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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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Learning Objectives

After completing this learning activity, participants should be able to describe the

relationshipbetweendiet and the followingconditions:acne, psoriasis, andurticaria.

Date of release: December 2014

Expiration date: December 2017

2014 by the American Academy of Dermatology, Inc.

http://dx.doi.org/10.1016/j.jaad.2014.06.015

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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 thistopic. This 2-part continuing medical education article summarizes the evidence to date to enablephysicians 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, foodallergy, 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 loadand 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 theprevention 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 frequentsource 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 DERMATITISKey pointsd Prenatal followed by postnatal probiotic

supplementation decreases the risk of atopicdermatitis

d Postnatal prebiotic supplementation decreasesthe 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 protectiveagainst atopic dermatitis for high-risk infants

d For infants at normal risk, breastfeeding isnot protective for atopic dermatitis

Seven recent Cochrane Reviews and numerousguidelines from professional societies have exploredthe role of diet in AD.1-10 The literature focuses ondietary supplementation, dietary exclusion, foodallergy, maternal diet, and breastfeeding.

Dietary supplementation A 2012 Cochrane review analyzed the evidence

for dietary supplements as treatments for AD.1

Eleven randomized, controlled trials (RCTs) with596 participants were included in the analysis, whichaddressed fish oil, zinc sulphate, selenium, vitaminD, vitamin E, pyridoxine, sea buckthorn seed oil,hempseed oil, sunflower oil, and docosahexaenoicacid. The reviewed studies were of poor quality and were too small to provide conclusive evidence forthe benefit of dietary supplements in AD.1

Vitamin DRecent interventional studies investigated the

impact of vitamin D supplementation on patients with AD. In 1 RCT, supplementation with 1600 IUdaily for 2 months significantly improved Scoring Atopic Dermatitis (SCORAD) and 3-item severity scores compared to placebo.11 Similarly, in across-sectional study, supplementation with 2000IU daily for 3 months in patients with low serum vitamin D levels significantly improved SCORAD.12

Conversely, in another RCT, supplementation with

Abbreviations used:

AD: atopic dermatitis AK: actinic keratosisBCC: basal cell carcinomaBO: borage oilEPO: evening primrose oilGI: glycemic indexGL: glycemic loadNMSC: nonmelanoma skin cancerRCT: randomized controlled trialSCC: squamous cell carcinomaUV: ultraviolet

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

University, 1 World’s Fair Dr, Ste 2400, Somerset, NJ 08873.

E-mail: [email protected].

0190-9622/$36.00

J A M A CAD DERMATOL

DECEMBER 20141039.e2 Bronsnick, Murzaku, and Rao

mailto:[email protected]





4000 IU daily for 2 months did not significantly impact the Eczema Area and Severity Index.13

Primrose and borage oilsEvening primrose oil (EPO) and borage oil (BO)

are sources of gamma-linolenic acid, which is anantiinflammatory fatty acid that is thought to bedeficient in patients with AD.3 A 2013 Cochranereview analyzed 27 studies with 1596 participantsthat investigated the oral intake of EPO or BO astreatment for AD. Taken together, there was nosignificant improvement in AD after short-termEPO or BO supplementation.3

Prebiotics and probioticsThe composition of intestinal bacteria is

postulated to impact food sensitization in thegastrointestinal tract and AD pathogenesis.

Prebiotics and probiotics alter intestinal microfloraand reduce intestinal inflammation. Prebioticsare nondigestible food components, commonly oligosaccharides, and probiotics are live microor-ganisms.4-6 A 2013 Cochrane review that analyzed 4studies including 1428 infants revealed a significantrisk reduction f or AD after prebiotic supplementa-tion in infants.4 Cochrane reviews of probiotics yielded conflicting results.5,6 One review of 12RCTs with 781 children found no significantdifference in AD s y mptoms or severity after probioticsupplementation.6 The other included 6 studies with

2080 infants and identified a significant reduction in AD with probiotic supplementation in high-riskinfants.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 significantrisk reduction of AD in 2- to 7-year-old children afterprenatal lactobacilli administration.14 These findings were supported by a metaanalysis of 16 RCTs thatfound that prenatal followed by postnatal probioticsupplementation was protecti ve 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 presumeto be responsible. While immunoglobulin E (IgE)emediated food allergies are reported in up to 40% of children with moderate AD, the contribution of theseallergies to AD is questionable.16

A 2008 Cochrane review assessed dietary exclusions for the treatment of AD.2 Data from 9RCTs were reviewed: 6 studies of egg and milk

exclusion, 1 study of few foods diet, and 2 studies of

elemental diet. There was no significant benefit of these diets for unselected patients with AD.2

Conversely, an egg-free diet improved AD extentand severit y in patients with positive egg-specificserum IgE.2 The observed lack of benefit fromexclusion diets in unselected patients may be relatedto a lack of allergy to the eliminated food in thesepatients.2

Two professional societies’ guidelines makerecommendations for the diagnosis and manage-ment of food allergy in AD patients.9,10 Diagnosis of an IgE-mediated food allergy relies on a combinationof medical history, skin prick test, serum IgE testing,and oral food challenges.9,10,16 History, skin pricktest, and allergen-specific serum IgE are notdiagnostic because of their limited positivepredictive value for clinical allergy.9,10,16-19 Thediagnostic criterion standard is a double-blind,

placebo-controlled food challenge, which is oftenimpractical in clinical practice, and is appropriately replaced by a single-blind or open foodchallenge.9,10 A challenge is preceded by theelimination of suspected foods for 2 to 8 weeksand is administered in a supervised medical setting toenable treatment of hypersensitivity reactions.9 If thechallenge does not elicit symptoms, an allergy to thatfood allergy is not present. A food allergy isconfirmed if the challenge elicits symptoms thatcorrelate with medical history, blood testing, andskin prick results.9

For patients with AD and a proven food allergy,elimination diets are appropriate and may decreasethe severity of AD.9,10,16 Nutritionist consultation isindicated to avoid nutritional deficiencies andgrowth restriction.20 In addition, because foodallergies often spontaneously resolve, patientsshould be reassessed regularly to avoid unnecessary elimination.21 For patients without a proven foodallergy, elimination diets should not be pursued tomanage AD, because there is no evidence to suggestthat this approach is helpful. In addition, these dietsmay 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 protectiveeffect of an antigen avoidance diet duringpregnancy, lactation, or both for prevention the of AD in infants up to 18 months of age.7 In addition,maternal antigen avoidance during pregnancy wasassociated with a decreased mean gestational weightgain and birth weight and increased risk of preterm

birth.

7

In 1 crossover study of 17 lactating women,


V OLUME 71, NUMBER 6 Bronsnick, Murzaku, and Rao 1039.e3



however, antigen avoidance was associated with anonsignificant decrease in infant AD severity.7

In 2008, the American Academy of Pediatricssummarized the evidence for maternal and infantnutrition in the context of AD.8 Akin to the Cochranereview, they reported that restriction of maternaldiet during pregnancy and lactation does notaffect subsequent AD development. Exclusivebreastfeeding for 4 months in high-risk infants wasreported to be protective against AD.8 A metaanalysisof 18 prospective studies and the German InfantNutritional Intervention studies found decreased ADincidence in high-risk infants who were breastfedcompared to those fed cow’s milk formula.22-24 Thisprotective effect also applied to hydrolyzedformula.8,25 Conversely, no significant effect of exclusive breastfeeding on AD was observed forinfants in the general population.22-27

ConclusionsThere is insufficient evidence to suggest a benefit

from supplementation with vitamin D, EPO, BO, fishoil, zinc sulphate, selenium, vitamin E, pyridoxine,sea buckthorn seed oil, hempseed oil, sunflower oil,and docosahexaenoic acid for AD. Evidencesuggests that prebiotic supplementation in infantsand prenatal followed by postnatal probioticsupplementation 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 duringpregnancy or lactation do not prevent AD. Exclusivebreastfeeding for 4 months or breastfeedingsupplemented with hydrolyzed formula is protectiveagainst AD in high-risk infants. For infants at normalrisk, breastfeeding does not affect the incidence of AD. Table I summarizes the recommendations along with providing the associated level of evidence.

ACNEKey pointsd Multiple randomized controlled trials with

biochemical and histopathologic evidencesupport the benefit of a low glycemicindex/load diet for acne patients

d While observational studies suggest that frequent milk consumption imparts a higher risk of acne, randomized controlled trialsare necessary before dietary recommenda-tions can be made

Many patients believe that diet contributes toacne.28-33 The relationship between diet and acnehas emerged as a hot topic, with[10 reviews being

devoted to the subject in the past 10 years.

34-46

The literature addresses many foods, includingfatty acids, chocolate, sugar, probiotics, andmultivitamins, but only the 2 most commonly addressed—glycemic index/load and milk—will bediscussed here.

Glycemic index/glycemic loadThe diets of Kitavan Islanders of Papua New

Guinea and the Ache hunter-gatherers of Paraguay are comprised of minimally processed plantand animal foods and devoid of typical Westerncarbohydrates.47 Acne is absent among thesepopulations, suggesting that a low glycemic loaddiet and subsequent lack of hyperinsulinemia with its associated endocrine cascade may beresponsible.47

Glycemic index (GI) is a numeric system thatmeasures the rise in blood glucose triggered by a

carbohydrate. Glycemic load (GL) ranks carbohy-drate content based on GI and portion size.48 Thedermatoendocrinologic mechanism that underliesthe link between dietar y GI/GL and acne has been well described.39,44,48,49 Briefly, a high GI/GL dietleads to hyperinsulinemia, which initiates asignaling cascade resulting in increased insulin andinsulin-like growth factor 1 (IGF-1) activity anddecreased IGF-binding protein 3 (IGFBP-3) activity.Decreased IGFBP-3 effectively increases thebioavailability of IGF-1, compounding its directactivation. IGF-1 is known to stimulate key

factors of acne pathogenesis, including keratinocyteproliferation, sebocyte proliferation, and lipogen-esis.39,44,48,49 Both insulin and IGF-1 increasegonadal and adrenal androgen synthesis, decreasethe hepatic synthesis of sex hormoneebindingglobulin (SHBG), and disinhibit androgen receptors,thereby directly activating and increasing thebioavailability of androgens. Androgens increasesebum production and contribute to acne pathogen-esis.48-51 Finally, IGFBP-3 is a potent proapoptoticfactor in keratinocytes and corneocytes.44

Smith et al52-55 published 4 interventional studies

investigating the effect of a low GI/GL diet comparedto a high GI/GL diet on acne. In 2 RCTs, low GI/GLgroups had a significant decrease in acne counts andfree androgen index and a significant increasein insulin sensitivit y and IGFBP compared to highGI/GL groups.52,53 Both studies, however, werelimited by the inability to isolate the effect of lowGI/GL diet from weight loss. A subsequent study found no difference in sebum outflow, but anincreased ratio of saturated to monounsaturated fatty acids in skin surface triglycerides in the low GI/GLgroup.54 The change in skin surface triglycerides

correlated with total lesion counts, suggesting that





low GI/GL af fects acne in part through sebaceouslipogenesis.54 Finally, in a small, nonrandomizedstudy, the low GI/GL group had a significant increasein insulin sensitivity and IGFBP-3, while the highGI/GL group had a significant increase in freeandrogen index and decrease in SHBG.55 This seriesof interventional studies provides compellingevidence that a low GI/GL diet improves acne. Weight loss, however, is a confounding factor.

A recent RCT supported the findings of Smithet al52-55 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 reducedsebaceous gland size and decreased expression of sterol regulatory element binding protein-1, aregulator of lipid synthesis, and interleukin-8, aninflammatory cytokine, with a low GI/GL diet.56

Observational studies have also shown anassociation between glycemic load and acne. A case control study revealed a significantly higherdietary 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 emphasizeslow GI foods,37 86.7% reported improved acne withdiet and 91%56 reported the ability to decrease doseor number of acne medications.58 A community-based case control study found that patientsconsuming a Mediterranean diet, another low GIdiet, were less likely to have acne.59 Finally, across-sectional study identified higher dietary GIamong participants with moderate to severe acnecompared to those with no or mild acne.33

Two studies do not support the association

between GI/GL and acne. A nonrandomizedtrial that tested the effect of high compared to alow GI/GL diet in acne patients did not findsignificant differences in acne severity, insulinsensitivity, free androgen index, SHBG, IGF-1, orIGFBP-3 between groups.60 A prospective cohortstudy also revealed no significant differences inGI/GL, serum glucose, insulin sensiti vit y, or IGF-1in acne patients compared to controls.61

Milk Akin to high GI carbohydrates, milk consumption

significantly elevates insulin and IGF-1 levels and

Table I. Dietary modifications for patients with atopic dermatitis with recommendations and the associatedlevel 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 IAZinc 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 allergyproven by observed food challenge IA

Maternal allergen avoidance

During pregnancy No IA

During lactation 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.





decreases IGFBP-3 levels.49 Milk also containsbovine IGF-1, which is identical to humanIGF-1 and binds with the same affinity to itsreceptor.62 Increased insulin and IGF-1 signalingpromote comedogenesis, sebaceous lipogenesis,

follicular inflammation, and androgenic stimula-tion.63 Milk also contains dihydrotestosteroneprecursors, including placenta-derived progester-one, 5a-pregnanedione, 5a-androstanedione, andnumerous growth-related factors.64

In a series of 3 studies, Abedamowo et al65-67

investigated the association between acne and milkconsumption. In a retrospective cohort study of 47,355 women, using data from the Nurses’ HealthStudy II, a self-reported history of physician-diagnosed severe acne was positively associated with the f requent 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 4273boys, self-reported acne was positively associated with skim milk intake only.67 In addition, 2 casecontrol studies and 1 cross-sectional study identifiedan increased risk of acne with more frequent milkconsumption.33,57,68 Finally, a recent case seriesreported acne in 5 male patients that wasprecipitated by whey protein supplementation.69

Whey protein comprises 20% of protein in cow’s

milk and is thought to be the insulinotropiccomponent.49 These patients experienced resolutionof their acne after discontinuation of whey proteinsupplementation.69

ConclusionsCurrently, there are well described biochemical

and physiologic mechanisms that explain theassociation of GI/GL and milk consumption withacne. There are multiple RCTs that have shown thebenefit of a low GI/GL diet in treating acne, sothis diet may be recommended to patients. While

observational studies support the link between milk

and acne, RCTs are required before milk restrictiondiets can be recommended to acne patients. Table IIsummarizes recommendations along with theassociated level of evidence.

NONMELANOMA SKIN CANCER Key pointsd 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 recommendedfor nonmelanoma skin cancer prevention

d Selenium supplementation may increase therisk of squamous cell carcinoma and total nonmelanoma skin cancer and should beavoided

d 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 betweenultraviolet (UV) exposure and tumor onset andincreases 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

Onecase control study found a direct relationship be-tween dietary fat consumption and NMSC,74 whereasanother reported an inverse association.75 Tenstudies, including 1 very large RCT with 48,835participants,76 5 cohort studies,76-81 4 case controlstudies,82-85 and 1 metaanalysis86 did not identify asignificant association between dietary fat andNMSC.

Vitamin A Vitamin A and its derivatives, b-carotene and

retinol, are important for epithelial cell proliferation

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


Low glycemic index/load diet Yes IB

Milk restriction Insufficient data for conclusive recommendation III






of respected authorities, or both.





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 conflictingresults. One case control study revealed a lowermean serum level of b-carotene and vitamin A inNMSC cases than controls and a significant inverserelationship 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 meanserum retinol concentration in NMSC patientscompared to controls.92 Two studies, however,reported a positi ve association between dietary vitamin A and BCC93 and higher serum retinol levelsin BCC cases compared to controls.94 Multiplestudies, including 6 case control83-85,95-97 and 8cohort 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 theeffect of retinol, isotretinoin, or b-carotene on NMSCincidence. Three RCTs found no significantdifference in NMSC incidence between interventionand control groups after b-carotene supplementa-tion.102-104 The study results for retinol and syntheticretinoids are more varied. One RCT revealed nosignificant difference in time to first NMSC or intotal number of tumors in retinol-treated versuscontrol high-risk patients.105 Conversely, in patients

with moderate risk, oral retinol supplementation

significantly decreased the hazard ratio for firstsquamous cell carcinoma (SCC), but did not affectBCC risk.106 Similarly, in a RCT, 10 mg of isotretinoindaily did not affect BCC development.107

Smaller studies of isotretinoin in patients withxeroderma pigmentosum108,109 and acitretin in renaltransplant patients110 identified statistically signifi-cant reductions in NMSC incidence in treatmentgroups. These studies suggest that the impact of

retinol and synthetic retinoids on NMSC may beaffected by individual patient risk factors andcomorbidities.

Vitamin D Vitamin D is obtained exogenously through foods

and endogenously through UV-induced calcitriolsynthesis. In vitro studies in BCC111 and SCC112-114

cell lines reveal differential expression and down-stream effects of key components of the vitamin Dsystem. Loss of the vitamin D receptor enhancessusceptibility to UV-induced tumorigenesis in a

mice.115

Vitamin D inhibits the hedgehog signalingpathway and upregulates nucleotide excision repairenzymes, potentially protecting against NMSC.116,117

Despite evidence from animal and in vitro studies,human studies are conflicting. One case controlstudy found an inverse relationship between vitaminD level and risk of NMSC.118 Conversely, 3 studiesidentified a significant positive association bet weenplasma vitamin D levels and NMSC risk.119-121 Sunexposure may confound these results, because UV radiation simultaneously increases serum vitamin Dlevels and promotes DNA mutations that are key in

the development of skin cancer. Three studies found

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


Low-fat diet No IB

Vitamin A supplementation

b-carotene No IBRetinol Consider to decrease SCC in patients with moderate risk IB

Synthetic retinoid

(eg, isotretinoin, acitretin)

Decrease NMSC in patients with xeroderma pigmentosum

or renal transplant

IIA and IB

Vitamin D supplementation 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






of respected authorities, or both.NMSC , Nonmelanoma skin cancer; SCC , squamous cell carcinoma.





no association between dietary vitamin D and risk of BCC.74,77,85

Vitamin ETopical application of a-tocopherol, the most

frequent naturally occurring form of vitamin E,inhibits ultraviolet B light (UVB)einduced DNA damage and carcinogenesis in mice.122-124 Humantrials, however, yield conflicting data. Three casecontrol studies reported a protecti ve effect of vitaminE on NMSC development.85,91,125 Decreased plasmalevels of a-tocopherol were found in patients with AK and BCC compared to controls.125 Inverseassociations between vitamin E dietary intake85 andsupplementation91 and subsequent BCC develop-ment were observed. Conversely, 2 cohort studiesfound a positive association between dietary andsupplemental vitamin E and BCC development,93,99

while others were unable to identify an associationbetween vitamin E supplementation or serumlevels and subsequent NMSC.74,77,81,84,94-96,98,101 Inaddition, a double-blind, placebo-controlled study did not find a clinical or histologic difference inresponse to UVB after 6 months of daily orala-tocopherol (400 IU) supplementation.126

Vitamin CIn 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 theantioxidative activity of a-tocopherol.127,128 VitaminC administration significantly inhibits UV-inducedDNA, RNA, and protein synthesis in BCC and SCCcell lines in mice and rats.129-131 The photoprotectiveproperties of topical vitamin C have been shown inporcine skin.132

In humans, studies of vitamin C and NMSC areinconsistent. Inverse relationships between theconsumption of vitamin Cecontaining foods,90

vitamin C supplements,91 and plasma levels of ascorbic acid125 with NMSC were identified in 3

case control studies. Conflicting results wereobtained in 2 cohort studies that identified a positiveassociation between BCC and the intake of vitaminCerich food or supplements.93,99 In addition, 3 casecontrol studies83-85 and 5 cohort studies74,77,79,81,98

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

Selenium Selenium protects against UVB-induced cytotox-

icity in human keratinocytes and carcinogenesisin mice.133-135 Studies have found a potentially

protective role of selenium for NMSC. In a case

control study, the mean plasma selenium level was significantly lower amongst NMSC cases thancontrols.136 Similarly, a cohort study found aninverse relationship between serum seleniumconcentration and subsequent NMSC.100 Finally,in a study of 8 women treated with topicalL-selenomethionine for 2 weeks, a significantincrease 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 nosignificant association with risk of BCC, but,interestingly, elevated risks of SCC and totalNMSC.138 Other studies found no significant associ-ation between dietary 84,85 or plasma selenium94,95

and NMSC.

ConclusionsIn conclusion, despite laboratory evidence

suggesting a link between dietary factors andNMSC, human studies have been contradictory and inconclusive. Observational studies provideconflicting results and often do not reveal asignificant association between dietary factors andNMSC. A large RCT of patients who were following alow-fat diet (n = 48,835) found no significantdifference in NMSC; therefore, a fat-restricted dietshould not be recommended for NMSC prevention.Based on a RCT, selenium supplementation may increase the risk of SCC and total NMSC and shouldbe avoided. Interventional studies suggest that theeffect of retinol and retinoid supplementation onNMSC varies based on risk factors, comorbidities,and skin cancer type. Table III summarizes therecommendations along with the associated levelof evidence.

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