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 ¹, ², ³, ⁴. 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 ⁴.

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 ⁵. 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 ⁶.

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 ², ³, ⁴. Vitamin E deficiency symptoms include peripheral neuropathy, ataxia, skeletal myopathy, retinopathy, and impairment of the immune response ¹, ⁷. 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 ⁸.

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) ⁸. Vitamin E deficiency secondary to abetalipoproteinemia causes such problems as poor transmission of nerve impulses, muscle weakness, and retinal degeneration that leads to blindness ⁹. 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 ¹⁰, ¹¹. 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 ⁹, ¹⁰, ¹¹.

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.

What is 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 ¹². 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) ¹², ². 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 ¹³, ¹⁴, ¹⁵, ¹⁶, ¹⁷.

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 ¹⁶. Therefore, alpha-tocopherol (α-tocopherol) is the predominant form of vitamin E found in your blood and tissues ¹⁸. 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 ¹⁶. 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) ¹⁶. 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 ¹⁹. Furthermore, beta-, gamma-, and delta-tocopherols, 4 tocotrienols, and several stereoisomers may also have important biologic activity ¹⁸.

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) ¹⁷. 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 ²⁰. 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 ¹⁸. Alpha-tocopherol inhibits the activity of protein kinase C, an enzyme involved in cell proliferation and differentiation in smooth muscle cells, platelets, and monocytes ¹⁹. 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 ²¹. 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 ²².

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 ¹⁹.

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) ¹², 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 ²³. 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 ²⁴, ²⁵. 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) ²⁶.

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) ²⁷. 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 ²⁸. 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 ¹⁴ ]

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 ²⁹, ³⁰. In the circulation, all lipoproteins (i.e., VLDLs, LDLs, and HDLs) are involved in the transport and tissue distribution of alpha-tocopherol ¹⁸. 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 ³¹.

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 are the functions of vitamin E?

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 ²⁰. 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 ¹², ³³, ³⁴. Alpha-tocopherol inhibits the activity of protein kinase C, an enzyme involved in cell proliferation and differentiation in smooth muscle cells, platelets, and monocytes ¹. 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 ¹. Moreover, vitamin E also helps improve nerve conduction ³⁵, maintain the structural integrity of the hemoglobin membrane ³⁶ and, along with vitamin A, plays a role in vision ³⁷. The specific mechanism of action for most of vitamin E effects is still relatively unknown ³⁸.

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) ¹⁸.

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 ²².

Tocotrienols and gamma-tocopherol are thought to be better scavengers of peroxyl radicals and reactive nitrogen species, respectively, than alpha-tocopherol ³⁹. 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 ⁴⁰, 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 ¹⁸.

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 ³⁹. Limited intervention studies highlighted in Jiang ³⁹ 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 ⁴¹, ⁴².

Numerous preclinical studies have also suggested that tocotrienols might be beneficial in the prevention of chronic diseases ⁴³. For instance, tocotrienols especially delta-tocotrienol have shown greater anti-proliferative and pro-apoptotic effects than tocopherols in malignant cell lines ⁴⁴. 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 ⁴⁵. There are currently no data available on the effectiveness of supplemental tocotrienols in humans ⁴³.

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 ¹⁸. For example, alpha-tocopherol can protect the physiological properties of lipid bilayer membranes and may influence the activity of membrane proteins and enzymes ⁴⁶. 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 ⁴⁷, ⁴⁸.

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 ¹⁶. Alpha-tocopherol has been shown to enhance specifically the T cell-mediated immune response that declines with advancing age ⁴⁹. 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 ⁴⁸. However, very few studies have addressed the potential association between alpha-tocopherol and immune function in humans ⁴⁹. 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 ⁵⁰. 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 ⁵¹.

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) ⁵². 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 ⁵³. 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 ⁵⁴. 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 ⁵⁵. For this reason, the depletion of the ozone layer increases UV transmission. UVA is associated with aging and pigmentation ⁵⁵. 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 ⁵⁶. UVB causes sunburn and DNA strand breaks. UVB causes pyrimidine dimer mutations, which are associated with nonmelanoma skin cancers ⁵⁷.

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 ⁵⁸. 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 ⁵⁹, ⁶⁰, ⁶¹, 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 ⁶². Three other mouse studies reported inhibition of UV-induced tumors in mice fed alpha-tocopherol acetate ⁶³, ⁶⁴, ⁶⁵, but one of these studies utilized vitamin E doses that were toxic to animals when combined with the UV treatment ⁶³. 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 ⁶⁶. 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 ⁶⁷. 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 ⁶⁸. Furthermore, multiple human studies have shown no effect of vitamin E on the prevention or development of skin cancers ⁶⁹, ⁷⁰.

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 ⁷¹, ⁷². The combination of vitamin C and vitamin E was associated with lower amounts of DNA damage after UV exposure ⁷³. 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 ⁷⁴. 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 ⁶⁶, ⁷⁵, ⁷⁶, ⁷⁷, limiting DNA damage ⁶⁶, ⁷⁸, ⁷⁹, ⁸⁰, and reducing the many chemical and structural changes to skin after UV exposure ⁸¹, ⁸², ⁸³, ⁸⁴. Vitamin E skin applications have also been shown to reduce UV-induced tumor formation in multiple mouse studies ⁸¹, ⁶⁴, ⁸⁵ and to reduce the effects of photo-activated toxins in the skin ⁸⁶, ⁸⁷, ⁸⁸, ⁸⁹. 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 ⁸³, ⁸⁴. 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) ⁹⁰. 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 ⁸³. In human subjects, the use of vitamin E on skin lowers peroxidation of skin surface lipids ⁹¹, decreases erythema ⁹², ⁹³ and limits immune cell activation after UV exposure ⁹⁴.

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 ⁹⁵, ⁹⁶, decrease DNA damage ⁹⁵, ⁹⁷, inhibit redness ⁹⁵, ⁹⁸, and decrease skin pigmentation after UV exposure ⁹⁸. Similar effects have been seen in human subjects ⁹⁹, ¹⁰⁰, ¹⁰¹.

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 ⁹¹. 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 ¹⁰², ¹⁰³. An analysis of the dietary intake of Japanese women showed no correlation between vitamin E consumption and skin wrinkling ¹⁰⁴.

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 ¹⁰⁴, ¹⁰⁵. However, two small studies have shown topical application of vitamin E can improve skin water-binding capacity after two to four weeks of use ¹⁰⁶, ¹⁰⁷. 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 ¹⁰⁸, ¹⁰⁹, ¹¹⁰ and lead to free radical damage that may compound the effects of UV exposure ¹¹⁰. Although not well studied, topical applications of vitamin E may reduce pollution-related free radical damage ¹⁰⁹.

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 ¹¹¹, ¹¹², ¹¹³, as well as limit inflammatory responses to lipid hydroperoxide exposure ¹¹⁴. In mice, dietary gamma-tocotrienol suppresses UV-induced COX-2 expression in the skin ¹¹³. 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 ¹¹⁵. In vitro studies (test tube lab studies) have shown similar anti-inflammatory effects of alpha- and gamma-tocopherol on immune cells ¹¹⁶, ¹¹⁷, ¹¹⁸.

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 ¹¹⁹, ¹²⁰ or in combination with vitamin C ¹²¹ or vitamin D ¹²², 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 ¹²³. 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 ¹²⁴, ¹²⁵. Vitamin E increases the breaking strength of wounds pre-treated with ionizing radiation ¹²⁶, 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 ¹²⁷.

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 ¹²⁸, ¹²⁹. 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 ¹³⁰, ¹³¹.

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 ¹³². 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 ¹³³.

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 ¹³⁴. 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 ¹³⁵.

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 ¹. 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 ¹³⁶.

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 ¹.

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 ¹⁷.
• 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 ¹³⁷.
• 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 ¹³⁸. Although a systematic review of randomized controlled trials has called this concern into question ¹³⁹, further research is needed to evaluate the potential risks and benefits of concurrent antioxidant supplementation with conventional therapies for cancer.

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 ¹⁴⁰:

• 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 ¹⁴¹
• 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 ¹⁴². 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) ¹⁴³. 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.

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.

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 ¹³². 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 ¹⁴⁴.

Ataxia with Vitamin E Deficiency (AVED)

Ataxia with vitamin E deficiency (AVED), also known as Familial Isolated Vitamin E deficiency, Isolated Vitamin E deficiency or Friedreich-like ataxia with vitamin E deficiency, is a rare progressive neurodegenerative disorder of autosomal recessive cerebellar ataxia (ARCA) ¹⁴⁵, ¹⁴⁶, ¹⁴⁷, ¹⁴⁸, ¹⁴⁹, ¹⁵⁰. The most prominent symptoms of ataxia with vitamin E deficiency (AVED) include progressive cerebellar ataxia (difficulty coordinating movements), slurred speech (dysarthria),  numbness in the hands and feet (peripheral neuropathy), absence of neurologic reflexes (areflexia), and progressive leg weakness ¹⁴⁸. 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) ¹⁵¹, ¹⁵². Ataxia with vitamin E deficiency (AVED) symptoms typically begin during childhood or adolescence and worsen with age, resulting in the need for a wheelchair by early adulthood ¹⁵³. 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) is caused by mutations in the alpha-tocopherol transfer protein (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 ¹⁵⁴. More than 20 mutations in the TTPA gene have been found to cause ataxia with vitamin E deficiency ¹⁵⁵. Some of these TTPA mutations cause no functional protein to be made, while others change a single protein building block (amino acid) in the alpha-tocopherol transfer protein (α-TTP), reducing its function ¹⁵⁵. As a result, the body cannot retain or use dietary vitamin E, which leads to reduced levels of vitamin E in your blood and the accumulation of free radicals. Mutations in the TTPA gene that cause no functional alpha-tocopherol transfer protein (α-TTP) to be made are associated with a severe form of ataxia that begins at a young age ¹⁵⁵. Mutations that reduce but do not eliminate the alpha-tocopherol transfer protein (α-TTP) function are associated with milder ataxia that occurs at a later age and progresses more slowly. One TTPA gene mutation that is found in the Japanese population changes the amino acid histidine to the amino acid glutamine at position 101 in the αTTP protein (written as His101Glu or H101Q). This mutation is associated with the development of an eye disorder called retinitis pigmentosa that causes vision loss in people with ataxia with vitamin E deficiency ¹⁵⁵.

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 ¹⁵⁶. 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 ¹⁴⁷. 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 ¹⁴⁷. 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 ¹⁵⁷, ¹⁵⁸, ¹⁵⁹, ¹⁶⁰, ¹⁶¹, ¹⁶², ¹⁶³, ¹⁶⁴, ¹⁶⁵. 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 ¹⁵⁴.

Marriotti et al. ¹⁶⁶ 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 ¹⁶⁷. The following criteria should be met to diagnose ataxia with vitamin E deficiency (AVED) ¹⁶⁸:

• 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 ¹⁶⁹. 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 ¹⁶⁸. 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 ¹⁷⁰.

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) ¹⁴³. Alpha-tocopherol transfer protein (αTTP) 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.

The mechanism of neurologic dysfunction in AVED is unknown, but neuronal oxidative injury has been hypothesized ¹⁴⁵. Brain imaging demonstrates cerebellar atrophy in up to 50% of cases ¹⁵⁸, ¹⁷¹. Other brain regions are also affected. Animal models of AVED and post-mortem studies of humans with secondary vitamin E deficiency have shown evidence of degenerative changes in the substantia nigra, posterior column, nerve roots, and peripheral nervous system ¹⁷², ¹⁷³, ¹⁷⁴, ¹⁷⁵, ¹⁷⁶, ¹⁷⁷, ¹⁷⁸:915–936. doi: 10.4049/jimmunol.0903008)). Post-mortem studies of patients with AVED demonstrate loss of cerebellar Purkinje cells, dying back-type posterior column degeneration with spheroids and corpora amylacea, and lipofuscin accumulation ¹⁷⁹, ¹⁸⁰. Ataxia in AVED is likely caused by a combination of cerebellar and posterior column degeneration ¹⁴⁵.

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.

Figure 7. Ataxia with vitamin E deficiency autosomal recessive inheritance pattern

People with specific questions about genetic risks or genetic testing for themselves or family members should speak with a genetics professional.

Resources for locating a genetics professional in your community are available online:

• The National Society of Genetic Counselors (https://www.findageneticcounselor.com/) offers a searchable directory of genetic counselors in the United States and Canada. You can search by location, name, area of practice/specialization, and/or ZIP Code.
• The American Board of Genetic Counseling (https://www.abgc.net/about-genetic-counseling/find-a-certified-counselor/) provides a searchable directory of certified genetic counselors worldwide. You can search by practice area, name, organization, or location.
• The Canadian Association of Genetic Counselors (https://www.cagc-accg.ca/index.php?page=225) has a searchable directory of genetic counselors in Canada. You can search by name, distance from an address, province, or services.
• The American College of Medical Genetics and Genomics (http://www.acmg.net/ACMG/Genetic_Services_Directory_Search.aspx) has a searchable database of medical genetics clinic services in the United States.

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) ¹⁵⁶. 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 ¹⁵⁶. If symptoms become very severe, an individual with AVED may require a wheelchair if they cannot walk ¹⁵⁶. 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) ¹⁸¹.

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 ¹⁵⁶. 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 ¹⁴⁷. In rare individuals, school performance declines secondary to loss of intellectual capacities ¹⁴⁷.

In addition to neurological symptoms, individuals with AVED may develop symptoms affecting other systems of the body including the eyes ¹⁵⁶. 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 ¹⁵². 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 ¹⁵⁶.

Some individuals with ataxia with vitamin E deficiency (AVED) may experience a form of dystonia ¹⁸², ¹⁴⁵. 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). These contractions result in twisting and repetitive movements. Dystonia can affect just one muscle, a group of muscles or all of your muscles. Symptoms can include tremors, voice problems or a dragging foot. Symptoms often start in childhood. They can also start in the late teens or early adulthood. Some cases worsen over time. Others are mild.

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 ¹⁴⁷:

• 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 ¹⁸³, 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 ¹⁴⁹, 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) ¹⁶⁰, ¹⁵⁸.
  • 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 ¹⁷⁰.
• Neuroimaging
  • No radiologic findings are specific to or diagnostic of AVED.
  • Cerebellar atrophy is present in approximately half of reported individuals ¹⁵⁸.
  • Small T2 high-intensity spots in the periventricular region and the deep white matter are inconsistent findings in some individuals ¹⁸⁴.

The diagnosis of ataxia with vitamin E deficiency (AVED) is established by molecular genetic testing with the identification of abnormalities in the TTPA gene ¹⁴⁷.

Figure 8. 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 ¹⁴⁷:

• 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 ¹⁸⁵, ¹⁸⁶, ¹⁸⁷. For some TTPA pathogenic variants, this stereoselective binding capacity is lost and affected individuals cannot discriminate between RRR- and SRR-alpha-tocopherol ¹⁶², ¹⁶⁰. 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 ¹⁸⁸, ¹⁴⁹.

No large-scale therapeutic studies have been performed to determine optimal vitamin E dosage and to evaluate outcomes ¹⁴⁷. The reported vitamin E dose ranges from 800 mg to 1,500 mg (or 40 mg/kg body weight in children) ¹⁸⁹, ¹⁹⁰, ¹⁸⁸, ¹⁶⁰, ¹⁷⁰, ¹⁹¹, ¹⁷¹, ¹⁵⁸. The ideal dose of vitamin E ranges from 800 mg to 1500 mg (40 mg/kg/day) in children ¹⁶⁶, ¹⁶⁹.

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 ¹⁴⁷.

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 ¹⁹².

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 ¹⁷⁰.

In older individuals, disease progression can be stopped, but deficits in proprioception and gait unsteadiness generally remain ¹⁷¹, ¹⁵⁸, ¹⁴⁹.

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 ¹⁴⁷.

Pregnancy Management

Because reduced vitamin E levels are associated with low fertility and embryo resorption in mice ¹⁹³ and α-tocopherol transfer protein is highly expressed in the human placenta ¹⁹⁴, it is advisable for women with AVED to maintain vitamin E levels in the high-normal range during pregnancy ¹⁴⁷.

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 ¹⁹⁵, ¹⁵⁸, ¹⁷¹. Older individuals usually remain deficient in proprioception and gait unsteadiness although the progression of the disease can be stopped with vitamin E supplementation ¹⁸¹.

Without treatment, most patients with ataxia with vitamin E deficiency (AVED) disease onset during childhood (age <18 years) become wheelchair-bound within 5–20 years of disease onset ¹⁴⁵.

The specific response of dystonia in AVED to vitamin E treatment is variable ¹⁴⁵. Dystonia has been reported to improve in two patients ¹⁵⁸, ¹⁸² and most patients with dystonia as a feature of their disease had stabilization or improvement of their other symptoms on high dose vitamin E ¹⁴⁵. One patient, however, experienced progressive dystonia despite escalating doses of vitamin E supplementation ¹⁹⁶. There are anecdotal reports of dystonia improvement in response to symptomatic treatment with botulinum toxin, trihexyphenidyl and clonazepam ¹⁹⁶, ¹⁸².

Vitamin E deficiency prevention

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 ¹. 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.

Recommended Dietary Allowance (RDA) is the average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%–98%) healthy people. The 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) ¹⁹⁷. Most vitamin E in American diets is in the form of gamma-tocopherol from soybean, canola, corn, and other vegetable oils and food products ²⁵.

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.

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) ¹⁶. For this reason, people who develop peripheral neuropathy, ataxia, or retinitis pigmentosa of unknown causes should be screened for vitamin E deficiency ⁴. Severe vitamin E deficiency individuals may present with profound muscle weakness and visual-field constriction ¹⁹⁹. Patients with severe, prolonged vitamin E deficiency may develop complete blindness, cardiac arrhythmia, and dementia ¹⁹⁹.

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 ²⁰⁰. 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 ²⁰⁰.

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 ²⁰¹. Supplementation with high-dose vitamin E (800-1,200 mg/day) is used to prevent neurologic deterioration in AVED subjects ⁴.

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 ⁴. 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 ¹⁶. 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 ⁶.

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 ¹⁴⁰. 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 ²⁰², ²⁰³, ²⁰⁴, ²⁰⁵. The recommended daily allowance of alpha-tocopherol is as follows ¹⁴⁰, ²⁰⁶:

• 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 ²⁰⁷, ²⁰⁶:

• 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 ⁹. 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 ²¹⁰.

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