Vitamin E: What is it?

Vitamin E is a fat-soluble vitamin that exists in eight different forms. Each form has its own biological activity, the measure of potency or functional use in the body (1). Alpha-tocopherol is the most active form of vitamin E in humans, and is a powerful biological antioxidant (2,3). Antioxidants such as vitamin E act to protect your cells against the effects of free radicals, which are potentially damaging by-products of the body’s metabolism. Free radicals can cause cell damage that may contribute to the development of cardiovascular disease and cancer. Studies are underway to determine whether vitamin E might help prevent or delay the development of those chronic diseases (2,3).

What foods provide vitamin E?
Vegetable oils, nuts, and green leafy vegetables are the main dietary sources of vitamin E. Fortified cereals are also an important source of vitamin E in the United States. The table of selected food sources of vitamin E suggests foods that contain vitamin E (4).

What is the Recommended Dietary Allowance for vitamin E for adults?
The Recommended Dietary Allowance (RDA) is the average daily dietary intake level that is sufficient to meet the nutrient requirements of nearly all (97-98%) healthy individuals in each life-stage and gender group (5). The 2000 RDAs for vitamin E (5) for adults, in milligrams (mg) and International Units (IUs) are:

The RDA for vitamin E is based on the alpha-tocopherol form because it is the most active, or usable, form (5, 6). Unlike other vitamins, the form of alpha-tocopherol made in the laboratory and found in supplements is not identical to the natural form, and is not quite as active as the natural form.

Results of two national surveys, the National Health and Nutrition Examination Survey (NHANES III 1988-91) and the Continuing Survey of Food Intakes of Individuals (1994 CSFII) indicated that the dietary intake of most Americans does not provide the recommended intake for vitamin E. However, a 2000 Institute of Medicine (IOM) report on vitamin E states that intake estimates of vitamin E may be low because energy and fat intake is often underreported in national surveys and because the kind and amount of fat added during cooking is often not known (5). The IOM states that most North American adults get enough vitamin E from their normal diets to meet current recommendations (5). However, they do caution individuals who consume low fat diets because vegetable oils are such a good dietary source of vitamin E. "Low-fat diets can substantially decrease vitamin E intakes if food choices are not carefully made to enhance alpha-tocopherol intakes" (5).

When can vitamin E deficiency occur?
Vitamin E deficiency is rare in humans. There are three specific situations when a vitamin E deficiency is likely to occur. It is seen in persons who cannot absorb dietary fat, has been found in premature, very low birth weight infants (birth weights less than 1500 grams, or 3 1/2 pounds) (3,6), and is seen in individuals with rare disorders of fat metabolism (9). A vitamin E deficiency is usually characterized by neurological problems due to poor nerve conduction.

Who may need extra vitamin E to prevent a deficiency?
Individuals who cannot absorb fat may require a vitamin E supplement because some dietary fat is needed for the absorption of vitamin E from the gastrointestinal tract. Anyone diagnosed with cystic fibrosis, individuals who have had part or all of their stomach removed, and individuals with malabsorptive problems such as Crohn’s disease may not absorb fat and should discuss the need for supplemental vitamin E with their physician (3). People who cannot absorb fat often pass greasy stools or have chronic diarrhea.

Very low birth weight infants may be deficient in vitamin E (3, 6). These infants are usually under the care of a neonatologist, a pediatrician specializing in the care of newborns, who evaluates and treats the exact nutritional needs of premature infants.

Abetalipoproteinemia is a rare inherited disorder of fat metabolism that results in poor absorption of dietary fat and vitamin E (9). The vitamin E deficiency associated with this disease causes problems such as poor transmission of nerve impulses, muscle weakness, and degeneration of the retina that can cause blindness (10). Individuals with abetalipoproteinemia may be prescribed special vitamin E supplements by a physician to treat this disorder.

What are some current issues and controversies about vitamin E?

Vitamin E and heart disease
Preliminary research has led to a widely held belief that vitamin E may help prevent or delay coronary heart disease (11). Researchers are fairly certain that oxidative modification of LDL-cholesterol (sometimes called "bad" cholesterol) promotes blockages in coronary arteries that may lead to atherosclerosis and heart attacks. Vitamin E may help prevent or delay coronary heart disease by limiting the oxidation of LDL-cholesterol (12). Vitamin E also may help prevent the formation of blood clots, which could lead to a heart attack. Observational studies have associated lower rates of heart disease with higher vitamin E intake. A study of approximately 90,000 nurses suggested that the incidence of heart disease was 30% to 40% lower among nurses with the highest intake of vitamin E from diet and supplements. The range of intakes from both diet and supplements in this group was 21.6 to 1,000 IU (32 to 1,500 mg), with the median intake being 208 IU (139 mg) (13). A 1994 review of 5,133 Finnish men and women aged 30 - 69 years suggested that increased dietary intake of vitamin E was associated with decreased mortality (death) from heart disease (14). But even though these observations are promising, randomized clinical trials raise questions about the role of vitamin E supplements in heart disease. The Heart Outcomes Prevention Evaluation (HOPE) Study followed almost 10,000 patients for 4.5 years who were at high risk for heart attack or stroke (15). In this intervention study the subjects who received 265 mg (400) IU of vitamin E daily did not experience significantly fewer cardiovascular events or hospitalizations for heart failure or chest pain when compared to those who received a sugar pill. The researchers suggested that it is unlikely that the vitamin E supplement provided any protection against cardiovascular disease in the HOPE study. This study is continuing, to determine whether a longer duration of intervention with vitamin E supplements will provide any protection against cardiovascular disease (5).

Vitamin E and cancer
Antioxidants such as vitamin E help protect against the damaging effects of free radicals, which may contribute to the development of chronic diseases such as cancer (5). Vitamin E also may block the formation of nitrosamines, which are carcinogens formed in the stomach from nitrites consumed in the diet. It also may protect against the development of cancers by enhancing immune function (16). Unfortunately, human trials and surveys that tried to associate vitamin E with incidence of cancer have been generally inconclusive.

Some evidence associates higher intake of vitamin E with a decreased incidence of prostate cancer and breast cancer (17). However, an examination of the effect of dietary factors, including vitamin E, on incidence of postmenopausal breast cancer in over 18,000 women from New York State did not associate a greater vitamin E intake with a reduced risk of developing breast cancer (18).

A study of women in Iowa provided evidence that an increased dietary intake of vitamin E may decrease the risk of colon cancer, especially in women under 65 years of age (19). On the other hand, vitamin E intake was not statistically associated with risk of colon cancer in almost 2,000 adults with cancer who were compared to controls without cancer (20). At this time there is limited evidence to recommend vitamin E supplements for the prevention of cancer.

Vitamin E and cataracts
Cataracts are growths on the lens of the eye that cloud vision. They increase the risk of disability and blindness in aging adults. Antioxidants are being studied to determine whether they can help prevent or delay cataract growth. Observational studies have found that lens clarity, which is used to diagnose cataracts, was better in regular users of vitamin E supplements and in persons with higher blood levels of vitamin E (21). A study of middle aged male smokers, however, did not demonstrate any effect from vitamin E supplements on the incidence of cataract formation (22). The effects of smoking, a major risk factor for developing cataracts, may have overridden any potential benefit from the vitamin E, but the conflicting results also indicate a need for further studies before researchers can confidently recommend extra vitamin E for the prevention of cataracts.

What is the health risk of too much vitamin E?
The health risk of too much vitamin E is low (23). A recent review of the safety of vitamin E in the elderly indicated that taking vitamin E supplements for up to four months at doses of 530 mg or 800 IU (35 times the current RDA) had no significant effect on general health, body weight, levels of body proteins, lipid levels, liver or kidney function, thyroid hormones, amount or kinds of blood cells, and bleeding time (24). Even though this study provides evidence that taking a vitamin E supplement containing 530 mg or 800 IU for four months is safe, the long term safety of vitamin E supplementation has not been tested. The Institute of Medicine has set an upper tolerable intake level for vitamin E at 1,000 mg (1,500 IU) for any form of supplementary alpha-tocopherol per day because the nutrient can act as an anticoagulant and increase the risk of bleeding problems. Upper tolerable intake levels "represent the maximum intake of a nutrient that is likely to pose no risk of adverse health effects in almost all individuals in the general population" (5).

Table of Selected Food Sources of vitamin E (4)
As the 2000 Dietary Guidelines for Americans state, "Different foods contain different nutrients. No single food can supply all the nutrients in the amounts you need" (25). The following table lists selected sources of vitamin E. As the tables indicate, vegetables oils, nuts, and green leafy vegetables are good dietary sources of vitamin E. Including these foods in your diet will help you meet your daily need for vitamin E, but it is still important to moderate total fat intake as recommended by the Dietary Guidelines for Americans.

Food manufacturers fortify many foods with vitamins and minerals. It is important to read the nutrition facts panel of the food label to determine whether a food provides vitamin E. If you want more information about building a healthful diet, refer to the Dietary Guidelines for Americans and the Food Guide Pyramid.

Table of Food Sources

This Fact Sheet was developed by the Clinical Nutrition Service, Warren Grant Magnuson Clinical Center, National Institutes of Health (NIH), Bethesda, MD, in conjunction with the Office of Dietary Supplements (ODS) in the Office of the Director of NIH. The mission of ODs is to strengthen knowledge and understanding of dietary supplements by evaluating scientific information, stimulating and supporting research, disseminating research results, and educating the public to foster an enhanced quality of life and health for the U.S. population. The Clinical Nutrition Service and the ODs would like to thank the expert scientific reviewers for their role in ensuring the scientific accuracy of the information discussed in this Fact Sheet.

Diet Rich in Foods with Vitamin E May Reduce Alzheimer's Disease Risk

A new population-based study of antioxidants, appearing in the June 26, 2002, Journal of the American Medical Association (JAMA), suggests that a diet rich in foods containing vitamin E may help protect some people against Alzheimer's disease (AD). The study is also noteworthy for its finding that vitamin E in the form of supplements was not associated with a reduction in the risk of AD. The latest in a series of reports on vitamin E and dementia, the study findings heighten interest in the outcome of clinical trials now underway to test the effectiveness of vitamin E and other antioxidants in preventing or postponing cognitive decline and AD.

The JAMA study was conducted by Martha Clare Morris, Sc.D., of the Rush Institute for Healthy Aging at Rush-Presbyterian-St.Luke's Medical Center, Chicago, IL, Denis A. Evans, M.D., and colleagues. A related study by Morris and colleagues, in press in the July 2002 Archives of Neurology, a JAMA publication, also associates vitamin E with protection against more general cognitive decline. (Reporting of additional detail on this study is embargoed for July 14, 2002, 4 p.m. ET.) Both studies were supported by the National Institute on Aging (NIA) at the National Institutes of Health.

The June 26 issue of JAMA includes similar findings from scientists in The Netherlands, who also reported a link between high dietary intake of vitamins C and E and protection against AD in certain people. In addition, the journal contains an editorial on the epidemiological study of dietary intake of antioxidants and the risk of AD by Daniel J. Foley, M.S., of the NIA's Laboratory of Epidemiology, Demography, and Biometry, and Lon White, M.D., Pacific Health Research Institute, Honolulu.

"This and a number of important population studies have pointed to vitamin E as possibly protective against oxidative damage or other mechanisms associated with cognitive decline and dementia," says Neil Buckholtz, Ph.D., head of the Dementias of Aging Branch at the NIA. "The only way this association can really be tested is through clinical studies and trials now underway. These will help us determine whether vitamin E in food or in supplements — or taken together — can prevent or slow down the development of mild cognitive impairment or AD."

It is not recommended, based on current evidence, that people take high-dose vitamin E supplements or other antioxidant pills in an effort to prevent mental decline, Buckholtz says. While population-based studies and animal research have suggested that antioxidants may be neuroprotective, clinical trials to test that notion are currently in progress. Little is known about safety, effectiveness, and dosages of various antioxidant supplements that are proposed for neuroprotective purposes, Buckholtz emphasizes. In excessively high doses (above 2,000 International Units daily, or IU/d), for example, vitamin E may be associated with increased risk of bleeding, and patients taking anti-coagulant medications may be especially at risk. Interactions with other medications commonly taken by older people are also of potential concern. People are advised to consult with their physicians before taking high doses of supplemental vitamin E or other antioxidants.

The 815 people participating in the Morris study were part of the Chicago Health and Aging Project (CHAP), a study of a large, diverse community of people age 65 and older. Participants were free of dementia at the start of the study and followed for an average of 3.9 years. At an average of 1.7 years from their baseline assessment, participants completed a questionnaire, asking them in detail about the kinds and quantities of foods consumed in the previous year.

Some 131 participants had been diagnosed with AD by the end of the study period, when researchers examined the relationship between intake of antioxidants, including dietary and supplemental vitamins E and C, beta carotene, and a multivitamin, and development of AD. The most significant protective effect was found among people in the top fifth of dietary vitamin E intake (averaging 11.4 IU/d), whose risk of AD was 67 percent lower when compared to people in the group with the lowest vitamin E consumption from food (averaging 6.2 IU/d). (The recommended dietary allowance of vitamin E is 22 IU/d.) No significant change in risk of AD was found when the scientists looked at vitamin E supplements, the other antioxidants and their supplements, or a general multivitamin. There was some evidence, though not statistically significant, that increased intake of dietary vitamin C and beta carotene was moving in a "protective direction," the researchers said.

The data were also analyzed to see if age, gender, race, education, or possible genetic risk for AD would influence the findings. Only the presence or lack of apoE-e4, one form of a protein associated with increased risk of late-onset AD, seemed to matter: the protective effect of vitamin E from food was strongest among people who did not have the apoE-e4 risk factor allele. "Dietary vitamin E may protect against Alzheimer's disease," says Morris, "but the protection may only occur among people without the apoE-e4 allele."

Morris suggests that further study in key areas is needed to confirm and explain some of the study's findings, including the link with apoE status and the study's striking distinction between dietary intake of vitamin E and use of supplements. For example, the lack of a protective effect for the supplements could be explained by several factors. Some participants in the study started taking supplements only recently and there may not have been sufficient time for the supplement to be found effective. Also, people who believe they have memory problems could be more likely to take the supplements in the first place. Another possible explanation might be variations in the forms of vitamin E, scientists note. Most vitamin E supplements consist of alpha tocopherol while foods are generally more rich in gamma tocopherol. These forms of vitamin E scavenge different types of free radicals, with one possibly more important than another in potentially reducing risk of cognitive decline. To help determine whether vitamin E might play a role in preventing AD, or at least in delaying its onset, a number of clinical trials are now being supported by the NIA.

VITAMIN E

The term vitamin E describes a family of eight antioxidants, four tocopherols, alpha (a), beta (b), gamma (g) and delta (d), and four tocotrienols (also a, b, g, and d).   a-Tocopherol is the only form of vitamin E that is actively maintained in the human body and is therefore, the form of vitamin E found in the largest quantities in the blood and tissue (1). Because a-tocopherol is the form of vitamin E that appears to have the greatest nutritional significance, it will be the primary topic of the following discussion. It is also the only form that meets the 2000 RDA for vitamin E.

FUNCTION

Alpha-tocopherol (a-tocopherol): The main function of a-tocopherol in humans appears to be that of an antioxidant.  Free radicals are formed primarily in the body during normal metabolism and also upon exposure to environmental factors such as cigarette smoke or pollutants. Fats, which are an integral part of all cell membranes, are vulnerable to destruction through oxidation by free radicals.  The fat-soluble vitamin, a-tocopherol, is uniquely suited to intercepting free radicals and preventing a chain reaction of lipid destruction.  Aside from maintaining the integrity of cell membranes throughout the body, a-tocopherol also protects the fats in low density lipoproteins (LDLs) from oxidation.  Lipoproteins are particles composed of lipids and proteins, which are able to transport fats through the blood stream.  LDL transport cholesterol from the liver to the tissues of the body.  Oxidized LDLs have been implicated in the development of cardiovascular diseases (See Disease Prevention).  When a molecule of a-tocopherol neutralizes a free radical, it is altered in such a way that its antioxidant capacity is lost.  However, other antioxidants, such as vitamin C, are capable of regenerating the antioxidant capacity of a-tocopherol (2).

Several other functions of a-tocopherol have been identified, which likely are not related to its antioxidant capacity. a-Tocopherol is known to inhibit the actvity of protein kinase C, an important cell signaling molecule, as well as to affect the expression and activity of immune and inflammatory cells. Additionally, a-tocopherol has been shown to inhibit platelet aggregation and to enhance vasodilation (3,4).

Gamma-tocopherol (g-tocopherol): The function of g-tocopherol in humans is presently unclear. Although the most common form of vitamin E in the American diet is g-tocopherol (see Food Sources), blood levels of g-tocopherol are generally ten times lower than those of a-tocopherol.  This phenomenon appears due to the action of the a-tocopherol transfer protein (a-TTP) in the liver, which preferentially incorporates a-tocopherol into lipoproteins that are circulated in the blood (1) and ultimately delivers a-tocopherol to different tissues in the body. See the Linus Pauling Institute Newsletter for more information about a-TTP and vitamin E adequacy. Because g-tocopherol is initially absorbed in the same manner as a-tocopherol, small amounts are detectable in blood and tissue.  Products of the metabolism of tocopherols, known as metabolites, can be detected in the urine. More g-tocopherol metabolites are excreted in the urine than a-tocopherol metabolites, suggesting less g-tocopherol is needed for use by the body (5). Limited research in the test tube and in animals indicates that g-tocopherol or its metabolites may play a role in the protection of the body from damage by free radicals (6,7), but these effects have not been convincingly demonstrated in humans. Recently, concern has been raised regarding the fact that taking a-tocopherol supplements lowers g-tocopherol levels in the blood.  However, no adverse effects of moderate a-tocopherol supplementation have been demonstrated, while many benefits have been documented (see Disease Prevention and Disease Treatment). In one recent prospective study, increased plasma g-tocopherol levels were associated with a significantly reduced risk of developing prostate cancer, while significant protective associations for increased levels of plasma a-tocopherol and toenail selenium were found only when g-tocopherol levels were also high (8). These limited findings, in addition to the fact that taking a-tocopherol supplements lower g-tocopherol levels in the blood, have led some scientists to call for additional research on the effects of dietary and supplemental g-tocopherol on health (9).

DEFICIENCY

Vitamin E deficiency has been observed in individuals with severe malnutrition, genetic defects affecting the a-tocopherol transfer protein, and fat malabsorption syndromes.  For example, children with cystic fibrosis or cholestatic liver disease, who have an impaired capacity to absorb dietary fat and therefore fat-soluble vitamins, may develop symptomatic vitamin E deficiency.  Severe vitamin E deficiency results mainly in neurological symptoms such as impaired balance and coordination, and muscle weakness.  The developing nervous system appears to be especially vulnerable to vitamin E deficiency because children with severe vitamin E deficiency from birth, who are not treated with vitamin E, develop neurological symptoms rapidly. In contrast, individuals who develop malabsorption of vitamin E in adulthood may not develop neurological symptoms for 10-20 years.  It should be noted that symptomatic vitamin E deficiency in healthy individuals who consume diets low in vitamin E has never been reported (10).

Although true vitamin E deficiency is rare, suboptimal intake of vitamin E is relatively common in the U.S. The National Health and Nutrition Examination Survey III (NHANES III) examined the dietary intake and blood levels of a-tocopherol in 16,295 multi-ethnic adults over the age of 18. Twenty seven % of white participants, 41 % of African Americans, 28% of Mexican Americans and 32% of the other participants were found to have blood levels of a-tocopherol less than 20 mmol/liter, a value chosen because the literature suggests an increased risk for cardiovascular disease below this level (11).

The Recommended Dietary Allowance (RDA):
The RDA for vitamin E was previously 8 mg/day for women and 10 mg/day for men. The RDA was revised by the Food and Nutrition Board of the Institute of Medicine in 2000 (3).  This new recommendation was based largely on the results of studies done in the 1950s in men fed vitamin E deficient diets. In a test tube analysis, hydrogen peroxide was added to blood samples and the breakdown of red blood cells, known as hemolysis, was used to indicate vitamin E deficiency.  Because hemolysis has also been reported in children with severe vitamin E deficiency, this analysis was considered to be a clinically relevant test of vitamin E status. Importantly, this means that the latest RDA for vitamin E continues to be based on the prevention of deficiency symptoms rather than on health promotion and the prevention of chronic disease.

DISEASE PREVENTION

Cardiovascular diseases (heart disease and stroke): The results of at least five large observational studies suggest that increased vitamin E consumption is associated with decreased risk of myocardial infarction (heart attack) or death from heart disease in both men and women.  Each study was a prospective study which measured vitamin E consumption in presumably healthy people and followed them for a number of years to determine how many of them were diagnosed with, or died as a result of heart disease.  In two of the studies, those individuals who consumed more than 7 mg of a-tocopherol in food were only approximately 35% as likely to die from heart disease as those who consumed less than 3-5 mg of a-tocopherol (12,13).  Two other large studies (14,15) found a significant reduction in the risk of heart disease only in those women and men who consumed a-tocopherol supplements of at least 100 IU (67 mg of RRR-a-tocopherol) daily, with the greatest benefit observed at an intake of 800 IU (536 mg RRR-a-tocopherol) daily (16). More recently, several studies have observed plasma or red blood cell levels of a-tocopherol to be inversely associated with the presence or severity of atherosclerosis detected using ultrasonography (17-20). In contrast, intervention studies with vitamin E supplements in patients with heart disease have not shown vitamin E to be effective in preventing heart attacks or death (see Disease Treatment).

Cancer: Many types of cancer are thought to result from oxidative damage to DNA caused by free radicals.  The ability of a-tocopherol to neutralize free radicals has made it the subject of a number of cancer prevention studies.  However, several large prospective studies have failed to find significant associations between a-tocopherol intake and the incidence of lung cancer or breast cancer (3).  A placebo-controlled intervention study designed to look at the effect of a-tocopherol supplementation on lung cancer in smokers found a 34% reduction in the incidence of prostate cancer in smokers given supplements of 50 mg of synthetic a-tocopherol (equivalent to 25 mg of RRR-a-tocopherol) daily (21).  Because of these findings a large randomized, placebo-controlled intervention study is currently being conducted to examine the effect of a-tocopherol supplementation on prostate cancer risk (22).

Cataracts: Cataracts appear to be formed by the oxidation of proteins in the lens of the eye, which may be prevented by antioxidants such as a-tocopherol.  To date, ten observational studies have examined the association between vitamin E consumption and the incidence and severity of cataracts. Of these studies, five found increased vitamin E intake to be associated with protection from cataracts, while five reported no association (23,24). A recent intervention trial of a daily antioxidant supplement containing 500 mg of vitamin C, 400 IU of vitamin E, and 15 mg of b-carotene in 4,629 men and women found that the antioxidant supplement was no different than a placebo in its effects on the development and progression of age-related cataracts over a 7-year period (25). Another intervention trial found that a daily supplement of 50 mg of synthetic a-tocopherol daily (equivalent to 25 mg of RRR- a-tocopherol) did not alter the incidence of cataract surgery in male smokers (26). Presently, the relationship between vitamin E intake and the development of cataracts requires further clarification before specific recommendations can be made.

Immune Function: a-Tocopherol has been shown to enhance specific aspects of the immune response that appear to decline as people age.  For example, 200 mg of synthetic a-tocopherol (equivalent to 100 mg of RRR-a-tocopherol) daily for several months increased the formation of antibodies in response to hepatitis B vaccine and tetanus vaccine in elderly adults (27). Whether a-tocopherol associated enhancements in the immune response actually translate to increased resistance to infections such as the flu (influenza virus) in older adults remains to be determined (28).

DISEASE TREATMENT

Cardiovascular diseases: Observational studies have suggested that supplemental a-tocopherol might have value in the treatment of cardiovascular disease.  For example, a small observational study of men who had previously undergone a coronary artery bypass graft found a reduction in the progression of coronary artery atherosclerosis by angiography in those men who took at least 100 IU of a-tocopherol (67 mg of RRR-a-tocopherol) daily (29).  A randomized, placebo-controlled intervention trial in Great Britain (the CHAOS study) found that supplementing heart diseasepatients with either 400 or 800 IU  of synthetic a-tocopherol (equivalent to 268 or 536 mg of RRR-a-tocopherol) for an average of 18 months resulted in a dramatic 77% reduction in nonfatal heart attacks.  However, total deaths from heart disease were not significantly reduced (30). Chronic renal dialysis patients are at much greater risk of dying from cardiovascular disease than the general population, and there is evidence that they are also under increased oxidative stress. Supplementation of renal dialysis patients with 800 IU of natural a-tocopherol (536 mg of RRR-a-tocopherol) for an average of 1.4 years resulted in a significantly reduced risk of heart attack compared to placebo (31). In contrast, three other intervention trials failed to find significant risk reductions with a-tocopherol supplementation.  One study, which was designed mainly to examine cancer prevention, found that 50 mg of synthetic a-tocopherol daily (equivalent to 25 mg of RRR-a-tocopherol) resulted in a non-significant decrease in nonfatal heart attacks in those participants who had had previous heart attacks (32) . However, two other large trials found that daily supplements of 400 IU of natural a-tocopherol (equivalent to 268 mg RRR-a-tocopherol) and 300 mg of synthetic a-tocopherol (equivalent to 150 mg of RRR-a-tocopherol) in individuals with evidence of cardiovascular disease (previous heart attack, stroke, or evidence of vascular disease) did not significantly change the risk of a subsequent heart attack or stroke (33,34). The results of several other large intervention trials, which are presently in progress may clarify the role of a-tocopherol supplementation in the treatment of cardiovascular disease.

A more thorough discussion of the complex issues involved in analyzing the results of recent trials of vitamin E in heart disease can be found in the Fall/Winter 1999 issue of the Linus Pauling Institute Newsletter: Fish Oil, Vitamin E, Genes, Diet, and CHAOS. For a discussion of some of the limitations of the HOPE study see the article, Vitamin E: Hope or Hopeless, in the Spring/Summer 2000 issue of the Linus Pauling Institute Newsletter.

Diabetes mellitus: a-Tocopherol supplementation of individuals with diabetes has been proposed because diabetes appears to increase oxidative stress and because cardiovascular complications (heart attack and stroke) are among the leading causes of death in diabetics.  A recent study found a biochemical marker of oxidative stress to be elevated in diabetic individuals (35).  Supplementation with 600 mg of synthetic a-tocopherol daily (equivalent to 300 mg of RRR-a-tocopherol) for 14 days resulted in a reduction in the oxidative stress marker.  Studies of the effect of a-tocopherol supplementation on blood glucose control have been contradictory.  One study reported improved control of blood glucose levels with supplementation of only 100 IU of synthetic a-tocopherol daily (equivalent to 45 mg RRR-a-tocopherol) (36), while studies using 900 to 1,600 IU of synthetic a-tocopherol daily (equivalent to 405 to 720 mg RRR-a-tocopherol) found either minimal or no improvement, respectively (37,38). Although there is reason to suspect that a-tocopherol supplementation may be beneficial for individuals with diabetes, evidence from well-controlled clinical trials is lacking.

Dementia (impaired cognitive function): The brain is particularly vulnerable to oxidative stress, which is thought to play a role in the pathology of neurodegenerative diseases, such as Alzheimer's disease (39). In a large placebo-controlled intervention trial, supplementation of individuals who had moderate neurological impairment with 2,000 IU of synthetic a-tocopherol daily for two years (equivalent to 900 mg/day of RRR-a-tocopherol) resulted in a significant slowing of the progression of Alzheimer's dementia (40). After Alzheimer's disease, vascular dementia (dementia resulting from strokes) is the most common cause of dementia in the U.S. A case-control study examining risk factors for vascular dementia in elderly Japanese-American men found that supplemental vitamin E and vitamin C intake was associated with a significantly decreased risk of vascular and other types of dementia, but not Alzheimer's dementia (41). Among those without dementia, vitamin E supplement use was associated with better scores on cognitive tests. Although these findings are promising, further studies are required to determine the role of a-tocopherol supplementation in the treatment of Alzheimer's disease and other types of dementia.

SOURCES

Food sources: Major sources of a-tocopherol in the American diet include vegetable oils (olive, sunflower, safflower oils), nuts, whole grains, and green leafy vegetables. All eight forms of vitamin E (a, b, g, d tocopherols and tocotrienols) occur naturally in foods, but in varying amounts. Before the body's preference for a-tocopherol was clarified, the vitamin E content of food was often expressed as mg of a-tocopherol equivalents or a-TE. Presently most food composition tables and databases provide vitamin E content information only in terms of a-TE, rather than as mg of a-tocopherol.  If you wish to check foods you eat frequently for their nutrient content, search the USDA food composition database. A rough approximation of the a-tocopherol content in foods can be calculated by multiplying the mg of a-TE by 0.8 (3).

Example: 2.0 mg a-TE x 0.8 = 1.6 mg a-tocopherol.

The a- and g-tocopherol values in the table below were measured in foods, rather than calculated from a-TE.

Supplements:

a-Tocopherol: The average intake of a-tocopherol from food in the U.S. is approximately 9 mg daily for men and 6 mg daily for women, well below the recently revised RDA of 15 mg/day of RRR-a-tocopherol (3).  Many scientists believe it is difficult for an individual to consume more than 15 mg/day of a-tocopherol from food alone, without also increasing fat intake above recommended levels (greater than 30% of total caloric intake). All a-tocopherol in food is the form of the isomer, RRR-a-tocopherol. The same is not always true for supplements. Vitamin E supplements generally contain from 100 IU to 1000 IU of a-tocopherol.  Supplements made from entirely natural sources contain only RRR-a-tocopherol (also labeled d-a-tocopherol). RRR-a-tocopherol is the isomer preferred for use by the body, making it the most bioavailable form of a-tocopherol.  Synthetic a-tocopherol, which is often found in food additives and nutritional supplements, is usually labeled all-rac-a-tocopherol or dl-a-tocopherol, meaning that all eight isomers of a-tocopherol are present in the mixture. Because some isomers of a-tocopherol present in all-rac-a-tocopherol are not usable by the body, synthetic a-tocopherol is less bioavailable and only about half as potent.  To calculate the number of mg of bioavailable a-tocopherol present in a supplement, use the following formulas:

RRR-a-tocopherol (natural or d-a-tocopherol):  IU x 0.67 = mg RRR-a-tocopherol.  Example: 100 IU = 67 mg

all-rac-a-tocopherol (synthetic or dl-a-tocopherol): IU x 0.45 = mg RRR-a-tocopherol.  Example: 100 IU = 45 mg

For more information on the Biological Activity of Vitamin E, see the article by Dr. Maret Traber in the Linus Pauling Institute Newsletter.

g-Tocopherol: g-Tocopherol supplements and mixed tocopherol supplements are also commercially available (42). The amounts of a- and g-tocopherol vary in mixed tocopherol supplements, so it is important to read the label to determine the amount of each tocopherol present in the supplement.

SAFETY

Toxicity: Few side effects have been noted in adults taking supplements of less than 2,000 mg of a-tocopherol daily (RRR- or all-rac-a-tocopherol).  However, most studies of toxicity or side effects of a-tocopherol supplementation have lasted only a few weeks to a few months, and side effects occurring as a result of long-term a-tocopherol supplementation have not been adequately studied.  The most worrisome possibility is that of impaired blood clotting resulting in an increased likelihood of hemorrhage in some individuals.  In addition to setting the new RDA for a-tocopherol in April of 2000, the Food and Nutrition Board of the Institute of Medicine also set a UL (tolerable upper intake level) for a-tocopherol supplements, citing the avoidance of hemorrhage as the basis for the upper limit.  The Board felt that a UL of 1,000 mg daily of a-tocopherol of any form (equivalent to1,500 IU of RRR-a-tocopherol or 1,100 IU of all-rac-a-tocopherol) would be the highest dose unlikely to result in hemorrhage in almost all adults (3).  Although only certain isomers of a-tocopherol are retained in the circulation, all forms are absorbed and the liver must break them down and eliminate them. The rationale that any form of of a-tocopherol (natural or synthetic) that can be absorbed potentially could have adverse effects is the basis for a UL that refers to all forms of a-tocopherol. Because hemorrhage is a potentially life threatening condition, the Linus Pauling Institute also recommends that individuals do not exceed 1,000 mg of a-tocopherol/day.  Premature infants appear to be especially vulnerable to adverse effects of a-tocopherol supplementation, which should be used only under controlled supervision by a pediatrician. Some physicians recommend that high-dose vitamin E supplementation be discontinued 1 month before elective surgery to decrease the risk of hemorrhage (42).

Drug interactions: Individuals on anticoagulant therapy (blood thinners) or individuals who are vitamin K deficient should not take a-tocopherol supplements without close medical supervision because of the increased risk of hemorrhage (3). A number of medications may decrease the absorption of vitamin E, including cholestyramine, colestipol, isoniazid, mineral oil, orlistat, sucralfate, and the fat substitute, olestra. Anticonvulsant drugs such as phenobarbitol, phenytoin, or carbamazepine may decrease plasma levels of vitamin E (3, 42).

A 3-year randomized controlled trial in 160 patients with documented coronary heart disease (CHD) and low HDL levels found that a combination of simvastatin (Zocor) and niacin increased HDL2 levels, inhibited the progression of coronary artery stenosis (narrowing), and decreased the frequency of cardiovascular events, such as myocardial infarction and stroke (43). However, concurrent therapy with antioxidants (1000 mg/d vitamin C, 800 IU/d a-tocopherol, 100 mcg/d of selenium, and 25 mg/d b-carotene) diminished the protective effects of the simvastatin-niacin combination. Although the mechanism for these effects is not known, some scientists have questioned the benefit of concurrent antioxidant therapy in patients on lipid lowering agents (44).

THE LINUS PAULING INSTITUTE RECOMMENDATION

Researchers at the Linus Pauling Institute feel there exists credible evidence that a dose of 200 mg of natural source d- or RRR-a-tocopherol daily  for adults may help protect against chronic diseases like heart disease, stroke, and some types of cancer.  The amount of a-tocopherol required for such beneficial effects appears to be much greater than that which could be achieved through diet alone (See Sources).  A supplement containing the equivalent of 200 mg/day of RRR-a-tocopherol is well below the upper level of 1,000 mg considered safe for most adults, but high enough to saturate plasma levels and systematically increase a-tocopherol levels in tissues. a-Tocopherol supplements are unlikely to be absorbed unless taken with food.

Older adults (65 years and older): The Linus Pauling Institute's recommendation of 200 mg/day of natural source d- or RRR-a-tocopherol is also appropriate for generally healthy older adults

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