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CONTINUING MEDICAL EDUCATION

Diet in dermatology

Part I. Atopic dermatitis, acne, and nonmelanoma skin cancer

Tara Bronsnick, MD, Era Caterina Murzaku, BS, and Babar K. Rao, MD New Brunswick, New Jersey

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Patients commonly inquire about dietary modifications as a means to prevent or manage skin disease. Answering these questions is often challenging, given the vast and conflicting evidence that exists on this topic. This 2-part continuing medical education article summarizes the evidence to date to enable physicians to answer patients’ questions in an evidence-based manner. Part I includes atopic dermatitis, acne, and nonmelanoma skin cancer. The role of dietary supplementation, dietary exclusion, food allergy, maternal diet, and breastfeeding in the development and/or prevention of atopic dermatitis is summarized. The dermatoendocrinologic mechanism for the effects of glycemic index/glycemic load and milk on acne is described, as well as related clinical evidence for dietary modifications. Finally, evidence and recommendations for restriction or supplementation of dietary factors in the prevention of nonmelanoma skin cancer, including fat, vitamins A, C, D, and E, and selenium, are reported. ( J Am Acad Dermatol 2014;71:1039.e1-12.)

Key words: acne; atopic dermatitis; basal cell carcinoma; diet; nonmelanoma skin cancer; nutrition; squamous cell carcinoma.

The role of diet in dermatology is a frequent source of patient inquiry and physician uncertainty. In part I of this continuing medical education article, we discuss the effect of diet on atopic dermatitis (AD), acne, and nonmelanoma skin cancer (NMSC).

ATOPIC DERMATITIS Key points

d

Prenatal followed by postnatal probiotic supplementation decreases the risk of atopic dermatitis

d

Postnatal prebiotic supplementation decreases the risk of atopic dermatitis

d

Elimination diets are only appropriate for patients who have a food allergy that has been proven by oral food challenge

d

Maternal allergen avoidance diets do not prevent atopic dermatitis

d

Exclusive breastfeeding and supplementa- tion with hydrolyzed formula is protective against atopic dermatitis for high-risk infants

d

For infants at normal risk, breastfeeding is not protective for atopic dermatitis

Seven recent Cochrane Reviews and numerous guidelines from professional societies have explored the role of diet in AD. 1-10 The literature focuses on dietary supplementation, dietary exclusion, food allergy, maternal diet, and breastfeeding.

Dietary supplementation A 2012 Cochrane review analyzed the evidence for dietary supplements as treatments for AD. 1

From the Department of Dermatology, Robert Wood Johnson Medical School, Rutgers University, New Brunswick. Funding sources: None. Conflicts of interest: None declared. Correspondence to: Tara Bronsnick, MD, Department of Dermatology, Robert Wood Johnson Medical School, Rutgers

Abbreviations used:

AD:

atopic dermatitis

AK:

actinic keratosis

BCC:

basal cell carcinoma

BO:

borage oil

EPO:

evening primrose oil

GI:

glycemic index

GL:

glycemic load

NMSC: nonmelanoma skin cancer

RCT:

randomized controlled trial

SCC:

squamous cell carcinoma

UV:

ultraviolet

Eleven randomized, controlled trials (RCTs) with 596 participants were included in the analysis, which addressed fish oil, zinc sulphate, selenium, vitamin D, vitamin E, pyridoxine, sea buckthorn seed oil, hempseed oil, sunflower oil, and docosahexaenoic acid. The reviewed studies were of poor quality and were too small to provide conclusive evidence for the benefit of dietary supplements in AD. 1

Vitamin D Recent interventional studies investigated the impact of vitamin D supplementation on patients with AD. In 1 RCT, supplementation with 1600 IU daily for 2 months significantly improved Scoring Atopic Dermatitis (SCORAD) and 3-item severity scores compared to placebo. 11 Similarly, in a cross-sectional study, supplementation with 2000 IU daily for 3 months in patients with low serum vitamin D levels significantly improved SCORAD. 12 Conversely, in another RCT, supplementation with

University, 1 World’s Fair Dr, Ste 2400, Somerset, NJ 08873. E-mail: tarabronsnick@gmail.com.

0190-9622/$36.00

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4000 IU daily for 2 months did not significantly

impact the Eczema Area and Severity Index. 13

Primrose and borage oils Evening primrose oil (EPO) and borage oil (BO) are sources of gamma-linolenic acid, which is an antiinflammatory fatty acid that is thought to be deficient in patients with AD. 3 A 2013 Cochrane review analyzed 27 studies with 1596 participants that investigated the oral intake of EPO or BO as treatment for AD. Taken together, there was no significant improvement in AD after short-term EPO or BO supplementation. 3

Prebiotics and probiotics The composition of intestinal bacteria is postulated to impact food sensitization in the gastrointestinal tract and AD pathogenesis. Prebiotics and probiotics alter intestinal microflora and reduce intestinal inflammation. Prebiotics are nondigestible food components, commonly oligosaccharides, and probiotics are live microor-

ganisms. 4-6 A 2013 Cochrane review that analyzed 4 studies including 1428 infants revealed a significant risk reduction for AD after prebiotic supplementa- tion in infants. 4 Cochrane reviews of probiotics yielded conflicting results. 5,6 One review of 12 RCTs with 781 children found no significant difference in AD symptoms or severity after probiotic supplementation. 6 The other included 6 studies with 2080 infants and identified a significant reduction in AD with probiotic supplementation in high-risk infants. 5 Additional support for the protective role of probiotics is derived from 2 metaanalyses of maternal supplementation during pregnancy. A

2012 metaanalysis of 7 RCTs revealed a significant

risk reduction of AD in 2- to 7-year-old children after prenatal lactobacilli administration. 14 These findings

were supported by a metaanalysis of 16 RCTs that found that prenatal followed by postnatal probiotic supplementation was protective for AD in both normal- and high-risk infants. 15

Dietary exclusion and food allergy Patients frequently report food as an exacerbating factor in AD and eliminate foods that they presume to be responsible. While immunoglobulin E (IgE) e mediated food allergies are reported in up to 40% of children with moderate AD, the contribution of these allergies to AD is questionable. 16 A 2008 Cochrane review assessed dietary exclusions for the treatment of AD. 2 Data from 9 RCTs were reviewed: 6 studies of egg and milk exclusion, 1 study of few foods diet, and 2 studies of

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elemental diet. There was no significant benefit of these diets for unselected patients with AD. 2 Conversely, an egg-free diet improved AD extent and severity in patients with positive egg-specific serum IgE. 2 The observed lack of benefit from exclusion diets in unselected patients may be related to a lack of allergy to the eliminated food in these patients. 2 Two professional societies’ guidelines make recommendations for the diagnosis and manage- ment of food allergy in AD patients. 9,10 Diagnosis of an IgE-mediated food allergy relies on a combination of medical history, skin prick test, serum IgE testing, and oral food challenges. 9,10,16 History, skin prick test, and allergen-specific serum IgE are not diagnostic because of their limited positive predictive value for clinical allergy. 9,10,16-19 The diagnostic criterion standard is a double-blind, placebo-controlled food challenge, which is often impractical in clinical practice, and is appropriately replaced by a single-blind or open food challenge. 9,10 A challenge is preceded by the elimination of suspected foods for 2 to 8 weeks and is administered in a supervised medical setting to enable treatment of hypersensitivity reactions. 9 If the challenge does not elicit symptoms, an allergy to that food allergy is not present. A food allergy is confirmed if the challenge elicits symptoms that correlate with medical history, blood testing, and skin prick results. 9 For patients with AD and a proven food allergy, elimination diets are appropriate and may decrease the severity of AD. 9,10,16 Nutritionist consultation is indicated to avoid nutritional deficiencies and growth restriction. 20 In addition, because food allergies often spontaneously resolve, patients should be reassessed regularly to avoid unnecessary elimination. 21 For patients without a proven food allergy, elimination diets should not be pursued to manage AD, because there is no evidence to suggest that this approach is helpful. In addition, these diets may cause nutritional deficiencies, growth deficits, and anaphylaxis on reexposure to previously tolerated foods. 2,9,10,16,20,21

Maternal diet and breastfeeding A 2012 Cochrane review analyzing 5 RCTs with 952 participants found no significant protective effect of an antigen avoidance diet during pregnancy, lactation, or both for prevention the of AD in infants up to 18 months of age. 7 In addition, maternal antigen avoidance during pregnancy was associated with a decreased mean gestational weight gain and birth weight and increased risk of preterm birth. 7 In 1 crossover study of 17 lactating women,

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however, antigen avoidance was associated with a nonsignificant decrease in infant AD severity. 7 In 2008, the American Academy of Pediatrics summarized the evidence for maternal and infant nutrition in the context of AD. 8 Akin to the Cochrane review, they reported that restriction of maternal diet during pregnancy and lactation does not affect subsequent AD development. Exclusive breastfeeding for 4 months in high-risk infants was reported to be protective against AD. 8 A metaanalysis of 18 prospective studies and the German Infant Nutritional Intervention studies found decreased AD incidence in high-risk infants who were breastfed compared to those fed cow’s milk formula. 22-24 This protective effect also applied to hydrolyzed formula. 8,25 Conversely, no significant effect of exclusive breastfeeding on AD was observed for infants in the general population. 22-27

Conclusions There is insufficient evidence to suggest a benefit from supplementation with vitamin D, EPO, BO, fish oil, zinc sulphate, selenium, vitamin E, pyridoxine, sea buckthorn seed oil, hempseed oil, sunflower oil, and docosahexaenoic acid for AD. Evidence suggests that prebiotic supplementation in infants and prenatal followed by postnatal probiotic supplementation decrease the risk of AD. Elimination diets are only appropriate for patients who have a food allergy that is proven by oral food challenge. Maternal allergen avoidance diets during pregnancy or lactation do not prevent AD. Exclusive breastfeeding for 4 months or breastfeeding supplemented with hydrolyzed formula is protective against AD in high-risk infants. For infants at normal risk, breastfeeding does not affect the incidence of AD. Table I summarizes the recommendations along with providing the associated level of evidence.

ACNE

Key points

d Multiple randomized controlled trials with biochemical and histopathologic evidence support the benefit of a low glycemic index/load diet for acne patients d While observational studies suggest that frequent milk consumption imparts a higher risk of acne, randomized controlled trials are necessary before dietary recommenda- tions can be made

Many patients believe that diet contributes to acne. 28-33 The relationship between diet and acne has emerged as a hot topic, with [10 reviews being devoted to the subject in the past 10 years. 34-46

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The literature addresses many foods, including fatty acids, chocolate, sugar, probiotics, and multivitamins, but only the 2 most commonly addressed—glycemic index/load and milk—will be discussed here.

Glycemic index/glycemic load The diets of Kitavan Islanders of Papua New Guinea and the Ache hunter-gatherers of Paraguay are comprised of minimally processed plant and animal foods and devoid of typical Western carbohydrates. 47 Acne is absent among these populations, suggesting that a low glycemic load diet and subsequent lack of hyperinsulinemia with its associated endocrine cascade may be responsible. 47 Glycemic index (GI) is a numeric system that measures the rise in blood glucose triggered by a carbohydrate. Glycemic load (GL) ranks carbohy- drate content based on GI and portion size. 48 The dermatoendocrinologic mechanism that underlies the link between dietary GI/GL and acne has been well described. 39,44,48,49 Briefly, a high GI/GL diet leads to hyperinsulinemia, which initiates a signaling cascade resulting in increased insulin and insulin-like growth factor 1 (IGF-1) activity and decreased IGF-binding protein 3 (IGFBP-3) activity. Decreased IGFBP-3 effectively increases the bioavailability of IGF-1, compounding its direct activation. IGF-1 is known to stimulate key factors of acne pathogenesis, including keratinocyte proliferation, sebocyte proliferation, and lipogen- esis. 39,44,48,49 Both insulin and IGF-1 increase gonadal and adrenal androgen synthesis, decrease the hepatic synthesis of sex hormone e binding globulin (SHBG), and disinhibit androgen receptors, thereby directly activating and increasing the bioavailability of androgens. Androgens increase sebum production and contribute to acne pathogen- esis. 48-51 Finally, IGFBP-3 is a potent proapoptotic factor in keratinocytes and corneocytes. 44 Smith et al 52-55 published 4 interventional studies investigating the effect of a low GI/GL diet compared to a high GI/GL diet on acne. In 2 RCTs, low GI/GL groups had a significant decrease in acne counts and free androgen index and a significant increase in insulin sensitivity and IGFBP compared to high GI/GL groups. 52,53 Both studies, however, were limited by the inability to isolate the effect of low GI/GL diet from weight loss. A subsequent study found no difference in sebum outflow, but an increased ratio of saturated to monounsaturated fatty acids in skin surface triglycerides in the low GI/GL group. 54 The change in skin surface triglycerides correlated with total lesion counts, suggesting that

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Table I. Dietary modifications for patients with atopic dermatitis with recommendations and the associated level of evidence

Dietary modification

Recommendation

Level of evidence

Supplementation with Vitamin D

Insufficient data for conclusive recommendation

IB

Fish oil

Insufficient data for conclusive recommendation

IA

Zinc sulphate

Insufficient data for conclusive recommendation

IA

Selenium

Insufficient data for conclusive recommendation

IA

Vitamin E

Insufficient data for conclusive recommendation

IA

Pyridoxine

Insufficient data for conclusive recommendation

IA

Sea buckthorn seed oil

Insufficient data for conclusive recommendation

IA

Hempseed oil

Insufficient data for conclusive recommendation

IA

Sunflower oil

Insufficient data for conclusive recommendation

IA

Docosahexaenoic acid

Insufficient data for conclusive recommendation

IA

Evening primrose oil

No

IA

Borage oil

No

IA

Prebiotics

Yes, in infants

IA

Probiotics

Yes, prenatally and postnatally

IA

Elimination diets

Only for immunoglobulin Ee mediated food allergy

IA

Maternal allergen avoidance During pregnancy

proven by observed food challenge

IA

During lactation

No No

IA

Exclusive breastfeeding

Yes, for at least 4 months in high-risk infants

IB

Hydrolyzed formula

Yes, in high-risk infants

IB

Levels of evidence are based on the Journal of the American Academy of Dermatology guidelines. Level IA evidence includes evidence from metaanalysis of randomized controlled trials; level IB evidence includes evidence from $ 1 randomized controlled trial; level IIA evidence includes evidence from $ 1 controlled study without randomization; level IIB evidence includes evidence from $ 1 other type of experimental study; level III evidence includes evidence from nonexperimental descriptive studies, such as comparative studies, correlation studies, and case control studies; and level IV evidence includes evidence from expert committee reports or opinions or clinical experience of respected authorities, or both.

low GI/GL affects acne in part through sebaceous lipogenesis. 54 Finally, in a small, nonrandomized study, the low GI/GL group had a significant increase in insulin sensitivity and IGFBP-3, while the high GI/GL group had a significant increase in free androgen index and decrease in SHBG. 55 This series of interventional studies provides compelling evidence that a low GI/GL diet improves acne. Weight loss, however, is a confounding factor. A recent RCT supported the findings of Smith et al 52-55 and provided histopathologic support for the benefits of a low GI/GL diet on acne. 56 Low GI/ GL diet led to a significant decrease in acne counts. Histopathologic examination revealed reduced sebaceous gland size and decreased expression of sterol regulatory element binding protein-1, a regulator of lipid synthesis, and interleukin-8, an inflammatory cytokine, with a low GI/GL diet. 56 Observational studies have also shown an association between glycemic load and acne. A case control study revealed a significantly higher dietary GL in acne patients compared to healthy controls, even with multivariate analysis accounting for body mass index. 57 Among 2258 patients

consuming the South Beach Diet, which emphasizes low GI foods, 37 86.7% reported improved acne with diet and 91% 56 reported the ability to decrease dose or number of acne medications. 58 A community- based case control study found that patients consuming a Mediterranean diet, another low GI diet, were less likely to have acne. 59 Finally, a cross-sectional study identified higher dietary GI among participants with moderate to severe acne compared to those with no or mild acne. 33 Two studies do not support the association between GI/GL and acne. A nonrandomized trial that tested the effect of high compared to a low GI/GL diet in acne patients did not find significant differences in acne severity, insulin sensitivity, free androgen index, SHBG, IGF-1, or IGFBP-3 between groups. 60 A prospective cohort study also revealed no significant differences in GI/GL, serum glucose, insulin sensitivity, or IGF-1 in acne patients compared to controls. 61

Milk Akin to high GI carbohydrates, milk consumption significantly elevates insulin and IGF-1 levels and

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Table II. Dietary modifications for patients with acne with recommendations and the associated level of evidence

Dietary modification

Recommendation

Level of evidence

Low glycemic index/load diet

Yes

IB

Milk restriction

Insufficient data for conclusive recommendation

III

Levels of evidence are based on the Journal of the American Academy of Dermatology guidelines. Level IA evidence includes evidence from metaanalysis of randomized controlled trials; level IB evidence includes evidence from $ 1 randomized controlled trial; level IIA evidence includes evidence from $ 1 controlled study without randomization; level IIB evidence includes evidence from $ 1 other type of experimental study; level III evidence includes evidence from nonexperimental descriptive studies, such as comparative studies, correlation studies, and case control studies; and level IV evidence includes evidence from expert committee reports or opinions or clinical experience of respected authorities, or both.

decreases IGFBP-3 levels. 49 Milk also contains bovine IGF-1, which is identical to human IGF-1 and binds with the same affinity to its receptor. 62 Increased insulin and IGF-1 signaling promote comedogenesis, sebaceous lipogenesis, follicular inflammation, and androgenic stimula- tion. 63 Milk also contains dihydrotestosterone precursors, including placenta-derived progester- one, 5 a -pregnanedione, 5 a -androstanedione, and numerous growth-related factors. 64 In a series of 3 studies, Abedamowo et al 65-67 investigated the association between acne and milk consumption. In a retrospective cohort study of 47,355 women, using data from the Nurses’ Health Study II, a self-reported history of physician- diagnosed severe acne was positively associated with the frequent consumption of total milk and skim milk. 65 Similarly, a prospective cohort study including 6094 girls found that self-reported acne was positively associated with total, whole, low fat, and skim milk consumption. 66 In a study of 4273 boys, self-reported acne was positively associated with skim milk intake only. 67 In addition, 2 case control studies and 1 cross-sectional study identified an increased risk of acne with more frequent milk consumption. 33,57,68 Finally, a recent case series reported acne in 5 male patients that was precipitated by whey protein supplementation. 69 Whey protein comprises 20% of protein in cow’s milk and is thought to be the insulinotropic component. 49 These patients experienced resolution of their acne after discontinuation of whey protein supplementation. 69

Conclusions Currently, there are well described biochemical and physiologic mechanisms that explain the association of GI/GL and milk consumption with acne. There are multiple RCTs that have shown the benefit of a low GI/GL diet in treating acne, so this diet may be recommended to patients. While observational studies support the link between milk

and acne, RCTs are required before milk restriction diets can be recommended to acne patients. Table II summarizes recommendations along with the associated level of evidence.

NONMELANOMA SKIN CANCER Key points

d

d

d

A large randomized controlled trial found no significant effect of a low-fat diet on nonmelanoma skin cancer; therefore, a fat restricted diet should not be recommended for nonmelanoma skin cancer prevention

Selenium supplementation may increase the risk of squamous cell carcinoma and total nonmelanoma skin cancer and should be avoided

The effect of retinol and retinoid supple- mentation on nonmelanoma skin cancer varies based on risk factors, comorbidities, and cancer type

Fat Animal studies suggest that dietary fat intake significantly influences the occurrence of NMSC. 70 Higher dietary fat decreases time latency between ultraviolet (UV) exposure and tumor onset and increases the number of tumors in mice. 71 In a RCT of 115 patients with skin cancer history, the low-fat diet group developed fewer actinic keratoses (AKs) and NMSCs than controls. 71-73 One case control study found a direct relationship be- tween dietary fat consumption and NMSC, 74 whereas another reported an inverse association. 75 Ten studies, including 1 very large RCT with 48,835 participants, 76 5 cohort studies, 76-81 4 case control studies, 82-85 and 1 metaanalysis 86 did not identify a significant association between dietary fat and NMSC.

Vitamin A Vitamin A and its derivatives, b -carotene and retinol, are important for epithelial cell proliferation

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Table III. Dietary modifications for patients with nonmelanoma skin cancer with recommendations and the associated level of evidence

Dietary modification

Recommendation

Level of evidence

Low-fat diet

No

IB

Vitamin A supplementation b-carotene

No

IB

Retinol

Consider to decrease SCC in patients with moderate risk IB

Synthetic retinoid

Decrease NMSC in patients with xeroderma pigmentosum

IIA and IB

(eg, isotretinoin, acitretin) Vitamin D supplementation

or renal transplant Insufficient data for conclusive recommendation

III

Vitamin E supplementation

Insufficient data for conclusive recommendation

III

Vitamin C supplementation

Insufficient data for conclusive recommendation

III

Selenium supplementation

Avoid due to increased risk of SCC and NMSC

IB

Levels of evidence are based on the Journal of the American Academy of Dermatology guidelines. Level IA evidence includes evidence from metaanalysis of randomized controlled trials; level IB evidence includes evidence from $ 1 randomized controlled trial; level IIA evidence includes evidence from $ 1 controlled study without randomization; level IIB evidence includes evidence from $ 1 other type of experimental study; level III evidence includes evidence from nonexperimental descriptive studies, such as comparative studies, correlation studies, and case control studies; and level IV evidence includes evidence from expert committee reports or opinions or clinical experience of respected authorities, or both. NMSC, Nonmelanoma skin cancer; SCC, squamous cell carcinoma.

and differentiation, possess antioxidant properties, and protect against skin tumorigenesis in mice. 87-89 As such, they are postulated to play a role in NMSC. Human studies that investigate the association between vitamin A and NMSC yield conflicting results. One case control study revealed a lower mean serum level of b -carotene and vitamin A in NMSC cases than controls and a significant inverse relationship between dietary intake of b -carotene and NMSC. 90 Similarly, another case control study found that vitamin A consumption was associated with a reduced risk of basal cell carcinoma (BCC). 91 In addition, a cohort study found lower mean serum retinol concentration in NMSC patients compared to controls. 92 Two studies, however, reported a positive association between dietary vitamin A and BCC 93 and higher serum retinol levels in BCC cases compared to controls. 94 Multiple studies, including 6 case control 83-85,95-97 and 8 cohort studies, 74,77,79,81,98-101 were unable to identify a significant association between dietary intake of vitamin A derivatives, plasma or serum retinol levels, and NMSC. Multiple interventional studies have evaluated the effect of retinol, isotretinoin, or b -carotene on NMSC incidence. Three RCTs found no significant difference in NMSC incidence between intervention and control groups after b -carotene supplementa- tion. 102-104 The study results for retinol and synthetic retinoids are more varied. One RCT revealed no significant difference in time to first NMSC or in total number of tumors in retinol-treated versus control high-risk patients. 105 Conversely, in patients with moderate risk, oral retinol supplementation

significantly decreased the hazard ratio for first squamous cell carcinoma (SCC), but did not affect BCC risk. 106 Similarly, in a RCT, 10 mg of isotretinoin daily did not affect BCC development. 107 Smaller studies of isotretinoin in patients with xeroderma pigmentosum 108,109 and acitretin in renal transplant patients 110 identified statistically signifi- cant reductions in NMSC incidence in treatment groups. These studies suggest that the impact of retinol and synthetic retinoids on NMSC may be affected by individual patient risk factors and comorbidities.

Vitamin D Vitamin D is obtained exogenously through foods and endogenously through UV-induced calcitriol synthesis. In vitro studies in BCC 111 and SCC 112-114 cell lines reveal differential expression and down- stream effects of key components of the vitamin D system. Loss of the vitamin D receptor enhances susceptibility to UV-induced tumorigenesis in a mice. 115 Vitamin D inhibits the hedgehog signaling pathway and upregulates nucleotide excision repair enzymes, potentially protecting against NMSC. 116,117 Despite evidence from animal and in vitro studies, human studies are conflicting. One case control study found an inverse relationship between vitamin D level and risk of NMSC. 118 Conversely, 3 studies identified a significant positive association between plasma vitamin D levels and NMSC risk. 119-121 Sun exposure may confound these results, because UV radiation simultaneously increases serum vitamin D levels and promotes DNA mutations that are key in the development of skin cancer. Three studies found

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no association between dietary vitamin D and risk of

BCC. 74,77,85

Vitamin E Topical application of a -tocopherol, the most frequent naturally occurring form of vitamin E, inhibits ultraviolet B light (UVB) e induced DNA damage and carcinogenesis in mice. 122-124 Human trials, however, yield conflicting data. Three case control studies reported a protective effect of vitamin E on NMSC development. 85,91,125 Decreased plasma levels of a -tocopherol were found in patients with AK and BCC compared to controls. 125 Inverse associations between vitamin E dietary intake 85 and supplementation 91 and subsequent BCC develop- ment were observed. Conversely, 2 cohort studies found a positive association between dietary and supplemental vitamin E and BCC development, 93,99 while others were unable to identify an association between vitamin E supplementation or serum levels and subsequent NMSC. 74,77,81,84,94-96,98,101 In addition, a double-blind, placebo-controlled study did not find a clinical or histologic difference in response to UVB after 6 months of daily oral a -tocopherol (400 IU) supplementation. 126

Vitamin C In vitro studies of human keratinocyte cell lines show that ascorbic acid, which is a stable form of vitamin C, decreases UVB-induced cytotoxicity as a free radical scavenger and a potentiator of the antioxidative activity of a -tocopherol. 127,128 Vitamin C administration significantly inhibits UV-induced DNA, RNA, and protein synthesis in BCC and SCC cell lines in mice and rats. 129-131 The photoprotective properties of topical vitamin C have been shown in porcine skin. 132 In humans, studies of vitamin C and NMSC are inconsistent. Inverse relationships between the consumption of vitamin C e containing foods, 90 vitamin C supplements, 91 and plasma levels of ascorbic acid 125 with NMSC were identified in 3 case control studies. Conflicting results were obtained in 2 cohort studies that identified a positive association between BCC and the intake of vitamin

C e rich food or supplements. 93,99 In addition, 3 case control studies 83-85 and 5 cohort studies 74,77,79,81,98

failed to identify a significant association between vitamin C and NMSC.

Selenium Selenium protects against UVB-induced cytotox- icity in human keratinocytes and carcinogenesis in mice. 133-135 Studies have found a potentially protective role of selenium for NMSC. In a case

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control study, the mean plasma selenium level was significantly lower amongst NMSC cases than controls. 136 Similarly, a cohort study found an inverse relationship between serum selenium concentration and subsequent NMSC. 100 Finally, in a study of 8 women treated with topical L-selenomethionine for 2 weeks, a significant increase in minimal erythema dose after UV irradiation was observed, suggesting a possibly photoprotective effect of topical selenium. 137 The only RCT that has investigated the impact of oral selenium supplementation on NMSC found no significant association with risk of BCC, but, interestingly, elevated risks of SCC and total NMSC. 138 Other studies found no significant associ- ation between dietary 84,85 or plasma selenium 94,95 and NMSC.

Conclusions In conclusion, despite laboratory evidence suggesting a link between dietary factors and NMSC, human studies have been contradictory and inconclusive. Observational studies provide conflicting results and often do not reveal a significant association between dietary factors and NMSC. A large RCT of patients who were following a low-fat diet (n = 48,835) found no significant difference in NMSC; therefore, a fat-restricted diet should not be recommended for NMSC prevention. Based on a RCT, selenium supplementation may increase the risk of SCC and total NMSC and should be avoided. Interventional studies suggest that the effect of retinol and retinoid supplementation on NMSC varies based on risk factors, comorbidities, and skin cancer type. Table III summarizes the recommendations along with the associated level of evidence.

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