AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Vitamin E is a fat-soluble vitamin that acts as an antioxidant and free radical scavenger in lipophilic environments. It is consumed by approximately 20% of the US population. Vitamin E requires bile for absorption, and 25% of it is absorbed orally. Storage of the vitamin occurs in adipose tissue, liver, and muscle.

Dietary supplements of vitamin E are labeled in International Units (IU). (IU is not a Joint Commission on Accreditation of Healthcare Organizations [JACHO]–approved abbreviation, and it must be spelled out in patients' charts and prescriptions.) One milligram of synthetic vitamin E (all-rac-alpha-tocopherol acetate) is equivalent to 1 IU of vitamin E. One milligram of natural vitamin E (RRR–alpha tocopherol) is equivalent to 0.45 IU of vitamin E.
 
In a 2000 report, the Food and Nutrition Board of the National Academy of Sciences specified the recommended dietary allowance (RDA) of vitamin E as 15 mg/d and listed the tolerable upper intake level (UL) of any alpha-tocopherol form as 1000 mg/d. The UL is the upper level that is likely to pose no risk of adverse health effects to almost all people in the general population.

While in most healthy adults, short-term supplementation with up to 1600 IU of vitamin E appears to be well tolerated and have minimal side effects, the long-term safety is questionable.¹ Data suggest a possible increase in mortality and in the incidence of heart failure with long-term use of vitamin E (400 IU or more) in patients with chronic diseases.² Therefore, a UL of 1000 mg/d may be too high (see Mortality/Morbidity).

Related eMedicine topics:
Toxicity, Vitamin
Vitamin E Deficiency

Pathophysiology

• Hematologic - Vitamin E can prolong the prothrombin time (PT) in animal models by inhibiting vitamin K–dependent carboxylase. Administration of vitamin K corrects this. High doses increase the vitamin K requirement and, therefore, cause coagulopathy only in patients who are deficient in vitamin K.^{3, 4} Vitamin E at dosages of 1600 IU/d also reduces platelet thromboxane production. Vitamin E supplementation may impair the hematologic response to iron in children with iron-deficiency anemia.
• Lipoprotein effects - In the Heart Protection Study, a combination of vitamin E (600 IU), vitamin C, and beta carotene did not affect mortality. However, it did cause a significant, albeit small, increase in total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides, as well as a decrease in high-density lipoprotein (HDL). In 2 randomized trials, an antioxidant cocktail that included vitamin E blunted the beneficial increase in HDL2 levels associated with niacin and simvastatin therapy.^{5, 6}
• Immunologic - Vitamin E can depress leukocyte oxidative bactericidal activity and mitogen-induced lymphocyte transformation.

Related eMedicine topics:
Vitamin K Deficiency

Mortality/Morbidity

The literature on vitamin E toxicity was reviewed by Hathcock and colleagues.⁷ Most studies using up to 3200 IU/d of vitamin E did not observe significant acute clinical or biochemical adverse effects. They concluded that for most adults, the use of up to 1600 IU/d of vitamin E appears to be safe.

Three meta-analysis articles published in 2003 and 2004 evaluated the effect of vitamin E on cardiovascular disease.⁸ They found that vitamin E supplementation at different doses did not significantly increase or decrease cardiovascular events or mortality. In the Women's Antioxidant Cardiovascular Study, women 40 years and older and at high risk of cardiovascular disease were randomized to receive a relatively small dose of Vitamin E (600 IU every other day) for a mean duration of 9.4 years.⁹ Vitamin E produced no overall effects on cardiovascular death or events.

Meta-analyses from Miller and colleagues and from Bjelakovic and coauthors found that vitamin E supplementation increases all-cause mortality. These studies raised concerns on the long-term safety of high-dose vitamin E supplementation.^{2, 10}

• Increased mortality - Miller's meta-analysis looked at dose-response relationships between vitamin E supplementation and total mortality.² Nine out of 11 trials using high doses of vitamin E (400 IU or more) showed a significant increase in all-cause mortality in the vitamin E group. As the authors pointed out, however, the extent to which these findings can be generalized is unclear, because the high-dose trials were often small and were conducted on patients with chronic diseases.² In Bjelakovic's meta-analysis, vitamin E, singly or combined with other antioxidants, was associated with a small but nonetheless significant (relative risk [RR], 1.04; 95% confidence interval [CI], 1.01-1.07) mortality increase.¹⁰
• Congestive heart failure - The Heart Outcomes Prevention Evaluation-The Ongoing Outcomes (HOPE-TOO) was a randomized trial examining the effects of 400 IU of vitamin E versus those of a placebo in patients with diabetes or vascular disease. After a mean 7.2 years of follow-up, vitamin E did not decrease the incidence of cancer deaths or vascular events, but evidence indicated that it did increase the incidence of heart failure (reference range, 1.19, P=.007).^{8, 11, 12, 13, 14, 15, 16, 17}
• Coagulopathy - An increased risk of bleeding has been observed with coadministration of vitamin E and warfarin, with an increased PT due to the depletion of vitamin K–dependent clotting factors. This does not occur in healthy individuals with normal vitamin K levels. Increased gingival bleeding also was observed in patients taking vitamin E and aspirin.¹⁸ The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study showed that compared with placebo, alpha tocopherol at dosages of 50 mg/d increased the risk of fatal subarachnoid hemorrhage by 181% (95% CI, 37-479%; P=.01) in men aged 50-69 years who smoked cigarettes. The risk of cerebral infarction was decreased by 14% (95% CI, -25 to -1%, P=.03) in the vitamin E group, with no significant net effect of vitamin E on mortality from total strokes. These results had not been found in previous studies.^{19, 20}
• Impaired immunity - An increased risk of sepsis occurred in a clinical trial (14% vs 6%) in which vitamin E was administered to premature neonates with a birthweight of less than 1500 g. When high-dose vitamin E of up to 30 mg/kg/d was administered to this population to prevent retrolental fibroplasia, necrotizing enterocolitis occurred. Incidence of necrotizing enterocolitis increased 2-fold (12%) in 2 studies; however, others have shown no difference. These findings may be secondary to the compounding effects of prematurity and the effect of vitamin E on the immune system. No other population has demonstrated these findings.
• Constitutional and GI effects - Fatigue and weakness were reported in 2 case series in which vitamin E was administered at dosages of 800 IU/d. The symptoms resolved with removal of the drug. Another study reported emotional disturbances in several women taking the same dosages. These symptoms have not been observed in other large series. Transient nausea and gastric distress have been observed in a few patients taking high dosages (2000-2500 IU/d) of vitamin E. Diarrhea and intestinal cramps have been reported at a dosage of 3200 IU/d. Other nonspecific, adverse effects of vitamin E, although reported only rarely, include fatigue, muscle weakness, delayed wound healing, and headache.

Related Medscape topic:
CME Multivitamins Do Not Reduce Risk for Lung Cancer, and Vitamin E May Raise It
CME Vitamin E May Not Reduce Risk for Age-Related Cataracts

Race

• No race-associated differences exist for the incidence of vitamin E toxicity.

Sex

• Women taking vitamin E have reported emotional disturbances, but no other sex-related differences in incidence exist.
• Men who smoke have an increased risk of subarachnoid hemorrhage, as reported by one study.¹⁹ The risk of intracranial hemorrhage has not been studied in women.

Age

• Premature infants with low birthweight have suffered life-threatening adverse effects from vitamin E, with sepsis and necrotizing enterocolitis have occurred in these, but not in other, infants.
• A syndrome of ascites, hepatomegaly, and thrombocytopenia resulting in death occurred in the 1980s in association with an intravenous vitamin E preparation used in premature infants with low birthweight. Presumably, the cause was a polysorbate carrier of the vitamin, and the syndrome has not occurred since its removal.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• It is likely that patients with vitamin E toxicity have been using vitamin E supplements; obtain the dose and duration of vitamin E usage.
• Assess concurrent use of anticoagulants or aspirin.
• A nutritional assessment for vitamin K deficiency is useful in patients who present with bleeding or an elevated PT.

Physical

• Physical examination findings are likely to be normal in patients with vitamin E toxicity; however, evidence of easy bleeding may be present if the PT is elevated.
• Patients with intracranial hemorrhage may show signs of focal neurologic deficits on a detailed neurologic examination or may have a decreased level of consciousness.

Causes

• Hypervitaminosis E is caused by an excess intake of vitamin E supplements.

• Adverse effects usually are observed only at very high dosages, but Miller's meta-analysis showed a possible increase in mortality at dosages of 400 IU/d and higher.²
• Concomitant use of vitamin E and anticoagulants can increase the risk of bleeding complications.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to Be Considered

An elevated international normalized ratio (INR) may be due to excessive doses of warfarin anticoagulants in patients taking these medications. Vitamin K deficiency and liver failure can prolong the PT and raise the INR.

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Monitor PT in patients who are taking anticoagulants concurrently with vitamin E or in patients suggested to have vitamin K deficiency while taking vitamin E, because the PT may be elevated.
• The plasma concentration of alpha tocopherol (normal, 6-14 mcg/mL) can be measured to confirm that high levels of vitamin E are in the blood.

Imaging Studies

• Perform a computed tomography (CT) scan of the brain, without contrast, only if the PT is significantly prolonged and the patient has either a decreased level of consciousness or a focal neurologic deficit.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Management of vitamin E toxicity consists of discontinuing vitamin E supplements and monitoring the PT if bleeding complications develop.
• Vitamin K replacement through the oral or subcutaneous route should reverse the elevated PT and decrease the risk of bleeding in patients who are taking anticoagulants or who have vitamin K deficiency.

Consultations

• Consult a neurosurgeon if evidence of CNS hemorrhage is present.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

No medical treatments are specific to the management of vitamin E toxicity, with the exception of vitamin K, which should be replaced in patients with bleeding or an elevated PT.

Drug Category: Vitamin replacement/nutritional supplements

Essential in many metabolic processes.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Patients with vitamin E toxicity require hospitalization only if bleeding complications, including intracranial hemorrhage, occur.
• • If an intracranial hemorrhage is suggested or the patient has focal neurologic findings on examination, order a head CT scan without contrast to rule out an existing hemorrhage.
  • If hemorrhage is present, the patient should receive inpatient medical management, with a neurosurgeon consulted for possible drainage of the fluid collection.
• Patients who present with other forms of bleeding should receive vitamin K and should be observed until they are stable, with follow-up evaluation provided on an outpatient basis.

Further Outpatient Care

• Patients with vitamin E toxicity who are stable can be treated in an outpatient setting, with periodic monitoring of the PT to ensure its return to normal levels if bleeding develops.

Deterrence/Prevention

• Individuals can avoid vitamin E toxicity by adhering to the daily recommended dosages of the vitamin and through monitoring of PT when anticoagulants are being taken.
• Patients with nutritional deficiency should increase their intake of vitamin K to prevent bleeding complications.

Prognosis

• In most patients with vitamin E toxicity, the prognosis is excellent once the supplements are discontinued.
• Patients with mild bleeding episodes are likely to fully recover once vitamin K is administered and the vitamin E supplements are discontinued.
• Patients with intracranial hemorrhage have an increased mortality rate; however, with proper diagnosis and management, many patients with this condition survive and recover some or all of their previous functions.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• A medical and/or legal problem could arise if a patient develops a significant bleeding complication as a result of a physician-prescribed combination of oral anticoagulants and vitamin E without warning the patient of the increased risk of bleeding and elevated INR.
• If a patient is taking vitamin E while on oral anticoagulants, warn the patient of the possible adverse bleeding effects and recommend limiting vitamin E intake to the RDA (15 mg/d).
• Warn patients taking high doses of vitamin E (400 IU or more) that no compelling evidence exists that vitamin E reduces cardiovascular risk or cancer and that it may increase heart failure and mortality, especially in patients with chronic diseases.
• Warn patients taking lipid-lowering agents that vitamin E may blunt the beneficial effect on HDL.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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2. Miller ER 3rd, Pastor-Barriuso R, Dalal D, et al. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med. Jan 4 2005;142(1):37-46. [Medline]. [Full Text].
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Article Last Updated: Aug 12, 2008