Vitamin E (alpha and gamma tocopherol)

Evaluate vitamin E deficiency in hemolytic disease in premature infants, and neuromuscular disease in infants (and adults) with chronic cholestasis; evaluate patients on long-term parenteral nutrition; patients with malignancy or malabsorption (eg, patients with cystic fibrosis, cases of intestinal bypass surgery); investigate brown-bowel syndrome This test was developed and its performance characteristics determined by LabCorp. It has not been cleared or approved by the Food and Drug Administration. The term vitamin E refers to a class of plant-derived, lipid-soluble compounds which possess a substituted chromanol ring attached to a long phytyl side chain.1-3,12,13 The ring structure is necessary to confer vitamin E activity. The human diet includes eight vitamin E compounds: the a-, ß-, ?-, and d-tocopherals and the a-, ß-, ?-, and d-tocotrienols.1-3,13 Mammals do not interconvert the tocopherol(TC) isoforms.13 ?-TC is found in corn and soybean oil as well as walnuts, pecans, pistachios, and sesame seeds.20 The main sources of ß-TC and d-TC are corn, corn oil, and rapeseed oil. Other good sources of d-TC are tomato seeds, rice germ, and soybean oil.14 a-TC is found predominantly in peanuts, almonds, and sunflower seeds. a-TC is the only form of vitamin E that is actively retained by the body.1 The TCs are extremely hydrophobic molecules.3 Consequently, the delivery of a-TC into target tissues and cells requires the presence of a specific enzyme, a-TC transfer protein (a-TTP).3-5 a-TTP also facilitates the intracellular trafficking of a-TC from lysosomes to the plasma membrane and from hepatocytes to circulating lipoproteins.4,13 The critical role of this protein and its ligand are revealed by the debilitating pathologies that characterize individuals with mutations in the a-TTP gene.3,4 Heritable mutations in this protein lead to severe vitamin E deficiency characterized by progressive neurodegeneration, ataxia and eventually death if vitamin E is not provided in large quantities to overcome the lack of a-TTP.2 Due to lack of specific transfer mechanisms, other tocopherols and tocotrienols are not efficiently retained by the liver, and are instead metabolized, and predominantly eliminated.21 As a result, tissue levels of a-TCs are 10-fold higher than the levels of other TCs.4,13 a-TC acts as a lipid-soluble peroxyl radical scavenger that disrupts the chain reaction by which lipid peroxidation propagates.3,6 During lipid oxidation, oxidized tocopheroxyl radicals are produced that can be recycled back to the active, reduced form through reduction by vitamin C.13 This process prevents oxidative damage to long-chain polyunsaturated fatty acids in cell membranes during times of oxidative stress.1,2,3,6 Consequently, vitamin E adequacy is critical for numerous physiologic functions that rely on bilayer integrity such as cell permeability and adhesion.6 a-TC is also thought to play a role in controlling the expression of several genes.7 Symptomatic dietary vitamin E deficiency is rare.3 The main manifestation of deficiency is peripheral neuropathy associated with the degeneration of the large-caliber axons of sensory neurons.10 Clinical features include dysarthria, clumsiness of the hands, loss of proprioception, areflexia, dysdiadochokinesia, decreased visual acuity, and positive Babinski sign. Primary deficiency is seen in cases of the autosomal recessive disorder ataxia due to heritable mutations in a-TTP.3 Primary deficiency is associated by very low plasma vitamin E levels.3 Secondary deficiency occurs in disorders of lipid absorption or lipoprotein metabolism and transport.3 Compromised intestinal fat absorption diseases including cholestatic liver disease, short bowl syndrome, Crohn's disease, and abetalipoproteinemia can cause secondary vitamin E deficiency.3 Cystic fibrosis associated fat malabsorption can also cause deficiency in fat-soluble vitamins, including vitamin E. Diseases caused by molecular defects that affect lipid transport and trafficking, including Niemann-Pick disease-type C and Tangier disease are also associated with vitamin E deficiency. Vitamin E deficiency is also seen in some hematological disorders including, beta-thalassemia major, sickle-cell anemia, and glucose-6-phosphate dehydrogenase deficiency.1 A number of animal studies, observational human studies, and clinical trials have investigated the possibility that vitamin E may have a cardioprotective effect.8 a-TC has been shown to increase oxidative resistance in vitro and to reduce atherosclerotic plaque formation in mouse models. In addition, a-TC inhibits oxidation of low- density lipoprotein cholesterol and modulates expression of proteins involved in the uptake, transport, and degradation of atherogenic lipids.14 Consumption of foods rich in a-TC has been associated with decreased risk of coronary heart disease in middle-aged to older men and women. While some reports have been encouraging, the majority of clinical studies have not demonstrated a benefit of vitamin E supplementation in the primary and secondary prevention of cardiovascular disease.8,14 Animal studies have reported preventive effects of vitamin E on Alzheimer's disease neuropathology.26 A recent study found that a-TC was effective in slowing the functional decline of mild to moderate Alzheimer disease and was also effective in reducing caregiver time in assisting patients.15 However, the therapeutic effect seen was modest and related to disease symptoms and not to the reversal of the disease process.16 Vitamin E isoforms may also have a role in the production and clearance of amyloid beta.23 Until recently, most research on vitamin E has focused on a-TC, because it is the predominant form of vitamin E in tissues and low intake of a-TC is associated with clinical manifestations including peripheral neuropathy and ataxia.14 However, there is accumulating evidence for a role for another member of the vitamin E family, ?-TC in health and disease.14,20 ?-TC is the major form of vitamin E in the corn and soybean oils that are a major staple of the American diet.14 ?-TC is low in other oils such as sunflower and olive oil that are more prevalent in European diets.13,17 The average serum concentrations of a-TC are similar among these populations while serum ?-TC levels in United States are 2- to 6-fold higher than levels in Europeans.13,18 It has been suggested that the conflicting outcomes of a number of vitamin E studies performed in different countries may, in part, reflect differences in the serum levels of ?-TC in foods and supplements administered.14,18 Reactive oxygen species (ROS) are produced as byproducts of the aerobic cellular metabolism and lipid oxidation.14 a- and ?-TC have similar capacity to scavenge these ROS.13,19,20 This process produces oxidized TC radicals that are recycled back to their active, reduced forms via reduction by vitamin C.13 ROS accumulation beyond the body's ability to scavenge them results in "oxidative stress," which has been implicated in the pathophysiology of numerous diseases.14,19,22 Unlike a-TC, ?-TC also reacts with reactive nitrogen species (RNS) that are produced by neutrophilic inflammation.13,18,20 It has been suggested that the ?-TC's ability to scavenge RNS may reduce inflammation.18,19 Recent studies reveal disparate effects from supplementation with a- ?- and TC in clinical studies of asthma and atherosclerosis.13,17,18,20 It has been suggested that excess a-TC taken in supplements causes a reduction of ?-TC concentration in plasma due to more rapid metabolism of ?-TC.24 Reports indicate that allergic inflammation is inhibited by supplementation with a-TC but elevated by supplementation with ?-TC.13 Studies suggest that ?-TC elevates inflammation in experimental asthma and ablates the anti-inflammatory benefit of a-TC treatment.17 A recent clinical study found that a-TC supplementation produced improved spirometric parameters while