Continuing Education Activity

Vitamin E toxicity can cause major bleeding events, including the potential for intracranial hemorrhage. To avoid the morbidity and mortality associated with vitamin E toxicity, it is important to identify the cause and know how to treat it. This activity discusses vitamin E toxicity, its diagnosis, treatment, and all healthcare team members' role in avoiding polypharmacy and drug toxicity.

Objectives:

• Identify the foods that contain vitamin E along with the reasons why patients take vitamin E supplementation.

• Assess the pathophysiology of vitamin E toxicity.

• Evaluate the complications that occur due to vitamin E toxicity.

Introduction

Vitamin E is a major lipid-soluble antioxidant obtained exclusively from the diet. It was discovered in the 1920s as an essential dietary element required by rats for reproduction.[1] There are approximately 8 vitamin E-related molecules, but alpha-tocopherol is the dominant molecule in humans. Tocotrienols are the other molecules that are widely studied for vitamin E supplementation. These 2 molecules have been studied in various dosages and for various health purposes. Vitamin E has peroxyl radical scavenger properties. While vitamin E toxicity is associated with an increased risk of bleeding, its deficiency has been associated with neurologic diseases and anemia.[2]

Etiology

Vitamin E is quite common in diet and is found in spinach, avocado, seeds, vegetable oil, and almonds. It is also present in breast milk.[3][4] Patients who follow a Mediterranean diet are more likely to have greater vitamin E levels.[5] Although the recommended dietary allowance of vitamin E is 15 mg/day, many supplements are produced at much higher daily dosages, such as 100 to 1000 mg.[3] Symptoms are not noticed in most patients until levels beyond 1000 mg are ingested daily. However, drug-drug interactions have been reported in patients ingesting more than 300 mg of vitamin E daily. 

A patient who consumes vitamin E in their diet has, on average, a level of circulating alpha-tocopherol of approximately 20 micromol/L. Patients with additional vitamin E supplementation have 30 micromol/L or greater levels. No data supports any detrimental effects from the dietary intake of vitamin E-rich foods without exogenous supplementation.[6] Excessive supplementation, however, may lead to vitamin E toxicity, most notably manifested in an increased risk of bleeding. Vitamin E deficiency is rare and is characterized by the development of progressively worsening peripheral neuropathy, ataxia, and hyporeflexia. It may develop in patients with difficulty absorbing fat, such as cystic fibrosis, Crohn disease, and chronic pancreatitis. In these cases, vitamin E supplementation may be needed.[7]

Epidemiology

There are many reasons patients take vitamin E supplementation in larger dosages. In rat models, it was found that topical alpha-tocopherol at lower concentrations was useful in prolonging the onset of cataracts. At higher levels, it increased the onset of cataracts.[8] Studies reported the effects of vitamin E on rats with diabetic nephropathy, showing improved kidney function, improved blood sugars, and improved lipid levels. Both alpha-tocopherol and tocotrienols have been shown to decrease the amount of glutamate.[8] Since many neurodegenerative diseases have increased amounts of glutamate, vitamin E supplementation was linked to potentially preventing neural cytotoxicity and neurodegeneration induced by increased glutamate concentrations.[8]

Vitamin E has been explored in osteoporosis as an antioxidant and anti-inflammatory with mixed benefits. In diabetes, alpha-tocopherol was found to help with wound healing. In inflammatory diseases, such as asthma, Crohn, and rheumatoid arthritis, it has been shown that tocotrienols are more effective compared to alpha-tocopherols at decreasing inflammation. In patients exposed to large amounts of radiation, vitamin E is effective in helping hematopoiesis after radiation.[8] There has been increasing evidence that tocotrienols over tocopherols have greater anti-cancer activities and a good safety profile.[9]

Vitamin E has been used in cardiovascular disease prevention, such as stroke, coronary heart disease, and myocardial infarction. Tocotrienols were more beneficial in coronary artery disease and strokes than alpha-tocopherols.[7] In a large retrospective analysis completed in 2017, there was found to be no difference in the cognitive decline of patients who were supplemented with Vitamin E versus placebo in both patients diagnosed with Alzheimer disease and mild cognitive impairment.[10] Levels of exogenous alpha-tocopherol greater than 400 I.U. daily were found to be harmful to patients in an acute stroke setting.[11] Still, many patients use vitamin supplementation based on the theoretical benefits.

Pathophysiology

Vitamin E is absorbed in intestinal cells and is transported to the liver by chylomicrons.[12] This is why levels of cholesterol play such an important role in the levels of circulating alpha-tocopherols. In cases of extremely high or low cholesterol levels, vitamin E circulating levels can be greatly influenced. It is known that the mechanism for processing vitamin E involves using the cytochrome P450 system initially, then using beta-oxidation and conjugation, followed by transportation out of the liver.[12] The process concludes with excretion in the biliary and urinary systems.[12]

The current literature describes several different mechanisms of vitamin E's action on coagulation and platelet function. Vitamin K precursors need enzymes to convert into their active forms. It is thought that vitamin E may challenge these precursors for these enzymes. As a result, the circulation of vitamin-K-induced coagulation factors is decreased.[3] Vitamin K-dependent proteins such as factors II, VII, IX, and X, along with proteins C and S, are involved in the clotting cascade.[13] If vitamin K concentrations are reduced, these factors are also decreased, promoting bleeding. 

Glutamate is needed for factor IX production, and vitamin E reduces glutamate production.[3] In patients who take warfarin and vitamin E, vitamin K antagonism is increased, thus increasing their risk of bleeding. Platelet aggregation was found to be decreased in patients taking vitamin E supplementation. The exact mechanism is unknown but is thought to be related to protein kinase C inhibition, which is linked to the inhibition of platelet aggregation.[14] Through these mechanisms, it is easy to see why vitamin E can be associated with higher risks for bleeding, especially in patients taking oral anticoagulants or antiplatelet medications. “Toxic” vitamin E levels do not concentrate in the body in the same fashion as other fat-soluble vitamins like vitamins A and D.[12] Although vitamin E is a lipid-soluble vitamin, excess alpha-tocopherols are excreted in the urine and bile, thereby decreasing the accumulation of circulating alpha-tocopherols.[12] As a result, toxic effects are not observed in most healthy patients taking less than 1000 mg of vitamin E daily.[6]

History and Physical

Since an increased risk of bleeding is the major concern with vitamin E toxicity, a thorough medication history must be obtained, including any anticoagulation or antiplatelet agents. The history should also include any over-the-counter supplements with exact dosages, as patients may be taking many available supplements at their discretion. The history of weight loss or weight gain may also be important when considering the malabsorption of fat-soluble vitamins. With vitamin E toxicity, other fat-soluble vitamins can be decreased.[12] Some of the major drugs that vitamin E can interact with can cause complications with increased bleeding, hepatobiliary dysfunction, and malabsorption of other fat-soluble vitamins. Prescription medication interactions can occur when vitamin E levels are supplemented at levels greater than 300 mg daily. These common medications include aspirin, warfarin, cyclosporine, and tamoxifen.[15] Physical findings should include a thorough skin exam for bruising, petechiae, and pallor. Important findings for hepatobiliary dysfunction include scleral icterus, hepatomegaly, and jaundice. 

Evaluation

To detect vitamin E toxicity, serum levels of circulating alpha-tocopherol can be obtained. The average range of plasma alpha-tocopherol in a patient who eats a well-balanced diet is 20 micromoles/liter.[7] A patient on vitamin E supplementation may have plasma levels of 30 micromoles/liter or greater.[7] The normal lab range for circulating alpha-tocopherols is 5.7 to 19.9 mg/L.[3] The levels of circulating alpha-tocopherol are very dependent on the lipid content of the blood. In patients with extremely high or extremely low cholesterol levels, the levels of circulating alpha-tocopherol are not an accurate measure of vitamin E. In a patient with average cholesterol levels, the levels of circulating alpha-tocopherol are still not an accurate measure of vitamin E. This is due to the upregulation of biliary and urinary excretion once vitamin E levels are increased.[12] Because of these irregularities in vitamin E metabolism, there is no set cut-off level of circulating alpha-tocopherols considered universally toxic.

In a study performed on patients with intracranial hemorrhages and taking vitamin E supplementation, alpha-tocopherol levels ranged from 23.3 micromoles/L to 46.7 micromoles/L in patients who were discovered to have intracranial hemorrhages.[3] In another study that correlated the vitamin E levels and risk of bleeding in patients taking oral anticoagulation, a ratio of circulating alpha-tocopherols to total serum cholesterol concentration was used. This was thought to represent the true circulating vitamin E levels most accurately.[5] Although there is a concern regarding the reliability of these circulating alpha-tocopherol levels correlating to vitamin E levels, this is still the most widely used test in the literature regarding quantifying vitamin E when describing its effects.

Treatment / Management

The mainstay treatment for vitamin E toxicity is stopping the exogenous vitamin supplementation. This is effective since vitamin E toxicity does not occur without an exogenous supplementation.[6] If there is significant bleeding, vitamin K supplementation should be considered in patients taking vitamin E supplementation. There can be inhibition of a clotting cascade that is vitamin K-dependent when there are higher vitamin E concentrations. This can occur whether the patient is on warfarin or not. Vitamin E also impedes platelet aggregation. This can occur regardless of whether the patient takes antiplatelet agents. Therefore, giving vitamin K to patients who are actively bleeding or have a severe hemorrhage should be considered.[5]

Differential Diagnosis

The differential diagnosis for a patient with vitamin E toxicity would include bleeding disorders such as hemophilia, von Willebrand disease, drug-induced coagulopathy, and DIC. Other manifestations of vitamin E toxicity include gastrointestinal upset, generalized weakness, and emotional liability. The differential diagnosis for patients with gastrointestinal upset (nausea, vomiting, diarrhea) includes gastroenteritis, infectious diarrhea, small bowel obstruction, pancreatitis, and cholestasis. The differential diagnosis for weakness can be extremely broad and includes an infectious etiology (urinary tract infection, pneumonia, etc), anemia, acute kidney failure, electrolyte abnormalities, congestive heart failure, hypothyroidism, etc. 

Prognosis

In general, the prognosis of patients with vitamin E toxicity due to excessive supplementation is usually good as long as they discontinue the supplement. Prognosis may be poor in cases of severe bleeding, especially in cases of hemorrhagic strokes. 

Complications

Although the major hazardous complications of elevated vitamin E levels include bleeding, there have been others mentioned. These include thyroid problems, weakness, emotional disorder, gastrointestinal derangement, tenderness of breasts, and thrombophlebitis. 

Deterrence and Patient Education

Many patients are not concerned about the side effects of over-the-counter supplements and the serious health detriments that they can cause. Careful history must be taken, and patients should be educated regarding the importance of disclosing all of their prescribed and over-the-counter medications to avoid drug-drug interactions.

Pearls and Other Issues

Vitamin E toxicity occurs due to excessive vitamin supplementation, not due to diet alone. Vitamin E can interact with many different medications. One of the more serious complications of vitamin E toxicity is increased bleeding risk, especially in patients already on anticoagulation or antiplatelet therapy. 

Bleeding episodes can occur anywhere in the body, and serious life-threatening hemorrhagic strokes have been reported. Other complications include gastrointestinal manifestations, weakness, fatigue, and emotional lability. The treatment for vitamin E toxicity includes discontinuing vitamin E supplementation and considering vitamin K therapy if serious bleeding occurs. Vitamin E supplementation should be kept to a lower dosage to prevent vitamin E toxicity. 

Enhancing Healthcare Team Outcomes

To provide the best outcome for patients, healthcare teams must work together to educate the patient on the importance of disclosing all medications, over-the-counter supplements, and their dosages. This includes medical assistants, nurses, mid-level providers, physicians, and pharmacists responsible for reviewing and updating patients' medication records. When multiple providers are recommending different medications or treatments, drug-drug interactions and toxicity may result, leading to poor patient outcomes. A systematic review determined that having involvement with a pharmacist in a healthcare team improved the effectiveness of the drug regimen, safety profiles, and hospitalization outcomes.[16] A pharmacist's involvement in these healthcare teams has also improved physicians' and nurses' knowledge about medications and their interactions.[17] With consistent and regular communication between the healthcare team members, the patient is more likely to have a safe and successful treatment plan.