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.1, 2, 3, 4, 5 Patients receiving large doses of vitamin E may experience a halt in the progression of the disease.
This vitamin is thought to have a role in preventing atherosclerosis by inhibiting the oxidation of low-density lipoprotein (LDL).6, 7 Several epidemiologic studies have indicated that high dietary intake of vitamin E is associated with high serum concentrations of alpha tocopherol, as well as with lower rates of ischemic heart disease.8 However, although the Cambridge Heart Antioxidant Study supported this hypothesis, a subsequent report, the prospective Heart Outcomes Prevention Evaluation Study, did not.7, 9, 10
Vitamin deficiencies related to cystic fibrosis, chronic cholestatic liver disease, abetalipoproteinemia, short-bowel syndrome, isolated vitamin E deficiency syndrome, and other malabsorption syndromes may lead to varying degrees of neurologic deficits.2, 4, 5 One milligram is equivalent to 1.5 international units (IU).
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Abnormalities relating vitamin E deficiency progress from hyporeflexia, ataxia, limitation in upward gaze, and strabismus to long-tract defects, including visual-field constriction and profound muscle weakness.4 Complete blindness, cardiac arrhythmia, and dementia may occur in patients in whom vitamin E deficiency has been prolonged and severe.
Mechanism of action
Vitamin E appears to act through several mechanisms; it functions as an antioxidant, and it acts through immunomodulation, as well as through an antiplatelet effect.
Vitamin E appears to act within membranes by preventing the propagated oxidation of saturated fatty acids.8, 11 Oxidized LDL particles are taken up more readily by macrophages than by native LDLs, which leads to the formation of cholesterol-laden foam cells found in the fatty streak of early atherosclerosis. It is hypothesized that vitamin E reduces atherosclerosis and subsequent coronary heart disease by preventing oxidative changes to LDLs.
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 Heart Outcomes Prevention Evaluation prospective study failed to confirm the efficacy of vitamin E in reducing coronary artery disease.10
Vitamin E appears to enhance lymphocyte proliferation, decrease the production of immunosuppressive prostaglandin E2, and decrease levels of immunosuppressive serum lipid peroxides.12
Vitamin E has been demonstrated to inhibit platelet adhesion, as measured by a laminar flow chamber when blood from patients who have taken vitamin E supplements is tested. This effect appears to be related to a 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 a 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, vitamin E appears to inhibit platelet adhesion effectively and to inhibit platelet aggregation weakly. Vitamin E also inhibits protein kinase C activity, which can contribute to the 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).
Epidemiologic evidence indicates a strong dose response between decreased risk of heart disease and increased vitamin E intakes from 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 no 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.
Patients with vitamin E deficiency may show signs and symptoms of hyporeflexia that 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.
Neurologic findings follow a pattern of progression that can be divided into early and late stages.3
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, as well as 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.
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.2 These conditions are characterized as follows:
Cystic fibrosis13 – This disease causes failure to secrete sufficient pancreatic enzymes, which leads to steatorrhea. If measured, vitamin E levels are low; neurologic complications rarely are reported.
Abetalipoproteinemia – This is a rare genetic, autosomal-recessive, inborn error of lipoprotein production and transport. Infants present with steatorrhea from the time of birth. Patients have pigmented retinopathy and progressive ataxia, and they develop acanthosis of red blood cells in the first decade of life.
Chronic cholestatic hepatobiliary disease3 – Profound deficits in infants as young as 2 years may result from this condition. Decreased bile flow and micelle formation lead to malabsorption of vitamin E. Neurologic findings are less frequent in adult patients with cholestasis secondary to cirrhosis.
Short-bowel syndrome – This may develop from intestinal pseudo-obstruction, surgical resection, or mesenteric vascular thrombosis. Only after 10-20 years of malabsorption do neurologic symptoms become clinically apparent.
Isolated vitamin E deficiency syndrome – Developing in the absence of fat malabsorption, this syndrome 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 significantly influence the outcome; therefore, screening for the deficiency is beneficial for patients with movement disorders or neuropathies that are of 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; in such cases, 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.
As a vitamin E deficiency becomes more advanced, the patient’s response to therapy will become more limited. It is therefore necessary for patients who are at risk for a deficiency to undergo a thorough neurologic examination, as well as periodic testing of serum vitamin E levels.4
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