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 and is consumed by approximately 20% of the US population. It requires bile for absorption, and 25% of the vitamin 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.
 
The United States National Academy of Sciences, Food and Nutrition Board published a report in 2000 that recommends a dietary allowance (RDA) of vitamin E of 15 mg/d and a tolerable upper intake level (UL) of any alpha-tocopherol form of 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 short-term supplementation with vitamin E up to 1600 IU appears to be well tolerated with minimal side effects in most healthy adults, the long-term safety is questionable. Recent data suggest a possible increase in mortality and incidence of heart failure with long-term use of vitamin E (400 IU or more) in patients with chronic diseases (see Mortality/Morbidity).

Pathophysiology

• Hematologic: Vitamin E can prolong the prothrombin time (PT) by inhibition of vitamin K–dependent carboxylase in animal models. 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. 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, but it caused a significant, even if small, increase in total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides, with 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.
• Immunologic: Vitamin E can depress leukocyte oxidative bactericidal activity and mitogen-induced lymphocyte transformation.

Mortality/Morbidity

Hathcock et al (2005) reviewed the literature on vitamin E.¹ Most studies using vitamin E up to 3200 IU/d did not observe significant acute clinical or biochemical adverse effects. They concluded that vitamin E appears to be safe for most adults in amounts up to 1600 IU/d.

Three meta-analysis articles published in 2003 and 2004 evaluated the effect of vitamin E on cardiovascular disease. They found that vitamin E supplementation at different doses did not significantly increase or decrease cardiovascular events or mortality. 

The meta-analysis from Miller et al (2005) found that using 400 IU/d or more of vitamin E increases all-cause mortality in patients with chronic diseases. This study raised concerns on the long-term safety of high-dose vitamin E supplementation.²

• Increased mortality: The meta-analysis by Miller et al (2005) looked at dose-response relationships between vitamin E supplementation and total mortality. 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, the generalizability of these findings is unclear because the high-dose trials were often small and were on patients with chronic diseases.²
• Congestive heart failure: The Heart Outcomes Prevention Evaluation-The Ongoing Outcomes (HOPE-TOO) was a randomized trial of 400 IU of vitamin E versus placebo in patients with diabetes or vascular disease. After a mean 7.2 years of follow-up, the vitamin E did not decrease the incidence of cancer deaths or vascular events, but increased the incidence of heart failure (reference range 1.19, P=.007).
• Coagulopathy: An increased risk of bleeding has been observed with coadministration of vitamin E and warfarin, with an increased PT due to 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. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study has shown that alpha-tocopherol at dosages of 50 mg/d increased the risk of fatal subarachnoid hemorrhage by 181% (95% confidence interval [CI], 37-479%, P=.01) compared with placebo in men aged 50-69 years who smoked cigarettes. The risk of cerebral infarction was decreased 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 any previous studies.
• Impaired immunity: An increased risk of sepsis occurred in one clinical trial (14% vs 6%) of premature neonates with a birth weight less than 1500 g to whom vitamin E was administered. 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 the vitamin on the immune system. No other population has demonstrated these findings.
• Constitutional and GI effects: Fatigue and weakness were reported in 2 case series of vitamin E 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 of vitamin E, 2000-2500 IU/d. Diarrhea and intestinal cramps have been reported at a dosage of 3200 IU/d. Other nonspecific adverse effects, which have been reported rarely, include fatigue, muscle weakness, delayed wound healing, and headache.

Race

• No racial difference in incidence exists.

Sex

• Women have reported emotional disturbances, but no other sex difference in incidence exists.
• Men who smoke have an increased risk of subarachnoid hemorrhage, as reported by one study. Risk of intracranial hemorrhage has not been studied in women.

Age

• Premature infants with low birthweight have shown life-threatening adverse effects from vitamin E. Sepsis and necrotizing enterocolitis have occurred only in premature infants with low birthweight.
• 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

• Patients with vitamin E toxicity are likely to use 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 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 one meta-analysis showed a possible increase in mortality at dosages of 400 IU/d and higher.

• 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 taking anticoagulants concurrently with vitamin E or in those suggested to have vitamin K deficiency while taking vitamin E because it may be elevated.



• Plasma concentration of alpha-tocopherol (normal, 6-14 mcg/mL) can be measured to confirm high levels of the vitamin in the blood.

Imaging Studies

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

TREATMENT

Section 6 of 10  

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

Medical Care

• Management consists of discontinuing the 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 taking anticoagulants or with 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 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

• The only patients who require hospitalization for vitamin E toxicity are those with bleeding complications, including intracranial hemorrhage.
• • If an intracranial hemorrhage is suggested or the patient has focal neurologic findings upon 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 consultation with a neurosurgeon 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 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

• Vitamin E toxicity can be avoided by adhering to the daily recommended dosages and monitoring PT when taking anticoagulants.
• Patients with nutritional deficiency should increase their intake of vitamin K to prevent bleeding complications.

Prognosis

• The prognosis is excellent in most patients with vitamin E toxicity once the supplements are discontinued.
• Patients with mild bleeding episodes are likely to recover fully once vitamin K is administered and the 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 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 RDI dose of 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 it may increase mortality and heart failure, 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

1. Hathcock JN, Azzi A, Blumberg J, et al. Vitamins E and C are safe across a broad range of intakes. Am J Clin Nutr. Apr 2005;81(4):736-45.
2. Miller ER 3rd, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med. Jan 4 2005;142(1):37-46.
3. Bardosi A, Dickmann U. Necrotizing myopathy with paracrystalline inclusion bodies in hypervitaminosis E. Acta Neuropathol (Berl). 1987;75(2):166-72. [Medline].
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Article Last Updated: Jun 11, 2007