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Vitamin E Toxicity

Angela Gentili, MD, Director of Geriatrics Fellowship Program, Associate Professor, Department of Internal Medicine, Virginia Commonwealth University Health System and McGuire Veterans Affairs Medical Center
Robert A Adler, MD, Chief of Endocrinology and Metabolism, McGuire Veterans Affairs Medical Center; Professor, Departments of Internal Medicine and Epidemiology and Community Health, Virginia Commonwealth University

Updated: Aug 12, 2008

Introduction

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).

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.

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.

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

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.

Differential Diagnoses

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

Laboratory 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

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

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.

Vitamin replacement/nutritional supplements

Essential in many metabolic processes.


Vitamin K, phytonadione (AquaMEPHYTON)

Fat-soluble vitamin absorbed by the gut and stored in the liver. Vitamin K is necessary for the function of clotting factors in the coagulation cascade. It is used to replace essential vitamins not obtained in sufficient quantities in the diet or to further supplement levels.

Dosing

Adult

10 mg PO/IV/IM/SC should replete the liver stores

Pediatric

1 mg IM

Interactions

Effects of warfarin, sodium, and dicumarol are antagonized

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Ineffective in hereditary hypoprothrombinemia; rapid infusion may result in flushing and a feeling of constriction in the chest; relatively nontoxic, even in massive doses

Follow-up

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

Medicolegal 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

  1. Vatassery GT, Bauer T, Dysken M. High doses of vitamin E in the treatment of disorders of the central nervous system in the aged. Am J Clin Nutr. Nov 1999;70(5):793-801. [Medline]. [Full Text].

  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].

  3. Corrigan JJ Jr, Marcus FI. Coagulopathy associated with vitamin E ingestion. JAMA. Dec 2 1974;230(9):1300-1. [Medline].

  4. Diplock AT. Safety of antioxidant vitamins and beta-carotene. Am J Clin Nutr. Dec 1995;62(6 Suppl):1510S-6S. [Medline]. [Full Text].

  5. Brown BG, Zhao XQ, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med. Nov 29 2001;345(22):1583-92. [Medline]. [Full Text].

  6. Cheung MC, Zhao XQ, Chait A, et al. Antioxidant supplements block the response of HDL to simvastatin-niacin therapy in patients with coronary artery disease and low HDL. Arterioscler Thromb Vasc Biol. Aug 2001;21(8):1320-6. [Medline]. [Full Text].

  7. 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.

  8. Vivekananthan DP, Penn MS, Sapp SK, et al. Use of antioxidant vitamins for the prevention of cardiovascular disease: meta-analysis of randomised trials. Lancet. Jun 14 2003;361(9374):2017-23. [Medline].

  9. [Best Evidence] Cook NR, Albert CM, Gaziano JM, et al. A randomized factorial trial of vitamins C and E and beta carotene in the secondary prevention of cardiovascular events in women: results from the Women's Antioxidant Cardiovascular Study. Arch Intern Med. Aug 13-27 2007;167(15):1610-8. [Medline].

  10. Bjelakovic G, Nikolova D, Gluud LL, et al. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA. Feb 28 2007;297(8):842-57. [Medline].

  11. Lonn E, Bosch J, Yusuf S, et al. Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA. Mar 16 2005;293(11):1338-47. [Medline]. [Full Text].

  12. Eidelman RS, Hollar D, Hebert PR, et al. Randomized trials of vitamin E in the treatment and prevention of cardiovascular disease. Arch Intern Med. Jul 26 2004;164(14):1552-6. [Medline].

  13. MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. Jul 6 2002;360(9326):23-33. [Medline].

  14. Shekelle PG, Morton SC, Jungvig LK, et al. Effect of supplemental vitamin E for the prevention and treatment of cardiovascular disease. J Gen Intern Med. Apr 2004;19(4):380-9. [Medline]. [Full Text].

  15. Orrell RW, Lane RJ, Ross M. A systematic review of antioxidant treatment for amyotrophic lateral sclerosis/motor neuron disease. Amyotroph Lateral Scler. Mar 14 2008;1-16. [Medline].

  16. Lane JS, Magno CP, Lane KT, et al. Nutrition impacts the prevalence of peripheral arterial disease in the United States. J Vasc Surg. Jun 27 2008;[Medline].

  17. Mahabir S, Schendel K, Dong YQ, et al. Dietary alpha-, beta-, gamma- and delta-tocopherols in lung cancer risk. Int J Cancer. Sep 1 2008;123(5):1173-80. [Medline].

  18. Liede KE, Haukka JK, Saxén LM, et al. Increased tendency towards gingival bleeding caused by joint effect of alpha-tocopherol supplementation and acetylsalicylic acid. Ann Med. Dec 1998;30(6):542-6. [Medline].

  19. Leppala JM, Virtamo J, Fogelholm R, et al. Controlled trial of alpha-tocopherol and beta-carotene supplements on stroke incidence and mortality in male smokers. Arterioscler Thromb Vasc Biol. Jan 2000;20(1):230-5. [Medline]. [Full Text].

  20. Handelman GJ. High-dose vitamin supplements for cigarette smokers: caution is indicated. Nutr Rev. Oct 1997;55(10):369-70. [Medline].

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  24. Kappus H, Diplock AT. Tolerance and safety of vitamin E: a toxicological position report. Free Radic Biol Med. 1992;13(1):55-74. [Medline].

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Keywords

vitamin E toxicity, hypervitaminosis E, vitamin poisoning, vitamin toxicity, vitamin E, alpha tocopherol, alpha-tocopherol, all-rac-alpha-tocopherol acetate, RRR–alpha tocopherol, RRR-alpha-tocopherol, antioxidant, free radical scavenger, fat-soluble vitamin, Alpha-Tocopherol, Beta Carotene Cancer Prevention Study, fatal subarachnoid hemorrhage, increased risk of bleeding, increased prothrombin time, necrotizing enterocolitis, intracranial hemorrhage, vitamin K

Contributor Information and Disclosures

Author

Angela Gentili, MD, Director of Geriatrics Fellowship Program, Associate Professor, Department of Internal Medicine, Virginia Commonwealth University Health System and McGuire Veterans Affairs Medical Center
Angela Gentili, MD is a member of the following medical societies: American Geriatrics Society
Disclosure: Nothing to disclose.

Coauthor(s)

Robert A Adler, MD, Chief of Endocrinology and Metabolism, McGuire Veterans Affairs Medical Center; Professor, Departments of Internal Medicine and Epidemiology and Community Health, Virginia Commonwealth University
Robert A Adler, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians, American Federation for Medical Research, American Society for Bone and Mineral Research, and Endocrine Society
Disclosure: Eli Lilly Consulting fee Consulting

Medical Editor

Harris C Taylor, MD, Clinical Professor of Medicine, Division of Clinical and Molecular Endocrinology, Case Western Reserve University School of Medicine
Harris C Taylor, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians, American Thyroid Association, and Endocrine Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Romesh Khardori, MD, Chief, Division of Endocrinology, Metabolism and Molecular Medicine, Professor, Department of Internal Medicine, Southern Illinois University School of Medicine
Romesh Khardori, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Medical Association, American Society of Andrology, Endocrine Society, and Illinois State Medical Society
Disclosure: Nothing to disclose.

CME Editor

Mark Cooper, MBBS, PhD, FRACP, Head, Diabetes & Metabolism Division, Baker Heart Research Institute, Professor of Medicine, Monash University
Disclosure: Nothing to disclose.

Chief Editor

George T Griffing, MD, Professor of Medicine, St Louis University School of Medicine
George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Medical Practice Executives, American College of Physician Executives, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical Research, Endocrine Society, International Society for Clinical Densitometry, and Southern Society for Clinical Investigation
Disclosure: Nothing to disclose.

Acknowledgments

We wish to thank Christy L Henry, MD, and Don S Schalch, MD, for their previous contributions to this article.

Further Reading

Related eMedicine topics:
 Toxicity, Vitamin
Vitamin E Deficiency
Vitamin K Deficiency

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