Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Clinics in Dermatology (2010) 28, 371–379 Nutrition and the deleterious side effects of nutritional supplements Marcia S. Driscoll, MD a,⁎, Eun-Kyung M. Kwon, BA a , Hadas Skupsky, BA a , Soon-You Kwon, MD a , Jane M. Grant-Kels, MD b a Department of Dermatology, University of Maryland School of Medicine, 419 W Redwood St, Ste 160, Baltimore, MD 21201, USA b Department of Dermatology, University of Connecticut Health Center, 21 South Rd, Farmington, CT 06030, USA Abstract The potential adverse effects associated with some of the more common oral vitamin supplements—vitamins A, D, and E and niacin (forms include nicotinic acid and nicotinamide), and mineral supplements—zinc, copper, and iron, used in dermatology are manifold. Although the dermatologist may be familiar with adverse effects of vitamins A and D, less well-known adverse effects, such as hematologic and neurologic effects from zinc, are presented. © 2010 Elsevier Inc. All rights reserved. Introduction The use of nutritional supplements to correct for nutritional deficiencies, prevent birth defects, and treat specific dermatologic conditions can undisputedly help many patients and improve quality of life; however, if one consumes supplements in amounts above the recommended dietary allowance (RDA), potentially severe adverse effects may occur. Multiple factors may enhance the risk for excessive intake of nutritional supplements, including easy accessibility and availability of supplements, patients' selfdiagnosis and treatment, and lack of knowledge of possible deleterious effects. Patients who observe improvement in a condition or symptom associated with a certain dose may choose to increase their daily intake. In dermatology, nutritional supplements are recommended for a wide variety of skin conditions and sometimes are co-prescribed with other medications (eg, folic acid with ⁎ Corresponding author. Tel.: +1 410 328 3167; fax: +1 410 328 1323. E-mail address: [email protected] (M.S. Driscoll). 0738-081X/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.clindermatol.2010.03.023 methotrexate). Specific nutrients are also included in the formulations of certain medications that are prescribed. This contribution presents an overview of the nutritional supplements most widely used in dermatology. We review their relevance to dermatology, how to monitor patients who have been prescribed these supplements, possible drug-drug interactions, RDAs when applicable, and potential adverse effects at therapeutic and toxic levels. We predominantly focus on oral supplements and, therefore, topical nutrients are only briefly discussed. Important information concerning selected vitamins and minerals are summarized in Table 1. Mineral supplements Zinc Zinc is a trace element used as a mineral supplement in the treatment of certain dermatologic conditions, including acrodermatitis enteropathica (AE), acquired bullous AE, necrolytic acral erythema, rosacea, and acne vulgaris. AE is a 372 Table 1 M.S. Driscoll et al. Summary of vitamin and mineral use and doses Nutrient Dermatologic conditions RDA UL Zinc Acrodermatitis enteropathica, necrolytic acral erythema Men: 11 mg/d; women: 8 mg/d Adults: 40 mg/d Copper Tissue formation and repair Children: 340 μg/d; adults: 900 μg/d Children: 1000 μg/d; adults: 10,000 μg/d Iron Alopecia Men: 8 mg/d; premenopausal women: 18 mg/d Adults: 45 mg/d Vitamin Phrynoderma, pityriasis rubra A pilaris, wound healing Men: 900 μg RAE/d (3000 IU/d); women: 700 μg RAE/d (2310 IU/d) Adults: 3000 μg/d (10,000 IU/d) Niacin Acne vulgaris, rosacea, necrobiosis lipoidica, dermatitis herpetiformis, bullous pemphigoid Vitamin Keratinocyte growth and D differentiation, acne, psoriasis, immune modulation Men: 16 mg/d; women: Adults: 35 mg/d 14 mg/d (pregnancy: 18 mg/d) Children: 5 μg/d (200 IU/d); adults: 5-15 μg/d (200-600 IU/d) Children: 50 μg/d (2000 IU/d); adults: 250 μg/d (10,000 IU/d) Vitamin Antioxidant, immune E modulation, reduction of erythema Adults: 15 mg/d (22.4 IU/d) Adults: 1000 mg/d (1500 IU/d) Adverse effects Hypocupremia, sideroblastic anemia, myelopathy, GI symptoms Weakness, lethargy, anorexia, GI symptoms, cirrhosis, cardiac and renal failure Constipation, dark stools, nausea, caution in pregnancy and liver disease Caution in liver disease and hemodialysis, pseudotumor cerebri, skeletal changes, teratogenic Flushing, GI symptoms, caution in liver disease, gout, diabetes Hypercalcemia, weakness, polyuria, anorexia, GI symptoms, metastatic calcification, renal failure Stomatitis, fatigue, thrombophlebitis, GI symptoms GI, gastrointestinal; RDA, recommended dietary allowance. UL, tolerable upper intake level; RAE, retinol activity equivalents. rare autosomal-recessive disorder that presents with diarrhea, alopecia, and a periorificial and acral dermatitis at the time of weaning from breast milk.1 The defect in AE causes inadequate absorption of zinc from the diet. Vesiculobullous, eczematous, and psoriasiform skin lesions are typical manifestations of the disorder.2 Acquired bullous AE can present at any age secondary to zinc deficiency and has similar clinical findings as AE.3 Necrolytic acral erythema may be associated with hepatitis C virus infection.4 Recent case reports have indicated the effective treatment of necrolytic acral erythema with oral zinc supplementation. Patients were treated with 210 to 220 mg of oral zinc sulfate twice daily, with resolution of plaques by 7 to 8 weeks.5-7 Zinc is also found in Nicomide (Sirius Laboratories, Inc. Vernon Hills, IL), which contains 750 mg nicotinamide, 25 mg zinc oxide, 1.5 mg cupric oxide, and 500 μg folic acid, and has been recommended for acne vulgaris and rosacea.8,9 In addition, zinc has been used for treatment of wounds, oral ulcers, and viral warts.10-12 According to the Institute of Medicine of the National Academy of Sciences, the RDA for zinc is 8 mg/d for women and 11 mg/d for men.13 The median intake of zinc from food in the United States of America is 9 mg/d for women and 14 mg/d for men. The tolerable upper intake level (UL), defined as the maximal daily intake unlikely to cause adverse health effects, is 40 mg/d for adults. Zinc was included in two studies, describing the effects of antioxidant supplementation on skin cancer risk.14,15 The Supplementation in Vitamins and Mineral Antioxidants (SUVIMAX) study examined the effects of nutritional doses of antioxidants on reducing cancer and ischemic heart disease risk in the general population.14 The SUVIMAX study randomized 7876 women and 5141 men who were supplemented with 120 mg of vitamin C, 30 mg of vitamin E, 6 mg of β-carotene, 100 μg of selenium, and 20 mg of zinc daily, or a matching placebo, and monitored for a median of 7.5 years. A fourfold higher risk of melanoma was reported in the women supplemented with antioxidants, but not in the men. The results of the recent large, population-based prospective cohort study, the Vitamins and Lifestyle (VITAL) study, were inconsistent with the SUVIMAX study.15 In the VITAL study, 69,671 men and women reported their intake of multivitamins and supplemental antioxidants during the previous 10 years and were evaluated for melanoma risk factors based on a questionnaire. The results showed no increase in melanoma risk in men and women who took vitamin C, vitamin E, β-carotene, selenium, and zinc supplementation in doses similar to the SUVIMAX study. The authors emphasized that the SUVIMAX study had methodologic flaws that may have accounted for the enhanced risk of melanoma in women associated with antioxidant supplementation. Deleterious side effects of nutritional supplements Chronic toxic effects of zinc have been reported in patients who consume well beyond the UL of 40 mg/d. Case reports describe acne patients self-medicating with zinc at doses ranging from 300 up to 1000 mg/d for 1 to 2 years.16-18 These patients were found to have hypocupremia, anemia, sideroblastic anemia, neutropenia, and leukopenia. The most likely mechanism for zinc-induced copper deficiency can be explained by the competitive absorption between zinc and copper in enterocytes of the small intestine. Metallothionein is a protein that binds both zinc and copper, with a higher affinity for copper. Excess zinc intake stimulates the production of metallothionein. Enterocytes are then shed, causing the excess zinc bound to metallothionein to be excreted. Copper, however, has a higher affinity for metallothionein, so it displaces zinc and is subsequently excreted, leading to hypocupremia. Copper as a ceruloplasmin is important for enzymatic reactions in red blood cells for iron transport and utilization. Because iron is needed for hemoglobin synthesis, copper deficiency would subsequently cause anemia. Several cases of zinc-induced copper deficiency have been described. A patient diagnosed with AE was prescribed a daily dose of 50 to 150 mg of zinc, but he took approximately 600 mg/d to “control his symptoms.” Hematologic monitoring and bone marrow biopsy revealed neutropenia and anemia with vacuolization of granulocytic and erythroid precursors and the presence of ringed sideroblasts.2 Sideroblastic anemia and neutropenia developed in a 19-year-old woman with Hallervorden-Spatz syndrome who took 50 mg of zinc twice daily for 5 years.19 In addition to hematologic syndromes, neurologic adverse effects due to zinc excess have also been reported. Myelopathy and demyelination has been associated with zinc-induced copper deficiency. 20-22 A 52-year-old woman presented with myelopathy with spastic paraparesis and dorsal column loss manifest by a generalized lower motor neuron deficit with atrophy and paralysis of muscles below the knee and weakness of the proximal legs and distal hand muscles.22 The patient's serum copper was less than 200 μg/L and her serum zinc was 2108 μg/L (normal, 58-1060 μg/L), with a 24-hour urine zinc excretion level of 19,290 μg/d (normal, 75-530 μg/d). These levels suggested that she ingested or was exposed to 50 to 200 mg of zinc daily, an amount of zinc well above the average daily intake of 10 to 15 mg. Therapy with 2.5 mg/d of oral copper improved the patient's anemia and neutropenia. The neurologic symptoms persisted 1 year later, however, along with enhanced levels of urine zinc excretion. The authors concluded that the zinc-induced copper deficiency was the probable cause of the patient's neurologic abnormalities. Another study reported four additional patients who experienced numbness, weakness, spastic gait, ataxia, and significant dorsal column deficits secondary to hyperzincemia and hypocupremia due to inadvertent ingestion of denture cream.23 373 Clinical signs and symptoms of acute zinc toxicity include epigastric pain, diarrhea, nausea, vomiting, and dizziness.17 Among the other deleterious side effects are gastric erosion, proconvulsant effects, tumor growth, and genitourinary complications.17,24-27 Copper Copper is a component of several vital metalloenzymes, including tyrosinase, that function in melanin production. Beyond melanin pigmentation, copper is also essential for the production of mature collagen and elastin.28 Copper has a stimulating effect on the proliferation of keratinocytes and fibroblasts in monolayers, has a vital role in the activation of key enzyme systems specific to tissue formation and repair, and participates in the cross-linking and maturation of collagen in healing wounds.29-31 In addition, copper has antimicrobial and anti-inflammatory properties that have led to the use of topical preparations to enhance wound healing. The RDA for copper is 340 μg/d for young children and rises to 900 μg/d for adults. The UL is 1000 μg/d in young children and 10,000 μg/d for adults.13 Chronic copper toxicity primarily affects the liver and may lead to hepatocellular necrosis as well as damage to renal tubules, the brain, and other organs. Symptoms can progress to coma, hepatic necrosis, vascular collapse, and death.32 Acute copper poisoning causes gastrointestinal symptoms, including abdominal pain, diarrhea, and vomiting, along with weakness, lethargy, and anorexia in the early stages. Subsequent erosion of the epithelial lining of the gastrointestinal tract, hepatocellular necrosis, and acute tubular necrosis in the kidney may occur. In more severe overdosage, progressive cardiac, liver, and renal failure, encephalopathy, and ultimately, death may ensue. The estimated lethal dose of copper in an untreated adult is about 10 to 20 g.33 Several mechanisms have been proposed to explain copper-induced cellular toxicity. The propensity of free copper ions to participate in the formation of reactive oxygen species is the most likely etiology.33 No correlation was found between plasma copper concentrations and prognosis.34 Although serum ceruloplasmin levels rise in patients with acute copper toxicity due to increased hepatic synthesis as an acute-phase reactant, the ceruloplasmin level cannot be used to predict toxicity.35 Therefore, clinical monitoring of the patient is vital when there is a suspicion of copper overdosage. Iron Iron deficiency has been associated with hair loss as in alopecia areata, androgenetic alopecia, and telogen effluvium.36-38 Some patients with pruritus may have abnormal iron or ferritin levels, or both, and restoration to normal levels of serum ferritin with iron supplementation may lead to improvement.39 The RDA for iron is 8 mg/d for 374 men and postmenopausal women and 18 mg/d for premenopausal women.13 The UL is 45 mg/d of iron for adults. Various complications associated with iron supplementation have been reported. Gastrointestinal side effects of excess iron include constipation, dark stools, and nausea. Oral liquid forms of iron supplementation may cause teeth stains. Excess iron supplementation may also cause pregnant women to have an increased risk for hypertension and newborns with low birth weight.40 In a randomized, doubleblinded, placebo-controlled study, 370 pregnant women with a hemoglobin level of 13.2 g/dL or higher during the second trimester ingested one 50-mg tablet of elemental iron daily and were compared with 357 controls. The study group had a greater incidence of hypertension during pregnancy, and newborns considered small for gestational age compared with controls.40 Some have questioned this study and suggested assessing hematic ferritin concentrations rather than iron status using hemoglobin concentration.41 Another potential adverse effect of iron supplementation is an increased risk of type 2 diabetes mellitus in women.42 Iron can also potentially interact with other minerals, such as copper and zinc, resulting in decreased serum copper and zinc levels.43 Finally, dermatologists should be cautious when prescribing iron supplementation for patients with liver diseases and hemochromatosis. Iron accumulation can cause cirrhosis of the liver and hepatocellular carcinoma in HFE-related hemochromatosis.44 HFE-related hereditary hemochromatosis is an inherited iron overload disorder in which patients are homozygous for the C282Y mutation in the HFE gene.45 These patients have increased levels of serum ferritin and transferrin saturation and, therefore, iron supplementation should be avoided.46 Vitamin supplements Vitamin A Dermatologic conditions for which vitamin A supplementation has been indicated include phrynoderma, pityriasis rubra pilaris, and wound healing. Phrynoderma is a form of follicular hyperkeratosis associated with nutritional deficiency. These lesions have been shown to resolve after treatment with vitamin A.47-50 Before the introduction of retinoids, vitamin A was used as therapy for pityriasis rubra pilaris.51,52 The antioxidant effects of vitamin A have made it efficacious as a topical application in the treatment of photoaging, inflammatory dermatoses, acne vulgaris, pigmentation disorders, and wound healing in combination with other antioxidants.53 The RDA for vitamin A is 900 μg retinol activity equivalents (RAE)/d for men and 700 μg RAE/d for women.13 The UL for preformed vitamin A is 3,000 μg/d for adults. Acute hypervitaminosis A occurs at greater than 500,000 IU (100× RDA). Hepatitis and dialysis patients are M.S. Driscoll et al. at increased risk for vitamin A toxicity with doses as low as 25,000 IU/d. Patients have been reported to overdose on vitamin A supplements prescribed for dermatologic disorders in the past, particularly in the early 1970s. Ready availability of vitamins and publicity about vitamin A for the treatment and prevention of acne vulgaris, aging skin, skin cancers, and other dermatologic conditions has led to patients' selfmedicating and overdosing.54 In recent years, the dermatologist who prescribes systemic retinoids must also ask patients about their vitamin intake. Avoidance of supplemental vitamin A during treatment with retinoids is important to minimize the incidence and severity of adverse effects. Deleterious side effects associated with vitamin A toxicity vary according to whether the patient ingested an extremely high dose of vitamin A (N5× RDA) in a short period (2 to 3 weeks; ie, acute hypervitaminosis A), or continuously for a longer period (months to years; ie, chronic hypervitaminosis A). In acute hypervitaminosis A, infants may present with bulging fontanels and adults may present with headaches secondary to increased intracranial pressure. Nausea, vomiting, fever, vertigo, visual disorientation, and desquamation of the skin may occur.55 Once excess vitamin A intake is discontinued, levels return to normal and the symptoms, for the most part, resolve.54 A variety of systemic and cutaneous manifestations are associated with chronic hypervitaminosis A. Many of these are well known to dermatologists who prescribe systemic retinoids. Systemic adverse effects include anorexia, increased intracranial pressure, hepatomegaly (children), pseudotumor cerebri, fatigue, menstrual disturbances in women, and elevated blood lipid levels. In children, hepatomegaly and bone changes associated with pain and tenderness can occur. Vitamin A has also been shown to cause anxiety and depression in humans and animal models.54,55 One possible mechanism for psychologic effects is the elevation in caspase3 activity in rat cerebral cortex reported after 28 days of vitamin A supplementation at 1000 to 9000 IU/kg/d .56 Hypervitaminosis A has been observed to induce bone resorption, hypercalcemia, bone abnormalities, low bone density, osteoporosis, and increased fracture risk. 57-60 Serum levels of retinol greater than 86 μg/dL may increase the risk of fracture.59 Chronic vitamin A intake may also lead to hypercalcemia, which can also potentially lead to osteoporosis.61 Another deleterious effect of hypervitaminosis A is hepatotoxicity. The liver contains 50% to 80% of the body's total vitamin A stores, and 90% of the total vitamin A stores in the liver are transferred to and reside within hepatic stellate cells.62 Vitamin A activation causes the hepatic stellate cells to acquire a myofibroblast-like phenotype and produce a large amount of extracellular matrix. An association has been shown between daily vitamin A intake and severity of perisinusoidal fibrosis.63 Deleterious side effects of nutritional supplements Teratogenicity associated with systemic retinoids as well as with hypervitaminosis A in pregnant women is well established.64,65 Birth defects associated with hypervitaminosis A include an increased risk of abnormalities in a wide range of organ systems, including musculoskeletal, craniofacial, central nervous system, thymic, cardiac, neural tube, urogenital, and gastrointestinal.66 Some of the common cutaneous signs and symptoms of chronic vitamin A toxicity include alopecia, desquamation, erythema and exanthems of skin, brittle nails, cheilitis, petechiae, and pruritus.54,55,67 Niacin Nicotinic acid and nicotinamide are the two common forms of the vitamin most often referred to as niacin. Through a series of biochemical reactions in the mitochondria, niacin, nicotinamide, and tryptophan form nicotinamide adenine dinucleotide (NAD) and NAD phosphate (NADP). NAD and NADP are the active forms of niacin. As essential components of oxidation-reduction reactions and hydrogen transport, NAD and NADP are crucial in the synthesis and metabolism of carbohydrates, fatty acids, and proteins.28 In moderate to high doses (1 to 3 g/d) niacin is a wellestablished antihyperlipidemic agent, decreasing total and low-density lipoprotein cholesterol.68 A deficiency of this vitamin manifests clinically as pellagra, with the triad of diarrhea, dermatitis, and dementia. The dermatitis manifests as a photodistributed hyperpigmented skin eruption.28 Nicotinamide has several therapeutic uses in dermatology. It has been used for acne vulgaris as an alternative to antimicrobial agents because of its anti-inflammatory properties without promotion of antimicrobial resistance. One study found topically applied 4% nicotinamide gel was equivalent in efficacy to 1% clindamycin gel in patients with moderate inflammatory acne vulgaris.69 Nicotinamide has also been used systemically for the treatment of other cutaneous disorders, including necrobiosis lipoidica and dermatitis herpetiformis.70-72 The combination of nicotinamide (500 mg three times daily) and tetracycline (500 mg four times daily) has been promoted as an alternative to systemic steroids in the treatment of bullous pemphigoid.73 Together these agents may act by inhibiting the chemotaxis of eosinophils and neutrophils in pemphigoid. Nicotinamide may also act by electron scavenging, inhibiting the release of proteases from granulocytes, and blocking degranulation of mast cells and their release of histamine.70,73,74 The vasodilatory action of nicotinamide has been used therapeutically in peripheral vascular disorders such as Raynaud syndrome.75 The RDA for niacin is 16 mg/d for men and 14 mg/d for women, rising to 18 mg/d during pregnancy and 17 mg/d during lactation.76 These doses are far below the antihyperlipidemic doses of niacin and are not associated with toxicity. The risks associated with a daily dose exceeding 1 gram of nicotinic acid may be tolerable when it is used as an 375 antihyperlipidemic drug under the care and monitoring of a physician. Higher doses of nicotinic acid for the treatment of dermatologic conditions should be reserved for recalcitrant disease, and patients must be cautioned against unsupervised use. The most common adverse effect of niacin is a flushing reaction associated with the crystalline nicotinic acid. Mild flushing can be experienced even when doses are as small as 10 mg/d. Despite the patient's concern about this reaction, there are no serious sequelae from flushing.77 In pharmacologic doses (1 to 3 g/d), other common adverse effects of niacin in addition to flushing include nausea, vomiting, pruritus, urticaria, elevation in serum aminotransferases, and constipation.78 A niacin-induced myopathy has also been described.79 Caution should be used in patients with a history of gout, because niacin is also known to elevate serum uric acid concentration.80 Although most reported adverse reactions to niacin have occurred with ingestion of 2 to 6 g/d,81 nicotinic acid toxicity has been reported with less than 1 g/d.82 A long-acting vs short-acting formula of niacin was studied in two groups of participants, with each group starting at 500 mg/d. When the niacin dose was raised every 6 weeks by about 500 mg, there was no gastrointestinal or liver toxicity at doses below 1000 mg/d. The extent of the toxicity was minimal and mostly gastrointestinal in the immediate-release group, whereas mild liver enzyme elevation was noticed only in the slowrelease niacin group.83 Nicotinamide usually lacks the vasodilatory, gastrointestinal, hepatic, and hypolipemic effects described for nicotinic acid and niacin. Flushing, gastrointestinal upset, pruritus, and hepatotoxicity are not typically associated with nicotinamide administration at doses usually prescribed by dermatologists (750 to 1500 mg/d). At higher doses, however, adverse effects similar to nicotinic acid and niacin may occur. Vitamin D The biologically active vitamin D metabolite, 1,25dihydroxyvitamin D3 (1,25(OH)2D3), regulates calcium and bone metabolism. Skin is the only site of vitamin D photosynthesis, and plays a key role in attaining sufficient vitamin D levels. In keratinocytes and other cell types, 1,25 (OH)2D3 regulates growth and differentiation.84 Consequently, vitamin D analogues have been introduced for the treatment of the hyperproliferative skin diseases, such as psoriasis.85 Recent identification of sebocytes as 1,25(OH) 2D3-responsive target cells suggests a potential role for vitamin D analogues in the treatment of acne.86 Additional emerging functions of vitamin D analogues include immune modulation, and protection against cancer and autoimmune and infectious diseases.84 Evidence is accumulating that the vitamin D pathway may play a chemoprotective role in melanoma.87 Epidemiologic studies of the association of vitamin D and melanoma risk have 376 shown conflicting results, however.88-90 In the recent VITAL study, the risk of melanoma was not affected by Vitamin D supplementation. 91 As a fat-soluble vitamin, vitamin D can be toxic in excess doses. Vitamin D intoxication is characterized by hypercalcemia and the resultant loss of appetite, nausea, weight loss, weakness, polyuria, polydipsia, mental depression, and calcific keratitis. Metastatic calcification can be seen in the skin as calcinosis cutis. Generalized calcinosis can ensue.28 Renal calcification can lead to kidney failure and death. The intake at which the dose of vitamin D becomes toxic is not clear. Previous data suggested that the UL for vitamin D is 50 μg/d (2000 IU/d) for healthy adults, children 1 to 18 years, and pregnant and lactating women92; however, newer data indicates that higher doses may be safe. An analysis of the vitamin D intoxication literature and the recent controlled dosing studies show that essentially no cases of confirmed intoxication have been reported at serum 25(OH)D levels below 500 nmol/L.93 Correspondingly, the oral intake needed to produce such levels are in excess of 20,000 IU/d (and usually above 50,000 IU/d) in otherwise healthy adults.94 These findings have led some to select 10,000 IU/d as the tolerable UL.93 A higher intake could probably be defended, but 10,000 IU/d is substantially more than is apparently needed for any recognized efficacy end point.94 It is noteworthy that one minimum erythema dose of total body solar exposure, such as might be achieved in a few minutes on a summer day, produces a vitamin D input in the range of 10,000 to 20,000 IU, depending upon skin type.95,96 Despite such cutaneous synthesis, there has never been a case of vitamin D intoxication reported as a result of sun exposure.96 Patients with systemic sarcoidosis, mycobacterial infections, and those treated with thiazide diuretics are reported to have increased sensitivity to excessive vitamin D.97-99 Vitamin E Vitamin E is a family of eight antioxidants derived from tocopherols and tocotrienols. The main form of vitamin E in human tissues is α-tocopherol, which functions as the main lipid-soluble, membrane-preserving antioxidant. Additional functions of vitamin E include immune modulation, inhibition of platelet aggregation, and vasodilatation.100 Vitamin E is a commonly used supplement, taken daily, usually as 400 IU α-tocopherol, by 22% of American adults aged older than 55 years. In human skin, vitamin E is the predominant physiologic barrier antioxidant.101 Vitamin E and synergistic antioxidants such as vitamin C are commonly added to sunscreens to enhance photoprotection.102 Several studies have demonstrated a reduction in erythema, edema, and sunburn cell formation with topical vitamin E application before ultraviolet light exposure.103 Pure topical vitamin E has an emollient effect on the skin and is thought to enhance barrier function.104 Topical vitamin E M.S. Driscoll et al. preparations have been promoted to prevent scar formation, presumably due to inhibition of collagen synthesis and reduction of fibroblast proliferation and inflammation.105,106 In vivo studies of topical vitamin E, however, have yielded conflicting results with respect to the prevention and treatment of scars.104,106,107 Use of topical vitamin E for the enhancement of wound healing is supported by evidence from studies on diabetic mouse models.108,109 A significant improvement of melasma and hyperpigmentation secondary to contact dermatitis was reported with a combination of topical vitamins E and C in a double-blinded controlled study. The combination of these topical antioxidants was superior to treatment with a single vitamin.110 Although numerous topical skin care products claim to contain vitamin E, the formulations can include active vitamin E as well as several esters and other derivatives in various concentrations and vehicles. Dose-response studies defining the optimal dosage of vitamin E are lacking. One recent study found that topical formulations containing 0.1% to 1% α-tocopherol are likely to be effective for enhancing protection against lipid peroxidation in the stratum corneum.111 Vitamin E esters, such as vitamin E acetate, are commonly present in over-the-counter topicals for improved shelf life, but their photoprotective effects appear to be less pronounced than α-tocopherol.112 Vitamin E esters act as a prodrug and are converted to the active α-tocopherol upon penetration into the stratum corneum. The extent to which this conversion takes place is controversial.113 Clinical side effects have been described with the use topicals containing vitamin E, including local and generalized contact dermatitis, contact urticaria, and eruptions resembling erythema multiforme.112 In 1992, approximately 1000 cases of allergic contact dermatitis were attributed to αtocopherol linoleate in a Swiss cosmetic line.114 Therefore, it would be prudent to avoid topical vitamin E in patients who have recently undergone dermabrasion or chemical peels. Because vitamin E is now ubiquitous in over-the-counter topical preparations, and use is widespread, it is fortunate that the adverse effects of topical vitamin E are minimal. There are a few reported uses of systemic vitamin E in dermatology. Systemic vitamin E for melasma has shown some benefit, although studies are limited to combination therapies. A recent double-blinded, placebo-controlled trial of oral procyanidin with vitamins A, C, and E reported this regimen was safe and effective for the treatment of melasma among Filipino women. 115 Small trials and case reports support the use of systemic vitamin E supplementation in the treatment of yellow-nail syndrome, vibration disease, epidermolysis bullosa, cancer prevention, claudication, cutaneous ulcers, and wound healing.116 Oral vitamin E has also been shown to be an effective therapeutic adjunct for atopic dermatitis. In a placebo-controlled study of 96 atopic dermatitis patients, oral supplementation with 400 IU/d for 8 months resulted in a 62% decrease in serum immunoglobulin E and near-remission of atopic dermatitis in the treatment group.117 Deleterious side effects of nutritional supplements Evidence for the contribution of oxidative stress in the pathogenesis of melanoma and nonmelanoma skin cancer has led to speculation that antioxidants, such as vitamin E, may have a role in the prevention and treatment of malignancy.118 Despite these and other promising results, well-designed controlled trials are sparse, and further research is needed to clarify the role of vitamin E in dermatologic diseases. The RDA of oral vitamin E is 15 mg/d with a UL of 1000 mg/d, although recent literature suggests that this UL may be too high.119 An important change in the paradigm since the early trials of antioxidant supplements is that highdose oral antioxidants can no longer be assumed to be safe. This was an unexpected outcome in the Alpha-Tocopherol Beta-Carotene Trial, and subsequent trials have confirmed this finding.119,120 A meta-analysis of 19 randomized controlled trials involving more than 135,000 participants showed that high-dose oral supplementation with vitamin E (N400 IU/d for N1 year) resulted in a small but statistically significant increase in all-cause mortality.121 In 10 of the 19 studies analyzed, vitamin E was included with other nutritional supplements, thereby limiting conclusions concerning the effects of this nutrient alone. Subsequent studies, however, have consistently shown that large doses of vitamin E should be prescribed with caution. 122,123 Concomitant use of vitamin E and anticoagulants can increase the risk of bleeding complications.124 Excess intake of vitamin E supplements can result in thrombophlebitis, pulmonary embolism, hypertension, fatigue, gastrointestinal effects, and gynecomastia. Dermatologic manifestations of hypervitaminosis E include stomatitis, cheilitis, urticaria, and impaired wound healing.28 The plasma concentration of αtocopherol (normal, 6-14 μg/mL) can be measured to confirm excess levels of vitamin E in the blood. Conclusions Supplements of minerals and vitamins may enhance health, improve some cutaneous diseases, and result in a sense of well-being. They are often believed to be benign because they are readily available without prescription; however, deleterious side effects have been reported with these supplements. It is prudent for physicians to be aware of the supplements' recommended dietary allowance, upper limits, and acute and chronic manifestations of excess intake. References 1. Heath ML, Sidbury R. Cutaneous manifestations of nutritional deficiency. Curr Opin Pediatr 2006;18:417-22. 2. Willis MS, Monaghan SA, Miller ML, et al. Zinc-induced copper deficiency: a report of three cases initially recognized on bone marrow examination. Am J Clin Pathol 2005;123:125-31. 377 3. Lee WJ, Kang SM, Won JH, et al. Vesiculobullous lesions on the dorsum of the foot—quiz case. Arch Dermatol 2009;145:829-34. 4. el Darouti M, Abu el Ela M. Necrolytic acral erythema: a cutaneous marker of viral hepatitis C. Int J Dermatol 1996;35:252-6. 5. Abdallah MA, Hull C, Horn TD. Necrolytic acral erythema: a patient from the United States successfully treated with oral zinc. Arch Dermatol 2005;141:85-7. 6. de Carvalho Fantini B, Matsumoto FY, Arnone M, Sotto MN, Junior WB. Necrolytic acral erythema successfully treated with oral zinc. Int J Dermatol 2008;47:872-3. 7. Khanna VJ, Shieh S, Benjamin J, et al. Necrolytic acral erythema associated with hepatitis C: effective treatment with interferon alfa and zinc. Arch Dermatol 2000;136:755-7. 8. Niren NM, Torok HM. The Nicomide Improvement in Clinical Outcomes Study (NICOS): results of an 8-week trial. Cutis 2006;77 (1 suppl):17-28. 9. Sharquie KE, Najim RA, Al-Salman HN. Oral zinc sulfate in the treatment of rosacea: a double-blind, placebo-controlled study. Int J Dermatol 2006;45:857-61. 10. Merchant HW, Gangarosa LP, Glassman AB, Sobel RE. Zinc sulfate supplementation for treatment of recurring oral ulcers. South Med J 1977;70:559-61. 11. Al-Gurairi FT, Al-Waiz M, Sharquie KE. Oral zinc sulphate in the treatment of recalcitrant viral warts: randomized placebo-controlled clinical trial. Br J Dermatol 2002;146:423-31. 12. Yaghoobi R, Sadighha A, Baktash D. Evaluation of oral zinc sulfate effect on recalcitrant multiple viral warts: a randomized placebocontrolled clinical trial. J Am Acad Dermatol 2009;60:706-8. 13. Food and Nutrition Board of the Institute of Medicine. Dietary reference intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc 2000. Available at: http://www.nap.org. Accessed: Nov 16, 2009. 14. Hercberg S, Ezzedine K, Guinot C, et al. Antioxidant supplementation increases the risk of skin cancers in women but not in men. J Nutr 2007;137:2098-105. 15. Asgari MM, Maruti SS, Kushi LH, White E. Antioxidant supplementation and risk of incident melanomas: results of a large prospective cohort study. Arch Dermatol 2009;145:879-82. 16. Igic PG, Lee E, Harper W, Roach KW. Toxic effects associated with consumption of zinc. Mayo Clin Proc 2002;77:713-6. 17. Porea TJ, Belmont JW, Mahoney Jr DH. Zinc-induced anemia and neutropenia in an adolescent. J Pediatr 2000;136:688-90. 18. Salzman MB, Smith EM, Koo C. Excessive oral zinc supplementation. J Pediatr Hematol Oncol 2002;24:582-4. 19. Irving JA, Mattman A, Lockitch G, Farrell K, Wadsworth LD. Element of caution: a case of reversible cytopenias associated with excessive zinc supplementation. CMAJ 2003;169:129-31. 20. Greenberg SA, Briemberg HR. A neurological and hematological syndrome associated with zinc excess and copper deficiency. J Neurol 2004;251:111-4. 21. Kumar N, Gross Jr JB, Ahlskog JE. Myelopathy due to copper deficiency. Neurology 2003;61:273-4. 22. Prodan CI, Holland NR, Wisdom PJ, Burstein SA, Bottomley SS. CNS demyelination associated with copper deficiency and hyperzincemia. Neurology 2002;59:1453-6. 23. Nations SP, Boyer PJ, Love LA, et al. Denture cream: an unusual source of excess zinc, leading to hypocupremia and neurologic disease. Neurology 2008;71:639-43. 24. Johnson AR, Munoz A, Gottlieb JL, Jarrard DF. High dose zinc increases hospital admissions due to genitourinary complications. J Urol 2007;177:639-43. 25. Haase H, Overbeck S, Rink L. Zinc supplementation for the treatment or prevention of disease: current status and future perspectives. Exp Gerontol 2008;43:394-408. 26. Green AL, Weaver DF. Potential proconvulsant effects of oral zinc supplementation: a case report. Neurotoxicology 2008;29:476-7. 378 27. Schrauzer GN. Antioxidant supplementation increases skin cancer risk, or, why zinc should not be considered an antioxidant. J Nutr 2008;138:820 author reply 821-2. 28. Ryan AS, Goldsmith LA. Nutrition and the skin. Clin Dermatol 1996; 14:389-406. 29. Tenaud I, Sainte-Marie I, Jumbou O, Litoux P, Dreno B. In vitro modulation of keratinocyte wound healing integrins by zinc, copper and manganese. Br J Dermatol 1999;140:26-34. 30. Agren MS. Studies on zinc in wound healing. Acta Derm Venereol Suppl (Stockh) 1990;154:1-36. 31. Cangul IT, Gul NY, Topal A, Yilmaz R. Evaluation of the effects of topical tripeptide-copper complex and zinc oxide on open-wound healing in rabbits. Vet Dermatol 2006;17:417. 32. Winge DR, Mehra RK. Host defenses against copper toxicity. Int Rev Exp Pathol 1990;31:47-83. 33. Gaetke LM, Chow CK. Copper toxicity, oxidative stress, and antioxidant nutrients. Toxicology 2003;189:147-63. 34. Wahal PK, Mehrotra MP, Kishore B, et al. Study of whole blood, red cell and plasma copper levels in acute copper sulphate poisoning and their relationship with complications and prognosis. J Assoc Physicians India 1976 Mar;24:153-8. 35. Saravu K, Jose J, Bhat M, Jimmy B, Shastry B. Acute ingestion of copper sulphate: A review on its clinical manifestations and management. Indian J Crit Care Med 2007;11:74. 36. Deloche C, Bastien P, Chadoutaud S, et al. Low iron stores: a risk factor for excessive hair loss in non-menopausal women. Eur J Dermatol 2007;17:507-12. 37. Kantor J, Kessler LJ, Brooks DG, Cotsarelis G. Decreased serum ferritin is associated with alopecia in women. J Invest Dermatol 2003; 121:985-8. 38. Trost LB, Bergfeld WF, Calogeras E. The diagnosis and treatment of iron deficiency and its potential relationship to hair loss. J Am Acad Dermatol 2006;54:824-44. 39. Bharati A, Yesudian PD. Positivity of iron studies in pruritus of unknown origin. J Eur Acad Dermatol Venereol 2008;22:617-8. 40. Ziaei S, Norrozi M, Faghihzadeh S, Jafarbegloo E. A randomised placebo-controlled trial to determine the effect of iron supplementation on pregnancy outcome in pregnant women with haemoglobin N or = 13.2 g/dl. BJOG 2007;114:684-8. 41. Giorlandino C, Cignini P. Iron supplementation in non-anaemic women did not improve pregnancy outcomes and may be harmful to both mother and baby. Arch Dis Child Educ Pract Ed 2009;94:94. 42. Rajpathak S, Ma J, Manson J, Willett WC, Hu FB. Iron intake and the risk of type 2 diabetes in women: a prospective cohort study. Diabetes Care 2006;29:1370-6. 43. Ziaei S, Janghorban R, Shariatdoust S, Faghihzadeh S. The effects of iron supplementation on serum copper and zinc levels in pregnant women with high-normal hemoglobin. Int J Gynaecol Obstet 2008; 100:133-5. 44. Adams PC. The natural history of untreated HFE-related hemochromatosis. Acta Haematol 2009;122:134-9. 45. Alexander J, Kowdley KV. HFE-associated hereditary hemochromatosis. Genet Med 2009;11:307-13. 46. Allen KJ, Gurrin LC, Constantine CC, et al. Iron-overload-related disease in HFE hereditary hemochromatosis. N Engl J Med 2008;358: 221-30. 47. Armstrong AW, Setyadi HG, Liu V, Strasswimmer J. Follicular eruption on arms and legs. Phrynoderma. Arch Dermatol 2008;144:1509-14. 48. Bleasel NR, Stapleton KM, Lee MS, Sullivan J. Vitamin A deficiency phrynoderma: due to malabsorption and inadequate diet. J Am Acad Dermatol 1999;41:322-4. 49. Girard C, Dereure O, Blatiere V, Guillot B, Bessis D. Vitamin a deficiency phrynoderma associated with chronic giardiasis. Pediatr Dermatol 2006;23:346-9. 50. Neill SM, Pembroke AC, du Vivier AW, Salisbury JR. Phrynoderma and perforating folliculitis due to vitamin A deficiency in a diabetic. J R Soc Med 1988;81:171-2. M.S. Driscoll et al. 51. Cohen PR, Prystowsky JH. Pityriasis rubra pilaris: a review of diagnosis and treatment. J Am Acad Dermatol 1989;20:801-7. 52. Randle HW, Diaz-Perez JL, Winkelmann RK. Toxic doses of vitamin A for pityriasis rubra pilaris. Arch Dermatol 1980;116:888-92. 53. Burgess C. Topical vitamins. J Drugs Dermatol 2008;7(7 suppl):S2-6. 54. Bendich A, Langseth L. Safety of vitamin A. Am J Clin Nutr 1989;49: 358-71. 55. Myhre AM, Carlsen MH, Bohn SK, Wold HL, Laake P, Blomhoff R. Water-miscible, emulsified, and solid forms of retinol supplements are more toxic than oil-based preparations. Am J Clin Nutr 2003;78:1152-9. 56. de Oliveira MR, Oliveira MW, Moreira JC. Pharmacological doses of vitamin A increase caspase-3 activity selectively in cerebral cortex. Fundam Clin Pharmacol 2009, doi:10.1111/j.1472-8206.2009.00789.x [published online]. 57. Feskanich D, Singh V, Willett WC, Colditz GA. Vitamin A intake and hip fractures among postmenopausal women. JAMA 2002;287:47-54. 58. Melhus H, Michaelsson K, Kindmark A, et al. Excessive dietary intake of vitamin A is associated with reduced bone mineral density and increased risk for hip fracture. Ann Intern Med 1998;129:770-8. 59. Michaelsson K, Lithell H, Vessby B, Melhus H. Serum retinol levels and the risk of fracture. N Engl J Med 2003;348:287-94. 60. Penniston KL, Tanumihardjo SA. The acute and chronic toxic effects of vitamin A. Am J Clin Nutr 2006;83:191-201. 61. Frame B, Jackson CE, Reynolds WA, Umphrey JE. Hypercalcemia and skeletal effects in chronic hypervitaminosis A. Ann Intern Med 1974;80: 44-8. 62. Cheruvattath R, Orrego M, Gautam M, et al. Vitamin A toxicity: when one a day doesn't keep the doctor away. Liver Transpl 2006;12:1888-91. 63. Nollevaux MC, Guiot Y, Horsmans Y, et al. Hypervitaminosis Ainduced liver fibrosis: stellate cell activation and daily dose consumption. Liver Int 2006;26:182-6. 64. Geelen JA. Hypervitaminosis A induced teratogenesis. CRC Crit Rev Toxicol 1979;6:351-75. 65. Underwood BA. Teratogenicity of vitamin A. Int J Vitam Nutr Res Suppl 1989;30:42-55. 66. Rothman KJ, Moore LL, Singer MR, Nguyen US, Mannino S, Milunsky A. Teratogenicity of high vitamin A intake. N Engl J Med 1995;333: 1369-73. 67. Hathcock JN, Hattan DG, Jenkins MY, McDonald JT, Sundaresan PR, Wilkening VL. Evaluation of vitamin A toxicity. Am J Clin Nutr 1990;52:183-202. 68. Altschul R, Hoffer A, Stephen JD. Influence of nicotinic acid on serum cholesterol in man. Arch Biochem 1955;54:558-9. 69. Shalita AR, Smith JG, Parish LC, Sofman MS, Chalker DK. Topical nicotinamide compared with clindamycin gel in the treatment of inflammatory acne vulgaris. Int J Dermatol 1995;34:434-7. 70. Berk M, Lorincz A. The treatment of bullous pemphigoid with tetracycline and niacinamide. Arch Dermatol 1986;122:670-4. 71. Handfield-Jones S, Jones S, Peachey R. High dose nicotinamide in the treatment of necrobiosis lipoidica. Br J Dermatol 1988;118:693-6. 72. Zemtsov A, Neldner KH. Successful treatment of dermatitis herpetiformis with tetracycline and nicotinamide in a patient unable to tolerate dapsone. J Am Acad Dermatol 1993;28:505-6. 73. Fivenson DP, Breneman DL, Rosen GB, Hersh CS, Cardone S, Mutasim D. Nicotinamide and tetracycline therapy of bullous pemphigoid. Arch Dermatol 1994;130:753. 74. Thornfeldt CR, Menkes AW. Bullous pemphigoid controlled by tetracycline. J Am Acad Dermatol 1987;16:305-10. 75. Sunderland GT, Belch JJF, Sturrock RD, Forbes CD, McKay AJ. A double blind randomised placebo controlled trial of hexopal in primary Raynaud's disease. Clin Rheumatol 1988;7:46-9. 76. Food and Nutrition Board of the Institute of Medicine. Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline 1998. Available at: http://www.nap.org. Accessed Nov 16, 2009. 77. Bean W. Some aspects of pharmacologic use and abuse of watersoluble vitamins. In: Hathcock JN, Coon J, editors. Nutrition Deleterious side effects of nutritional supplements 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96. 97. 98. 99. 100. 101. 102. 103. 104. and drug interrelations. New York: Academic Press; 1978. p. 667-85. DiPalma J, Thayer W. Use of niacin as a drug. Annu Rev Nutr 1991; 11:169-87. Gharavi AG, Diamond JA, Smith DA, Phillips RA. Niacin-induced myopathy. Am J Cardiol 1994;74:841-2. Capuzzi DM, Guyton JR, Morgan JM, et al. Efficacy and safety of an extended-release niacin (Niaspan): a long-term study. Am J Cardiol 1998;82:74U-81U. Hathcock J. Vitamins and minerals: efficacy and safety. Am J Clin Nutr 1997;66:427. Rader JI, Calvert RJ, Hathcock JN. Hepatic toxicity of unmodified and time-release preparations of niacin. Am J Med 1992;92:77-81. McKenney J, Proctor J, Harris S, Chinchili V. A comparison of the efficacy and toxic effects of sustained-vs immediate-release niacin in hypercholesterolemic patients. JAMA 1994;271:672. Reichrath J. Vitamin D and the skin: an ancient friend, revisited. Exp Dermatol 2007;16:618-25. Stewart DG, Lewis HM. Vitamin D analogues and psoriasis. J Clin Pharm Ther 1996;21:143-8. Reichrath J, Schuler C, Seifert M, Zouboulis C, Tilgen W. The vitamin D endocrine system of human sebocytes. Exp Dermatol 2006;15:643. Osborne J, Hutchinson P. Vitamin D and systemic cancer: is this relevant to malignant melanoma? Br J Dermatol 2002;147:197-213. Millen AE, Tucker MA, Hartge P, et al. Diet and melanoma in a casecontrol study. Cancer Epidemiol Biomarkers Prev 2004;13:1042-51. Veierod MB, Thelle DS, Laake P. Diet and risk of cutaneous malignant melanoma: a prospective study of 50, 757 Norwegian men and women. Int J Cancer 1997;71:600-4. Nurnberg B, Schadendorf D, Gartner B, et al. Progression of malignant melanoma is associated with reduced 25-hydroxyvitamin D serum levels. Exp Dermatol 2008;17:627. Asgari MM, Maruti SS, Kushi LH, White E. A cohort study of vitamin D intake and melanoma risk. J Invest Dermatol 2009;129:1675. Food and Nutrition Board of the Institute of Medicine. Dietary reference intakes for calcium, phosphorus, magnesium, vitamin D, fluoride 2000. Available at: https://www.nap.org. Accessed Nov 16, 2009. Hathcock JN, Shao A, Vieth R, Heaney R. Risk assessment for vitamin D. Am J Clin Nutr 2007;85:6. Heaney RP. Vitamin D: criteria for safety and efficacy. Nutr Rev 2008; 66(suppl 2):S178-81. Holick MF. Sunlight “D” ilemma: risk of skin cancer or bone disease and muscle weakness. Lancet 2001;357:4-6. Armas LAG, Dowell S, Akhter M, et al. Ultraviolet-B radiation increases serum 25-hydroxyvitamin D levels: the effect of UVB dose and skin color. J Am Acad Dermatol 2007;57:588-93. Sharma OP. Vitamin D, calcium, and sarcoidosis. Chest 1996;109: 535. Dai G, Phalen S, McMurray DN. Nutritional modulation of host responses to mycobacteria. Front Biosci 1998;3:e110-22. Crowe M, Wollner L, Griffiths R. Hypercalcaemia following vitamin D and thiazide therapy in the elderly. Practitioner 1984;228:312-3. Curran JN, Crealey M, Sadadcharam G, Fitzpatrick G, O'Donnell M. Vitamin E: patterns of understanding, use, and prescription by health professionals and students at a university teaching hospital. Plast Reconstr Surg 2006;118:248. Thiele JJ, Schroeter C, Hsieh SN, Podda M, Packer L. The antioxidant network of the stratum corneum. Curr Probl Dermatol 2001;29:26-42. Thiele JJ, Ekanayake-Mudiyanselage S. Vitamin E in human skin: organ-specific physiology and considerations for its use in dermatology. Mol Aspects Med 2007;28:646-67. Ritter EF, Axelrod M, Minn KW, et al. Modulation of ultraviolet lightinduced epidermal damage: beneficial effects of tocopherol. Plast Reconstr Surg 1997;100:973. Zampieri N, Zuin V, Burro R, Ottolenghi A, Camoglio FS. A prospective study in children: pre-and post-surgery use of vitamin E in 379 105. 106. 107. 108. 109. 110. 111. 112. 113. 114. 115. 116. 117. 118. 119. 120. 121. 122. 123. 124. surgical incisions. J Plast Reconstr Aesthet Surg 2009 Sept 17 [Epub ahead of print]. Ehrlich HP, Tarver H, Hunt TK. Inhibitory effects of vitamin E on collagen synthesis and wound repair. Ann Surg 1972;175:235-40. Baumann LS, Md JS. The effects of topical vitamin E on the cosmetic appearance of scars. Dermatol Surg 1999;25:311-5. Jenkins M, Alexander JW, MacMillan BG, Waymack JP, Kopcha R. Failure of topical steroids and vitamin E to reduce postoperative scar formation following reconstructive surgery. J Burn Care Rehabil 1986;7:309-12. Altavilla D, Saitta A, Cucinotta D, et al. Inhibition of lipid peroxidation restores impaired vascular endothelial growth factor expression and stimulates wound healing and angiogenesis in the genetically diabetic mouse. Diabetes 2001;50:667. Galeano M, Torre V, Deodato B, et al. Raxofelast, a hydrophilic vitamin E-like antioxidant, stimulates wound healing in genetically diabetic mice. Surgery 2001;129:-7. Hayakawa R, Ueda H, Nozaki T, et al. Effects of combination treatment with vitamins E and C on chloasma and pigmented contact dermatitis. A double blind controlled clinical trial. Acta Vitaminol Enzymol 1981;3:31-8. Ekanayake-Mudiyanselage S, Tavakkol A, Polefka T, Nabi Z, Elsner P, Thiele J. Vitamin E delivery to human skin by a rinse-off product: penetration of α-tocopherol versus wash-out effects of skin surface lipids. Skin Pharmacol Physiol 2005;18:20-6. Thiele JJ, Hsieh SN, Ekanayake-Mudiyanselage S. Vitamin E: critical review of its current use in cosmetic and clinical dermatology. J Dermatol Surg 2005;31:805-13. Nabia Z, Tavakkol A, MarekDobke TGP. Bioconversion of vitamin E acetate in human skin. Oxidants Antioxid Cutan Biol 2001;29:175-86. Perrenoud D, Homberger HP, Auderset PC, et al. An epidemic outbreak of papular and follicular contact dermatitis to tocopheryl linoleate in cosmetics. Swiss Contact Dermatitis Research Group. Dermatology 1994;189:225-33. Handog EB, Galang DAVF, de Leon-Godinez MA, Chan GPA. randomized, double-blind, placebo-controlled trial of oral procyanidin with vitamins A, C, E for melasma among Filipino women. Int J Dermatol 2009;48:896-901. Pehr K, Forsey R. Why don't we use vitamin E in dermatology? CMAJ 1993;149:1247-53. Tsoureli-Nikita E, Hercogova J, Lotti T, Menchini G. Evaluation of dietary intake of vitamin E in the treatment of atopic dermatitis: a study of the clinical course and evaluation of the immunoglobulin E serum levels. Int J Dermatol 2002;41:146-50. Sander C, Hamm F, Elsner P, Thiele J. Oxidative stress in malignant melanoma and non-melanoma skin cancer. Br J Dermatol 2003;148: 913-22. Miller III ER, Guallar E. Vitamin E supplementation: what's the harm in that? Clin Trials 2009;6:47-9. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med 1994; 330:1029-35. Miller ER, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 2005;142:37-46. Greenberg ER. Vitamin E supplements: good in theory, but is the theory good? Ann Intern Med 2005;142:75-6. Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA 2007;297:842. Liede KE, Haukka JK, Saxen LM, Heinonen OP. Increased tendency towards gingival bleeding caused by joint effect of alphatocopherol supplementation and acetylsalicylic acid. Ann Med 1998; 30:542-6.