Vitamin E

Scientific Name(s): Alpha-tocopherol

Common Name(s): Vitamin E

Uses

Routine use of high-dose vitamin E for cancer, cardiovascular disease, diabetes, and epilepsy is not recommended. Vitamin E supplementation may have a role in treating age-related macular degeneration, dysmenorrhea, preeclampsia, rheumatoid arthritis, and tardive dyskinesia. Topical use of vitamin E has been investigated for the reduction of scarring.

Dosing

Doses in clinical trials range from 400 to 1,600 units/day. The established safe upper limit is 1,000 mg/day (1,500 units/day), but consequent to the findings from meta-analyses, a lower safe dosage of 150 to 200 units/day has been suggested.

Contraindications

Contraindications have not been identified.

Pregnancy/Lactation

Trials have been conducted in pregnant women (see Uses and Pharmacology). The majority of trials report no increase in negative fetal outcome, but results regarding birth-weight are conflicting. Considering the evidence of harm (all-cause mortality), high-dose vitamin E supplementation, should be used with caution. Natural food sources are preferred.

Interactions

Orlistat may reduce vitamin E absorption. Vitamin E may increase the anticoagulant effect of warfarin and may decrease the benefits of atorvastatin therapy.

Adverse Reactions

Meta-analyses of trials investigating high-dose vitamin E supplementation have found evidence of harm. Low-dose vitamin E supplementation (150 mg/day) does not appear to have any serious adverse reactions. High doses of vitamin E may prolong bleeding time.

Toxicology

Vitamin E is a known antioxidant. However, it may be a pro-oxidant, causing oxidation and consequent damage to cells. The use of high-dose vitamin E supplementation may increase the risk of cancer in certain populations and also increase mortality.

History

Vitamin E was discovered in 1922 when reproductive abnormalities in rats reared on a basic diet were cured by a substance isolated from vegetable oils. A pure fraction was chemically identified in 1938 and named tocopherol after the Greek words tokos and phero meaning “child birth” and “to bring forth.” 1

Chemistry

Vitamin E is a generic term for a group of tocol and tocotrienol derivatives. It is a fat-soluble vitamin that exists in a variety of forms in many foods (eg, asparagus, mangoes, nuts, olives, spinach, sunflower seeds, vegetable oils, wheat germ, whole-wheat breads). Its most common form in a Western diet is alpha-tocopherol. 2 The most important chemical characteristic is its antioxidant property.

Vitamin E is fairly stable to heat and acids, but unstable to alkalis, ultraviolet light, and oxygen. It is destroyed when in contact with rancid fats, lead, and iron. Esters of tocopherol are more stable, with tocopherol acetate accounting for the most common, naturally occurring form. 1

Uses and Pharmacology

Vitamin E has been extensively studied for several decades, with the large number of clinical trials making animal experiments largely redundant.

A number of meta-analyses and systematic reviews have found no positive effect of vitamin E on mortality in cardiovascular disease or cancer. 3 , 4 , 5 , 6 Furthermore, high-dose vitamin E supplementation has been associated with increased risk of morbidity and mortality. 3 , 4 , 6 , 7 A Cochrane meta-analysis of all randomized clinical trials evaluating the effect of antioxidant supplements on primary and secondary disease prevention found that antioxidants had no significant effect on all-cause mortality (relative risk [RR] 1.02; 95% confidence interval [CI] = 0.99 to 1.06). Supplementation with vitamin E alone in trials with a low risk of bias showed significantly increased mortality (RR 1.04; 95% CI = 1.01 to 1.07). 6

Age-related macular degeneration and visual loss

Systematic reviews report the effects of vitamin E on the prevention and progression of age-related macular degeneration. 8 , 9 The majority of trials were conducted by the Age-Related Eye Disease Study Research Group. 10

The analyses conclude that vitamin E supplementation has a modest, borderline protective effect (odds ratio [OR] 0.83; 95% CI = 0.69 to 1.01), 9 and people with moderate to severe degeneration may experience a slight delay in progression of disease with antioxidant supplementation. 8 Harm from long-term use should be considered. 8

A similar, small study investigated the effect of 4 months of therapy with high-dose vitamin E (1,600 units/day) for uveitis-associated macular edema. Supplementation did not affect visual acuity or retinal thickening, and the study was terminated early. 11

Cancer

Despite epidemiological studies suggesting favorable outcomes with vitamin E supplementation in reducing the risks and mortality of cancer, meta-analyses of clinical trials 12 , 13 , 14 , 15 , 16 , 17 , 18 found no beneficial effect and suggest evidence for harm. 3 , 4 , 5 , 6 , 7 , 19 , 20

A role in reducing the risk of prostate cancer is possible, with limited smaller trials showing a protective, but not statistically significant, effect. 21 , 22 The SELECT (Selenium and Vitamin E Cancer Prevention Trial) study was halted earlier than planned because of a lack of positive effect. 22 Among Finnish smokers, a high baseline alpha-tocopherol level was associated with a lower total mortality risk, 23 despite negative findings for pancreatic cancer from the same trial. 15 In the Women's Health Study, vitamin E 600 units on alternate days did not increase the risk of cancer or death from cancer, nor did it increase total mortality. 24

In vitro studies are directing attention to the role of vitamin E analogs, especially alpha-tocopheryl succinate, on inducing apoptosis of malignant cells, but clinical trials are lacking. 25 , 26 , 27 , 28 , 29 , 30 Complications from chemotherapy, such as mucositis 31 , 32 and paclitaxel-induced peripheral neuropathy, 33 may benefit from vitamin E supplementation, but data from quality trials are limited.

Cardiovascular disease

Despite epidemiological studies in favor of vitamin E supplementation in reducing the risks of cardiovascular disease 4 , 34 , 35 , 36 and as a plausible mechanism for antioxidant action, 37 , 38 , 39 , 40 meta-analyses of landmark trials 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 found no evidence for effect and suggested evidence for harm. 3 , 4 , 5 , 6 , 34 , 35 , 50 The American Heart Association does not support the routine use of antioxidants in people with cardiovascular disease. 51

Trials evaluating subgroup populations subsequent to the Cochrane meta-analysis 6 have found varying effects. In men and women with hypercholesterolemia, no effect documented cardiovascular risk despite a variety of tocotrienol isomers tested. 52 In smokers 50 years of age or older, ultrasound showed no effect on atherosclerosis after 5 years of vitamin E supplementation. 35 In the Women's Antioxidant and Cardiovascular Study, no impact from supplementation on total mortality was observed in women at high risk for cardiovascular events, but a marginal effect was reported in women with a previous cardiovascular event. 53 A null effect was documented in another study for vitamin E supplementation, with increased mortality in certain disease groups and a reduced risk in others. 54

CNS effects/Alzheimer disease/Mild cognitive impairment

Animal experiments and epidemiological studies suggest a correlation between low-serum vitamin E levels and memory performance in elderly patients. 55 However, clinical trials demonstrate equivocal results. A trial evaluating vitamin E supplementation (2,000 units/day) showed no difference in conversion from mild cognitive impairment to Alzheimer disease over 2 years compared with donepezil or placebo 56 , 57 ; other trials found a prolonged time to end point for vitamin E but no improvement in cognitive tests. 55 , 58 A Cochrane review reported few trials meeting the inclusion criteria. In 1 trial, fewer patients on vitamin E supplementation reached end point (death, institutionalization, or loss of 2 out of 3 basic activities) within 2 years but experienced more falls. Overall, the review revealed no statistically significant difference compared with placebo, in the probability of progression from mild impairment to Alzheimer disease. 59 If vitamin E supplementation is considered beneficial (versus the potential for harm), then low-dose supplementation is recommended. 60

Amyotrophic lateral sclerosis/Motor neuron disease

Conflicting evidence exists. Epidemiological data suggest vitamin E supplementation taken for longer than 10 years is associated with a 50% decreased risk of death from amyotrophic lateral sclerosis than in those individuals not taking supplementation. 55 However, a review of available data found poor methodology and insufficient evidence for antioxidants in general for motor neuron disease. 61

Epilepsy

A Cochrane review of trials from 1966 through 2006 discuss poor trial methodology and did not find sufficient evidence to support routine use of vitamin E in the management of epilepsy. 62

Parkinson disease

Animal studies have produced conflicting results. In humans receiving alpha-tocopherol 2,000 units/day, no benefit was demonstrated in 1 trial, whereas high-dose vitamin E (3,200 units/day) with vitamin C (3 g/day) delayed the progression of Parkinson disease by 2.5 years. 55

Tardive dyskinesia

A meta-analysis of neuroleptic-induced tardive dyskinesia, including 10 studies from 1966 through 2001, showed that vitamin E protected against deterioration but did not improve the symptoms of tardive dyskinesia. 63 A trial evaluating vitamin E 1,200 units/day versus placebo over 12 weeks reported a mean improvement in Abnormal Involuntary Movements Scale (AIMS) scores. 64 In combination with vitamin C 200 mg/day, vitamin E 1,800 mg/day reduced tardive symptoms in a small trial (N = 8). Theoretically, the combination reduces vitamin E radicals formed when vitamin E scavenges oxygen radicals. 65

Diabetes mellitus

The role of vitamin E in diabetes was not determined in any of the major meta-analyses 3 , 5 , 6 ; however, the risk of harm raised in these analyses should not be overlooked. A number of clinical trials found no effect of vitamin E on outcomes, 66 , 67 , 68 , 69 , 70 while others showed unexpected increases in blood pressure. 71 , 72 Some small trials have reported improvements in surrogate outcomes. 47 , 48 , 70 The American Diabetes Association does not consider the evidence to be sufficient to support routine use of antioxidants in people with diabetes. 73

Dysmenorrhea

A few trials demonstrated a reduction in menstrual pain, with maximum effect after 3 months of vitamin E at dosages up to 200 units for 5 days, when starting 2 days prior to menses. 74 , 75 A meta-analysis confirms evidence for effect. Harm or adverse reactions, however, were not reported. 76 , 77

Pregnancy and preeclampsia

As a consequence of earlier trials and a meta-analysis revealing a reduction in the risk of preeclampsia, 78 , 79 , 80 several large multicenter and international trials have been or are being conducted to investigate the effect of antioxidant supplementation on the rate of preeclampsia. 81 , 82 Of the available data, vitamin E 400 units in combination with vitamin C 1,000 mg does not affect the risk of preeclampsia versus placebo. 83 , 84 , 85 , 86 A meta-analysis of trials from 2006 found no effect of antioxidant supplementation on the rate of preeclampsia versus placebo. 87

The outcomes of ongoing preeclampsia trials, together with the findings of harm for vitamin E supplementation in large meta-analyses, 3 , 6 will need to be considered when data are available. 81

Fetal outcomes

Varying results on fetal outcomes have been obtained from these trials, with most showing no effect. 83 , 84 , 85 , 86 A study investigating the effect of maternal concentrations of alpha-tocopherol on fetal growth suggested a positive relationship, with a decreased risk for small-for-gestational-age births. 88 A negative association was suggested for wheeze (in the absence of a cold) in the second year of life in children of mothers who took vitamin E supplements during pregnancy. 89 A follow-up at 5 years exposed an association between childhood asthma and low maternal vitamin E intake. 90 Similarly, a negative association for childhood eczema and maternal vitamin E intake was found. 89

Preterm infants

The use of vitamin E for the prevention of morbidity and mortality in preterm infants has been investigated. A meta-analysis concluded that routine use of vitamin E supplementation via the intravenous route is not supported by evidence because of the increased risk for harm. 2 , 91 A small study evaluated the effects of vitamin E supplementation (50 units/day) on erythropoiesis in premature infants. No effect was reported at that dosage, and no increased harm was detected. 92

Rheumatoid arthritis

Clinical trials present conflicting results. 49 , 93 , 94 Overall, vitamin E supplementation exhibits a low level of evidence for effectiveness in rheumatoid arthritis. The value of vitamin E may only be evident in patients with increased oxidative stress or at dosages higher than the 400 units/day. 95

Other

Vitamin E has been evaluated for use in immuno-deficient states and for topical use in reducing scarring. 96

Dosage

Deficiencies in vitamin E are uncommon, and dietary sources are preferred over supplementation. 97

Doses in clinical trials range from 400 to 1,600 units/day. Higher doses have been used in some trials. 3 , 6

The established safe upper limit is 1,000 mg/day (1,500 units/day), 97 but consequent to the findings from meta-analyses, a lower safe dosage of 150 to 200 units/day has been suggested. 3 , 6 The American Heart Association's guidelines for prevention of heart disease and stroke in women advise against antioxidant use, and the Alzheimer's Association recommends use only under the care of a health care provider. 97

Pregnancy/Lactation

Trials have been conducted in pregnant women (see Uses and Pharmacology). The majority of trials report no increase in negative fetal outcome, but results regarding birth-weight are conflicting. 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90

Considering the evidence of harm (all-cause mortality), high-dose vitamin E supplementation, should be used with caution. Natural food sources are preferred. 3 , 4 , 5 , 6

Interactions

Atorvastatin

Vitamin E at 400 units/day impaired the positive endothelial effects of low-dose atorvastatin in a trial of patients with heart failure. 98

Orlistat

Orlistat administration may reduce the biologic and therapeutic effect of vitamin E by decreasing GI absorption of the vitamin. In 12 healthy subjects receiving Orlistat (120 mg 3 times daily for 4 days), administration of vitamin E (400 units alpha-tocopheryl acetate) on the fourth day of Orlistat treatment decreased the area under the curve and peak plasma level of vitamin E 60% and 43%, respectively, compared with placebo. 99 , 100

Warfarin

Vitamin E may interfere with vitamin K-dependent clotting factors, adding to the anticoagulant effects of warfarin. A markedly prolonged prothrombin time and bleeding occurred in a 55-year-old man stabilized on warfarin for 2 months after he started taking vitamin E supplementation (1,200 units/day or less). Taking more than vitamin E 400 units/day may cause additive hypo-prothrombinemic effects to occur. 101 , 102

Adverse Reactions

High levels of vitamin E can adversely affect the absorption of vitamins A and K. Long-term use of high doses may cause nausea, diarrhea, blurred vision, and prolonged bleeding time. 103

Toxicology

Vitamin E is a known antioxidant. However, it may be a pro-oxidant, causing oxidation and consequent damage to cells. 7 The use of high-dose vitamin E supplementation may increase the risk of cancer in certain populations 7 and also increase mortality. 6

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