Focus On: Vitamin E
In 1997 the U.S. Food and Drug Administration granted an indication for the use of the Thin-layer Rapid-Use Epicutaneous (T.R.U.E.) test panels 1.1 and 2.1 as valuable, first-line screening tools in the diagnosis of allergic contact dermatitis (ACD). Many dermatologists utilize the T.R.U.E. test in their practices and refer to contact dermatitis referral centers when the T.R.U.E test fails to identify a relevant allergen.
Specifically, the T.R.U.E. test screens for 44 distinct allergens and the Balsam of Peru (myroxylon perierea) mixture. The test is thought to adequately identify an allergen in approximately 24.5% of patients with ACD.1 This being said, many relevant allergens are not detected by use of this screening tool alone and, for this reason, “Allergen Focus” has been expanded to cover the notorious Allergens of the Year and the North American Contact Dermatitis Standard Group (NACDG) Standard Allergens series. “Allergen Focus” is a column designed to concentrate on common allergens and is intended to answer some of the most frequent questions relating to their origin and most common uses.
This month, we highlight vitamin E, a naturally occurring family of eight antioxidants. This fat-soluble vitamin has been frequently used in topical medications and cosmeceuticals due to its antioxidant properties. Because of its rising popularity as a common ingredient in various over-the-counter preparations and cosmeceuticals, vitamin E is working its way up the ladder as an important contact allergen.
The contact dermatides include irritant contact dermatitis, contact urticaria, and ACD.
Irritant contact dermatitis, the most common form, accounts for approximately 80% of environmental-occupational based dermatoses.
Contact urticaria (wheal and flare reaction) represents an IgE and mast cell-mediated immediate-type hypersensitivity reaction that can lead to anaphylaxis, the foremost example of this would be latex protein hypersensitivity. While this will be discussed in relation to allergy to vitamin E, an in-depth discussion is beyond the scope of this section. Because this form of hypersensitivity reaction may be severe and potentially fatal, we direct the reader to key reference sources.2,3
Allergic contact dermatitis is an important disease with high impact both in terms of patient morbidity and economics. Allergic contact dermatitis represents a T-helper cell, Type 1 [Th1]-dependent, delayed-type (Type IV) hypersensitivity reaction. The instigating exogenous antigens are primarily small lipophilic chemicals (haptens) with a molecular weight less than 500 Daltons. On direct antigen exposure to the skin or mucosa, an immunologic cascade is initiated that includes cytokines (i.e., interleukin 2 [IL-2] and interferon gamma [IFN-g]), T cells and Langerhan cells. This complex interaction leads to the clinical picture of ACD.
A 32-year-old woman presented to the contact dermatitis evaluation clinic with an itchy vesicular dermatitis involving a mildly hypertrophic scar from a recent skin biopsy on her right thigh. She revealed that the scar had been itchy as it healed and had been spreading. She had bought vitamin E pills at the advice of her sister and had been applying pure vitamin E from the capsules twice daily to the scar and surrounding area. She did not notice improvement of the scar and noticed that the rash had appeared after she used the topical vitamin E for 6 weeks.
Discovery of Vitamin E
Vitamin E was discovered in 1922 at the University of California in Berkeley by Dr. Herbert Evans, a research physician, and his assistant, Katherine S. Bishop.4 They studied the effects of a special semi-purified diet on rats and found that while the diet supported normal growth, the females would resorb their fetuses. After supplementing the diets of the rats with lettuce and wheat germ, the two researchers observed that the rats were able to achieve healthy pups.
Evans and Bishop realized that there was a missing dietary factor resulting in these abortions. They initially decided to coin this unknown substance “Factor X.” Continuing their investigations, Evans and Bishop revealed that Factor X was a component of the lipid extract of lettuce.
At around the same time, Dr. Bennett Sure at the University of Arkansas independently observed that a missing factor in the diet of rats was causing sterility. He proposed the name “vitamin E” 1 year earlier than Evans.5 Because this compound allowed rats to have offspring, Evans proceeded to name it “tocopherol” from the Greek word “tocos,” meaning “offspring” and the word “phero” meaning “to provide a person with power.” The chemical ending “ol” indicated that it is an alcohol. It took several years before vitamin E was isolated from wheat germ and the chemical formula C29H50O2 was determined.6
Sources of Vitamin E
Vitamin E, in its various forms, is one of the most widely distributed vitamins. It is found in both animal and plant foods. Animal sources tend to be fairly poor in vitamin E, with the exception of liver, milk fat, butter, and egg yolk. The richest sources of vitamin E are found in vegetable oils such as palm oil, corn, sunflower, soybean, and olive oil. Whole grains, green leafy vegetables, nuts, sunflower seeds, kiwi and wheat germ are all excellent sources.7 The U.S. Dietary Reference Intake Recommended Daily Allowance for a 25-year-old male is 15 mg/day.
Physiologic Role of Vitamin E
Vitamin E is a generic term used to describe a family of eight fat-soluble antioxidants, four tocopherols and four tocotrienols. The tocopherols are further sub-classified as alpha-, beta-, gamma- and delta-tocopherol, and the tocotrienols are also sub-classified as alpha-, beta-, gamma- and delta-tocotrienol. Most of the literature examining vitamin E focuses on alpha-tocopherol, which is traditionally recognized as the most abundant of the eight forms in our bodies.7 Vitamin E contained in food is absorbed in the intestines and transported to the liver via chylomicrons. It is then incorporated into very low-density lipoproteins and transported throughout the body.6
Vitamin E has several physiologic roles, the first of which is to serve as an antioxidant by protecting unsaturated fatty acids, protein and DNA from oxidation. The antioxidant role of alpha-tocopherol is to scavenge lipid peroxyl radicals. This is a very important mechanism by which alpha-tocopherol arrests the chain of propagation that leads to cell membrane and low-density lipoprotein damage during oxidation.8 In addition, alpha-tocopherol serves as an inhibitor of protein kinase C, an important cell-signaling protein, a modulator of the activity of inflammatory cells, an inhibitor of platelet function, and an enhancer of vasodilation.7
Given its role in preventing free radical damage, alpha-tocopherol has been used to treat many different diseases. Numerous studies have shown that alpha-tocopherol consumption leads to a decreased risk of myocardial infarction or death from heart disease. Alpha-tocopherol has also been purported to prevent cataracts, slow the progression of Alzheimer’s disease, and decrease the rate of certain cancers, including prostate.7
Vitamin E As a Topical Therapy
In recent years, vitamin E has emerged as a popular treatment of numerous skin disorders owing to its antioxidant effects. Studies have shown that reactive oxygen species have the ability to alter the biosynthesis of collagen and glycosaminoglycans in skin.9
Most of the topical vitamin E preparations are in an ester form such as vitamin E acetate. These pro-drugs are then hydrolyzed to the active form of vitamin E (alpha-tocopherol) upon penetration of the skin. Other topical formulations include tocopherol linoleate, tocopherol nicotinate, tocopherol succinate, potassium ascorbyl tocopheryl phosphate, and tocophersolan.
Vitamin E has shown minimal efficacy in a limited number of conditions as demonstrated by double-blind controlled studies, some of which include yellow nail syndrome and melasma.10,11 Vitamin E has been used to treat other conditions for which there are mixed claims of its effectiveness. For example, the efficacy of vitamin E has been supported by a few case reports in the treatment of epidermolysis bullosa. Other studies showed no effect. Conflicting evidence exists on the role of vitamin E in the treatment of claudication and ulcers.10
One of the more popular applications of vitamin E is the treatment of burns, surgical scars and other wounds. However, studies looking at the efficacy of vitamin E in the treatment of burns and scars have been disappointing.
Baumann and Spencer studied the effects of cosmetic outcomes by treating Mohs post-surgical scars with topical vitamin E. Their study showed no benefit to the cosmetic outcome of scars by applying vitamin E after skin surgery, and 33% of the patients in the study developed contact dermatitis.12
Jenkins et al conducted a prospective randomized study designed to determine whether steroids or vitamin E applied topically would reduce scar formation when used during the early postoperative period following reconstructive procedures and found no benefit of vitamin E treatment. Instead, they actually observed that the patients’ scars spread.13 Current evidence in the literature does not support the proposition that vitamin E topically reduces scar formation.
Vitamin E has proven to be ineffective in cases of atopic dermatitis, psoriasis, dermatitis herpetiformis, subcorneal pustular dermatoses, porphyria, and erythema caused by UV exposure.10 In addition, there are many dermatologic conditions for which claims of vitamin E’s effectiveness have been made, but further studies are needed to support these claims. Some of these conditions include pityriasis rubra pilaris, Hailey-Hailey disease, acne vulgaris, and morphea.10
Beyond its role as a medication, vitamin E can also be found in many over-the-counter preparations, including bath products, deodorants, aftershave lotions, and makeup preparations. After many years of research on vitamin E, it is still unclear as to whether the millions of dollars worth of vitamin E products paid for by patients and consumers have been of benefit.10
Topical Vitamin E As an Allergen
Despite the ubiquity of vitamin E in various topical preparations, it is still considered a rare contact allergen in the patch testing literature. However, one recent study examining its effects in scar formation found that 33% of their patients had a “contact dermatitis.”12 In addition, an increasing number of case reports illustrate the role vitamin E plays as a contact allergen.
It is important to note that a contact dermatitis to vitamin E can present in different fashions. Vitamin E as a contact allergen can cause irritant contact dermatitis, including generalized eczema, urticaria and erythema multiforme.14
Saperstein reported two cases of erythema-multiforme-like eruptions and positive patch tests to dl-alpha-tocopherol in vitamin E oil and cream.15
Goldman and Rapaport described allergic contact dermatitis with positive patch tests to tocopheryl acetate in cosmetic creams.16 In Switzerland in 1992, there was an epidemic outbreak of approximately 1,000 cases of allergic papular and follicular contact dermatitis caused by tocopherol linoleate in a cosmetic line. The authors found that the compound was easily oxidized under suboptimal storing conditions, leading to secondary and tertiary oxidation products, which may or may not have caused the contact dermatitis.17
Parsad et al reported a case of a 30-year-old woman who was prescribed topical vitamin E by her physician for post-inflammatory hyperpigmentation and subsequently developed a contact dermatitis, which evolved into a xanthomatous reaction.18
Systemic side effects are rare, but the anecdotal reports of topical contact allergy to vitamin E have heightened our awareness of vitamin E as a potential contact allergen.
At this time, there is not a commercially available dl-alpha-tocopherol allergen. Patch testing with vitamin E as is, from the pill, is not ideal due to the potential skin irritation that is observed in some patients. Textbooks advise patch testing with dl-alpha-tocopherol at a concentration of 10% to 20% petrolatum. This can be compounded by mixing the commercially available dl-alpha-tocopherol with white petrolatum to the desired concentration. Patch testing to dl-alpha-tocopherol does not adequately evaluate any of the isomers or esters of tocopherol. The patient’s own vitamin E-containing product can also be tested as is, either as a repeat open application test, or applied as a patch test.
Value of This Patient Case
Vitamin E is a commonly used dietary supplement and important vitamin for human consumption. As a vitamin, it is a necessity in the diet. For topical use, vitamin E is a potential allergen. This case illustrates the most common scenario of a patient using vitamin E for its supposed improvements in the appearance of scars, but who actually ends up with an itchy rash and a worsened scar. Many topical products tout the benefits of the antioxidant properties of vitamin E. At least in the few studies that have been done, the risk of ACD and worsening of the appearance of scars seems real. These risks probably outweigh the perceived cosmetic improvements. Therefore topical vitamin E is not recommended for daily use for scars and may not be beneficial as an additive to other topical cosmetic or cosmeceutical products.
For information on the educational programs offered by the ACDS, see www.contactderm.org.