Continuing Education Activity

Vitamin E or tocopherol is a fat-soluble vitamin that functions as an antioxidant, protecting the cell membrane. As with all vitamins, the body does not form vitamin E. It solely forms from the photosynthetic processes of plants and therefore must be consumed from outside sources in small quantities. Vitamin E is a medication used to manage and treat vitamin E deficiency states and disease prevention. This activity outlines the indications, action, adverse reactions, contraindications, and other key elements of vitamin E therapy in the clinical setting as relates to the essential points needed by members of an interprofessional team managing the care of patients with vitamin E deficiency and applications of vitamin E in disease prevention.

Objectives:

• Identify the mechanism of action of vitamin E.
• Describe the potential adverse effects of vitamin E.
• Review the appropriate monitoring when patients are taking vitamin E.
• Summarize interprofessional team strategies for improving care coordination and communication to advance vitamin E treatment and improve outcomes.

Indications

Vitamin E or tocopherol is a fat-soluble vitamin that functions as an antioxidant, protecting the cell membrane. As with all vitamins, the body does not form vitamin E. It solely forms from the photosynthetic processes of plants and therefore must be consumed from outside sources in small quantities. It is found abundantly in olive and sunflower oils, as well as nuts, soybeans, avocados, wheat, and green leafy vegetables.[1]

Vitamin E encompasses eight forms, including alpha, beta, gamma, and delta-tocopherol and alpha, beta, gamma, and delta-tocotrienol. However, only alpha-tocopherol is found in abundance and maintained well in human plasma.[2][3] Vitamin E supplements usually contain all isomers of alpha-tocopherol and have about half the activity level of natural sources. While other forms of tocopherols exist, only the alpha form or equivalents are measured for standard dietary sufficiency.

As with all fat-soluble vitamins, transport and absorption require intact fat digestion mechanisms. Fat metabolism involves both lingual and gastric lipases, bile salts, pancreatic enzymes, and intestinal absorption. Pancreatic enzymes break down tocopheryl-ester bonds.[4] Chylomicrons then transport alpha-tocopherol through the lymphatics to the liver. Once broken down in the liver, tocopherol is released from the chylomicrons. Alpha-tocopherol transfer protein is selective for alpha-tocopherol over other vitamin E forms and helps package the molecule with low-density lipoprotein, which is subsequently secreted into the bloodstream.[4]

Of the fat-soluble vitamins, deficiency of vitamin E is uncommon. Disorders leading to disruption of fat metabolism are the usual causes of deficiency.[5][6][7] Cystic fibrosis or chronic pancreatitis can lead to pancreatic enzyme insufficiency. Disorders such as primary biliary cholangitis, primary sclerosing cholangitis, or decompensated cirrhosis will lead to cholestasis. This condition, in turn, will lead to an insufficient amount of bile necessary for normal fat absorption. Long-standing, severe cholestasis will eventually lead to low levels of vitamin E.[6][7] Resection of the bowel or disease of the small intestine can also cause deficiency due to decreased absorption of vitamin E. Bile acids are absorbed in the terminal ileum, and therefore, Crohn disease or amyloid infiltration will reduce the pool of bile acids and hence decrease fat absorption.[6][7]

Ataxia with vitamin E deficiency (AVED) is a genetic disease caused by a mutation in the alpha-tocopherol transport protein, TTPA.[8][9] AVED usually manifests in the pre-teen to teenage years and clinically manifests with ataxia, dysarthria, decreased proprioception, vibratory sensation, and decreased reflexes due to the neurologic dysfunction linked to vitamin E deficiency, despite normal intake of the vitamin. A mutation of microsomal triglyceride transfer protein will lead to abetalipoproteinemia. In this disorder, there are absent or very low levels of low-density lipoproteins and, consequently, low levels of vitamin E transport, as well as other fat-soluble vitamins.[10] Vitamin E deficiency can clinically manifest with neuromuscular disruption. Neuropathy has variable involvement in the peripheral nervous system, causing gait disturbance and loss of proprioceptive and vibratory sense.[8][11] Red blood cell lifespan is shortened in chronic vitamin E deficient patients, clinically presenting with hemolysis.[5]

The use of alpha-tocopherol as a preventative antioxidant has been studied concerning cardiovascular disease, cancer, age-related macular degeneration, nonalcoholic fatty liver disease, and Alzheimer disease. The theory is that lipid oxidation plays a pivotal role in developing cardiovascular disease and that the use of antioxidants as adjunctive therapy is useful for prevention. However, studies of vitamin E in the prevention of cardiovascular disease have not proven beneficial, with inconsistent outcomes and inherent study limitations.[12][13]

Antioxidant use of vitamin E in the prevention of cancers has also not been shown to be effective and may increase the risk of prostate cancer. In the SELECT trial, researchers studied selenium and vitamin E to see what role there was for supplementation in decreasing the incidence of prostate cancer. Participants were randomly assigned to either supplementation with selenium, vitamin E, both, or placebo. The study resulted in an increase in incidence in those in the vitamin E-only group. Other trials on the role of vitamin E and prostate cancer showed conflicting results.[4][13][14]

The progression of nonalcoholic fatty liver disease has been shown to be decreased by high-dose supplementation of alpha-tocopherol.[15] Long-term studies remain necessary to show continued benefits. With age-related macular degeneration, a combination of antioxidants as an adjunctive therapy has shown to slow progression but has not proven to prevent development. Additionally, high-dose vitamin E correlates with an increased progression of retinitis pigmentosa.[16][17] Alpha-tocopherol high dose supplements may also play a role in slowing the progression of Alzheimer disease.[18]

Mechanism of Action

The primary mechanism of action of alpha-tocopherol is as a scavenger of free radicals. It binds to free radicals, protecting cellular components from oxidative damage. Peroxidation of polyunsaturated fatty acids in the cell membrane from free radicals leads to cellular injury. Vitamin E plays a protective role. It also inhibits the aggregation of platelets, monocyte adhesion, and proliferation of cells.[1][4]

Vitamin E is hepatically metabolized and is primarily excreted in the bile and feces but also the urine. It is also stored in the body's adipose tissues.

Administration

Vitamin E is available in capsules of 100, 200, 400, 600, and 1000 international units. Tablet dose forms are 100 and 200 units. A solution formulation has 1150 units per 1.25 mL, 400 units per mL, and 15 units per 0.3 mL.

Routine supplementation of vitamin E is not recommended for non-deficient children or adults. If a deficiency is detected or a person suffers from a disorder leading to absent or low levels of vitamin E, oral supplementation is available over the counter.

Adult dosing:

• Vitamin E deficiency: take 60 to 75 units by mouth daily.
  • The maximum dose is 1000 units daily. Cystic fibrosis patients should get 100 to 400 units per day. The liquid form is recommended in instances of malabsorption.
• Tardive dyskinesia (Off-label indication): 1600 units orally each day

Pediatric dosing:

• Vitamin E deficiency
  • Ages 1 month to 12 years: 1 unit/kg/dose by mouth daily.
    • Maximum dosing:
      • Ages 1 month to 3 years of age: 200 units daily
      • Ages 4 to 8: 300 units daily
      • Ages 9 to 13: 600 units daily
      • Ages 14 to 18: 800 units daily

Renal and hepatic dose adjustments are not defined.

Intramuscular vitamin E is not readily available but may be necessary for severe cholestasis or those with genetic disorders, with injections occurring weekly.[16]

Adverse Effects

Common side effects of alpha-tocopherol supplementation include nausea, headache, changes in vision, gastrointestinal upset, risk of hemorrhagic stroke, mild increase in urine creatinine, and necrotizing enterocolitis. There is a potential risk of increased bleeding intraoperatively, as vitamin E is known to inhibit the aggregation of platelets. Yet, it has not been shown in those who are not already on antiplatelet or anticoagulants.[19] 

Alpha-tocopherol undergoes metabolism in the liver CYP450 enzymes and therefore monitoring for drug interactions if the patient is on medications that inhibit or induce these enzymes is recommended.[4]

Contraindications

Vitamin E supplementation is contraindicated in persons with known allergies to the vitamin or components of the formulation.

Monitoring

Deficiency in vitamin E is uncommon, and therefore monitoring of levels is not routinely conducted. However, disorders leading to fat malabsorption can cause deficiency, and consequently, the measurement of serum alpha-tocopherol is warranted. These disorders include cystic fibrosis, chronic pancreatitis, diseases leading to cholestasis, genetic mutations leading to abetalipoproteinemia, and low levels of alpha-tocopherol transport protein. Levels of alpha-tocopherol less than 0.5 mg/dL are considered a deficiency.[20] 

The provider must remember that serum alpha-tocopherol depends on serum lipids and proteins. Therefore, in patients with high total lipid levels, the measurement of serum alpha-tocopherol is best estimated by dividing the level by the total lipid. Additionally, since vitamin E and other fat-soluble vitamins require carrier proteins, those with other hypoproteinemic states may have lower measurements of such vitamins.

Toxicity

Hypervitaminosis E is rare and the least toxic of the fat-soluble vitamins. For adults, the upper limits of vitamin E replacement are 1500 to 2200 international units depending on whether the patient is using a natural or synthetic source, respectively. Daily limits for children depend on the child's age, starting at 200 international units at one year of age to 800 international units by 18 years old. Staying well below these levels, however, is recommended for daily supplementation.[16] 

Studies of high-dose Vitamin E supplementation have been small in number but suggest an associated increase in all-cause mortality. Decreased absorption of other fat-soluble vitamins is known to occur with high serum vitamin E leading to impairment of bone mineralization, coagulopathies, and decreased vitamin A storage.[21][12] Discontinuation of vitamin E intake and supportive care are recommended in the setting of toxicity.

Enhancing Healthcare Team Outcomes

As with many supplements, vitamin E supplements are readily available over the counter. It is the responsibility of the interprofessional health care team, including clinicians (MDs, DOs, NPs, PAs), nurses, and pharmacists, to guide preventative health measures and the therapeutic use of vitamin E. All interprofessional team members must communicate across disciplinary lines about all drugs and supplements the patient is taking to operate from the same data and optimize patient care. [Level 5]

As deficiency is rare, routine supplementation is not a recommended practice, and the patient should be encouraged to eat a balanced diet to obtain the proper alpha-tocopherol levels. If the recommendation is for supplementation, monitoring for common adverse reactions, medication interactions, and risks for bleeding, especially if the patient is taking aspirin or other anticoagulants, should be conducted during the health visit.