AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

Vitamin E, one of the most important lipid-soluble antioxidant nutrients, is found in nut oils, sunflower seeds, whole grains, wheat germ, and spinach. Severe deficiency, as may occur in persons with abetalipoproteinemia or fat malabsorption, profoundly affects the central nervous system and can cause ataxia and a peripheral neuropathy resembling Friedreich ataxia. Patients receiving large doses of vitamin E may experience a halt in progression of the disease.

This vitamin is thought to have a role in preventing atherosclerosis by inhibiting oxidation of low-density lipoprotein (LDL). Several epidemiological studies show an association between high dietary intake and high serum concentrations of alpha tocopherol and lower rates of ischemic heart disease. However, while the Cambridge Heart Antioxidant Study supported this hypothesis, the more recent prospective Heart Outcomes Prevention Evaluation study did not.

Cystic fibrosis, chronic cholestatic liver disease, abetalipoproteinemia, short-bowel syndrome, isolated vitamin E deficiency syndrome, and other malabsorption syndromes all may cause varying degrees of neurologic deficits due to related vitamin deficiencies. One milligram is equivalent to 1.5 international units (IU).

Pathophysiology

Classic abnormalities progress from hyporeflexia, ataxia, limitation in upward gaze, and strabismus to long-tract defects, including profound muscle weakness and visual-field constriction. Patients with severe prolonged deficiency may develop complete blindness, cardiac arrhythmia, and dementia.

Mechanism of action

Vitamin E appears to act through several mechanisms; it acts as an antioxidant, it acts through immunomodulation, and it acts through an antiplatelet effect.

Antioxidant effect

Vitamin E appears to act within membranes by preventing propagated oxidation of saturated fatty acids. This vitamin is hypothesized to reduce atherosclerosis and subsequent coronary heart disease by preventing oxidative changes to LDLs. Oxidized LDL particles are taken up more readily by macrophages than by native LDLs, which leads to formation of cholesterol-laden foam cells found in the fatty streak of early atherosclerosis.

Atherogenesis also may be promoted by the following activities of oxidized LDLs: (1) chemotactic action on monocytes, (2) cytotoxicity to endothelial cells, (3) stimulation of the release of growth factors and cytokines, (4) immunogenicity, and (5) possible arterial vasoconstrictor actions. Notwithstanding the attractiveness of these hypotheses, the recent Heart Outcomes Prevention Evaluation prospective study failed to confirm the efficacy of vitamin E in reducing coronary artery disease.

Immunomodulation

Vitamin E appears to enhance lymphocyte proliferation, decrease production of immunosuppressive prostaglandin E2, and decrease levels of immunosuppressive serum lipid peroxides.

Antiplatelet effect

Vitamin E has been demonstrated to inhibit platelet adhesion as measured by a laminar flow chamber when testing blood from patients who have taken vitamin E supplements. This effect appears to be related to reduced development of pseudopodia, which normally occurs upon platelet activation. It may be related to changes in fatty acylation of platelet structural proteins. Although vitamin E inhibits platelet aggregation in vitro, its effect in vivo has not been consistent.

Chemical evidence of lipid oxidation is apparent at all stages of atherosclerosis, especially in macrophage-rich and early atherosclerotic lesions. Alpha tocopherol, the most active form of vitamin E, is the predominant lipophilic antioxidant for LDL. However, patients with advanced coronary atherosclerosis are at much greater risk of myocardial infarction, which usually occurs as a result of rupture of mature atheromatous plaques. The prevailing hypothesis of how antioxidants may contribute to the reduction of coronary heart disease is that they protect LDL from oxidative modification. However, another effect of vitamin E in vitro is modulation of prostaglandin metabolism, leading to inhibition of platelet aggregation. In vivo, it appears to inhibit platelet adhesion effectively and to inhibit platelet aggregation weakly. Vitamin E also inhibits protein kinase C activity, which can contribute to proliferation of smooth-muscle cells in arterial walls.

Several studies on the effect of vitamin E on heart disease and its risk factors show protective effects associated with intakes well above the recommended daily allowance (RDA).

Epidemiological evidence indicates a strong dose response between decreased risk of heart disease and increased vitamin E intakes from both supplements and diet.

Significant protection is thought to be gained beginning at daily intakes of 67 mg/d of alpha tocopherol equivalents (1 mg is equivalent to 1.5 IU). LDL cholesterol oxidation decreased significantly in blood taken from subjects receiving more than 400 IU/d but not less than 200 IU/d. Again, note that the prospective Heart Outcomes Prevention Evaluation study did not validate these previous studies.

CLINICAL

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History

• Patients may have signs and symptoms of hyporeflexia, which progress to ataxia, including limitations in upward gaze.
• Patients may present with profound muscle weakness and visual-field constriction.
• Patients with severe prolonged vitamin E deficiency may develop complete blindness, cardiac arrhythmia, and dementia.

Physical

• Neurologic findings follow a pattern of progression that can be divided into early and late stages.
• • Early findings include hyporeflexia, decreased proprioception, decreased vibratory sense, distal muscle weakness, nyctalopia (night blindness), and normal cognition.

  • With continued deficiency, neurologic symptoms progress and patients can develop truncal and limb ataxia and diffuse muscle weakness. Further eye problems may develop, including limited upward-gaze nystagmus and dissociated nystagmus.

  • Late manifestations include areflexia, loss of proprioception and vibratory sense, dysphagia and dysarthria, cardiac arrhythmias, ophthalmoplegia, and possible blindness. Cognition may be affected in later stages, and dementia can occur.

• By contrast, patients with abetalipoproteinemia tend to have a predominance of eye problems, including decline in visual fields and pigmented retinopathy. Children with cholestatic disorders and patients with isolated vitamin E deficiency almost never develop retinopathy. Patients with cholestatic liver disease have a high incidence of behavioral and personality disorders.
• Results of certain tests, such as finger-to-nose and rapid alternating movement tests, are notably affected in vitamin E deficiency. After treatment, patients' ability to perform such tests may remain somewhat impaired but should show some improvement.

Causes

Absorption of vitamin E depends on normal pancreatic biliary function, biliary secretion, micelle formation, and penetration across intestinal membranes. Interference with any of these processes could result in a deficiency state. Cystic fibrosis, abetalipoproteinemia, chronic cholestatic hepatobiliary disease, short-bowel syndrome, and isolated vitamin E deficiency syndrome are all potential causes of a deficiency state.

• Cystic fibrosis causes failure to secrete sufficient pancreatic enzymes, which leads to steatorrhea. If measured, vitamin E levels are low; neurologic complications rarely are reported.
• Abetalipoproteinemia is a rare genetic autosomal-recessive inborn error of lipoprotein production and transport. Infants present with steatorrhea from the time of birth. They have pigmented retinopathy and progressive ataxia and develop acanthosis of red blood cells in the first decade of life.
• Chronic cholestatic hepatobiliary disease may cause profound deficits in infants as young as 2 years. Decreased bile flow and micelle formation result in malabsorption of vitamin E. Neurologic findings are less frequent in adult patients with cholestasis secondary to cirrhosis.
• Short-bowel syndrome may develop from intestinal pseudoobstruction, surgical resection, or mesenteric vascular thrombosis. Only after 10-20 years of malabsorption do neurologic symptoms become clinically apparent.
• Isolated vitamin E deficiency syndrome develops in the absence of fat malabsorption. This is caused by an autosomal-recessive genetic disorder involving chromosome arm 8q. Neurologic findings develop within the first decade of life, and no clinical findings distinguish deficiency from ataxia and movement disorders. Vitamin replacement can influence outcome significantly; therefore, screening for the deficiency is beneficial for patients with movement disorders or neuropathies of an unknown cause.
• Intramuscular administration of vitamin E is necessary when vitamin E deficiency occurs because of a low concentration of bile salts in the lumen of the small intestine; as such, patients are unable to absorb an oral preparation.
• Vitamin E deficiency usually is reversible in the early stages, but it can have severe complications if allowed to progress.
• The more advanced the deficit of vitamin E, the more limited the response to therapy. Therefore, thorough neurologic examination and periodic testing of serum vitamin E levels are essential in patients at risk of vitamin E deficiency.

DIFFERENTIALS

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Other Problems to be Considered

Cholestatic hepatobiliary disease
Chronic cholestasis

WORKUP

Section 5 of 11  

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Lab Studies

• Serum alpha tocopherol level

TREATMENT

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Medical Care

• Intramuscular administration is necessary when the deficiency occurs because of a low concentration of bile salts in the lumen of the small intestine because these patients are unable to absorb any oral preparation.
• Treatment must be tailored to the underlying cause of the deficiency and may include oral or parenteral vitamin supplementation.

Consultations

Consult a gastroenterologist if biliary problems are the underlying cause.

MEDICATION

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The RDA of alpha tocopherol according to age (see Image 1) is as follows:

• Age 0-6 months - 3 mg



• Age 6-12 months - 4 mg



• Age 1-3 years - 6 mg



• Age 4-10 years - 7 mg



• Adults and elderly individuals - 8-10 mg

Replacement recommendations according to disease state are as follows:

• Abetalipoproteinemia - 100-200 IU/kg/d



• Chronic cholestasis - 15-25 IU/kg/d



• Cystic fibrosis - 5-10 IU/kg/d



• Short-bowel syndrome - 200-3600 IU/d



• Isolated vitamin E deficiency - 800-3600 IU/d

Pregnancy/lactation: Vitamin E is in the US Food and Drug Administration (FDA) pregnancy category A. Breastfeeding is safe.

Drug Category: Vitamins

Essential for normal cell function.

FOLLOW-UP

Section 8 of 11  

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Deterrence/Prevention

• Overdose of vitamin E is difficult to achieve and, thus, is extremely uncommon.

Patient Education

• Vitamin E has been used as a preventive agent for heart disease; however, this use has not been approved by the FDA.

MISCELLANEOUS

Section 9 of 11  

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Medical/Legal Pitfalls

• Even though vitamin E has been used as a preventive agent for heart disease, it has virtually no major harmful effects; therefore, no significant legal pitfalls are likely.

MULTIMEDIA

Section 10 of 11  

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Media file 1:  Comparison of the recommended daily allowance (RDA), deficiency replacement dose, and preventive dose in international units (IUs) and milligrams.
	View Full Size Image
Media type:  Graph

REFERENCES

Section 11 of 11

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• Benomar A, Yahyaoui M, Marzouki N, et al. Vitamin E deficiency ataxia associated with adenoma. J Neurol Sci. Jan 1 1999;162(1):97-101. [Medline].
• Fuller CJ, Huet BA, Jialal I. Effects of increasing doses of alpha-tocopherol in providing protection of low-density lipoprotein from oxidation. Am J Cardiol. Jan 15 1998;81(2):231-3. [Medline].
• Hathcock JN. Vitamins and minerals: efficacy and safety. Am J Clin Nutr. Aug 1997;66(2):427-37. [Medline].
• Micromedex. Vitamin E [database online]. Englewood, Colo:. Micromedex;1999.
• Sokol RJ. Vitamin E and neurologic deficits. Adv Pediatr. 1990;37:119-48. [Medline].
• Sokol RJ, Guggenheim MA, Heubi JE, et al. Frequency and clinical progression of the vitamin E deficiency neurologic disorder in children with prolonged neonatal cholestasis. Am J Dis Child. Dec 1985;139(12):1211-5. [Medline].
• Stephens NG, Parsons A, Schofield PM, et al. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet. Mar 23 1996;347(9004):781-6. [Medline].
• Tanyel MC, Mancano LD. Neurologic findings in vitamin E deficiency. Am Fam Physician. Jan 1997;55(1):197-201. [Medline].
• Virtamo J, Rapola JM, Ripatti S, et al. Effect of vitamin E and beta carotene on the incidence of primary nonfatal myocardial infarction and fatal coronary heart disease. Arch Intern Med. Mar 23 1998;158(6):668-75. [Medline].
• Yusuf S, Dagenais G, Pogue J, et al. Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. Jan 20 2000;342(3):154-60. [Medline].

Article Last Updated: Jul 19, 2006