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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Date of release: December 2014

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1039.e1

J AM ACAD DERMATOL

1039.e2 Bronsnick, Murzaku, and Rao

DECEMBER 2014

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
Postnatal prebiotic supplementation decreases
the risk of atopic dermatitis
Elimination diets are only appropriate for
patients who have a food allergy that has
been proven by oral food challenge
Maternal allergen avoidance diets do not
prevent atopic dermatitis
Exclusive breastfeeding and supplementation with hydrolyzed formula is protective
against atopic dermatitis for high-risk infants
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:
AK:
BCC:
BO:
EPO:
GI:
GL:
NMSC:
RCT:
SCC:
UV:

atopic dermatitis
actinic keratosis
basal cell carcinoma
borage oil
evening primrose oil
glycemic index
glycemic load
nonmelanoma skin cancer
randomized controlled trial
squamous cell carcinoma
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 Worlds Fair Dr, Ste 2400, Somerset, NJ 08873.
E-mail: tarabronsnick@gmail.com.
0190-9622/$36.00

J AM ACAD DERMATOL
VOLUME 71, NUMBER 6

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 microorganisms.4-6 A 2013 Cochrane review that analyzed 4
studies including 1428 infants revealed a significant
risk reduction for AD after prebiotic supplementation 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

Bronsnick, Murzaku, and Rao 1039.e3

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 management 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,

1039.e4 Bronsnick, Murzaku, and Rao

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 cows 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
While observational studies suggest that
frequent milk consumption imparts a higher
risk of acne, randomized controlled trials
are necessary before dietary recommendations 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

J AM ACAD DERMATOL

DECEMBER 2014

The literature addresses many

fatty acids, chocolate, sugar,
multivitamins, but only the 2
addressedglycemic index/load
discussed here.

foods, including
probiotics, and
most commonly
and milkwill be

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 carbohydrate 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 lipogenesis.39,44,48,49 Both insulin and IGF-1 increase
gonadal and adrenal androgen synthesis, decrease
the hepatic synthesis of sex hormoneebinding
globulin (SHBG), and disinhibit androgen receptors,
thereby directly activating and increasing the
bioavailability of androgens. Androgens increase
sebum production and contribute to acne pathogenesis.48-51 Finally, IGFBP-3 is a potent proapoptotic
factor in keratinocytes and corneocytes.44
Smith et al52-55 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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Bronsnick, Murzaku, and Rao 1039.e5

VOLUME 71, NUMBER 6

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

Supplementation with
Vitamin D
Fish oil
Zinc sulphate
Selenium
Vitamin E
Pyridoxine
Sea buckthorn seed oil
Hempseed oil
Sunflower oil
Docosahexaenoic acid
Evening primrose oil
Borage oil
Prebiotics
Probiotics
Elimination diets
Maternal allergen avoidance
During pregnancy
During lactation
Exclusive breastfeeding
Hydrolyzed formula

Recommendation

Insufficient
Insufficient
Insufficient
Insufficient
Insufficient
Insufficient
Insufficient
Insufficient
Insufficient
Insufficient

data
data
data
data
data
data
data
data
data
data

for
for
for
for
for
for
for
for
for
for

conclusive
conclusive
conclusive
conclusive
conclusive
conclusive
conclusive
conclusive
conclusive
conclusive
No
No

recommendation
recommendation
recommendation
recommendation
recommendation
recommendation
recommendation
recommendation
recommendation
recommendation

Yes, in infants
Yes, prenatally and postnatally
Only for immunoglobulin Eemediated food allergy
proven by observed food challenge
No
No
Yes, for at least 4 months in high-risk infants
Yes, in high-risk infants

Level of evidence

IB
IA
IA
IA
IA
IA
IA
IA
IA
IA
IA
IA
IA
IA
IA

IA
IA
IB
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 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 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 communitybased 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

J AM ACAD DERMATOL

1039.e6 Bronsnick, Murzaku, and Rao

DECEMBER 2014

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

Low glycemic index/load diet

Milk restriction

Recommendation

Level of evidence

Yes
Insufficient data for conclusive recommendation

IB
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 stimulation.63 Milk also contains dihydrotestosterone
precursors, including placenta-derived progesterone, 5a-pregnanedione, 5a-androstanedione, and
numerous growth-related factors.64
In a series of 3 studies, Abedamowo et al65-67
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 physiciandiagnosed 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 cows
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

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 supplementation 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 between 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 metaanalysis86 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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Bronsnick, Murzaku, and Rao 1039.e7

VOLUME 71, NUMBER 6

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

Low-fat diet
Vitamin A supplementation
b-carotene
Retinol
Synthetic retinoid
(eg, isotretinoin, acitretin)
Vitamin D supplementation
Vitamin E supplementation
Vitamin C supplementation
Selenium supplementation

Recommendation

Level of evidence

No

IB

No
Consider to decrease SCC in patients with moderate risk
Decrease NMSC in patients with xeroderma pigmentosum
or renal transplant
Insufficient data for conclusive recommendation
Insufficient data for conclusive recommendation
Insufficient data for conclusive recommendation
Avoid due to increased risk of SCC and NMSC

IB
IB
IIA and IB
III
III
III
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 BCC93 and higher serum retinol levels
in BCC cases compared to controls.94 Multiple
studies, including 6 case control83-85,95-97 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 supplementation.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 pigmentosum108,109 and acitretin in renal
transplant patients110 identified statistically significant 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 BCC111 and SCC112-114
cell lines reveal differential expression and downstream 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

1039.e8 Bronsnick, Murzaku, and Rao

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)einduced 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 intake85 and
supplementation91 and subsequent BCC development 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 Cecontaining foods,90
vitamin C supplements,91 and plasma levels of
ascorbic acid125 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
Cerich food or supplements.93,99 In addition, 3 case
control 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 cytotoxicity in human keratinocytes and carcinogenesis
in mice.133-135 Studies have found a potentially
protective role of selenium for NMSC. In a case

J AM ACAD DERMATOL

DECEMBER 2014

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 association between dietary84,85 or plasma selenium94,95
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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