopherol supplementation can reverse vitamin E deficiency symptoms ⁴⁾, ⁵⁾, ⁶⁾, ⁷⁾, ⁸⁾.

In the human liver, alpha-tocopherol (α-tocopherol) is the form of vitamin E that is preferentially bound to alpha-tocopherol transfer protein (α-TTP) and incorporated into lipoproteins that transport alpha-tocopherol (α-tocopherol) in the blood for delivery to tissues outside your liver ⁹⁾. Therefore, alpha-tocopherol (α-tocopherol) is the predominant form of vitamin E found in your blood and tissues ¹⁰⁾. In addition, alpha-tocopherol (α-tocopherol) appears to be the form of vitamin E with the greatest nutritional significance. Natural alpha-tocopherol (α-tocopherol) made by plants found in food has an RRR-configuration at the 2, 4’, and 8’-position of the alpha-tocopherol molecule wrongly referred to as d-α-tocopherol ¹¹⁾. Chemically synthesized all-racemic-α-tocopherol (all-rac-α-tocopherol) incorrectly labeled dl-α-tocopherol is a mixture of eight stereoisomers of alpha-tocopherol (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 (see Figure 2) ¹²⁾. While all vitamin E stereoisomers have equal in vitro (test tube studies) antioxidant activity, only the forms in the R-conformation at position 2 (noted 2R) meet the vitamin E requirements in humans ¹³⁾. Furthermore, beta-, gamma-, and delta-tocopherols, 4 tocotrienols, and several stereoisomers may also have important biologic activity ¹⁴⁾.

In your body, vitamin E acts a fat-soluble antioxidant, helping to protect your cells from the damage caused by free radicals, which are molecules that contain an unshared electron. Unshared electrons are highly energetic and react rapidly with oxygen to form reactive oxygen species (ROS) ¹⁵⁾. Free radicals are compounds formed when your body converts the food you eat into energy. People are also exposed to free radicals in the environment from cigarette smoke, air pollution, and ultraviolet radiation from the sun. Free radicals damage cells and might contribute to the development of cardiovascular disease and cancer ¹⁶⁾. Vitamin E is believed to serve as a chain-breaking antioxidant that stops the oxidative degradation of fats, thus preventing free radical production and harm to the cell. Scientists are investigating whether, by limiting free-radical production and possibly through other mechanisms, vitamin E might help prevent or delay the chronic diseases associated with free radicals.

In addition to its activities as an antioxidant, vitamin E is involved in immune function and, as shown primarily by in vitro studies (test tube lab studies) of cells, cell signaling, regulation of gene expression, and other metabolic processes ¹⁷⁾. Alpha-tocopherol inhibits the activity of protein kinase C, an enzyme involved in cell proliferation and differentiation in smooth muscle cells, platelets, and monocytes ¹⁸⁾. Vitamin-E–packed endothelial cells lining the interior surface of blood vessels are better able to resist blood-cell components adhering to this surface. Vitamin E also increases the expression of two enzymes that suppress arachidonic acid metabolism, thereby increasing the release of prostacyclin from the endothelium, which, in turn, dilates blood vessels and inhibits platelet aggregation ¹⁹⁾.

Your body also needs vitamin E to boost its immune system so that it can fight off invading bacteria and viruses. It helps to widen blood vessels and keep blood from clotting within them. In addition, cells use vitamin E to interact with each other and to carry out many important functions. Scientists are investigating whether, by limiting free-radical production and possibly through other mechanisms, vitamin E might help prevent or delay the chronic diseases associated with free radicals.

Aside from maintaining the integrity of cell membranes throughout the body, alpha tocopherol protects the fats in low-density lipoproteins (LDLs) from oxidation ²⁰⁾. Lipoproteins are particles composed of lipids and proteins that transport fats through the bloodstream. LDLs (bad cholesterol) specifically transport cholesterol from the liver to the tissues of the body. Oxidized LDLs (bad cholesterol) have been implicated in the development of cardiovascular disease ²¹⁾.

Vitamin E is absorbed in the intestinal lumen, which is dependent upon various factors such as pancreatic secretions, micelle formation, and most importantly, chylomicron secretions. Chylomicron secretion is necessary for vitamin E absorption. Vitamin E is found in sunflower seeds, nuts, some oils, spinach, butternut squash, and many other food sources. Vitamin E deficiency has been linked to peripheral neuropathy in addition to spinocerebellar ataxia, skeletal myopathy and pigmented retinopathy. Interestingly, studies have reported vitamin E level in association to the development of cataracts ²²⁾.

Serum concentrations of vitamin E (alpha-tocopherol) depend on your liver, which takes up the nutrient after the various forms are absorbed from the small intestine. Yet, in the body, alpha-tocopherol (α-tocopherol) is preferentially retained in the liver by the binding to alpha-tocopherol transfer protein (α-TTP) ²³⁾, which incorporates α-tocopherol into lipoproteins for delivery to extrahepatic tissues; and other forms of vitamin E other than alpha-tocopherol (α-tocopherol) are actively broken down and excreted ²⁴⁾. As a result, blood and cellular concentrations of other forms of vitamin E are lower than those of alpha-tocopherol and have been the subjects of less research ²⁵⁾, ²⁶⁾. Plasma tocopherol levels vary with total plasma lipid levels. Normally, the plasma alpha-tocopherol level is 5 to 20 mcg/mL (11.6 to 46.4 mcmol/L) ²⁷⁾.

Vitamin E is safe for pregnancy and breastfeeding. Both vitamin K and omega-6 fatty acids requirements may increase with high doses of vitamin E.

Some food and dietary supplement labels still list vitamin E in International Units (IUs) rather than milligrams (mg). 1 IU of the natural form of vitamin E is equivalent to 0.67 mg. 1 IU of the synthetic form of vitamin E is equivalent to 0.45 mg.

International Units and Milligrams

Vitamin E is listed on the new Nutrition Facts and Supplement Facts labels in milligrams (mg) ²⁸⁾. The U.S. Food and Drug Administration (FDA) required manufacturers to use these new labels starting in January 2020, but companies with annual sales of less than $10 million may continue to use the old labels that list vitamin E in international units (IUs) until January 2021 ²⁹⁾. Conversion rules are as follows:

To convert from mg to IU:

• 1 mg of alpha-tocopherol is equivalent to 1.49 IU of the natural form or 2.22 IU of the synthetic form.

To convert from IU to mg:

• 1 IU of the natural form is equivalent to 0.67 mg of alpha-tocopherol.
• 1 IU of the synthetic form is equivalent to 0.45 mg of alpha-tocopherol.

For example, 15 mg of natural alpha-tocopherol would equal 22.4 IU (15 mg x 1.49 IU/mg = 22.4 IU). The corresponding value for synthetic alpha-tocopherol would be 33.3 IU (15 mg x 2.22 IU/mg).

Figure 1. Vitamin E chemical structure

Figure 2. Vitamin E chemical structures

Footnote: The differences in the α, β, γ and δ forms are in the number and position of the methyl groups on the chromanol ring. Only the β- and γ- forms of tocopherols or tocotrienols can be called isomers, having the same formula but a different arrangement of atoms in the molecule. The difference between the tocopherols and the tocotrienols is in the presence of three double bonds in the side chain of the latter.

[Source ³⁰⁾ ]

Figure 3. Vitamin E metabolism

Footnote: Schematic representation of vitamin E metabolism. The mechanism of vitamin E digestion and uptake into intestinal cells (enterocytes) is unclear but requires bile acids and pancreatic enzymes, and the packaging along with dietary fat into chylomicrons. The efficiency of vitamin E absorption increases with the amount of fat in ingested food, such that vitamin E absorption from supplements is likely to be minimal with low-fat meals ³¹⁾, ³²⁾. In the circulation, all lipoproteins (i.e., VLDLs, LDLs, and HDLs) are involved in the transport and tissue distribution of alpha-tocopherol ³³⁾. Increased concentrations of fats (cholesterol and triglycerides) in the blood have been correlated to higher serum alpha-tocopherol concentrations. However, if a high blood concentration of fats is associated with a slower turnover of lipoproteins, then the distribution of alpha-tocopherol to tissues may be substantially altered ³⁴⁾.

Abbreviations: LCMs = long-chain-metabolites; MCMs = multi-cycling metabolites; SCMs = short-chain-metabolites; CEHCs = carboxyethyl hydroxychromans (natural vitamin E metabolites); VE = vitamin E; LPL = lipoprotein lipase.

What does Vitamin E do?

Vitamin E is a fat-soluble antioxidant that stops the production of reactive oxygen species (ROS) formed when fat undergoes oxidation. Scientists are investigating whether, by limiting free-radical production and possibly through other mechanisms, vitamin E might help prevent or delay the chronic diseases associated with free radicals.

Antioxidants protect cells from the damaging effects of free radicals, which are molecules that contain an unshared electron. Free radicals damage cells and might contribute to the development of cardiovascular disease and cancer ³⁶⁾. Unshared electrons are highly energetic and react rapidly with oxygen to form reactive oxygen species. The body forms reactive oxygen species endogenously when it converts food to energy, and antioxidants might protect cells from the damaging effects of reactive oxygen species. The body is also exposed to free radicals from environmental exposures, such as cigarette smoke, air pollution, and ultraviolet radiation from the sun. Reactive oxygen species are part of signaling mechanisms among cells.

The body also needs vitamin E to boost its immune system so that it can fight off invading bacteria and viruses. It helps to widen blood vessels and keep blood from clotting within them.

In addition to vitamin E activities as an antioxidant, vitamin E is involved in immune function and, as shown primarily by in vitro studies of cells, cell signaling, regulation of gene expression, and other metabolic processes ³⁷⁾, ³⁸⁾, ³⁹⁾. Alpha-tocopherol inhibits the activity of protein kinase C, an enzyme involved in cell proliferation and differentiation in smooth muscle cells, platelets, and monocytes ⁴⁰⁾. Vitamin-E–replete endothelial cells lining the interior surface of blood vessels are better able to resist blood-cell components adhering to this surface. Vitamin E also increases the expression of two enzymes that suppress arachidonic acid metabolism, thereby increasing the release of prostacyclin from the endothelium, which, in turn, dilates blood vessels and inhibits platelet aggregation ⁴¹⁾. Moreover, vitamin E also helps improve nerve conduction ⁴²⁾, maintain the structural integrity of the hemoglobin membrane ⁴³⁾ and, along with vitamin A, plays a role in vision ⁴⁴⁾. The specific mechanism of action for most of vitamin E effects is still relatively unknown ⁴⁵⁾.

Vitamin E inhibits platelet adhesion by preventing oxidative changes to low-density lipoprotein (LDL) cholesterol also called bad cholesterol and inhibition of platelet aggregation by reducing prostaglandin E2. Another effect is inhibiting protein kinase C causing smooth-muscle proliferation.

Even though research has shown that vitamin E assists with the prevention of heart disease and atherosclerosis it has not been approved for this use by the United States Food and Drug Administration (FDA).

Antioxidant activity

The main function of alpha-tocopherol in humans is that of a fat-soluble antioxidant. Fats, which are an integral part of all cell membranes, are vulnerable to damage through lipid peroxidation by free radicals. Alpha-tocopherol is uniquely suited to intercept peroxyl radicals and thus prevent a chain reaction of lipid oxidation (Figure 4). When a molecule of α-tocopherol neutralizes a free radical, it is oxidized and its antioxidant capacity is lost. Other antioxidants, such as vitamin C, are capable of regenerating the antioxidant capacity of α-tocopherol (Figure 4) ⁴⁶⁾.

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 ⁴⁷⁾.

Tocotrienols and gamma-tocopherol are thought to be better scavengers of peroxyl radicals and reactive nitrogen species, respectively, than alpha-tocopherol ⁴⁸⁾. Yet, in the body, alpha-tocopherol is preferentially retained in the liver by the binding to alpha-tocopherol transfer protein (α-TTP), which incorporates α-tocopherol into lipoproteins for delivery to extrahepatic tissues; and forms of vitamin E other than α-tocopherol are actively metabolized and excreted. Hence, while gamma-tocopherol is the most common form of vitamin E in the American diet ⁴⁹⁾, its plasma and tissue concentrations are generally significantly lower than those of alpha-tocopherol and more gamma-tocopherol is excreted in urine than alpha-tocopherol, suggesting less gamma-tocopherol is needed for use by the body ⁵⁰⁾.

Studies conducted in vitro (test tubes lab studies) and in animals have indicated that gamm-tocopherol and its major metabolite, gamma-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 ⁵¹⁾. Limited intervention studies highlighted in Jiang ⁵²⁾ have not convincingly demonstrated a potential anti-inflammatory effect of gamma-tocopherol in humans. Yet, in two recent randomized, placebo-controlled studies, the supplementation of smokers with gamma-tocopherol potentiated short-term benefits of smoking cessation (with or without nicotine replacement therapy) on vascular endothelial function ⁵³⁾, ⁵⁴⁾.

Numerous preclinical studies have also suggested that tocotrienols might be beneficial in the prevention of chronic diseases ⁵⁵⁾. For instance, tocotrienols especially delta-tocotrienol have shown greater anti-proliferative and pro-apoptotic effects than tocopherols in malignant cell lines ⁵⁶⁾. 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 ⁵⁷⁾. There are currently no data available on the effectiveness of supplemental tocotrienols in humans ⁵⁸⁾.

Figure 4. Alpha-tocopherol antioxidant activity

Figure 5. Vitamin E antioxidant reactions

Footnote: (1) Hexose monophosphate shunt and GSH-reductase activity; (2) Membrane GSH-peroxidase activity.

Abbreviations: L = membrane lipids; Vitamin E° = tocopheryl radical; Vitamin C°, ascorbyl radical; GSH = reduced glutathione; GSSG =oxidized glutathione; NADP+ = oxidized nicotinamide-adenine-dinucleotide phosphate; NADPH = reduced nicotinamide-adenine-dinucleotide phosphate

Immune function

Other functions of alpha-tocopherol are likely to be related to its antioxidant capacity ⁶¹⁾. For example, alpha-tocopherol can protect the physiological properties of lipid bilayer membranes and may influence the activity of membrane proteins and enzymes ⁶²⁾. In cell culture studies, alpha-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 ⁶³⁾, ⁶⁴⁾.

The natural age-related decline of the immune function is accompanied by an increased susceptibility to infections, a poorer response to immunization, and higher risks of developing cancers and autoimmune diseases ⁶⁵⁾. Alpha-tocopherol has been shown to enhance specifically the T cell-mediated immune response that declines with advancing age ⁶⁶⁾. T cell impaired response has been partly associated with a reduced capacity of naive T cells to be activated during antigen presentation, and to produce interleukin-2 (IL-2) and proliferate as a result ⁶⁷⁾. However, very few studies have addressed the potential association between alpha-tocopherol and immune function in humans ⁶⁸⁾. In a small intervention study in older adults (mean age, 70 years), supplementation with 200 mg/day of all-rac-alpha-tocopherol (equivalent to 100 mg of RRR-α-tocopherol) for three months significantly improved natural killer (NK) cytotoxic activity, neutrophil chemotaxis, phagocytic response, and enhanced mitogen-induced lymphocyte proliferation and interleukin-2 (IL-2) production compared to baseline ⁶⁹⁾. In an earlier trial, daily supplementation of healthy older adults (≥65 years of age) with 200 mg of all-rac-alpha-tocopherol for 235 days also improved T lymphocyte-mediated immunity — as measured with the delayed-type hypersensitivity skin test and increased the production of antibodies in response to hepatitis B and tetanus vaccines ⁷⁰⁾.

Lower alpha-tocopherol doses failed to improve the delayed-type hypersensitivity response compared to a placebo in another study in healthy participants (ages, 65-80 years) ⁷¹⁾. A randomized, placebo-controlled trial in 617 nursing home residents (≥65 years of age) reported that daily supplementation with 200 IU of synthetic alpha-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 ⁷²⁾. More research is needed to examine whether supplemental vitamin E might enhance immune function and reduce risk of infection in older adults.

Reduction of ultraviolet (UV) radiation-induced skin damage

The primary role of vitamin E in the skin is to prevent damage induced by free radicals and reactive oxygen species (ROS); therefore, the use of vitamin E in the prevention of ultraviolet (UV) radiation-induced skin damage has been extensively studied. Ultraviolet (UV) radiation has an immunosuppressive effect on the antigen-presenting cells (APCs) within the epidermis and contributes to the likelihood of skin cancer ⁷³⁾. The sun is by far the strongest source of ultraviolet radiation in our environment. Solar emissions include visible light, heat and ultraviolet (UV) radiation. Just as visible light consists of different colors that become apparent in a rainbow, there are three types of ultraviolet (UV) radiation: UVC, UVB, and UVA. As sunlight passes through the atmosphere, all UVC and most UVB is absorbed by ozone, water vapor, oxygen and carbon dioxide. UVA is not filtered as significantly by the atmosphere.

The ozone layer absorbs 100% of UVC, 90% of UVB, and a minimal amount of UVA ⁷⁴⁾. For this reason, the depletion of the ozone layer increases UV transmission. UVA is associated with aging and pigmentation ⁷⁵⁾. It penetrates deep into the skin layer and produces free radical oxygen species, indirectly damaging DNA. UVA increases the number of inflammatory cells in the dermis and decreases the number of antigen-presenting cells ⁷⁶⁾. UVB causes sunburn and DNA strand breaks. UVB causes pyrimidine dimer mutations, which are associated with nonmelanoma skin cancers ⁷⁷⁾.

Although molecules in the vitamin E family can absorb light in the UVB spectrum, the “sunscreen” activity of vitamin E is considered limited since it cannot absorb UVA light or light in higher wavelengths of the UVB spectrum ⁷⁸⁾. Therefore, the primary photoprotective effect of vitamin E is attributed to its role as a lipid-soluble antioxidant.

Many studies in cell culture models (test tube lab studies) have found protective effects of vitamin E molecules on skin cells ⁷⁹⁾, ⁸⁰⁾, ⁸¹⁾, but these models do not recreate the complex structure of skin tissues. Therefore, human studies are needed.

Studies using orally administered vitamin E have reported mixed results on its photoprotective potential. An early study of vitamin E supplementation in hairless mice found no effect of dietary α-tocopherol acetate on UV-induced carcinogenesis ⁸²⁾. Three other mouse studies reported inhibition of UV-induced tumors in mice fed alpha-tocopherol acetate ⁸³⁾, ⁸⁴⁾, ⁸⁵⁾, but one of these studies utilized vitamin E doses that were toxic to animals when combined with the UV treatment ⁸⁶⁾. Another study in mice found a reduction of UV-induced DNA damage with dietary α-tocopherol acetate, but no effects on other free radical damage were observed in the skin ⁸⁷⁾. One human study reported that subjects taking 400 IU/day of alpha-tocopherol had reduced UV-induced lipid peroxidation in the skin but concluded there was no overall photoprotective effect ⁸⁸⁾. This was supported by another human study that found that 400 IU/day of alpha-tocopherol for six months provided no meaningful protection to skin ⁸⁹⁾. Furthermore, multiple human studies have shown no effect of vitamin E on the prevention or development of skin cancers ⁹⁰⁾, ⁹¹⁾.

In contrast to oral supplementation with alpha-tocopherol alone, multiple studies have found that the combination of vitamin C and vitamin E protects the skin against UV damage. Human subjects orally co-supplemented with vitamins C and E show increased Minimal Erythemal Dose (MED), the lowest dose of ultraviolet radiation that will produce a detectable redness 24 hours after UV exposure ⁹²⁾, ⁹³⁾. The combination of vitamin C and vitamin E was associated with lower amounts of DNA damage after UV exposure ⁹⁴⁾. Results of another study suggest a mixture of tocopherols and tocotrienols may be superior to α-tocopherol alone, as the mixture showed reduced sunburn reactions and tumor incidence after UV exposure in mice ⁹⁵⁾. However, further trials with dietary tocotrienol/tocopherol mixtures are needed in human subjects.

Topical application of vitamin E is generally effective for increasing photoprotection of the skin. In rodent models, the application of alpha-tocopherol or alpha-tocopherol acetate before UV exposure reduces UV-induced skin damage by reducing lipid peroxidation ⁹⁶⁾, ⁹⁷⁾, ⁹⁸⁾, ⁹⁹⁾, limiting DNA damage ¹⁰⁰⁾, ¹⁰¹⁾, ¹⁰²⁾, ¹⁰³⁾, and reducing the many chemical and structural changes to skin after UV exposure ¹⁰⁴⁾, ¹⁰⁵⁾, ¹⁰⁶⁾, ¹⁰⁷⁾. Vitamin E skin applications have also been shown to reduce UV-induced tumor formation in multiple mouse studies ¹⁰⁸⁾, ¹⁰⁹⁾, ¹¹⁰⁾ and to reduce the effects of photo-activated toxins in the skin ¹¹¹⁾, ¹¹²⁾, ¹¹³⁾, ¹¹⁴⁾. Skin application of vitamin E also reduces the effects of UV radiation when applied after the initial exposure. In mice, alpha-tocopherol acetate prevents some of the redness, edema, skin swelling, and skin thickening if applied immediately after UV exposure ¹¹⁵⁾, ¹¹⁶⁾. A similar effect has been shown in rabbits, where applying alpha-tocopherol to skin immediately after UV increased the Minimal Erythemal Dose (the lowest dose of ultraviolet radiation that will produce a detectable redness 24 hours after UV exposure) ¹¹⁷⁾. While the greatest effect was seen when vitamin E was applied immediately after UV exposure, one study showed a significant effect of application eight hours after the insult ¹¹⁸⁾. In human subjects, the use of vitamin E on skin lowers peroxidation of skin surface lipids ¹¹⁹⁾, decreases erythema ¹²⁰⁾, ¹²¹⁾ and limits immune cell activation after UV exposure ¹²²⁾.

Like oral supplementation with vitamin C and vitamin E, skin preparations with both vitamin C and vitamin E have also been successful. Together, the application of these antioxidants to the skin of animals before UV exposure has been shown to decrease sunburned cells ¹²³⁾, ¹²⁴⁾, decrease DNA damage ¹²⁵⁾, ¹²⁶⁾, inhibit redness ¹²⁷⁾, ¹²⁸⁾, and decrease skin pigmentation after UV exposure ¹²⁹⁾. Similar effects have been seen in human subjects ¹³⁰⁾, ¹³¹⁾, ¹³²⁾.

While a majority of studies have found benefit of topical alpha-tocopherol, there is much less evidence for the activity of esters of vitamin E in photoprotection ¹³³⁾. As described above, vitamin E esters require cellular metabolism to produce “free” vitamin E. Thus, skin use of vitamin E esters may provide only limited benefit or may require a delay after administration to provide significant UV protection.

Other skin functions

There is limited information concerning the effects of vitamin E supplementation on photoaging, photodamage, solar damage, or sun damage, which is commonly observed as skin wrinkling. Although vitamin E can protect mice exposed to UV from excessive skin wrinkling, this is a photoprotective effect rather than treatment of pre-existing wrinkles. Other reports using vitamin E to treat photodamage or reduce wrinkles are poorly controlled studies or unpublished observations ¹³⁴⁾, ¹³⁵⁾. An analysis of the dietary intake of Japanese women showed no correlation between vitamin E consumption and skin wrinkling ¹³⁶⁾.

Vitamin E and oils containing tocopherols or tocotrienols have been reported to have moisturizing properties, but data supporting these roles are limited. Cross-sectional studies have shown no association between vitamin E consumption and skin hydration in healthy men and women ¹³⁷⁾, ¹³⁸⁾. However, two small studies have shown topical application of vitamin E can improve skin water-binding capacity after two to four weeks of use ¹³⁹⁾, ¹⁴⁰⁾. Long-term studies with topical vitamin E are needed to establish if these moisturizing effects can be sustained.

Environmental pollutants like ozone can decrease vitamin E levels in the skin ¹⁴¹⁾, ¹⁴²⁾, ¹⁴³⁾ and lead to free radical damage that may compound the effects of UV exposure ¹⁴⁴⁾. Although not well studied, topical applications of vitamin E may reduce pollution-related free radical damage ¹⁴⁵⁾.

Anti-inflammatory effects

Vitamin E has been considered an anti-inflammatory agent in the skin, as several studies have supported its prevention of inflammatory damage after UV exposure. As mentioned above, topical vitamin E can reduce UV-induced skin swelling, skin thickness, erythema, and edema — all signs of skin inflammation. In cultured keratinocytes, α-tocopherol and γ-tocotrienol have been shown to decrease inflammatory prostaglandin synthesis, interleukin production, and the induction of cyclooxygenase-2 (COX-2) and NADPH oxidase by UV light ¹⁴⁶⁾, ¹⁴⁷⁾, ¹⁴⁸⁾, as well as limit inflammatory responses to lipid hydroperoxide exposure ¹⁴⁹⁾. In mice, dietary gamma-tocotrienol suppresses UV-induced COX-2 expression in the skin ¹⁵⁰⁾. Furthermore, topical application of α-tocopherol acetate or a gamma-tocopherol derivative inhibited the induction of COX-2 and nitric oxide synthase (iNOS) following UV exposure ¹⁵¹⁾. In vitro studies (test tube lab studies) have shown similar anti-inflammatory effects of alpha- and gamma-tocopherol on immune cells ¹⁵²⁾, ¹⁵³⁾, ¹⁵⁴⁾.

Many of these anti-inflammatory effects of vitamin E supplementation have been reported in combination with its photoprotective effects, making it difficult to distinguish an anti-inflammatory action from an antioxidant action that would prevent inflammation from initially occurring. Despite these limitations, there are many reports of vitamin E being used successfully in chronic inflammatory skin conditions, either alone ¹⁵⁵⁾, ¹⁵⁶⁾ or in combination with vitamin C ¹⁵⁷⁾ or vitamin D ¹⁵⁸⁾, therefore suggesting a true anti-inflammatory action.

Wound healing

Skin lesions have been reported in rats suffering from vitamin E deficiency, although their origin is unclear. Vitamin E levels decrease rapidly at the site of a cutaneous wound, along with other skin antioxidants, such as vitamin C or glutathione ¹⁵⁹⁾. Since skin antioxidants slowly increase during normal wound healing, these observations have stimulated additional studies on the effect of vitamin E on the wound healing process. However, no studies have demonstrated a positive effect of vitamin E supplementation on wound repair in normal skin. Studies have shown that α-tocopherol supplementation decreases wound closure time in diabetic mice, but no effects have been observed in normal mice ¹⁶⁰⁾, ¹⁶¹⁾. Vitamin E increases the breaking strength of wounds pre-treated with ionizing radiation ¹⁶²⁾, but this is likely due to antioxidant functions at the wound site akin to a photoprotective effect. In contrast, intramuscular injection of α-tocopherol acetate in rats has been suggested to decrease collagen synthesis and inhibit wound repair ¹⁶³⁾.

In humans, studies with topical alpha-tocopherol have either found no effects on wound healing or appearance or have found negative effects on the appearance of scar tissue ¹⁶⁴⁾, ¹⁶⁵⁾. However, these studies are complicated by a high number of skin reactions to the vitamin E preparations, possibly due to uncontrolled formation of tocopherol radicals in the solutions used. Despite these results, vitamin E, along with zinc and vitamin C, is included in oral therapies for pressure ulcers (bed sores) and burns ¹⁶⁶⁾, ¹⁶⁷⁾.

Vitamin C interactions

A few human studies using conditions of oxidative stress have demonstrated the importance of vitamin C (ascorbic acid) in the recycling of oxidized alpha-tocopherol back to its reduced state (see Figure 4). Oxidative stress caused by cigarette smoking accelerates the depletion of plasma alpha-tocopherol in smokers compared to nonsmokers ¹⁶⁸⁾. In a double-blind, placebo-controlled trial in 11 smokers and 13 nonsmokers given alpha-tocopherol and gamma-tocopherol that was labeled with deuterium (hence traceable), supplementation with vitamin C reduced the rate of vitamin E loss in plasma, most probably by regenerating tocopheryl radicals back to nonoxidized forms ¹⁶⁹⁾.

Vitamin K interactions

One study in adults with normal blood clotting (coagulation) status found that daily supplementation with 1,000 IU (670 mg) of RRR-alpha-tocopherol for 12 weeks decreased gamma-carboxylation of prothrombin, a vitamin K-dependent factor in the coagulation cascade ¹⁷⁰⁾. Individuals taking anticoagulant drugs like warfarin and those who are vitamin K deficient should not take vitamin E supplements without medical supervision because of the increased risk of bleeding ¹⁷¹⁾.

Vitamin E Supplements

Vitamin E supplements come in different amounts and forms. Supplements of vitamin E typically provide only alpha-tocopherol, although “mixed” products containing other tocopherols and even tocotrienols are available such as gamma-tocopherol, tocotrienols, and mixed tocopherols. Scientists do not know if any of these forms are superior to alpha-tocopherol in supplements.

Two main things to consider when choosing a vitamin E supplement are:

1. The amount of vitamin E: Most once-daily multivitamin-mineral supplements provide about 13.5 mg of vitamin E, whereas vitamin E-only supplements commonly contain 67 mg or more. The doses in most vitamin E-only supplements are much higher than the recommended amounts. Some people take large doses because they believe or hope that doing so will keep them healthy or lower their risk of certain diseases.
2. The form of vitamin E: Although vitamin E sounds like a single substance, it is actually the name of eight related compounds in food, including alpha-tocopherol. Each form has a different potency, or level of activity in the body.

Naturally occurring alpha-tocopherol exists in one stereoisomeric form, commonly listed as ”D-alpha-tocopherol” on food packaging and supplement labels. In contrast, synthetically produced (laboratory-made) alpha-tocopherol contains equal amounts of its eight possible stereoisomers, commonly listed as ”DL-alpha-tocopherol”; serum and tissues maintain only four of these stereoisomers ¹⁷²⁾. A given amount of synthetic alpha-tocopherol (all rac-alpha-tocopherol; commonly labeled as “DL” or “dl”) is therefore only half as active as the same amount (by weight in mg) of the natural form (RRR-alpha-tocopherol; commonly labeled as “D” or “d”). People need approximately 50% more IU of synthetic alpha tocopherol from dietary supplements and fortified foods to obtain the same amount of the nutrient as from the natural form.

• The natural vitamin E (D-alpha-tocopherol) is more potent; 1 mg vitamin E = 1 mg d-alpha-tocopherol (natural vitamin E) = 2 mg dl-alpha-tocopherol (synthetic vitamin E).

Some food and dietary supplement labels still list vitamin E in International Units (IUs) rather than mg. 1 IU of the natural form of vitamin E is equivalent to 0.67 mg. 1 IU of the synthetic form of vitamin E is equivalent to 0.45 mg.

Some vitamin E supplements provide other forms of the vitamin, such as gamma-tocopherol, tocotrienols, and mixed tocopherols. Scientists do not know if any of these forms are superior to alpha-tocopherol in supplements.

Most vitamin-E-only supplements provide ≥100 IU of the nutrient. These amounts are substantially higher than the recommended dietary allowances. The 1999–2000 National Health and Nutrition Examination Survey (NHANES) found that 11.3% of adults took vitamin E supplements containing at least 400 IU ¹⁷³⁾.

Alpha-tocopherol in dietary supplements and fortified foods is often esterified to prolong its shelf life while protecting its antioxidant properties. The body hydrolyzes and absorbs these esters (alpha-tocopheryl acetate and succinate) as efficiently as alpha-tocopherol ¹⁷⁴⁾.

Vitamin E interactions with medications

Vitamin E supplements have the potential to interact with several types of medications. A few examples are provided below. People taking these and other medications on a regular basis should discuss their vitamin E intakes with their healthcare providers.

Vitamin E has a few interactions with medications that are listed below:

• Anticoagulation and antiplatelet medications: due to vitamin E inhibiting platelet aggregation and disrupting vitamin K clotting factors there is a protentional increase risk of bleeding combining these two. Vitamin E can inhibit platelet aggregation and antagonize vitamin K-dependent clotting factors. As a result, taking large doses with anticoagulant or antiplatelet medications, such as warfarin (Coumadin®), can increase the risk of bleeding, especially in conjunction with low vitamin K intake. The amounts of supplemental vitamin E needed to produce clinically significant effects are unknown but probably exceed 400 IU/day ¹⁷⁵⁾.
• Simvastatin and niacin: Vitamin E can reduce the amount of high-density lipoprotein (HDL or “good” cholesterol) which is the opposite desired effect of taking simvastatin and/or niacin. Some people take vitamin E supplements with other antioxidants, such as vitamin C, selenium, and beta-carotene. This collection of antioxidant ingredients blunted the rise in high-density lipoprotein (HDL) cholesterol levels, especially levels of HDL, the most cardioprotective HDL component, among people treated with a combination of simvastatin (brand name Zocor®) and niacin ¹⁷⁶⁾.
• Chemotherapy and radiotherapy: Oncologists generally advise against the use of antioxidant supplements during cancer chemotherapy or radiotherapy because they might reduce the effectiveness of these therapies by inhibiting cellular oxidative damage in cancerous cells ¹⁷⁷⁾. Although a systematic review of randomized controlled trials has called this concern into question ¹⁷⁸⁾, further research is needed to evaluate the potential risks and benefits of concurrent antioxidant supplementation with conventional therapies for cancer.

Vitamin E health benefits

Scientists are studying vitamin E to understand how it affects health. Here are several examples of what this research has shown.

Many claims have been made about vitamin E’s potential to promote health and prevent and treat disease. The mechanisms by which vitamin E might provide this protection include its function as an antioxidant and its roles in anti-inflammatory processes, inhibition of platelet aggregation, and immune enhancement.

A primary barrier to characterizing the roles of vitamin E in health is the lack of validated biomarkers for vitamin E intake and status to help relate intakes to valid predictors of clinical outcomes ¹⁷⁹⁾.

Vitamin E and Coronary Heart Disease

For a time, vitamin E supplements looked like an easy way to prevent heart disease. Promising observational studies, including the Nurses’ Health Study ¹⁸⁰⁾ and Health Professionals Follow-Up Study ¹⁸¹⁾,  suggested 20 to 40 percent reductions in coronary heart disease risk among individuals who took vitamin E supplements (usually containing 400 IU or more) for least two years ¹⁸²⁾.

The results of several randomized trials have dampened enthusiasm for vitamin E’s ability to prevent heart attacks or deaths from heart disease among individuals with heart disease or those at high risk for it. In the GISSI Prevention Trial, the results were mixed but mostly showed no preventive effects after more than three years of treatment with vitamin E among 11,000 heart attack survivors ¹⁸³⁾. Results from the Heart Outcomes Prevention Evaluation (HOPE) trial also showed no benefit of four years worth of vitamin E supplementation among more than 9,500 men and women already diagnosed with heart disease or at high risk for it ¹⁸⁴⁾, ¹⁸⁵⁾. In fact, when the HOPE trial was extended for another four years, researchers found that study volunteers who took vitamin E had a higher risk of heart failure ¹⁸⁶⁾. In the HOPE-TOO followup study, almost 4,000 of the original participants continued to take vitamin E or placebo for an additional 2.5 years ¹⁸⁷⁾. HOPE-TOO study found that vitamin E provided no significant protection against heart attacks, strokes, unstable angina, or deaths from cardiovascular disease or other causes after 7 years of treatment ¹⁸⁸⁾. Participants taking vitamin E, however, were 13% more likely to experience, and 21% more likely to be hospitalized for, heart failure, a statistically significant but unexpected finding not reported in other large studies.

The HOPE and HOPE-TOO trials provide compelling evidence that moderately high doses of vitamin E supplements do not reduce the risk of serious cardiovascular events among men and women >50 years of age with established heart disease or diabetes ¹⁸⁹⁾. These findings are supported by evidence from the Women’s Angiographic Vitamin and Estrogen study, in which 423 postmenopausal women with some degree of coronary stenosis took supplements with 400 IU vitamin E (form not specified) and 500 mg vitamin C twice a day or placebo for >4 years ¹⁹⁰⁾. Not only did the supplements provide no cardiovascular benefits, but all-cause mortality was significantly higher in the women taking the supplements. Based on such studies, the American Heart Association has concluded that “the scientific data do not justify the use of antioxidant vitamin supplements [such as vitamin E] for cardiovascular disease risk reduction.” ¹⁹¹⁾.

It’s possible that in people who already have heart disease or are high risk of heart disease, the use of drugs such as aspirin, beta blockers, and ACE inhibitors mask a modest effect of vitamin E, and that vitamin E may have benefits among healthier people. But large randomized controlled trials of vitamin E supplementation in healthy women and men have yielded mixed results.

In the Women’s Health Study, which followed 40,000 healthy women ≥45 years of age who were randomly assigned to receive either vitamin E supplements of 600 IU of natural vitamin E (402 mg) on alternate days or placebo and who were followed for an average of 10 years ¹⁹²⁾. The investigators found no significant differences in rates of overall cardiovascular events (combined nonfatal heart attacks, strokes, and cardiovascular deaths) or all-cause mortality between the groups. However, the study did find two positive and significant results for women taking vitamin E: they had a 24% reduction in cardiovascular death rates, and those ≥65 years of age had a 26% decrease in nonfatal heart attack and a 49% decrease in cardiovascular death rates ¹⁹³⁾. A later analysis found that women who took the vitamin E supplements also had a lower risk of developing serious blood clots in the legs and lungs, with women at the highest risk of such blood clots receiving the greatest benefit ¹⁹⁴⁾.

The most recent published clinical trial of vitamin E and men’s cardiovascular health included almost 15,000 healthy physicians ≥50 years of age who were randomly assigned to receive 400 IU synthetic alpha-tocopherol (180 mg) every other day, 500 mg vitamin C daily, both vitamins, or placebo ¹⁹⁵⁾. During a mean follow-up period of 8 years, intake of vitamin E (and/or vitamin C) had no effect on the incidence of major cardiovascular events, myocardial infarction, stroke, or cardiovascular morality. Furthermore, use of vitamin E was associated with a significantly increased risk of hemorrhagic stroke ¹⁹⁶⁾.

Other heart disease prevention trials in healthy people have not been as promising, however. The SU.VI.MAX trial found that seven years of low-dose vitamin E supplementation (as part of a daily antioxidant pill) reduced the risk of cancer and the risk of dying from any cause in men, but did not show these beneficial effects in women; the supplements did not offer any protection against heart disease in men or women ¹⁹⁷⁾. Discouraging results have also come from the Physicians’ Health Study II, an eight-year trial that involved nearly 15,000 middle-aged men, most of whom were free of heart disease at the start of the study. Researchers found that taking vitamin E supplements of 400 IU every other day, alone or with vitamin C, failed to offer any protection against heart attacks, strokes, or cardiovascular deaths ¹⁹⁸⁾.

More recent evidence suggests that vitamin E may have potential benefits only in certain subgroups of the general population: A trial of high dose vitamin E in Israel, for example, showed a marked reduction in coronary heart disease among people with type 2 diabetes who have a common genetic predisposition for greater oxidative stress ¹⁹⁹⁾. So we certainly have not heard the last word on vitamin E and heart disease prevention.

In general, clinical trials have not provided evidence that routine use of vitamin E supplements prevents cardiovascular disease or reduces its morbidity and mortality. However, participants in these studies have been largely middle-aged or elderly individuals with demonstrated heart disease or risk factors for heart disease. Some researchers have suggested that understanding the potential utility of vitamin E in preventing coronary heart disease might require longer studies in younger participants taking higher doses of the supplement ²⁰⁰⁾. Further research is needed to determine whether supplemental vitamin E has any protective value for younger, healthier people at no obvious risk of cardiovascular disease.

Vitamin E and Cancer

Antioxidant nutrients like vitamin E protect cell constituents from the damaging effects of free radicals that, if unchecked, might contribute to cancer development. Vitamin E might also block the formation of carcinogenic nitrosamines formed in the stomach from nitrites in foods and protect against cancer by enhancing immune function ²⁰¹⁾.

Evidence to date is insufficient to support taking vitamin E to prevent cancer. In fact, daily use of large-dose vitamin E supplements (400 IU of synthetic vitamin E [180 mg]) may increase the risk of prostate cancer. Taken as a whole, observational studies have not found vitamin E in food or supplements to offer much protection against cancer in general, or against specific cancers ²⁰²⁾, ²⁰³⁾, ²⁰⁴⁾, ²⁰⁵⁾, ²⁰⁶⁾, ²⁰⁷⁾, ²⁰⁸⁾, ²⁰⁹⁾, ²¹⁰⁾, ²¹¹⁾. Some observational studies and clinical trials, however, suggested that vitamin E supplements might lower the risk of advanced prostate cancer in smokers ²¹²⁾, ²¹³⁾, ²¹⁴⁾, ²¹⁵⁾.

Investigators had hoped that the Selenium and Vitamin E Cancer Prevention Trial (SELECT) would give more definitive answers on vitamin E and prostate cancer. SELECT’s 18,000 men were assigned to follow one of four pill regimens—vitamin E plus selenium, vitamin E plus a selenium placebo, selenium plus a vitamin E placebo, or a double placebo—and were supposed to be tracked for 7 to 12 years. But investigators halted the study halfway though, in 2008, when early analyses showed that vitamin E offered no cancer or prostate cancer prevention benefit ²¹⁶⁾. Though the trial ended, researchers continued to follow the men who had participated. In 2011, they reported a 17 percent higher risk of prostate cancer among men assigned to take vitamin E; there was no significant increased risk of prostate cancer among men who took vitamin E and selenium ²¹⁷⁾. The additional 2011 data show that the men who took vitamin E alone had a 17 percent relative increase in numbers of prostate cancers compared to men on placebo. This difference in prostate cancer incidence between the vitamin E only group and the placebos only group is now statistically significant, and not likely to be due to chance ²¹⁸⁾.

Though these results, on the face of it, sound worrisome, two other major trials of vitamin E and prostate cancer had quite different results: The Alpha Tocopherol Beta Carotene (ATBC) randomized trial, for example, followed nearly 30,000 Finnish male smokers for an average of six years ²¹⁹⁾. It found that men assigned to take daily vitamin E supplements had a 32 percent lower risk of developing prostate cancer—and a 41 percent lower risk of dying from prostate cancer—than men given a placebo. However, there are many reasons why the vitamin E supplements may not have prevented prostate cancer. Two of the most likely reasons, looking back at the Alpha-Tocopherol Beta Carotene (ATBC) Cancer Prevention trial, a study designed to test vitamin E and beta carotene for lung cancer prevention in smokers ²²⁰⁾. In the The Alpha Tocopherol Beta Carotene trial, a reduction in prostate cancer incidence was observed, but this secondary finding may have been due to chance, as the study was not designed to determine prostate cancer risk ²²¹⁾. Another possible reason that men in ATBC had a reduction in prostate cancer incidence, while men on SELECT did not, is that the dose of vitamin E used in SELECT (400 IU/day) was higher than the dose used in the ATBC (50 IU/day) ²²²⁾. Researchers sometimes talk about a “U-shaped response curve” where very low or very high blood levels of a nutrient are harmful but more moderate levels are beneficial; while the ATBC dose may have been preventive, the SELECT dose may have been too large to have a prevention benefit ²²³⁾.

The large and long-term Physicians’ Health Study II trial, meanwhile, found that vitamin E supplements had no effect on the risk of prostate cancer or any other cancer ²²⁴⁾.

Bear in mind that prostate cancer develops slowly, and any study looking at prostate cancer prevention needs to track men for a long time. By stopping the SELECT trial early, there’s no way to tell if vitamin E could have helped protect against prostate cancer in some men if they had continued the trial over a longer period of time. Very few cases in the SELECT Trial were of advanced prostate cancer, further limiting the interpretation of the findings.

One study of women in Iowa provides evidence that higher intakes of vitamin E from foods and supplements could decrease the risk of colon cancer, especially in women <65 years of age ²²⁵⁾. The overall relative risk for the highest quintile of intake (>35.7 IU/day, form not specified) compared to the lowest quintile (<5.7 IU/day, form not specified) was 0.32. However, prospective cohort studies of 87,998 women in the Nurses’ Health Study and 47,344 men in the Health Professionals Follow-up Study failed to replicate these results ²²⁶⁾. Although some research links higher intakes of vitamin E with decreased incidence of breast cancer, an examination of the impact of dietary factors, including vitamin E, on the incidence of postmenopausal breast cancer in >18,000 women found no benefit from the vitamin ²²⁷⁾.

The American Cancer Society conducted an epidemiologic study examining the association between use of vitamin C and vitamin E supplements and bladder cancer mortality. Of the almost one million adults followed between 1982 and 1998, adults who took supplemental vitamin E for 10 years or longer had a reduced risk of death from bladder cancer ²²⁸⁾; vitamin C supplementation provided no protection.

Should men take vitamin E or selenium supplements for cancer prevention?

No. Scientists do not understand how these supplements really work and more importantly, the interactions that these supplements have together or with foods, drugs, or other supplements. There are no clinical trials that show a benefit from taking vitamin E or selenium to reduce the risk of prostate cancer or any other cancer or heart disease ²²⁹⁾, ²³⁰⁾, ²³¹⁾, ²³²⁾, ²³³⁾, ²³⁴⁾. While the men in SELECT who took both vitamin E and selenium did not have a statistically significant increase in their risk for prostate cancer, they also did not have a reduced risk of prostate cancer or any other cancer or heart disease. SELECT researchers were surprised by the findings in the men who took both vitamin E and selenium, and while the 2014 analysis suggests possible reasons for the findings, the mechanism remains unclear ²³⁵⁾.

Evidence to date is insufficient to support taking vitamin E to prevent cancer. In fact, daily use of large-dose vitamin E supplements (400 IU) may increase the risk of prostate cancer ²³⁶⁾.

Vitamin E and Macular Degeneration

Age-related macular degeneration (AMD) and cataracts are among the most common causes of significant vision loss in older people. Their causes are usually unknown, but the cumulative effects of oxidative stress have been postulated to play a role. If so, nutrients with antioxidant functions, such as vitamin E, could be used to prevent or treat these conditions.

Prospective cohort studies have found that people with relatively high dietary intakes of vitamin E (e.g., 20 mg/day [30 IU]) have an approximately 20% lower risk of developing age-related macular degeneration than people with low intakes (e.g., <10 mg/day [<15 IU]) ²³⁷⁾. However, two randomized controlled trials in which participants took supplements of vitamin E (500 IU/day [335 mg] d-alpha-tocopherol in one study ²³⁸⁾ and 111 IU/day (50 mg) dl-alpha-tocopheryl acetate combined with 20 mg/day beta-carotene in the other study ²³⁹⁾ or a placebo failed to show a protective effect for vitamin E on age-related macular degeneration. The Age-Related Eye Disease Study (AREDS) ²⁴⁰⁾, a large randomized clinical trial, found that participants at high risk of developing advanced age-related macular degeneration (i.e., those with intermediate age-related macular degeneration or those with advanced age-related macular degeneration in one eye) reduced their risk of developing advanced age-related macular degeneration by 25% by taking a daily supplement containing vitamin E (400 IU [180 mg] dl-alpha-tocopheryl acetate), beta-carotene (15 mg), vitamin C (500 mg), zinc (80 mg), and copper (2 mg) compared to participants taking a placebo over 5 years. A follow-up AREDS2 study ²⁴¹⁾ confirmed the value of this and similar supplement formulations in reducing the progression of age-related macular degeneration over a median follow-up period of 5 years.

Overall, the available evidence is inconsistent with respect to whether vitamin E supplements, taken alone or in combination with other antioxidants, can reduce the risk of developing age-related macular degeneration or cataracts. However, the formulations of vitamin E, other antioxidants, zinc, and copper used in AREDS hold promise for slowing the progression of age-related macular degeneration in people at high risk of developing advanced age-related macular degeneration.

Vitamin E and Cataracts

Several observational studies have revealed a potential relationship between vitamin E supplements and the risk of cataract formation. One prospective cohort study found that lens clarity was superior in participants who took vitamin E supplements and those with higher blood levels of the vitamin ²⁴²⁾. In another study, long-term use of vitamin E supplements was associated with slower progression of age-related lens opacification ²⁴³⁾. However, in the AREDS trial, the use of a vitamin E-containing (as dl-alpha-tocopheryl acetate) formulation had no apparent effect on the development or progression of cataracts over an average of 6.3 years ²⁴⁴⁾. The AREDS2 study, which also tested formulations containing 400 IU (180 mg) vitamin E, confirmed these findings ²⁴⁵⁾.

Vitamin E and Cognitive Function

The brain has a high oxygen consumption rate and abundant polyunsaturated fatty acids in the neuronal cell membranes. Researchers hypothesize that if cumulative free-radical damage to neurons over time contributes to cognitive decline and neurodegenerative diseases, such as Alzheimer’s disease, then ingestion of sufficient or supplemental antioxidants (such as vitamin E) might provide some protection ²⁴⁶⁾. This hypothesis was supported by the results of a clinical trial in 341 patients with Alzheimer’s disease of moderate severity who were randomly assigned to receive a placebo, vitamin E (2,000 IU/day dl-alpha-tocopherol), a monoamine oxidase inhibitor (selegiline), or vitamin E and selegiline ²⁴⁷⁾. Over 2 years, treatment with vitamin E and selegiline, separately or together, significantly delayed functional deterioration and the need for institutionalization compared to placebo. However, participants taking vitamin E experienced significantly more falls.

Vitamin E consumption from foods or supplements was associated with less cognitive decline over 3 years in a prospective cohort study of elderly, free-living individuals aged 65–102 years ²⁴⁸⁾. However, a clinical trial in primarily healthy older women who were randomly assigned to receive 600 IU (402 mg) d-alpha-tocopherol every other day or a placebo for ≤4 years found that the supplements provided no apparent cognitive benefits ²⁴⁹⁾. Another trial in which 769 men and women with mild cognitive impairment were randomly assigned to receive 2,000 IU/day vitamin E (form not specified), a cholinesterase inhibitor (donepezil), or placebo found no significant differences in the progression rate of Alzheimer’s disease between the vitamin E and placebo groups ²⁵⁰⁾.

In summary, most research results do not support the use of vitamin E supplements by healthy or mildly impaired individuals to maintain cognitive performance or slow its decline with normal aging ²⁵¹⁾. More research is needed to identify the role of vitamin E, if any, in the management of cognitive impairment ²⁵²⁾.

Vitamin E and Neurodegenerative Diseases

The brain has a high oxygen consumption rate and abundant polyunsaturated fatty acids in the neuronal cell membranes. Researchers hypothesize that if cumulative free-radical damage to neurons over time contributes to cognitive decline and neurodegenerative diseases, such as Alzheimer’s disease, then ingestion of sufficient or supplemental antioxidants (such as vitamin E) might provide some protection ²⁵³⁾. This hypothesis was supported by the results of a clinical trial in 341 patients with Alzheimer’s disease of moderate severity who were randomly assigned to receive a placebo, vitamin E (2,000 IU/day dl-alpha-tocopherol), a monoamine oxidase inhibitor (selegiline), or vitamin E and selegiline ²⁵⁴⁾. Over 2 years, treatment with vitamin E and selegiline, separately or together, significantly delayed functional deterioration and the need for institutionalization compared to placebo. However, participants taking vitamin E experienced significantly more falls.

Scientists seeking to untangle the causes of Alzheimer’s, Parkinson’s, and other diseases of the brain and nervous system have focused on the role that free radical damage plays in these diseases’ development ²⁵⁵⁾. But to date, there is little evidence as to whether vitamin E can help protect against these diseases or that it offers any benefit to people who already have these diseases.

Vitamin E and Dementia

Some prospective studies suggest that vitamin E supplements, particularly in combination with vitamin C, may be associated with small improvements in cognitive function or lowered risk of Alzheimer’s disease and other forms of dementia, while other studies have failed to find any such benefit ²⁵⁶⁾, ²⁵⁷⁾, ²⁵⁸⁾, ²⁵⁹⁾. A three-year randomized controlled trial in people with mild cognitive impairment—often a precursor to Alzheimer’s disease—found that taking 2,000 IU of vitamin E daily failed to slow the progression to Alzheimer’s disease ²⁶⁰⁾. Keep in mind, however, that the progression from mild cognitive impairment to Alzheimer’s disease can take many years, and this study was fairly short, so it is probably not the last word on vitamin E and dementia.

Vitamin E and Parkinson’s disease

Some, but not all, prospective studies suggest that getting higher intakes of vitamin E from diet—not from high-dose supplements—is associated with a reduced risk of Parkinson’s disease ²⁶¹⁾, ²⁶²⁾, ²⁶³⁾. In people who already have Parkinson’s, high-dose vitamin E supplements do not slow the disease’s progression ²⁶⁴⁾. Why the difference between vitamin E from foods versus that from supplements ? It’s possible that foods rich in vitamin E, such as nuts or legumes, contain other nutrients that protect against Parkinson’s disease. More research is needed.

Vitamin E and Amyotrophic Lateral Sclerosis (ALS)

One large prospective study that followed nearly 1 million people for up to 16 years found that people who regularly took vitamin E supplements had a lower risk of dying from ALS than people who never took vitamin E supplements ²⁶⁵⁾. More recently, a combined analysis of multiple studies with more than 1 million participants found that the longer people used vitamin E supplements, the lower their risk of ALS ²⁶⁶⁾. Clinical trials of vitamin E supplements in people who already have ALS have generally failed to show any benefit, however ²⁶⁷⁾. This may be a situation where vitamin E is beneficial for prevention, rather than treatment, but more research is needed.

Vitamin E and Fatty liver diseases

The increasing incidence of nonalcoholic fatty liver disease (NAFLD) in children and adults in industrialized countries is mainly attributed to the ongoing epidemic of obesity and type 2 diabetes mellitus. NAFLD (nonalcoholic fatty liver disease) results from the abnormal accumulation of fat (steatosis) in the liver in the absence of heavy alcohol consumption ²⁶⁸⁾, ²⁶⁹⁾. Although the condition is considered to be largely benign, NAFLD can progress to a more severe disease called nonalcoholic steatohepatitis (NASH) with increased risks of cirrhosis, hepatocellular carcinoma (liver cancer), and cardiovascular disease ²⁷⁰⁾, ²⁷¹⁾, ²⁷²⁾. Both environmental and genetic factors are contributing to the development of non-alcoholic fatty liver disease (NAFLD) and its progression ²⁷³⁾. Oxidative stress is thought to be one of the possible mechanisms responsible for prompting inflammatory processes that can lead to the progression of NAFLD to NASH ²⁷⁴⁾, ²⁷⁵⁾, ²⁷⁶⁾.

There is currently no established treatment for NAFLD and NASH other than interventions that encourage lifestyle changes and the use of medicines to control or treat metabolic disorders ²⁷⁷⁾, ²⁷⁸⁾, ²⁷⁹⁾. In the multicenter PIVENS (PIoglitazone versus Vitamin E versus placebo for the treatment of Nonalcoholic Steatohepatitis) trial, 247 nondiabetic subjects with nonalcoholic steatohepatitis (NASH) were randomized to receive 30 mg/day of pioglitazone (an insulin-sensitizing drug), 800 IU/day (536 mg/day) of RRR-alpha-tocopherol, or a placebo for 96 weeks ²⁸⁰⁾. Only vitamin E supplementation significantly increased the overall rate of improvement in histological abnormalities that characterize nonalcoholic steatohepatitis (NASH) on liver biopsies (i.e., hepatocellular ballooning, steatosis, and lobular inflammation) ²⁸¹⁾. Both active treatments improved some markers of liver function (i.e., alanine aminotransferase and aspartate aminotransferase) ²⁸²⁾. Yet, results from another two-year, randomized controlled trial — called TONIC for Treatment Of Nonalcoholic fatty liver disease In Children — in 173 children (ages, 8-17 years) with NAFLD 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 ²⁸³⁾. However, vitamin E supplementation significantly improved the overall disease activity score — used to quantify the severity of the disease. In addition, a recent meta-analysis of another six trials found that vitamin E significantly lowered circulating aminotransferase concentrations in NAFLD and NASH patients, suggesting liver function improvements ²⁸⁴⁾. Finally, in a small nonrandomized, unblinded, controlled study in 42 obese children (mean age, 8 years) with NAFLD, lifestyle recommendations combined with 600 mg/day of supplemental RRR-alpha-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 ²⁸⁵⁾. No such changes in markers of oxidative stress, liver function, and glucose utilization were reported in the lifestyle intervention only group ²⁸⁶⁾. Further randomized and well-controlled studies are needed to confirm these preliminary findings.

Vitamin E oil for Skin

Vitamin E is the most abundant lipophilic antioxidant found in human skin ²⁸⁷⁾. In humans, levels of vitamin E in the epidermis are higher than the dermis ²⁸⁸⁾. Although the predominant form of vitamin E in skin of unsupplemented individuals is alpha-tocopherol, skin may also contain measurable amounts of gamma-tocopherol ²⁸⁹⁾ and other diet-derived tocopherols and tocotrienols ²⁹⁰⁾.

Vitamin E first accumulates in the sebaceous glands before it is delivered to the skin surface through sebum ²⁹¹⁾. Following oral ingestion, it takes at least seven days before the vitamin E content of sebum is altered ²⁹²⁾. There are no transport proteins specific for vitamin E in the skin. Sebum is secreted to the surface of the stratum corneum, where it concentrates in the lipid-rich extracellular matrix of this layer ²⁹³⁾. Due to its lipophilic nature, vitamin E can also penetrate into all underlying layers of skin ²⁹⁴⁾. Skin vitamin E levels are higher in individuals with increased sebum production, as well as in skin types that naturally produce more sebum (e.g., “oily’ skin on the face vs. drier skin on the arm) ²⁹⁵⁾.

Exposures to UV light ²⁹⁶⁾ or ozone ²⁹⁷⁾ lower the vitamin E content in skin, primarily in the stratum corneum. Vitamin E concentrations in the human epidermis also decline with age ²⁹⁸⁾. Since epidermal structure changes with age ²⁹⁹⁾, this may be due to increased UV penetration of this layer.

Vitamin E deficiency may affect skin function, but there is little evidence from human studies. Vitamin E deficiency in rats has been reported to cause skin ulcerations ³⁰⁰⁾ and changes in skin collagen cross-linking ³⁰¹⁾, but the underlying cause of these effects is unknown.

Many people believe that there are special healing qualities to vitamin E on skin. Anecdotal reports claim that vitamin E speeds wound healing and improves the cosmetic outcome of burns and other wounds. Many lay people use vitamin E on a regular basis to improve the outcome of scars and several physicians recommend topical vitamin E after skin surgery or resurfacing.

In a very small double blinded clinical trial ³⁰²⁾ with 15 patients who had undergone skin cancer removal surgery. After the surgery, the patients were given two ointments each labeled A or B. A was a regular emollient, and the B was emollient mixed with vitamin E. The scars were randomly divided into parts A and B. Patients were asked to put the A ointment on part A and the B ointment on part B twice daily for 4 weeks. The physicians, a third blinded investigator and the patients independently evaluated the scars for cosmetic appearance on weeks 1, 4, and 12. The results of this study show that topically applied vitamin E does not help in improving the cosmetic appearance of scars and that the application of topical vitamin E may actually be detrimental to the cosmetic appearance of a scar. In 90% of the cases in this study, topical vitamin E either had no effect on, or actually worsened, the cosmetic appearance of scars. Of the patients studied, 33% developed a contact dermatitis to the vitamin E. Therefore the researchers conclude that use of topical vitamin E on surgical wounds should be discouraged ³⁰³⁾.

Skin application

Skin application of vitamin E has been used in a wide variety of forms throughout history, ranging from the application of oils to the skin surface to the use of modern cosmetic formulations. Just as sebum provides a delivery mechanism for vitamin E to the stratum corneum, topical applications of vitamin E permeate the epidermis and dermis ³⁰⁴⁾. The rate of percutaneous vitamin E absorption and factors that influence its penetration are largely unknown in humans, with a large range of concentrations and times used in various studies. It is generally assumed that solutions with vitamin E concentrations as low as 0.1% can increase vitamin E levels in the skin ³⁰⁵⁾. Interestingly, vitamin E levels in the dermis increase greatly after topical application, likely accumulating in the sebaceous glands ³⁰⁶⁾. However, although it is increased after topical delivery, the concentration of vitamin E in the dermis is lower than in the stratum corneum. Skin supplied only with dietary vitamin E primarily contains alpha- and gamma-tocopherol ³⁰⁷⁾; by contrast, skin supplied with synthetic vitamin E topically can contain a mixture of different tocopherols and/or tocotrienols ³⁰⁸⁾. In terms of penetration and absorption following topical application, tocotrienols and tocopherols accumulate in skin at varying rates, but the mechanisms governing these differences are unclear ³⁰⁹⁾.

After topical application, vitamin E accumulates not only in cell membranes but also in the extracellular lipid matrix of the stratum corneum, where vitamin E contributes to antioxidant defenses. However, much of a topically applied dose of vitamin E alone will be destroyed in the skin following exposure to UV light ³¹⁰⁾. This suggests that although vitamin E is working as an antioxidant, it is unstable on its own and easily lost from the skin. Thus, improving the stability of topical applications with vitamin E is important. Products containing both vitamin C and vitamin E have shown greater efficacy in photoprotection than either antioxidant alone.

The stability of topical vitamin E solutions may also be increased by the use of vitamin E conjugates. These vitamin E derivatives are usually commercially produced esters of tocopherol (although tocotrienol esters have been formulated) that are resistant to oxidation but can still penetrate the skin layers. Vitamin E conjugates, however, do not have antioxidant functions. To be effective, the molecule conjugated to vitamin E must be removed by enzymes within a cell. Since the stratum corneum contains metabolically inactive cells and the remaining layers of the epidermis and dermis may contain a large volume of extracellular proteins, it is unclear how efficiently ester conjugates are converted to “free” vitamin E in skin. Depending on the compound and the model system used, the effectiveness of these formulations can vary greatly ³¹¹⁾, and studies often do not compare the application of vitamin E conjugates to the application of unmodified vitamin E molecules.

Because vitamin E can absorb UV light to produce free radicals, there is the possibility that heavy sunlight exposure after topical application can cause skin reactions. However, concentrations of vitamin E between 0.1%-1.0% are generally considered safe and effective to increase vitamin E levels in the skin, but higher levels of α-tocopherol have been used with no apparent side effects ³¹²⁾. On the other hand, studies of dose-dependent vitamin E accumulation and effectiveness in skin protection are lacking. Some forms of vitamin E, especially ester conjugates, have led to adverse reactions in the skin, including allergic contact dermatitis and erythema. Although such reactions may be due to oxidation by-products, the emulsion creams used for topical delivery of compounds may also contribute to the observed effects ³¹³⁾.

Vitamin E functions in healthy skin

Photoprotection

The primary role of vitamin E in the skin is to prevent damage induced by free radicals and reactive oxygen species; therefore, the use of vitamin E in the prevention of ultraviolet (UV)-induced damage has been extensively studied. Although molecules in the vitamin E family can absorb light in the Ultraviolet B (UVB) spectrum, the “sunscreen” activity of vitamin E is considered limited since it cannot absorb Ultraviolet A (UVA) light or light in higher wavelengths of the Ultraviolet B (UVB) spectrum ³¹⁴⁾. Thus, the primary photoprotective effect of vitamin E is attributed to its role as a lipid-soluble antioxidant.

Many studies in cell culture models (in vitro studies) have found protective effects of vitamin E molecules on skin cells ³¹⁵⁾, but these models do not recreate the complex structure of skin tissues. Therefore, in vivo studies are needed.

Studies using orally administered vitamin E have reported mixed results on its photoprotective potential. An early study of vitamin E supplementation in hairless mice found no effect of dietary α-tocopherol acetate on UV-induced carcinogenesis ³¹⁶⁾. Three other mouse studies reported inhibition of UV-induced tumors in mice fed α-tocopherol acetate ³¹⁷⁾, but one of these studies utilized vitamin E doses that were toxic to animals when combined with the UV treatment ³¹⁸⁾. Another study in mice found a reduction of UV-induced DNA damage with dietary α-tocopherol acetate, but no effects on other free radical damage were observed in the skin ³¹⁹⁾. One human study reported that subjects taking 400 IU/day of α-tocopherol had reduced UV-induced lipid peroxidation in the skin but concluded there was no overall photoprotective effect ³²⁰⁾. This was supported by another human study that found that 400 IU/day of α-tocopherol for six months provided no meaningful protection to skin ³²¹⁾. Furthermore, multiple human studies have shown no effect of vitamin E on the prevention or development of skin cancers ³²²⁾.

In contrast to oral supplementation with α-tocopherol alone, multiple studies have found that the combination of vitamin C and vitamin E protects the skin against UV damage. Human subjects orally co-supplemented with vitamins C and E show increased Minimal Erythemal Dose (MED), the lowest dose of ultraviolet radiation that will produce a detectable redness 24 hours after UV exposure ³²³⁾. The combination of the two vitamins was associated with lower amounts of DNA damage after UV exposure ³²⁴⁾. Results of another study suggest a mixture of tocopherols and tocotrienols may be superior to α-tocopherol alone, as the mixture showed reduced sunburn reactions and tumor incidence after UV exposure in mice ³²⁵⁾. However, further trials with dietary tocotrienol/tocopherol mixtures are needed in human subjects.

Topical application of vitamin E is generally effective for increasing photoprotection of the skin. In rodent models, the application of α-tocopherol or α-tocopherol acetate before UV exposure reduces UV-induced skin damage by reducing lipid peroxidation ³²⁶⁾, limiting DNA damage ³²⁷⁾, and reducing the many chemical and structural changes to skin after UV exposure ³²⁸⁾. Vitamin E topical applications have also been shown to reduce UV-induced tumor formation in multiple mouse studies ³²⁹⁾ and to reduce the effects of photo-activated toxins in the skin ³³⁰⁾. Topical application of vitamin E also reduces the effects of UV radiation when applied after the initial exposure. In mice, α-tocopherol acetate prevents some of the erythema, edema, skin swelling, and skin thickening if applied immediately after UV exposure ³³¹⁾. A similar effect has been shown in rabbits, where applying α-tocopherol to skin immediately after UV increased the Minimal Erythemal Dose (the lowest dose of ultraviolet radiation that will produce a detectable redness 24 hours after UV exposure) ³³²⁾. While the greatest effect was seen when vitamin E was applied immediately after UV exposure, one study showed a significant effect of application eight hours after the insult ³³³⁾. In human subjects, the use of vitamin E on skin lowers peroxidation of skin surface lipids ³³⁴⁾, decreases erythema ³³⁵⁾, and limits immune cell activation after UV exposure ³³⁶⁾.

Like oral supplementation with vitamin C and vitamin E, topical preparations with both vitamins have also been successful. Together, the application of these antioxidants to the skin of animals before UV exposure has been shown to decrease sunburned cells ³³⁷⁾, decrease DNA damage ³³⁸⁾, inhibit erythema ³³⁹⁾, and decrease skin pigmentation after UV exposure ³⁴⁰⁾. Similar effects have been seen in human subjects ³⁴¹⁾.

While a majority of studies have found benefit of topical α-tocopherol, there is much less evidence for the activity of esters of vitamin E in photoprotection ³⁴²⁾. As described above, vitamin E esters require cellular metabolism to produce “free” vitamin E. Thus, topical use of vitamin E esters may provide only limited benefit or may require a delay after administration to provide significant UV protection.

Anti-inflammatory effects

Vitamin E has been considered an anti-inflammatory agent in the skin, as several studies have supported its prevention of inflammatory damage after UV exposure. As mentioned above, topical vitamin E can reduce UV-induced skin swelling, skin thickness, erythema, and edema — all signs of skin inflammation. In cultured keratinocytes, α-tocopherol and γ-tocotrienol have been shown to decrease inflammatory prostaglandin synthesis, interleukin production, and the induction of cyclooxygenase-2 (COX-2) and NADPH oxidase by UV light ³⁴³⁾, as well as limit inflammatory responses to lipid hydroperoxide exposure ³⁴⁴⁾. In mice, dietary γ-tocotrienol suppresses UV-induced COX-2 expression in the skin ³⁴⁵⁾. Furthermore, topical application of α-tocopherol acetate or a γ-tocopherol derivative inhibited the induction of COX-2 and nitric oxide synthase (iNOS) following UV exposure ³⁴⁶⁾. In vitro studies have shown similar anti-inflammatory effects of α- and γ-tocopherol on immune cells ³⁴⁷⁾.

Many of these anti-inflammatory effects of vitamin E supplementation have been reported in combination with its photoprotective effects, making it difficult to distinguish an anti-inflammatory action from an antioxidant action that would prevent inflammation from initially occurring. Despite these limitations, there are many reports of vitamin E being used successfully in chronic inflammatory skin conditions, either alone ³⁴⁸⁾ or in combination with vitamin C ³⁴⁹⁾ or vitamin D ³⁵⁰⁾, thus suggesting a true anti-inflammatory action.

Wound healing

As mentioned above, skin lesions have been reported in rats suffering from vitamin E deficiency, although their origin is unclear. Vitamin E levels decrease rapidly at the site of a cutaneous wound, along with other skin antioxidants, such as vitamin C or glutathione ³⁵¹⁾. Since skin antioxidants slowly increase during normal wound healing, these observations have stimulated additional studies on the effect of vitamin E on the wound healing process. However, no studies have demonstrated a positive effect of vitamin E supplementation on wound repair in normal skin. Studies have shown that α-tocopherol supplementation decreases wound closure time in diabetic mice, but no effects have been observed in normal mice ³⁵²⁾. Vitamin E increases the breaking strength of wounds pre-treated with ionizing radiation ³⁵³⁾, but this is likely due to antioxidant functions at the wound site akin to a photoprotective effect. In contrast, intramuscular injection of α-tocopherol acetate in rats has been suggested to decrease collagen synthesis and inhibit wound repair ³⁵⁴⁾.

In humans, studies with topical alpha-tocopherol have either found no effects on wound healing or appearance or have found negative effects on the appearance of scar tissue ³⁵⁵⁾, ³⁵⁶⁾. However, these studies are complicated by a high number of skin reactions to the vitamin E preparations, possibly due to uncontrolled formation of tocopherol radicals in the solutions used. Despite these results, vitamin E, along with zinc and vitamin C, is included in oral therapies for pressure ulcers (bed sores) and burns ³⁵⁷⁾, ³⁵⁸⁾.

Other skin functions

There is limited information concerning the effects of vitamin E supplementation on photodamage, which is commonly observed as skin wrinkling. Although vitamin E can protect mice exposed to UV from excessive skin wrinkling, this is a photoprotective effect rather than treatment of pre-existing wrinkles. Other reports using vitamin E to treat photodamage or reduce wrinkles are poorly controlled studies or unpublished observations ³⁵⁹⁾. An analysis of the dietary intake of Japanese women showed no correlation between vitamin E consumption and skin wrinkling ³⁶⁰⁾.

Vitamin E and oils containing tocopherols or tocotrienols have been reported to have moisturizing properties, but data supporting these roles are limited. Cross-sectional studies have shown no association between vitamin E consumption and skin hydration in healthy men and women ³⁶¹⁾, ³⁶²⁾. However, two small studies have shown topical application of vitamin E can improve skin water-binding capacity after two to four weeks of use ³⁶³⁾, ³⁶⁴⁾. Long-term studies with topical vitamin E are needed to establish if these moisturizing effects can be sustained.

Environmental pollutants like ozone can decrease vitamin E levels in the skin ³⁶⁵⁾ and lead to free radical damage that may compound the effects of UV exposure ³⁶⁶⁾. Although not well studied, topical applications of vitamin E may reduce pollution-related free radical damage ³⁶⁷⁾.

Vitamin E oil for skin summary

Vitamin E is an integral part of the skin’s antioxidant defenses, primarily providing protection against UV radiation and other free radicals that may come in contact with the epidermis. Oral supplementation with only vitamin E may not provide adequate protection for the skin, and co-supplementation of vitamin E and vitamin C may be warranted to effectively increase the photoprotection of skin through the diet. However, topical vitamin E seems to be an effective mechanism for both delivery to the skin and providing a photoprotective effect. Additional anti-inflammatory effects of topical vitamin E have been seen in the skin, although more studies are needed to determine if vitamin E primarily works as a free-radical scavenger or can have other effects on inflammatory signaling. Vitamin E is available commercially as a variety of synthetic derivatives, but the limited cellular metabolism in skin layers makes the use of such products problematic. Use of unesterified vitamin E, similar to that found in natural sources, has provided the most consistent data concerning its topical efficacy. The vitamin E family consists of eight different tocopherols and tocotrienols, and it will be important for future studies to determine if one or more of these molecules can have unique effects on skin function.

How much vitamin E do I need?

The amount of vitamin E you need each day depends on your age. Average daily recommended amounts are listed below in milligrams (mg) and in International Units (IU). Package labels list the amount of vitamin E in foods and dietary supplements in International Units (IU). Intake recommendations for vitamin E and other nutrients are provided in the Dietary Reference Intakes (DRIs) developed by the Food and Nutrition Board (FNB) at the Institute of Medicine of The National Academies ³⁶⁸⁾. Dietary Reference Intake (DRI) is the general term for a set of reference values used to plan and assess nutrient intakes of healthy people. These values, which vary by age and gender, include:

• Recommended Dietary Allowance (RDA): average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%–98%) healthy people.
• Adequate Intake (AI): established when evidence is insufficient to develop an RDA and is set at a level assumed to ensure nutritional adequacy.
• Tolerable Upper Intake Level (UL): maximum daily intake unlikely to cause adverse health effects.

The Food and Nutrition Board’s vitamin E recommendations are for alpha-tocopherol alone, the only form maintained in plasma. The Food and Nutrition Board (FNB) based these recommendations primarily on serum levels of the nutrient that provide adequate protection in a test measuring the survival of red blood cells when exposed to hydrogen peroxide, a free radical. Acknowledging “great uncertainties” in these data, the Food and Nutrition Board (FNB) has called for research to identify other biomarkers for assessing vitamin E requirements.

RDAs for vitamin E are provided in milligrams (mg) and are listed in Table 1. Because insufficient data are available to develop RDAs for infants, Adequate Intake (AI) were developed based on the amount of vitamin E consumed by healthy breastfed babies.

At present, the vitamin E content of foods and dietary supplements is listed on labels in international units (IUs), a measure of biological activity rather than quantity. Naturally sourced vitamin E is called RRR-alpha-tocopherol (commonly labeled as d-alpha-tocopherol); the synthetically produced form is all rac-alpha-tocopherol (commonly labeled as dl-alpha-tocopherol). Conversion rules are as follows:

To convert from mg to IU:

• 1 mg of alpha-tocopherol is equivalent to 1.49 IU of the natural form or 2.22 IU of the synthetic form.

To convert from IU to mg:

• 1 IU of the natural form is equivalent to 0.67 mg of alpha-tocopherol.
• 1 IU of the synthetic form is equivalent to 0.45 mg of alpha-tocopherol.

Table 1 lists the RDAs for alpha-tocopherol in both mg and IU of the natural form; for example, 15 mg x 1.49 IU/mg = 22.4 IU. The corresponding value for synthetic alpha-tocopherol would be 33.3 IU (15 mg x 2.22 IU/mg).

Table 1. Recommended Dietary Allowances (RDAs) for Vitamin E (Alpha-Tocopherol)

Footnote: *Adequate Intake (established when evidence is insufficient to develop an RDA and is set at a level assumed to ensure nutritional adequacy)

What foods provide vitamin E?

Numerous foods provide vitamin E. Nuts, seeds, and vegetable oils are among the best sources of alpha-tocopherol, and significant amounts are available in green leafy vegetables and fortified cereals (see Table 2 for a more detailed list) ³⁶⁹⁾. Most vitamin E in American diets is in the form of gamma-tocopherol from soybean, canola, corn, and other vegetable oils and food products ³⁷⁰⁾.

Vitamin E is found naturally in foods and is added to some fortified foods. You can get recommended amounts of vitamin E by eating a variety of foods including the following:

• Vegetable oils like wheat germ, sunflower, and safflower oils are among the best sources of vitamin E. Corn and soybean oils also provide some vitamin E.
• Nuts (such as peanuts, hazelnuts, and, especially, almonds) and seeds (like sunflower seeds) are also among the best sources of vitamin E.
• Green vegetables, such as spinach and broccoli, provide some vitamin E.
• Food companies add vitamin E to some breakfast cereals, fruit juices, margarines and spreads, and other foods. To find out which ones have vitamin E, check the product labels.

Vitamin E from natural (food) sources is commonly listed as “d-alpha-tocopherol” on food packaging and supplement labels. Synthetic (laboratory-made) vitamin E is commonly listed as “dl-alpha-tocopherol”. The natural form is more potent. For example, 100 IU of natural vitamin E is equal to about 150 IU of the synthetic form.

Some vitamin E supplements provide other forms of the vitamin, such as gamma-tocopherol, tocotrienols, and mixed tocopherols. Scientists do not know if any of these forms are superior to alpha-tocopherol in supplements.

The U.S. Department of Agriculture’s (USDA’s) FoodData Central (https://fdc.nal.usda.gov) lists the nutrient content of many foods, including, in some cases, the amounts of alpha-, beta-, gamma-, and delta-tocopherol arranged by nutrient content (https://ods.od.nih.gov/pubs/usdandb/VitaminE-Content.pdf) and by food name (https://ods.od.nih.gov/pubs/usdandb/VitaminE-Food.pdf).

Table 2. Food Sources of Vitamin E (Alpha-Tocopherol)

Footnote: *DV = Daily Value. DVs were developed by the FDA to help consumers compare the nutrient content of different foods within the context of a total diet. The DV for vitamin E is 30 IU (approximately 20 mg of natural alpha-tocopherol) for adults and children age 4 and older. However, the FDA does not require food labels to list vitamin E content unless a food has been fortified with this nutrient. Foods providing 20% or more of the DV are considered to be high sources of a nutrient, but foods providing lower percentages of the DV also contribute to a healthful diet.

Are you getting enough vitamin E?

The diets of most Americans provide less than the recommended amounts of vitamin E. Nevertheless, healthy people rarely show any clear signs that they are not getting enough vitamin E. Between 1988 and 1994, the US National Health and Nutrition Examination Survey 3 (NHANES 3) examined the dietary intake and blood concentrations of alpha-tocopherol in 16,295 adults. The study reported that about one-third of all participants had blood concentrations of alpha-tocopherol below 20 micromoles/liter (μmol/L) — a cutoff value chosen because of its initial association with an increased risk for cardiovascular disease ³⁷²⁾. More recent data from 18,063 participants in NHANES 2003-2006 indicated an average dietary intake of alpha-tocopherol from food including enriched and fortified sources among Americans adults of 7.2 mg/day ³⁷³⁾. This intake is well below the current recommended dietary allowance (RDA) of 15 mg/day ³⁷⁴⁾. At this level of dietary intake, more than 93% of American adults do not meet the estimated average requirement (EAR) of 12 mg/day for vitamin E ³⁷⁵⁾.

What happens if you don’t get enough vitamin E?

Vitamin E deficiency is very rare in healthy people. It is almost always linked to certain diseases where fat is not properly digested or absorbed. Examples include Crohn’s disease, cystic fibrosis, and certain rare genetic diseases such as abetalipoproteinemia and ataxia with vitamin E deficiency (AVED) ³⁷⁶⁾, ³⁷⁷⁾. Vitamin E needs some fat for the digestive system to absorb it.

Vitamin E deficiency can cause nerve and muscle damage that results in loss of feeling in the arms and legs, loss of body movement control, muscle weakness, and vision problems. Another sign of deficiency is a weakened immune system.

Vitamin E deficiency

Dietary vitamin E deficiency is common in developing countries due to malnutrition; vitamin E deficiency among adults in developed countries is uncommon and usually due to fat malabsorption, liver failure, and digestive tract diseases, which impair the absorption of dietary fats and therefore fat-soluble vitamins like vitamin E ³⁷⁸⁾, ³⁷⁹⁾, ³⁸⁰⁾, ³⁸¹⁾. Severe vitamin E deficiency has been associated with specific genetic defects affecting the transport of alpha-tocopherol by α-tocopherol transfer protein (α-TTP) and lipoproteins ³⁸²⁾.

Premature babies of very low birth weight (<1,500 grams) might be deficient in vitamin E. Vitamin E supplementation in these infants might reduce the risk of some complications, such as those affecting the retina, but they can also increase the risk of infections ³⁸³⁾. In addition, a recent 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 ³⁸⁴⁾.

Because the digestive tract requires fat to absorb vitamin E, people with fat-malabsorption disorders are more likely to become deficient than people without such disorders ³⁸⁵⁾, ³⁸⁶⁾, ³⁸⁷⁾. Vitamin E deficiency symptoms include peripheral neuropathy, ataxia, skeletal myopathy, retinopathy, and impairment of the immune response ³⁸⁸⁾, ³⁸⁹⁾. People with Crohn’s disease, cystic fibrosis, or an inability to secrete bile from the liver into the digestive tract, for example, often pass greasy stools or have chronic diarrhea; as a result, they sometimes require water-soluble forms of vitamin E, such as tocopheryl polyethylene glycol-1000 succinate ³⁹⁰⁾.

Some people with abetalipoproteinemia, a rare inherited disorder resulting in poor absorption of dietary fat, require enormous doses of supplemental vitamin E (approximately 100 mg/kg or 5–10 g/day) ³⁹¹⁾. Vitamin E deficiency secondary to abetalipoproteinemia causes such problems as poor transmission of nerve impulses, muscle weakness, and retinal degeneration that leads to blindness ³⁹²⁾. Ataxia and vitamin E deficiency (AVED) is another rare, inherited disorder in which the liver’s alpha-tocopherol transfer protein (α-TTP) is defective or absent ³⁹³⁾, ³⁹⁴⁾. People with AVED have such severe vitamin E deficiency that they develop nerve damage and lose the ability to walk unless they take large doses of supplemental vitamin E ³⁹⁵⁾, ³⁹⁶⁾, ³⁹⁷⁾.

Vitamin E deficiency causes fragility of red blood cells and degeneration of neurons, particularly peripheral axons and posterior column neurons.

The main symptoms of vitamin E deficiency are hemolytic anemia and neurologic deficits. Diagnosis is based on measuring the ratio of plasma alpha-tocopherol to total plasma lipids; a low ratio suggests vitamin E deficiency. Treatment consists of oral vitamin E, given in high doses if there are neurologic deficits or if deficiency results from malabsorption.

Vitamin E deficiency causes

In developed countries, it is unlikely that vitamin E deficiency occurs due to diet intake insufficiency and the more common causes are below ³⁹⁸⁾:

• In developing countries, the most common cause is inadequate intake of vitamin E.
• Premature low birth weight infants with a weight less than 1500 grams (3.3 pounds)
• Mutations in the alpha-tocopherol transfer protein (TTPA) gene causing impaired fat metabolism ³⁹⁹⁾
• Disrupted fat malabsorption as the small intestine requires fat to absorb vitamin E
• Patients with cystic fibrosis fail to secrete pancreatic enzymes to absorb vitamins A, D, E, and K
• Short-bowel syndrome patients may take years to develop symptoms. Short-bowel syndrome may develop from intestinal pseudo-obstruction, surgical resection, or mesenteric vascular thrombosis. Only after 10-20 years of malabsorption do neurologic symptoms become clinically apparent.
• Chronic cholestatic hepatobiliary disease leads to a decrease in bile flow and micelle formation that is needed for vitamin E absorption. Chronic cholestatic hepatobiliary disease in infants as young as 2 years may result from this condition ⁴⁰⁰⁾. Prior to age 1 year, neurologic function was normal in all children. Between ages 1 and 3 years, neurologic abnormalities were present in approximately 50% of the vitamin E-deficient children; after age 3 years, neurologic abnormalities were present in all vitamin E-deficient children. Areflexia was the first abnormality to develop between ages 1 and 4 years; truncal and limb ataxia, peripheral neuropathy, and ophthalmoplegia developed between ages 3 and 6 years. Neurologic dysfunction progressed to a disabling combination of findings by ages 8 to 10 years in the majority of vitamin E-deficient children. Neurologic findings are less frequent in adult patients with cholestasis secondary to cirrhosis.
• Crohn’s disease, exocrine pancreatic insufficiency, and liver disease may all not absorb fat
• Abetalipoproteinemia is a rare genetic, autosomal-recessive disease that causes an error in lipoprotein production and transportation. Infants present with steatorrhea from the time of birth. Patients have pigmented retinopathy and progressive ataxia, and they develop acanthosis of red blood cells in the first decade of life.
• Ataxia with vitamin E deficiency (AVED) also known as Familial Isolated Vitamin E Deficiency or Friedreich-like ataxia with vitamin E deficiency, is an autosomal recessive neurodegenerative disorder caused by alpha-tocopherol transfer protein (TTPA) gene mutations on chromosome 8q13 (long arm of chromosome 8) ⁴⁰¹⁾. Neurologic findings develop within the first decade of life, and no clinical findings distinguish deficiency from ataxia and movement disorders. Vitamin E replacement can significantly influence the outcome; therefore, screening for vitamin E deficiency is beneficial for patients with movement disorders or neuropathies that are of unknown cause.

Cigarette smoking is thought to increase the utilization of alpha-tocopherol such that smokers might be at increased risk of vitamin E deficiency compared with nonsmokers ⁴⁰²⁾. 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 alpha-tocopherol concentrations (>31 μmol/L vs. <23 μmol/L) at baseline had reduced risks of total and cause-specific mortality ⁴⁰³⁾.

Ataxia with Vitamin E Deficiency (AVED)

Ataxia with vitamin E deficiency (AVED), also known as Familial Isolated Vitamin E Deficiency or Friedreich-like ataxia with vitamin E deficiency, is a rare progressive neurodegenerative disorder of autosomal recessive cerebellar ataxia (ARCA) ⁴⁰⁴⁾, ⁴⁰⁵⁾, ⁴⁰⁶⁾, ⁴⁰⁷⁾, ⁴⁰⁸⁾, ⁴⁰⁹⁾. The most prominent symptoms of ataxia with vitamin E deficiency (AVED) include progressive cerebellar ataxia, absence of neurologic reflexes (areflexia), peripheral neuropathy and movement disorder ⁴¹⁰⁾. Ataxia with vitamin E deficiency (AVED) patients may also have retinitis pigmentosa (a group of rare eye diseases that affect the retina that causes severe vision impairment such as decreased vision at night or in low light and loss of side vision (tunnel vision)), a disease of the heart muscle (cardiomyopathy) and scoliosis (a sideways curvature of the spine) ⁴¹¹⁾, ⁴¹²⁾. Ataxia with vitamin E deficiency (AVED) is caused by mutations in the TTPA gene, which encodes the alpha-tocopherol transfer protein (α-TTP), which in turn binds alpha-tocopherol and transports vitamin E from liver cells to circulating lipoproteins ⁴¹³⁾. Vitamin E supplementation may prevent the worsening of the condition of patients with ataxia with vitamin E deficiency (AVED).

Ataxia with vitamin E deficiency (AVED) affects both males and females equally. Ataxia with vitamin E deficiency (AVED) is estimated to occur in fewer than 1 in 1,000,000 people ⁴¹⁴⁾. North African populations are most affected with AVED. Other cases have been reported in the Mediterranean region and Northern European countries. There have been cases in Asian countries such as Japan, China and the Philippines. The onset of AVED can occur during childhood or adulthood with cases reported ranging in children as young as 2 and adults as old as 52. Typically, the disease presents in individuals between ages 5 and 20 years. The disorder was first described in the medical literature in 1981.

Untreated ataxia with vitamin E deficiency (AVED) generally manifests between ages 5 and 15 years ⁴¹⁵⁾. The first signs and symptoms include progressive ataxia, clumsiness of the hands, loss of proprioception, and absence of neurologic reflexes (areflexia). Other features often observed are dysdiadochokinesia, dysarthria, positive Romberg sign, head titubation, decreased visual acuity, and positive Babinski sign ⁴¹⁶⁾. Although age of onset and disease course are more uniform within a given family, disease manifestations and their severity can vary even among siblings.

Ataxia with vitamin E deficiency (AVED) is caused by alpha-tocopherol transfer protein (TTPA) gene mutations on chromosome 8q13 (long arm of chromosome 8), which encodes the alpha-tocopherol transfer protein (α-TTP), which in turn binds alpha-tocopherol and transports vitamin E from liver cells to circulating lipoproteins ⁴¹⁷⁾, ⁴¹⁸⁾, ⁴¹⁹⁾, ⁴²⁰⁾, ⁴²¹⁾, ⁴²²⁾, ⁴²³⁾, ⁴²⁴⁾, ⁴²⁵⁾. When the alpha-tocopherol transfer protein (TTPA) gene is damaged, vitamin E cannot be distributed throughout the body. Vitamin E is important because it protects the cells of the neurological system (neurons) from damaging molecules called free radicals. Ataxia with vitamin E deficiency (AVED) is inherited in an autosomal recessive manner ⁴²⁶⁾.

Marriotti et al. ⁴²⁷⁾ reported cerebellar atrophy in some individuals with AVED. Spinal sensory demyelination with neuronal atrophy and axonal spheroids and neuronal lipofuscin accumulation in the third cortical layer of the cerebral cortex, thalamus, lateral geniculate body, spinal horns, and posterior root ganglia are the commonest histopathology findings ⁴²⁸⁾. The following criteria should be met to diagnose ataxia with vitamin E deficiency (AVED) ⁴²⁹⁾:

• Friedreich ataxia‐like neurologic phenotype
• Markedly reduced plasma vitamin E
• Normal lipoprotein profile
• Exclusion of disease that cause fat malabsorption.

Individuals with AVED are treated with high doses of vitamin E supplements, but recovery is slow and incomplete ⁴³⁰⁾. Early diagnosis and treatment can slow down or stop the progression of the disorder and in some people, even improve existing symptoms. Lifelong treatment with vitamin E will be needed. Genetic counseling is recommended for affected individuals and their families.

Vitamin E supplementation should be started as soon as possible, but the optimal dosage is still variable ⁴³¹⁾. The doses and the route of vitamin E supplementation depend on the causes of vitamin E deficiency. The treatment of choice for AVED is lifelong high‐dose oral vitamin E supplementation. The early use of vitamin E supplementation in the disease process helps to reverse some neurological symptoms like ataxia and intellectual deterioration ⁴³²⁾.

Figure 6. Ataxia with vitamin E deficiency (AVED) pathophysiology

Ataxia with Vitamin E Deficiency (AVED) causes

Ataxia with vitamin E deficiency (AVED) is caused by changes (mutations or pathogenic variants) in the TTPA gene, which provides instructions to synthesize the alpha-tocopherol transfer protein (αTTP) . This protein controls the distribution and transportation of vitamin E from the liver to other cells and tissues throughout the body, including the brain. Individuals with AVED have non-working genes for TTPA and therefore, vitamin E cannot be properly distributed throughout the body especially to the brain where it is necessary for proper function. AVED is characterized by very low levels of vitamin E in the blood and tissues in the brain. Without normal levels of vitamin E in the tissues, an individual with AVED experiences damage to the body from lack of protection from damaging free radicals.

Vitamin E deficiency often occurs secondary to disorders that impair the absorption of vitamin E from fat including liver disorders, disorders of fat metabolism and disorders of bile secretion. These disorders include choleostasis (a syndrome of various causes characterized by impaired bile secretion), cystic fibrosis (primarily a lung disorder that results in choleostasis), primary biliary cirrhosis (a liver disorder that results in choleostasis) and abetalipoproteinemia (a digestive disorder characterized by fat malabsorption). Premature infants may have low vitamin E levels due to small amounts of vitamin E cross the placenta. In rare cases vitamin E deficiency may be caused due to poor diet. (For more information on the above disorders, choose the specific disorder name as your search term in the Rare Disease Database.)

Ataxia with vitamin E deficiency (AVED) is inherited, or passed down from parent to child, in an autosomal recessive manner. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have a child with AVED is 25% with each pregnancy. The risk of having a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.

Ataxia with Vitamin E Deficiency (AVED) signs and symptoms

Individuals usually show symptoms between 5 and 20 years of age. Symptoms and the severity of ataxia with vitamin E deficiency (AVED) may be different from person to person. Without treatment, symptoms may get worse as the person grows older.

Untreated individuals with Ataxia with Vitamin E Deficiency (AVED)

Footnote: Frequency of signs and symptoms associated with untreated individuals with ataxia with vitamin E deficiency (AVED) based on findings in 132 individuals of North African heritage.

AVED affects the brain and spinal cord (central nervous system or CNS) as well as the motor and sensory nerves that connect the central nervous system (CNS) to the rest of the body (peripheral nervous system) ⁴³⁵⁾. This results in ataxia, which is difficulty controlling body movements and numbness of the hands and feet (peripheral neuropathy). Individuals with AVED develop increasing weakness of the legs, which may appear as an unsteady or staggering way of walking (gait) or trembling when standing still ⁴³⁶⁾. If symptoms become very severe, an individual with AVED may require a wheelchair if they cannot walk ⁴³⁷⁾. Clinical symptoms like progressive ataxia with decreased reflex remain the prominent symptoms of AVED. According to the study done in North Africa, most of the individuals with AVED had mild neuropathy and were mostly combined types of neuropathies (both sensory and motor) ⁴³⁸⁾.

Additional symptoms related to the central nervous system (CNS) include loss of proprioception, which is an awareness of joint position in relation to other parts of the body ⁴³⁹⁾. With time, reflexes in the legs may slow down or be absent (areflexia). Involvement of the throat muscles may lead to impaired swallowing or choking and may cause difficulty in eating. Slurred speech or difficulty speaking (dysarthria) may also be present. Some affected individuals may develop a tremor or shaking of the head (titubation). Intellect and emotions are rarely affected.

In some people with AVED, psychotic episodes and intellectual decline have been described ⁴⁴⁰⁾. In rare individuals, school performance declines secondary to loss of intellectual capacities ⁴⁴¹⁾.

In addition to neurological symptoms, individuals with AVED may develop symptoms affecting other systems of the body including the eyes ⁴⁴²⁾. Retinitis pigmentosa (RP) is a large group of rare eye diseases that cause progressive degeneration of the membrane lining the eyes (retina). This results in visual impairment or decreased vision. A high percentage of affected individuals (e.g., 8/11 individuals in one series) experience decreased visual acuity ⁴⁴³⁾. Some affected individuals may have yellow “fatty” deposits (xanthelasma) in the retina.

Affected individuals may also develop sideways curvature of the spine (scoliosis), degenerative changes of the heart muscle (cardiomyopathy) or “fatty” deposits (xanthomas) affecting the Achilles tendon around the ankle ⁴⁴⁴⁾. Some individuals with ataxia with vitamin E deficiency (AVED) may experience a form of dystonia. Dystonia is the name for a group of movement disorders generally characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions (postures).

Ataxia with Vitamin E Deficiency (AVED) diagnosis

A diagnosis of ataxia with vitamin E deficiency (AVED) is made upon a thorough clinical evaluation, a detailed patient history, and a variety of tests and characteristic findings (e.g., low levels of vitamin E with normal levels of lipoproteins and lipids with no evidence of fat malabsorption and abnormalities in the TTPA gene).

AVED should be suspected in an individual with the following clinical and laboratory findings and family history ⁴⁴⁵⁾:

• Family history
  • Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.
• Clinical features
  • Onset between ages 5 and 15 years
  • Progressive cerebellar findings including the following:
    • Gait ataxia
    • Clumsiness of the hands
    • Loss of proprioception (especially distal joint position and vibration sense)
    • Dysdiadochokinesia
    • Positive Romberg sign
    • Head titubation
  • Lower motor neuron involvement. Areflexia
  • Upper motor neuron involvement. Positive Babinski sign
  • Ophthalmologic involvement. Decreased visual acuity due to macular degeneration, pigmentary retinopathy
• Supportive laboratory findings
  • Normal lipid and lipoprotein profile
  • Very low plasma vitamin E (alpha-tocopherol, or α-tocopherol) concentration
    • Note: There is no universal normal range of plasma vitamin E concentration, as it depends on the test method and varies among laboratories.
    • In Finckh et al ⁴⁴⁶⁾, the plasma vitamin E (alpha-tocopherol, or α-tocopherol) concentration normal range lies between 9.0 and 29.8 µmol/L. In El Euch-Fayache et al ⁴⁴⁷⁾, the normal range is given as 16.3-34.9 µmol/L, while individuals with AVED had vitamin E levels between 0.00 and 3.76 µmol/L (mean 0.95 µmol/L). In individuals with AVED, the plasma vitamin E concentration is generally lower than 4.0 µmol/L (<1.7 mg/L) ⁴⁴⁸⁾, ⁴⁴⁹⁾.
  • Because oxidation of alpha-tocopherol (α-tocopherol) by air may invalidate test results, the following precautions with a blood sample should be taken:
    • Centrifugation of the EDTA blood soon after venipuncture
    • Quick separation of plasma from blood cells after centrifugation and subsequent flash freezing of the plasma in liquid nitrogen
    • Filling the space above the plasma with an inert gas (e.g., argon or nitrogen)
    • Protecting the sample from light by wrapping the container in aluminum foil, or using a black or light-shielded Eppendorf tube
    • Shipment of the sample to the test laboratory in dry ice
• Electrophysiologic findings
  • No electrophysiologic findings (motor nerve conduction velocities, compound muscle action potentials, or nerve sensory action potentials) are specific to or diagnostic of AVED; even the presence of a severe neuropathy does not exclude the diagnosis of AVED.
  • Somatosensory evoked potentials show increased central conduction time between the segment C1 (N13b) and the sensorimotor cortex (N20) and increased latencies of the N20 (median nerve) and P40 (tibial nerve) waves. The P40 wave may be missing completely ⁴⁵⁰⁾.
• Neuroimaging
  • No radiologic findings are specific to or diagnostic of AVED.
  • Cerebellar atrophy is present in approximately half of reported individuals ⁴⁵¹⁾.
  • Small T2 high-intensity spots in the periventricular region and the deep white matter are inconsistent findings in some individuals ⁴⁵²⁾.

The diagnosis of ataxia with vitamin E deficiency (AVED) is established by molecular genetic testing with the identification of abnormalities in the TTPA gene ⁴⁵³⁾.

Figure 7. Ataxia with vitamin E deficiency (AVED) diagnosis

Ataxia with Vitamin E Deficiency (AVED) treatment

Individuals with ataxia with vitamin E deficiency (AVED) are treated with high doses of vitamin E supplements. Early diagnosis and treatment can slow down or stop the progression of the disorder and in some people, even improve existing symptoms. The treatment of choice for ataxia with vitamin E deficiency (AVED) is lifelong high-dose oral vitamin E supplementation. With treatment, plasma vitamin E concentrations can become normal. Genetic counseling is recommended for affected individuals and their families.

One of the following vitamin E preparations is used ⁴⁵⁵⁾:

• The chemically manufactured racemic form, all-rac-alpha-tocopherol acetate
• The naturally occurring form, RRR-alpha-tocopherol
• It is currently unknown whether affected individuals should be treated with all-rac-alpha-tocopherol acetate or with RRR-alpha-tocopherol. It is known that alpha-tocopherol transfer protein (α-TTP) stereoselectively binds and transports 2R-alpha-tocopherols ⁴⁵⁶⁾, ⁴⁵⁷⁾, ⁴⁵⁸⁾. For some TTPA pathogenic variants, this stereoselective binding capacity is lost and affected individuals cannot discriminate between RRR- and SRR-alpha-tocopherol ⁴⁵⁹⁾, ⁴⁶⁰⁾. In this instance, affected individuals would also be able to incorporate non-2R-alpha-tocopherol stereoisomers into their bodies if they were supplemented with all-rac-alpha-tocopherol. Since potential side effects of the synthetic stereoisomers have not been studied in detail, it seems appropriate to treat with RRR-alpha-tocopherol, despite the higher cost.

When vitamin E treatment is initiated in presymptomatic individuals (e.g., younger age), manifestations of ataxia with vitamin E deficiency (AVED) do not develop ⁴⁶¹⁾, ⁴⁶²⁾.

No large-scale therapeutic studies have been performed to determine optimal vitamin E dosage and to evaluate outcomes ⁴⁶³⁾. The reported vitamin E dose ranges from 800 mg to 1,500 mg (or 40 mg/kg body weight in children) ⁴⁶⁴⁾, ⁴⁶⁵⁾, ⁴⁶⁶⁾, ⁴⁶⁷⁾, ⁴⁶⁸⁾, ⁴⁶⁹⁾, ⁴⁷⁰⁾, ⁴⁷¹⁾. The ideal dose of vitamin E ranges from 800 mg to 1500 mg (40 mg/kg/day) in children ⁴⁷²⁾, ⁴⁷³⁾.

Periodic follow‐up is required during vitamin E therapy. The plasma concentration of vitamin E should be measured in regular intervals, usually, every 6 months to maintain the level of vitamin E in the high normal range especially in children. Ideally the plasma vitamin E concentration should be maintained in the high-normal range ⁴⁷⁴⁾.

Individuals with AVED should avoid smoking and occupations requiring quick responses or good balance. Smoking reduces the total radical trapping antioxidant parameter of plasma (TRAP), which is regarded as the best prognostic marker during the supplementation of vitamin E, leading to the reduction in plasma vitamin level ⁴⁷⁵⁾.

Symptomatic individuals

Some clinical signs and symptoms (e.g., ataxia and intellectual deterioration) can be reversed in symptomatic individuals if treatment is initiated early in the disease process ⁴⁷⁶⁾.

In older individuals, disease progression can be stopped, but deficits in proprioception and gait unsteadiness generally remain ⁴⁷⁷⁾, ⁴⁷⁸⁾, ⁴⁷⁹⁾.

Supportive Care

The goals of supportive care in those with clinical signs and symptoms of AVED are to maximize function and reduce complications. Depending on the clinical signs and symptoms, it is recommended that each individual be managed by a multidisciplinary team of relevant specialists such as neurologists, occupational therapists, physical therapists, physiatrists, orthopedists, nutritionists, speech-language pathologists, pulmonologists, and mental health specialists ⁴⁸⁰⁾.

Pregnancy Management

Because reduced vitamin E levels are associated with low fertility and embryo resorption in mice ⁴⁸¹⁾ and α-tocopherol transfer protein is highly expressed in the human placenta ⁴⁸²⁾, it is advisable for women with AVED to maintain vitamin E levels in the high-normal range during pregnancy ⁴⁸³⁾.

Ataxia with Vitamin E Deficiency (AVED) prognosis

Ataxia with Vitamin E Deficiency (AVED) prognosis despite the supplementation of vitamin E depends on the timing of the supplementation and the age of the onset of vitamin E deficiency. Vitamin E treatment in pre‐symptomatic individuals with a history of family cases of AVED can help to prevent the individual from primary manifestations. The symptoms do not develop in the individuals with the initiation of vitamin E earlier in pre‐symptomatic individuals who are at risk ⁴⁸⁴⁾. Older individuals usually remain deficient in proprioception and gait unsteadiness although the progression of the disease can be stopped with vitamin E supplementation ⁴⁸⁵⁾.

Vitamin E deficiency signs and 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) ⁴⁸⁶⁾. For this reason, people who develop peripheral neuropathy, ataxia, or retinitis pigmentosa of unknown causes should be screened for vitamin E deficiency ⁴⁸⁷⁾. Severe vitamin E deficiency individuals may present with profound muscle weakness and visual-field constriction ⁴⁸⁸⁾. Patients with severe, prolonged vitamin E deficiency may develop complete blindness, cardiac arrhythmia, and dementia ⁴⁸⁹⁾.

The results of one randomized controlled trial in 601 patients with common forms of retinitis pigmentosa indicated that daily supplementation with 400 IU of all-rac-alpha-tocopherol (180 mg of RRR-α-tocopherol) modestly but significantly increased the loss of retinal function ⁴⁹⁰⁾. In contrast, daily supplementation with 15,000 IU of vitamin A (4,500 μg RAE) significantly slowed the loss of retinal function over a period of four to six years, suggesting that patients with common forms of retinitis pigmentosa may benefit from long-term vitamin A supplementation but should avoid high-dose supplemental vitamin E ⁴⁹¹⁾.

Inherited defects in alpha-tocopherol transfer protein (α-TTP) are associated with a characteristic syndrome called Ataxia with Vitamin E Deficiency (AVED). A recent case study reported that visual impairment in a middle-age patient with AVED was caused by both retinitis pigmentosa and early-onset macular degeneration ⁴⁹²⁾. Supplementation with high-dose vitamin E (800-1,200 mg/day) is used to prevent neurologic deterioration in AVED subjects ⁴⁹³⁾.

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 10-20 years ⁴⁹⁴⁾. 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 ⁴⁹⁵⁾. In addition, a recent 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 ⁴⁹⁶⁾.

If vitamin E deficiency is expected, a full neurological exam is recommended as well as a standard physical exam. Patients presenting early may show hyporeflexia, decreased night vision, loss/decreased vibratory sense, however, have normal cognition. A more moderate stage of this deficiency may show limb and truncal ataxia, profuse muscle weakness, and limited upward gaze. Late presentations may show cardiac arrhythmias and possible blindness with reduced cognition. Ataxia is the most common exam finding.

Patients that have abetalipoproteinemia have eye problems often including pigmented retinopathy and visual field issues. However, patients suffering from cholestatic liver disease often have personality and behavioral disorders.

Vitamin E deficiency diagnosis

A low alpha-tocopherol level or low ratio serum alpha-tocopherol to serum lipids measurement is the mainstay of diagnosis. In adults, alpha-tocopherol levels should be less than 5 mcg/mL. In an adult with hyperlipidemia, the abnormal lipids may affect the vitamin E levels and a serum alpha-tocopherol to lipids level, needing to be less than 0.8 mg/g) is more accurate. A pediatric patient with abetalipoproteinemia will have serum alpha-tocopherol levels that are not detectable.

Vitamin E deficiency treatment

Treatment addresses the underlying cause of the deficiency (fat malabsorption, fat metabolism disorders, among others) and then provide oral vitamin E supplementation ⁴⁹⁷⁾. Also, a modification in diet can assist in vitamin E supplementation, by increasing intake of leafy vegetables, whole grains, nuts, seeds, vegetable oils and fortified cereals is highly recommended. Though normally presented in our diets, adults need 15 mg of vitamin E per day. A supplement of 15 to 25 mg/kg once per day or mixed tocopherols 200 IU can both be used. If a patient has issues with the small intestine and/or oral ingestion intramuscular vitamin E injection is necessary ⁴⁹⁸⁾, ⁴⁹⁹⁾, ⁵⁰⁰⁾, ⁵⁰¹⁾. The recommended daily allowance of alpha-tocopherol is as follows ⁵⁰²⁾, ⁵⁰³⁾:

• Age 0 to 6 months: 3 mg
• Age 6 to 12 months: 4 mg
• Age 1 to 3 years: 6 mg
• Age 4 to 10 years: 7 mg
• Adults and elderly patients: 8 to 10 mg

Replacement recommendations vary by the disease and are as follows ⁵⁰⁴⁾, ⁵⁰⁵⁾:

• Abetalipoproteinemia: 100 to 200 IU/kg per day
• Chronic cholestasis: 15 to 25 IU/kg per day
• Cystic fibrosis: 5 to 10 IU/kg per day
• Short-bowel syndrome: 200 to 3600 IU per day
• Isolated vitamin E deficiency: 800 to 3600 IU per day

Larger doses are required in short-bowel syndrome and isolated vitamin E deficiency state.

The recommended doses of vitamin E for age group and associated causes are shown in Table 3.

Table 3. Recommended doses of vitamin E according to age group and associated causes

Vitamin E deficiency prognosis

If left untreated, vitamin E deficiency symptoms may worsen. However, once diagnosed, the outcome of vitamin E deficiency is very good as most symptoms will resolve quickly. However, as vitamin E deficiency becomes more pronounced, the therapy will be more restricted. Patients who are at risk for vitamin E deficiency should undergo a thorough neurologic examination, as well as periodic testing of serum vitamin E levels ⁵⁰⁹⁾. The results of a systematic review by Sherf-Dagan et al suggest that patients who undergo weight loss surgery (bariatric surgery), particularly malabsorptive procedures, are at greater risk for the development of vitamin E deficiency ⁵¹⁰⁾.

Vitamin E Side Effects and Toxicity

Research has not found any adverse effects from consuming vitamin E in food ⁵¹¹⁾. However, high doses of alpha-tocopherol supplements can cause hemorrhage, especially in patients already on anticoagulation or antiplatelet therapy and interrupt blood coagulation in animals, and in vitro data suggest that high doses inhibit platelet aggregation. Two clinical trials have found an increased risk of hemorrhagic stroke in participants taking alpha-tocopherol; one trial included Finnish male smokers who consumed 50 mg/day for an average of 6 years  ⁵¹²⁾ and the other trial involved a large group of male physicians in the United States who consumed 400 IU every other day for 8 years ⁵¹³⁾. Because the majority of physicians in the latter study were also taking aspirin, this finding could indicate that vitamin E has a tendency to cause bleeding.

Bleeding episodes can occur anywhere in the body, and serious life-threatening hemorrhagic strokes have been reported. Other vitamin E toxicity complications include gastrointestinal manifestations, weakness, fatigue, and emotional lability. The treatment for vitamin E toxicity includes discontinuation of vitamin E supplementation and consideration of vitamin K therapy if serious bleeding occurs. To prevent vitamin E toxicity, supplementation of vitamin E should be kept to a lower dosage.

The Food and Nutrition Board at the Institute of Medicine of The National Academies has established Tolerable Upper Intake Levels (ULs – the maximum daily intake unlikely to cause adverse health effects) for vitamin E based on the potential for hemorrhagic effects (see Table 4). The Tolerable Upper Intake Levels (ULs) apply to all forms of supplemental alpha-tocopherol, including the eight stereoisomers present in synthetic vitamin E. Doses of up to 1,000 mg/day (1,500 IU/day of the natural form or 1,100 IU/day of the synthetic form) in adults appear to be safe, although the data are limited and based on small groups of people taking up to 3,200 mg/day of alpha-tocopherol for only a few weeks or months. Long-term intakes above the Tolerable Upper Intake Level (UL) increase the risk of adverse health effects ⁵¹⁴⁾. Vitamin E Tolerable Upper Intake Levels (ULs) for infants have not been established.

Table 4. Tolerable Upper Intake Levels (ULs) for Vitamin E

Can vitamin E be harmful?

Eating vitamin E in foods is not risky or harmful ⁵¹⁶⁾. A patient who consumes vitamin E in their diet has, on average, a level of circulating alpha-tocopherol of approximately 20 micromol/L. Patients that have additional vitamin E supplementation have levels of 30 micromol/L or greater.

In supplement form, however, high doses of vitamin E might increase the risk of bleeding (by reducing the blood’s ability to form clots after a cut or injury) and of serious bleeding in the brain (known as hemorrhagic stroke) ⁵¹⁷⁾. High doses of alpha-tocopherol supplements can cause hemorrhage and interrupt blood coagulation in animals and test tube studies data suggest that high doses inhibit platelet aggregation. Two clinical trials have found an increased risk of hemorrhagic stroke in participants taking alpha-tocopherol; one trial included Finnish male smokers who consumed 50 mg/day for an average of 6 years ⁵¹⁸⁾ and the other trial involved a large group of male physicians in the United States who consumed 400 IU (180 mg) of synthetic vitamin E every other day for 8 years ⁵¹⁹⁾. Because the majority of physicians in the latter study were also taking aspirin, this finding could indicate that vitamin E has a tendency to cause bleeding.

Because of this risk, the upper limit for adults is 1,500 IU/day for supplements made from the natural form of vitamin E and 1,100 IU/day for supplements made from synthetic vitamin E. The upper limits for children are lower than those for adults. Some research suggests that taking vitamin E supplements even below these upper limits might cause harm. In one study, for example, men who took 400 IU of vitamin E each day for several years had an increased risk of prostate cancer.

Two meta-analyses of randomized trials have also raised questions about the safety of large doses of vitamin E, including doses lower than the Tolerable Upper Intake Level (UL). These meta-analyses linked supplementation to small but statistically significant increases in all-cause mortality. One analysis found an increased risk of death at doses of 400 IU/day (form not specified), although the risk began to increase at 150 IU ⁵²⁰⁾. In the other analysis of studies of antioxidant supplements for disease prevention, the highest quality trials revealed that vitamin E, administered singly (dose range 10 IU–5,000 IU/day; mean 569 IU [form not specified]) or combined with up to four other antioxidants, significantly increased mortality risk ⁵²¹⁾.

The implications of these analyses for the potential adverse effects of high-dose vitamin E supplements are unclear ⁵²²⁾. Participants in the studies included in these analyses were typically middle-aged or older and had chronic diseases or related risk factors. These participants often consumed other supplements in addition to vitamin E. Some of the studies analyzed took place in developing countries in which nutritional deficiencies are common. A review of the subset of studies in which vitamin E supplements were given to healthy individuals for the primary prevention of chronic disease found no convincing evidence that the supplements increased mortality ⁵²³⁾.

However, results from the recently published, large SELECT trial show that vitamin E supplements (400 IU/day [180 mg] as dl-alpha-tocopheryl acetate) may harm adult men in the general population by increasing their risk of prostate cancer ⁵²⁴⁾. Follow-up studies are assessing whether the cancer risk was associated with baseline blood levels of vitamin E and selenium prior to supplementation as well as whether changes in one or more genes might increase a man’s risk of developing prostate cancer while taking vitamin E.

Vitamin E toxicity complications

Although the major hazardous complications of elevated vitamin E levels include bleeding, there have been others mentioned. These include thyroid problems, weakness, emotional disorder, gastrointestinal derangement, tenderness of breasts, and thrombophlebitis ⁵²⁵⁾.

Vitamin E toxicity diagnosis

To detect vitamin E toxicity, serum levels of circulating alpha-tocopherol can be obtained. The average range of plasma alpha-tocopherol in a patient that eats a well-balanced diet is 20 micromoles/liter ⁵²⁶⁾. A patient on vitamin E supplementation may have plasma levels of 30 micromoles/liter or greater ⁵²⁷⁾. The normal lab range for circulating alpha-tocopherols is 5.7 to 19.9 mg/L ⁵²⁸⁾. The levels of circulating alpha-tocopherol are very dependent on the lipid content of the blood. In patients with extremely high or extremely low cholesterol levels, the levels of circulating alpha-tocopherol are not an accurate measure of vitamin E. In a patient with average cholesterol levels, the levels of circulating alpha-tocopherol are still not an accurate measure of vitamin E. This is due to the upregulation of biliary and urinary excretion once vitamin E levels are increased in the body ⁵²⁹⁾. Because of these irregularities in vitamin E metabolism, there is no set cut-off level of circulating alpha-tocopherols considered universally toxic.

In a study performed on patients with intracranial hemorrhages and taking vitamin E supplementation, alpha-tocopherol levels ranged from 23.3 micromoles/L to 46.7 micromoles/L in patients that were discovered to have intracranial hemorrhages ⁵³⁰⁾. In another study that correlated the vitamin E levels and risk of bleeding in patients taking oral anticoagulation, a ratio of circulating alpha-tocopherols to total serum cholesterol concentration was used. This was thought to most accurately represent the true circulating vitamin E levels ⁵³¹⁾. Although there is a concern regarding the reliability of these circulating levels of alpha-tocopherols correlating to vitamin E levels, this is still the most widely used test in the literature regarding quantifying vitamin E when describing its effects.

Vitamin E toxicity treatment

The mainstay treatment for vitamin E toxicity is stopping the exogenous vitamin supplementation. This is effective since vitamin E toxicity does not occur unless there is an exogenous supplementation ⁵³²⁾. If there is significant bleeding, vitamin K supplementation should be considered in patients taking vitamin E supplementation. There can be inhibition of a clotting cascade that is vitamin K dependent when there are higher concentrations of vitamin E. This can occur whether the patient is on warfarin or not. Vitamin E also impedes platelet aggregation. This can occur regardless of whether the patient takes antiplatelet agents. Therefore, giving vitamin K to patients who are actively bleeding or have a severe hemorrhage should be considered ⁵³³⁾.