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© 2019 EDIZIONI MINERVA MEDICA Giornale Italiano di Dermatologia e Venereologia 2019 December;154(6):669-80
Online version at http://www.minervamedica.it DOI: 10.23736/S0392-0488.19.06433-2

REVIEW

Vitamin D and the skin: what should a dermatologist know?

Christina BERGQVIST 1, Khaled EZZEDINE 1, 2 *

1Departmentof Dermatology, AP-HP, Henri Mondor University Hospital, Université Paris-Est Créteil, Créteil, France; 2EA 7379
EpidermE, Université Paris-Est Créteil, Créteil, France
*Corresponding author: Khaled Ezzedine, Dermatology Hôpital Henri Mondor, 51 avenue du Maréchal de Lattre de Tassigny, 94000 Créteil, France.
E-mail: khaled.ezzedine@aphp.fr

A B S TRA C T
Although first discovered in 1931, vitamin D has seen an increased interest in the scientific community over the past decades, including the
dermatology field. Vitamin D promotes calcium and phosphorus absorption; however, the actions of vitamin D are not confined to bone. Indeed,
there is now overwhelming and compelling scientific data that vitamin D plays a crucial role in a plethora of cellular function and in extra-
skeletal health. Except for fatty fish livers, very few foods naturally contain vitamin D; and the major source of vitamin D comes from skin
exposure to sunlight via ultraviolet B. Keratinocytes are unique in the body as not only do they provide the primary source of vitamin D for the
body, but they also possess both the enzymatic machinery to metabolize the vitamin D produced to active metabolites. This has been referred
to as the photoendocrine vitamin D system. Vitamin D regulates keratinocytes proliferation and differentiation; and plays a role in the defense
against opportunistic infections. Multiple factors are linked to vitamin D status; and a growing number of dermatologic diseases has been linked
to vitamin D status such as atopic dermatitis, psoriasis, vitiligo, and cutaneous cancers. In this article, we reviewed the potential determinants of
vitamin D status, as its implications in dermatologic diseases.
(Cite this article as: Bergqvist C, Ezzedine K. Vitamin D and the skin: what should a dermatologist know? G Ital Dermatol Venereol 2019;154:669-80.
DOI: 10.23736/S0392-0488.19.06433-2)
Key words: Vitamin D; Skin diseases; Vitiligo; Dermatitis, atopic.

V itamin D is a fat-soluble vitamin which has seen an

increased interest in the scientific community and the
general public over the past two decades.1 Except for fatty
fish livers, very few foods naturally contain vitamin D; and
the major natural source of vitamin D is its synthesis in the
dermis. Vitamin D promotes calcium and phosphorus ab-
sorption, helping to maintain normal serum levels of these
minerals and thus plays a central role in skeletal health.2
Moreover, the actions of vitamin D are not confined to
bone. Indeed, Vitamin D also regulate many other cellular
functions and has versatile functions in nearly all organs,
including cardiovascular system,3, 4 malignancies,5, 6 neu-
rologic diseases,7, 8 reproductive health,9, 10 autoimmune
diseases,11, 12 infections,13, 14 among others.
The fact that sunlight could cure rickets was first sci-
entifically discovered in 1919.15 This was followed by
the discovery in 1924 that an inactive lipid in the diet and
skin could be converted by UV light into an antirachitic
substance.16 Vitamin D was finally identified in 1931.17
While rickets and osteomalacia due to severe vitamin D
deficiency are uncommon nowadays, subclinical vitamin
D deficiency is quite common, and may lead to osteopo-
rosis and an increased risk of fractures and falls in older
adults.18, 19 Vitamin D provided from both the diet and der-
mal synthesis is biologically inactive and requires enzy-
matic conversion to active metabolites. Vitamin D is con-
verted enzymatically in the liver to 25-hydroxyvitamin D
(25[OH]D), the major circulating form of vitamin D, and
then in the kidney to 1,25-dihydroxyvitamin D, the active
form of vitamin D.20
Vitamin D is available in 2 distinct forms, ergocalcif-
erol (vitamin D2) and cholecalciferol (vitamin D3). Previ-
tamin D3 is an intermediate in the production of cholecal-
ciferol (vitamin D3). It is synthesized nonenzymatically
in skin from 7-dehydrocholesterol during exposure to the
ultraviolet (UV) rays in sunlight,21 specifically UVB22

Vol. 154 - No. 6 Giornale Italiano di Dermatologia e Venereologia 669

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BERGQVIST
7-Dehydro-
UVB
(sunlight)
Excess UV
exposure Inactive
Previtamin D3 metabolites
cholesterol
(Lumisterol,
Tachysterol)
SKIN
Small
Heat
intestine
Vitamin D2
Vitamin D3
Vitamin D
Diet/Supplementation
Liver CYP2R1
25-hydroxy-
vitamin D
Kidney CYP27B1
1,25-dihydroxy-
vitamin D
Figure 1.—Vitamin D synthesis and metabolism.
(Figure 1). Previtamin D3 then undergoes a temperature-
dependent rearrangement to form vitamin D3 (cholecalcif-
erol).23 This system is remarkably efficient; a whole-body
exposure to UVB radiation inducing the light pink color
of the minimal erythema dose for 15-20 minutes leads
to the production of up to 10,000 International Unit (IU)
of Vitamin D.24, 25 However, it is difficult to estimate the
sunlight equivalent of oral vitamin D intake on an indi-
vidual basis since it varies with skin type, latitude, season,
and day time.26, 27 It is important to note that prolonged
exposure of the skin to sunlight does not produce toxic
amounts of vitamin D3 because of photoconversion of
previtamin D3 and vitamin D3 to inactive metabolites.28, 29
Vitamin D2 (ergocalciferol) is found in yeasts and plants
and, after ingestion, it is subjected to the same metabolic
pathway as vitamin D3.30
Despite these multiple sources — dietary intake, dietary
supplementation and UV radiation exposure — hypovita-
minosis D remains prevalent worldwide.31, 32 This has in-
cited public health guidelines to encourage sun exposure
for maintenance of sufficient vitamin D levels.33 Neverthe-
less, UV radiation has a harmful potential on human health.
Indeed, the World Health Organization estimates that UV
exposure leads to a loss of 1.5 million disability-adjusted
life-years, 60,000 premature deaths worldwide annually,
including 200,000 melanomas, 12.8 million nonmelanoma
skin cancers and 30% of eight million cataracts.33 Very
few studies have investigated the risk/benefit ratio of sun
exposure to maintain optimal vitamin D levels.18, 34
Recent meta-analyses confirmed the finding that 10-20
μg per day of vitamin D can reduce all-cause mortality and
cancer mortality in middle-aged and older people. Indeed,
vitamin D supplementation was associated with a small
670 Giornale Italiano di Dermatologia e Venereologia December 2019
VITAMIN D AND THE SKIN
but significant 3% (95% CI 1-6) reduction in all-cause
mortality in middle-aged and older adults.35
The aim of the present review is to provide an overview
of the relationship between vitamin D and the skin, includ-
ing the role of sun exposure, effects of photoprotection on
25-hydroxyvitamin D (25[OH]D) levels, and the potential
role of vitamin D in skin diseases.
Factors determining vitamin D level
Sun exposure, skin phototype, dietary intake, sociodemo-
graphics, anthropometric, lifestyle, and genetic polymor-
phisms are all important factors that influence vitamin D
levels.36 The primary factors that can potentially deter-
mine an individual’s vitamin D level are listed in Table
I.24-30, 37-53
A quick and easy score called vitamin D insufficiency
prediction score (VDIP) for identifying adults at risk of
vitamin D insufficiency using only clinical data (gender,
latitude, physical activity, season, usual sun exposure, skin
phototype) was recently proposed.54 This simple and cost-
less score could avoid unwarranted blood testing and/or
supplementation.
Environmental factors
A number of environmental factors can interfere with the
amount of UVB radiation reaching the skin: latitude,37
season, time of day, weather conditions,55 amount of air
pollution and surface reflection.38, 39, 55-57 Summer season,
along with lower latitude and higher amounts of sunshine
and sun exposure, are associated with a lower risk of vita-
min D deficiency.36, 38, 40
Another important factor influencing UVB radiation is
the solar zenith angle (SZA). The SZA is the angle be-
tween the local vertical (zenith) and a line from the ob-
server to the sun. Smaller SZAs result in more intense UV
radiation. It was shown that seasonal variation of 25[OH]
D levels occur in all latitudes in the United States, with
peaks occurring in September and troughs in March.41 For
example, in Boston, MA, from April to October at 12 pm
EST an individual with type III skin, with 25.5% of the
body surface area exposed, would need to spend 3 to 8
minutes in the sun to synthesize 400 IU of vitamin D. In
Miami, FL, an individual with type III skin would need to
spend 3 to 6 minutes at 12 pm EST to synthesize 400 IU.26
Cutaneous factors
By absorbing electromagnetic radiation across the entire
UV range, melanin competes with 7-dehydrocholesterol
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VITAMIN D AND THE SKIN BERGQVIST

Table I.—Factors that influence vitamin D serum levels.

Factors that influence vitamin D levels Comment Reference
Dietary vitamin D intake The Recommended Dietary Allowance (RDA) of vitamin D for children 1 Tripkovic et al.;30 Working Group of
to 18 years and adults through age 70 years is 600 IU It increases to 800 the Australian and New Zealand,
IU daily after age 71 years. The recommended daily intake for infants up Bone and Mineral Society;51
to 12 months is 400 IU daily.
Vitamin D is available in 2 distinct forms, ergocalciferol (vitamin D2) and
cholecalciferol (vitamin D3). Vitamin D2 (ergocalciferol) is found in
yeasts and plants.
Natural dietary sources of vitamin D3 include salmon, sardines, mackerel,
tuna, cod liver oil, shiitake mushrooms, and egg yolk.
Sun exposure A whole-body exposure to UVB radiation inducing the light pink color of Stamp et al.;24 Krause et al.;25
the minimal erythema dose for 15–20 min leads to the production of up Terushkin et al.;26 Binkley et al.;27
to 10,000 International Unit (IU) of vitamin D. Holick et al.;28 Holick et al.29
Prolonged exposure of the skin to sunlight does not produce toxic amounts
of vitamin D3 because of photoconversion of previtamin D3 and vitamin
D3 to inactive metabolites
Latitude Higher vitamin D levels are found at lower latitudes Terushkin et al.;26 Touvier et al.;36
Holick et al.;38 Major et al.;40 Kroll
et al.41
Season Lower vitamin D levels are found during the winter season Terushkin et al.26
Skin phototype Individuals with high concentrations of melanin require longer UV Clemens et al.;42 Powe et al.;43
exposure times to generate an equivalent amount of vitamin D3 when Shirazi et al.53
compared to individuals with lightly-pigmented skin.
Lower 25-hydroxyvitamin D levels are found in individuals with darker
skin
Age Older individuals, even in countries with adequate sun exposure, have a Carrillo-Vega et al.;47
higher prevalence of Vitamin D deficiency. Arabi et al.48

Gender Women have often been found to have lower levels of 25[OH]D compared Touvier et al.;36, Hagenau et al.46
to men.
Body Mass Index (BMI) A high BMI is associated with low vitamin D levels. Bertrand et al.;37, Greene-Finestone et
al.;39, Daly et al.;49 Thuesen et al.50
Physical activity Increased physical activity is associated with higher vitamin D levels Touvier et al.;36, Bertrand et al.;37,
Finestone et al.;39 Daly et al.;49
Thuesen et al.50
Alcohol intake Higher 25-hydroxyvitamin D levels with moderate intake Bertrand et al.;37, Thuesen et al.;50
Lower levels with excessive intake Shirazi et al.53
Genetic polymorphism Certain genetic polymorphisms are associated with lower or higher Marques et al.;44 Vidigal Barry et al.45
vitamin D levels.

for UVB photons.58 Individuals with high concentrations
of melanin thus require longer UV exposure times to gen-
erate an equivalent amount of vitamin D3 when compared
to individuals with lightly-pigmented skin.42 Indeed, in
one study, the prevalence of hypovitaminosis D (serum
25[OH]D levels < 25 nmol/L) was found to be 20-fold
higher among African American women than Caucasians
(12.2% versus 0.5% respectively).59 In another study,
community-dwelling black Americans, as compared with
whites, had lower levels of total 25[OH]D and vitamin D-
binding protein, resulting in similar concentrations of es-
timated bioavailable 25-hydroxyvitamin D.43 The authors
postulated that racial differences in the prevalence of com-
mon genetic polymorphisms provided a likely explanation
for this observation. Furthermore, in light-skinned indi-
viduals, low-dose summer sunlight exposures confer vita-
min D sufficiency along with low-level, non-accumulating
DNA damage. On the other hand, the same exposures lead
to minimal DNA damage but less vitamin D in brown-
skinned people.60
Photoprotection
The risks and benefits of sun exposure is a major public
health concern. Over the past decades, photo-protective
measures, have been advocated by dermatologists to pre-
vent photoaging, skin cancer, or flares of photosensitive
disorders.
Photoprotection interferes with UVB–7-dehydrocho-

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BERGQVIST
lesterol by absorbing, reflecting or scattering incident UV
radiation. Multiple studies have investigated the impact of
sunscreen wear on vitamin D levels.61-63 For example, a
study of 20 long-term sunscreen users in the U.S. found
that their mean serum 25[OH]D level was significantly
lower than in 20 age- and sun exposure-matched control
subjects.64 However, other studies which included a much
larger number of patients, found that typical sunscreen use
is unlikely to lower vitamin D levels.62, 65
Factors related to the individual
The metabolism of vitamin D is complex, its receptor Vita-
min D Receptor (VDR) and proteins encoded by the genes
CYP27B2 and CYP24A1 can influence vitamin D serum
levels. Genetic polymorphisms are yet another important
determinants of vitamin D status.44, 45
Women have often been found to have lower levels of
25[OH]D compared to men.36, 46 Older individuals, even
in countries with adequate sun exposure, have a higher
prevalence of vitamin D deficiency.47, 48 A high body mass
index (BMI), low level of physical activity and excessive
alcohol intake are also associated with low vitamin D lev-
els.37, 39, 49, 50 Interestingly, increased physical activity was
found to be an independent predictor of vitamin D levels.36
The particular case of sunbeds
The sunbed industry has long been promoting the use of
sunbed devices, specifically providing the public with am-
biguous messages such as that sunbeds and sunlight are the
“only” way for the body to manufacture the necessary vi-
tamin D.66 In fact, sunbeds have been promoted by the in-
dustry as a vitamin D source.67 In a French cross-sectional
study, 6% or the population agreed with this argument, in
particular the youth.1 Several studies have confirmed that
sunbed use can increase the serum levels of 25[OH]D.18, 68
This increase, however, is not sustained if sunbed use is
not regular and continuous. And within few weeks after
the last exposure, serum 25[OH]D levels decreases to the
initial value.69, 70 On the other hand, sunbeds are carcino-
genic to humans, and several meta-analyses have repeat-
edly shown that chronic sunbed use increases melanoma
risk by 15– 25%.71-73 Sunbeds should therefore never be
considered as an option to achieve an appropriate vitamin
D status.18
Diet
Oral intake helps in maintaining adequate vitamin D lev-
els. Since very few foods naturally contain vitamin D, pri-
672 Giornale Italiano di Dermatologia e Venereologia December 2019
VITAMIN D AND THE SKIN
mary sources include fortified products and foods.74 Natu-
ral dietary sources of vitamin D include salmon, sardines,
mackerel, tuna, cod liver oil, shiitake mushrooms, and egg
yolk.51
The Recommended Dietary Allowance (RDA) of vita-
min D for children 1 to 18 years and adults through age 70
years is 600 IU daily according to the Institute of Medicine
(IOM) report released in 2010.75 It increases to 800 IU dai-
ly after age 71 years. The recommended daily intake for
infants up to 12 months is 400 IU daily. In obese patients,76
patients with malabsorption syndromes, and patients on
medications affecting vitamin D metabolism, a higher
dose, usually twice or three times higher, is suggested to
treat vitamin D deficiency. However, it is important to note
that estimates of vitamin D requirements vary and depend
in part on sun exposure and disease state. There has been a
debate regarding which form of vitamin D should be used
for supplementation. A meta-analysis demonstrated that
vitamin D3 is more efficacious at raising serum 25[OH]
D concentrations than is vitamin D2, and thus vitamin
D3 should be the preferred choice for supplementation.30
Depending on the country, vitamin D3 (cholecalciferol) is
available in doses ranging from 400 to 100,000 IU.
Vitamin D and skin biology
Keratinocytes are unique in the body as not only do they
provide the primary source of vitamin D for the body, but
they also possess both the enzymatic machinery to me-
tabolize the vitamin D produced to active metabolites (in
particular 1,25-dihydroxyvitamin D) and the VDR that
enables them to respond to the 1,25-dihydroxyvitamin D
thus generated.77 This has been referred to as the photo-
endocrine vitamin D system that is stimulated by UVB ir-
radiation.23
Vitamin D regulates keratinocytes proliferation and dif-
ferentiation
The active metabolite of vitamin D, 1,25-dihydroxyvita-
min D, suppresses keratinocytes proliferation while pro-
moting their differentiation through the VDR.78 Indeed, vi-
tamin D was shown to regulate terminal differentiation of
mouse epidermal cells in primary culture79 and to inhibit
keratinocyte proliferation in vitro;80 moreover, hyperpro-
liferative keratinocytes that lacked a vitamin D receptor
exhibited a reduced rate of apoptosis.81
Ceramide synthesis is stimulated by calcitriol (1,25-di-
hydroxyvitamin D) which induces a neutral Mg 2+ -depen-
dent sphingomyelinase, leading to an increase in the con-
 ©
or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access
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This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies (either sporadically
to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is not permitted. It is not permitted to remove,
VITAMIN D AND THE SKIN
version of sphingomyelin to ceramide;82 and in return, ce-
ramide enhances the pro-differentiating effect of calcitriol
on keratinocytes in a feedback loop.83 While pharmacolog-
ical concentrations of calcitriol exert a pro-apoptotic effect
on keratinocytes, physiological concentrations, however,
do not initiate apoptosis in cultured keratinocytes.84
Effects of vitamin D on the cutaneous immune system
The immunomodulatory role vitamin D on cells of the
adaptive and innate immune system has been extensively
reviewed in the literature.85-87 Vitamin D can inhibit B
cell proliferation and differentiation, thereby blocking im-
munoglobulin secretion.88, 89 Vitamin D can also inhibit
T cell proliferation,90 resulting in a shift from a Th1 to a
Th2 phenotype.91, 92 Moreover, vitamin D alters T cell dif-
ferentiation, skewing it away from the inflammatory Th17
phenotype93, 94 and enhances the induction of T regulatory
cells.95-98 This leads to a decrease inflammatory cytokine
(IL-17, IL-21) and an increase in anti-inflammatory cy-
tokines such as IL-10. Vitamin D also inhibits monocyte
production of inflammatory cytokines such as IL-1, IL-6,
IL-8, IL-12 and TNFα96. It additionally inhibits dendritic
cell differentiation and maturation allowing them to main-
tain an immature phenotype with a decreased expression
of MHC class II molecules, co-stimulatory molecules and
IL12.99-101
Furthermore, vitamin D plays a role in the defense
against opportunistic infections. Indeed, vitamin D strong-
ly upregulates antimicrobial peptide gene expression102-104
thereby contributing to the integrity of the cutaneous bar-
rier. Vitamin D is linked to the activation of Toll-like re-
ceptors and subsequent production of cathelicidin leading
to diminished sensitivity to bacterial infections.105, 106 In-
deed, binding of vitamin D on keratinocyte VDR enhances
the production of cathelicidins, which have potent micro-
bicidal activities and are a major component of the innate
immune system.107 It also induces autophagy in human
macrophages.108
Vitamin D and cutaneous disease
Atopic dermatitis
Atopic dermatitis (AD) is a common inflammatory skin
disorder with a multifaceted pathogenesis involving an
interplay among skin barrier deficiency and immunologi-
cal imbalance.109 Since Vitamin D has immunomodulatory
properties and enhances the cutaneous barrier, it is likely
that vitamin D plays a role in AD.110-112 Indeed, VDR poly-
Vol. 154 - No. 6 Giornale Italiano di Dermatologia e Venereologia
BERGQVIST
morphisms are increased in AD patients compared with
healthy controls, suggesting a crucial role of vitamin D in
the pathogenesis of the disease.113
As mentioned above, vitamin D plays a central role in
keratinocyte differentiation.114 Vitamin D has been shown
to stimulate filaggrin synthesis which plays a key role in
barrier formation.115
Furthermore, the active form of vitamin D enhances ex-
pression of antibacterial peptides, and thus prevent skin
infections116
Therefore, it is postulated that vitamin D deficiency
might exacerbate AD via disturbed epidermal barrier func-
tion and immunologic dysregulation, with subsequent im-
paired defense against infections. Low sun exposure and
subsequent low vitamin D production in the winter might
possibly partially explain the disease exacerbation during
this season.
A number of studies investigated the role of vitamin
D in AD. Several studies found low concentration of vi-
tamin D in patients with AD,117 and vitamin D supple-
mentation improved clinical signs of the disease.118, 119 A
recent meta-analysis showed that compared with healthy
controls, the serum 25[OH]D level was lower in the AD
patients of all ages and predominantly in the pediatric AD.
They also found that vitamin D supplementation showed
a higher mean difference in severity of AD symptoms.120
The results of these studies indicate that vitamin D supple-
mentation may have a therapeutic role in the disease with
a good safety profile. However, further trials involving
larger sample sizes and longer treatment periods will be
necessary to more fully assess vitamin D as a therapeutic
strategy in AD.
Psoriasis
Psoriasis is a chronic disease known for its frequent re-
lapses and difficult to treat. A meta-analysis has recently
demonstrated that circulating 25[OH]D levels are lower
in patients with psoriasis, and that a small but statistically
significant negative correlation exists between 25[OH]D
levels and psoriasis severity.121
Several studies have identified an association between
polymorphisms of VDR and psoriasis susceptibility.104 For
example, one study found that the A-1012G promoter poly-
morphism of the VDR gene is associated with psoriasis
risk through a lower expression of VDR mRNA, favoring
cutaneous barrier alteration and subsequent development
of psoriatic lesions.122 However, this association is likely
to be weak and potentially restricted to specific popula-
tions, since no genetic variant examined in the VDR gene
673
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BERGQVIST
showed a robust and reproducible association with risk for
psoriasis in a meta-analysis.123
On the therapeutic level, Vitamin D analogs have a fa-
vorable safety profile, and are effective in the treatment of
psoriasis.124 The therapeutic effects of topical vitamin D
occur via a VDR mediated inhibition of epidermal prolif-
eration as well as through inducing keratinocyte differen-
tiation by increasing intracellular calcium levels.125 More-
over, Vitamin D analogs were shown to differentially alter
antimicrobial peptide expression in lesional psoriatic skin
and cultured keratinocytes and to normalize the proinflam-
matory cytokine milieu and decrease interleukin (IL)-17A,
IL-17F and IL-8 transcription.126
One study demonstrated that oral calcitriol (1,25-di-
hydroxyvitamin D) resulted in psoriasis improvement in
88% of 85 patients with psoriasis; whereby 26.5% had
complete clearance, 36.2% had moderate improvement
and 25.3% had slight improvement.127 Another study dem-
onstrated that combining oral calcitriol to acitretin resulted
in a faster reduction of Psoriasis Area Severity Index in
patients of chronic plaque psoriasis.128 Further trials in-
volving larger sample sizes and longer treatment periods
will be necessary to more fully assess vitamin D as a thera-
peutic strategy in psoriasis. A randomized control trial is
currently studying the effect of vitamin D supplementation
on psoriasis severity (NCT03334136).
Vitiligo
Vitiligo is an acquired autoimmune pigmentary disorder
which results in the destruction of functional melanocytes
in the epidermis. The disease is often associated with an
autoimmune background and thyroid autoimmune dis-
eases are found in almost 20% to 30% of patients with
non-segmental vitiligo.129, 130 In turn, various autoimmune
disorders have been associated with decreased levels of
vitamin D;131 however, the exact mechanism of this as-
sociation remains to be elucidated. Interestingly, Vitamin
D analogues are effective topical therapies for repigment-
ing vitiligo;132, 133 and the combination of UVA or UVB
therapy with topical vitamin D analogs was shown to be
effective in treating vitiligo.133
There is evidence that vitiligo is significantly associ-
ated with lower serum vitamin D concentration. A pilot
study on 45 patients showed that vitamin D levels were
indeed low in patients with vitiligo; and very low levels
were associated with the presence of a comorbid autoim-
mune disease.134 A recent meta-analysis of observational
studies found a significantly lower concentration of serum
25[OH]D in patients with vitiligo compared with healthy
674 Giornale Italiano di Dermatologia e Venereologia December 2019
VITAMIN D AND THE SKIN
controls.135 Moreover, several studies have published as-
sociations between VDR polymorphisms and 25[OH]D
levels in vitiligo patients.136, 137 This association between
VDR polymorphisms, serum 25[OH]D levels, and vitiligo
caused significant clinical and epidemiological research in
recent years, but the reported results have been inconsis-
tent.136, 137 A recent meta-analysis revealed that the VDR
Apal locus (and not BsmI, TaqI, and FokI loci) increased
the susceptibility risk of vitiligo.138 It also confirmed that
serum 25[OH]D deficiency was positively associated with
the incidence of vitiligo. Monitoring 25[OH]D levels in
vitiligo patients is thus recommended in order to prevent
other complications of vitamin D deficiency.
Oral vitamin D has not been well studied in the treat-
ment of vitiligo. A single pilot study was done to assess
the efficacy and safety of prolonged high-dose vitamin D3
treatment (35,000 IU daily for 6 months) in patients with
psoriasis and vitiligo. Fourteen of 16 patients with vitiligo
had repigmentation ranging from 25–75% with no signifi-
cant change in metabolic parameters, thus suggesting that
high-dose vitamin D3 therapy may be effective and safe for
vitiligo patients.139
Skin cancer
Vitamin D has been extensively studied in various malig-
nancies. Although early studies showed an inverse rela-
tionship between circulating 25[OH]D levels and cancer
risk;140-142 more robust meta-analyses confirm that there is
currently no firm evidence that vitamin D supplementation
decreases or increases cancer occurrence.35, 143, 144
Cutaneous malignancies have also had their share of
vitamin D investigation; and several researchers had sug-
gested that oral intake of vitamin D could potentially de-
crease the risk of skin cancer.145-147
Deciphering the role of vitamin D in the pathogenesis
skin cancer in humans is extremely complex, since sun ex-
posure is responsible for both vitamin D production and
skin cancer. Most of the evidence is provided from in-vitro
studies or mouse models, with additional information from
epidemiological and genetic studies in humans.
For example, vitamin D was shown to regulate terminal
differentiation of mouse epidermal cells in primary cul-
ture79 and to inhibit keratinocyte proliferation in vitro;80
moreover, hyperproliferative keratinocytes that lacked a
vitamin D receptor exhibited a reduced rate of apoptosis.81
Vitamin D produced by skin exposure to UV radiation was
shown to inhibit murine basal cell carcinoma.148 Binding
of active Vitamin D to the VDR was shown to protect the
skin from UVB-induced tumor formation by interacting
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or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access
COPYRIGHT 2019 EDIZIONI MINERVA MEDICA
cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo, or other proprietary information of the Publisher.
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies (either sporadically
to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is not permitted. It is not permitted to remove,
VITAMIN D AND THE SKIN
with the β-catenin pathway.149 Vitamin D was also shown
to enhance the DNA repair process un human keratino-
cytes150 and to reduce UVR-induced cyclobutane pyrimi-
dine in vitro.151, 152 VDR polymorphisms were found to be
associated with altered prognosis in patients with malig-
nant melanoma whereby homozygosity for certain variant
alleles was significantly associated with thicker tumors.153
Regarding epidemiological data, here again, the litera-
ture provides conflicting results. A prospective study on
skin cancer incidence over an 11-year period in Austra-
lia performed baseline assessment of serum 25[OH]D in
1,191 adults and found a positive association between
baseline vitamin D levels and basal cell carcinoma (BCC)
and melanoma incidence and a negative association with
squamous cell carcinoma (SCC) incidence. Another pro-
spective study on women, demonstrated that plasma vita-
min D levels were positively associated with non-melano-
ma skin cancer risk.154 However, the positive association
between plasma vitamin D and non-melanoma skin cancer
is confounded by sun exposure, since most circulating vi-
tamin D is due to sun exposure, In contrast, an inverse
association was also found between non-melanoma skin
cancer and vitamin D status.155
A recent meta-analysis on vitamin D intake and skin
cancer found no association between the blood levels of
25[OH]D and cutaneous melanoma risk, and a statisti-
cally significant positive association with increasing risk
of non-melanoma skin cancer for high values of 25[OH]
D. They found that vitamin D taken from diet and/or sup-
plements is not associated with incidence of skin cancer.
Finally, they found that vitamin D serum levels seem to
be inversely associated with cutaneous melanoma Breslow
thickness at diagnosis.156
Other cutaneous disorders
As previously mentioned, vitamin D mediates immuno-
modulatory functions and its deficiency has been associ-
ated with autoimmune diseases.
Discoid lupus and subacute cutaneous lupus erythema-
tosus are UV triggered skin diseases, and photoprotection
is usually recommended in those diseases. Studies have
identified vitamin D deficiency in patients with cutaneous
lupus erythematosus throughout the year.157, 158Vitamin D
deficiency was also shown to be extremely common in sys-
temic sclerosis patients, reaching rates as high as 90%.159
Therefore, monitoring and correcting the vitamin D status
should be recommended in those patient population.
Vitamin D deficiency has also been reported in patients
with alopecia areata (AA). Vitamin D deficiency in AA
Vol. 154 - No. 6 Giornale Italiano di Dermatologia e Venereologia
BERGQVIST
was found to be inversely correlated with disease severity
and duration.160, 161 VDR expression in skin biopsies of AA
was reduced and inversely correlated with inflammation
histologically but did not correlate with serum vitamin D
levels, severity, pattern, or duration of illness.160
Vitamin D deficiency is common in patients with my-
cosis fungoides (MF),162, 163 and depressed vitamin D and
FokI polymorphism are potentially involved in the context
of MF.163 The prevalence of vitamin D deficiency among
cutaneous T-cell lymphoma patients was close to other
cancer patients compared with healthy controls.164
Vitamin D deficiency has also been reported in inherited
ichtyoses. One study on 53 patients with inherited ichtyo-
sis showed that more than 80% did not have an optimum
status of vitamin D, with nearly one-third showing vitamin
D deficiency.165 High grades of ichthyosis severity, dark
skin, and winter/spring seasons were identified as indepen-
dent risk factors for Vitamin D deficiency. In a smaller se-
ries on 9 adult patients with inherited ichtyosis, all patients
had abnormally low vitamin D (25[OH]D<30 ng/mL) and
three had Vitamin D deficiency [25[OH]D<10 ng/mL].166
Patients with polymorphic light eruption have decreased
serum levels of 25-hydroxyvitamin-D3 that increase upon
311 nm UVB photohardening. Thus, it was speculated that
boosting levels of vitamin D may be important in amelio-
rating PLE167 On the other hand, topical treatment with
calcitriol was shown to diminish PLE, suggesting a poten-
tial therapeutic benefit of topical 1,25-dihydroxyvitamin
D3 analogues as prophylactic treatment in patients with
PLE.168
Vitamin D excess
The dose of vitamin D intake at which it becomes toxic
is not well-defined. The IOM has defined the “tolerable
upper intake level” for vitamin D as 4000 IU daily for
healthy adults and children 9 to 18 years.75
Vitamin D intoxication is usually due to inappropriate
ingestion of massive doses vitamin D preparations in the
range of 50,000 to 1 million IU/d for several months to
years.169 Exogenous Vitamin D intoxication is diagnosed
by markedly elevated 25(OH)D concentrations (>150 ng/
mL) associated with severe hypercalcemia and suppressed
parathyroid hormone (PTH) activity. Prolonged exposure
of the skin to sunlight does not produce toxic amounts of
vitamin D3, due to photoconversion of previtamin D3 and
vitamin D3 to inactive metabolites.28, 29 Prolonged sun-
exposure results in a maximum serum 25[OH]D level of
<80 ng/mL.27, 170, 171
Symptoms of acute intoxication are due to hypercalce-
675
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or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access
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cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo, or other proprietary information of the Publisher.
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies (either sporadically
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BERGQVIST
mia and include polyuria, polydipsia, confusion, anorex-
ia, vomiting, and muscle weakness. Chronic intoxication
may cause nephrocalcinosis, bone demineralization, and
pain.169, 172
Conclusions
The skin plays a central role in Vitamin D metabolism; in
turn vitamin D plays an important role in skin biology by
modulating inflammation, directly affecting lymphocyte
function and cytokine secretion. It therefore comes as no
surprise that low vitamin D levels have been associated
with multiple dermatological disorders. Physicians should
be aware of the appropriate dose supplementation and
should promote awareness of safe sun protection. Further
trials involving larger sample sizes and longer treatment
periods will be necessary to better assess the role of vi-
tamin D as a therapeutic option in dermatologic diseases.
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or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access
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cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo, or other proprietary information of the Publisher.
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies (either sporadically
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Conflicts of interest.—The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.
Article first published online: July 12, 2019. - Manuscript accepted: July 8, 2019. - Manuscript received: July 3, 2019.
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