Vitamin D and the Skin: Focus on a Complex Relationship

Abstract

The “sunshine” vitamin is a hot topic that attracted ample attention over the past decade, specially that a considerable proportion of the worldwide population are deficient in this essential nutrient. Vitamin D was primarily acknowledged for its importance in bone formation, however; increasing evidence point to its interference with the proper function of nearly every tissue in our bodies including brain, heart, muscles, immune system and skin. Thereby its deficiency has been incriminated in a long panel of diseases including cancers, autoimmune diseases, cardiovascular and neurological disorders. Its involvement in the pathogenesis of different dermatological diseases is no exception and has been the subject of much research over the recent years. In the current review, we will throw light on this highly disputed vitamin that is creating a significant concern from a dermatological perspective. Furthermore, the consequences of its deficiency on the skin will be in focus.

Full text

REVIEW
Vitamin D and the skin: Focus on a
complex relationship: A review
Wedad Z. Mostafa *, Rehab A. Hegazy
Department of Dermatology, Faculty of Medicine, Cairo University, Cairo, Egypt
ARTICLE INFO
Article history:
Received 30 November 2013
Receivedinrevisedform 29 January 2014
Accepted 30 January 2014
Available online xxxx
Keywords:
Vitamin D
Deficiency
Dermatology
Immunological
ABSTRACT
The ‘‘sunshine’’ vitamin is a hot topic that attracted ample attention over the past decades, spe-
cially that a considerable proportion of the worldwide population are deficient in this essential
nutrient. Vitamin D was primarily acknowledged for its importance in bone formation, how-
ever; increasing evidence point to its interference with the proper function of nearly every tissue
in our bodies including brain, heart, muscles, immune system and skin. Thereby its deficiency
has been incriminated in a long panel of diseases including cancers, autoimmune diseases, car-
diovascular and neurological disorders. Its involvement in the pathogenesis of different derma-
tological diseases is no exception and has been the subject of much research over the recent
years. In the current review, we will throw light on this highly disputed vitamin that is creating
a significant concern from a dermatological perspective. Furthermore, the consequences of its
deficiency on the skin will be in focus.
ª2014 Production and hosting by Elsevier B.V. on behalf of Cairo University.
Introduction
It is somewhat ironic that vitamin D, through a historical acci-
dent, became classified as a ‘vitamin’, owing to the fact that
vitamin is conventionally defined as ‘essential item needed in
the diet’. The paradox with ‘vitamin D’ is that diet per se is
usually poor in vitamin D except for cod or other fish oils or
food fortified with this vitamin [1].
Vitamin D is actually a fat-soluble prohormone steroid that
has endocrine, paracrine and autocrine functions [2]. The
endocrine effects of vitamin D are mainly involved in serum
calcium homeostasis. Vitamin D and calcium are often used
in the same sentence because they work closely together, vita-
min D’s primary role is to control the levels of calcium found
in the bloodstream by constantly allowing calcium and phos-
phate absorption from the intestine or taking calcium from
bones. Furthermore, vitamin D is an enabling agent that, when
present in optimal concentrations, has no perceptible effect on
calcium absorption in its own right; however, it permits or
facilitates flexible physiologic response to varying calcium need
[3].
The paracrine and autocrine effects of vitamin D depend on
genetic transcription, unique to the type of cell expressing nu-
clear vitamin D receptors. These potential effects include inhi-
bition of cell proliferation, promotion of cell differentiation,
and apoptosis which may in turn have roles in cancer, immu-
nity, and many organ systems [4–8]. The potential myriad ef-
fects of this vitamin in human health and disease have led to
an escalating interest in vitamin D inadequacy and the best
methods to normalize suboptimal levels.
*Corresponding author. Tel.: +20 2 33377419, +20 122 2129027.
E-mail address: wedad_mostafa@kasralainy.edu.eg (W.Z. Mostafa).
Peer review under responsibility of Cairo University.
Production and hosting by Elsevier
Journal of Advanced Research (2014) xxx, xxx–xxx
Cairo University
Journal of Advanced Research
2090-1232 ª2014 Production and hosting by Elsevier B.V. on behalf of Cairo University.
http://dx.doi.org/10.1016/j.jare.2014.01.011
Please cite this article in press as: Mostafa WZ, Hegazy RA, Vitamin D and the skin: Focus on a complex relationship: A review, J Adv Res
(2014), http://dx.doi.org/10.1016/j.jare.2014.01.011

Sources of vitamin D
There are only 3 known sources of vitamin D; sunlight, diet,
and vitamin D supplements (Fig. 1)[2,9,10].
Sunlight
The most well-known source of vitamin D is via synthesis in
the skin induced by sun exposure. The first reference to the
physiological effect of sunlight on vitamin D was illustrated
by the Greek historian Herodotus. He visited the battlefield
where Cambyses (525 BC) overcame the Egyptians, and in-
spected the skulls of slain Persians and Egyptians. He noted
that the Persian skulls were so fragile that they broke even
when struck with a pebble, whereas those of the Egyptians
were strong and could scarcely be broken even when struck
with a stone. The Egyptians’ explanation to Herodotus was
that they went bareheaded from childhood exposing their
heads to sunlight, whereas Persians covered their heads with
turbans shading them from the sun resulting in skull bone
weakness. Later on, in the mid 17th century Francis Glisson,
Professor of Physics at Cambridge University, in his treatise
on rickets observed that the disease was common among in-
fants and young children of country farmers who ate well,
and whose diets were known to include eggs and butter, but -
who lived in rainy, misty parts of the country and who were
kept indoors during long severe winters [11].
Vitamin D synthesis in the skin
According to the Commission Internationale de l’Eclairage
(CIE) [12], the vitamin D effective radiation is described in
terms of its action spectrum (i.e., the efficiency of each wave-
length to synthesize vitamin D in skin) which covers the spec-
tral range (255–330 nm) with a maximum at about 295 nm
(UVB). A whole body exposure to UVB radiation inducing
the light pink color of the minimal erythema dose for 15–
20 min is able to induce the production of up to 250 lg vitamin
D (10,000 IU) [13,14].
Its precursor 7-dehydrocholesterol in the plasma mem-
branes of both epidermal basal and suprabasal keratinocytes
and dermal fibroblasts is converted to previtamin D
3
. Cutane-
ously synthesized vitamin D
3
is released from the plasma
membrane and enters the systemic circulation bound to vita-
min D-binding protein (DBP) [15]. Serum concentrations of
vitamin D
3
peak 24–48 h following exposure to UV radiation
[13]. Thereafter, vitamin D
3
levels decline exponentially with
a serum half-life ranging from 36 to 78 h [13,14]. As a lipid-
soluble molecule, vitamin D
3
can be taken up by adipocytes
and stored in subcutaneous or omental fat for later use [16].
The distribution of vitamin D
3
into adipose tissue prolongs
its total-body half-life to approximately two months as first
detected on experiments on submarine personnel [17–19].
Once in the circulation, vitamin D is converted by a hepatic
hydroxylase into 25-hydroxyvitamin D (25(OH)D; calcidiol).
The circulating 25(OH)D level is an indicator of the vitamin D
status. This level reflects both ultraviolet exposure and dietary
vitamin D intake. The serum half-life of 25(OH)D is approxi-
mately 15 days [2]. 25(OH)D is not biologically active except
at very high, non-physiological levels [20]. As needed,
25(OH)D is converted in the kidney to its active hormonal form
1,25-dihydroxyvitamin D (1,25(OH)
2
D; calcitriol) in a process
which is usually tightly controlled by the parathyroid hormone
which levels start rising at 25(OH)D cutoff levels of 75 nmol/L
or lower. In spite of this, inadequate vitamin D supply lowers
the circulating level of calcitriol [16]. Circulating calcitriol is also
adversely affected by a reduced number of viable nephrons, high
serum concentrations of fibroblast growth factor-23, and high
levels of inflammatory cytokines such as interleukin (IL)-1, IL-
6, and tumor necrosis factor-alpha (TNF-a)[19,21].
It is important to know that the conversion of previtamin
D
3
to the inactive photoproducts lumisterol and tachysterol
balances the cutaneous biosynthesis of vitamin D
3
as a feed-
back loop. This mechanism ensures that one cannot ‘‘over-
dose’’ on vitamin D
3
by photoexposure alone. After less than
1 minimal erythema dose (MED; i.e., the amount of photoex-
posure required to produce faint pinkness in the skin at 24 h
after exposure), the concentration of previtamin D
3
reaches
maximal levels and further UV radiation merely results in
the production of inactive metabolites [2].
Fig. 1 A diagram illustrating the different sources and forms of vitamin D.
2 W.Z. Mostafa and R.A. Hegazy
Please cite this article in press as: Mostafa WZ, Hegazy RA, Vitamin D and the skin: Focus on a complex relationship: A review, J Adv Res
(2014), http://dx.doi.org/10.1016/j.jare.2014.01.011

Dietary sources and supplements
Vitamin D is available in 2 distinct forms, ergocalciferol (vita-
min D
2
) and cholecalciferol (vitamin D
3
). Sunshine exposure
provides vitamin D in the form of D
3
only, while dietary
sources are able to provide both forms, which are officially re-
garded by many as equivalent and interchangeable [22–24].
However, several reasons have been suggested to argue against
this presumption including that both are different in their effi-
cacy at raising serum 25-hydroxyvitamin D, with diminished
binding of vitamin D
2
metabolites to vitamin D binding pro-
tein in plasma, as well as the detection of a nonphysiologic
metabolism and shorter shelf life for vitamin D
2
. Nevertheless,
still to this day, the major preparations of vitamin D for pre-
scription are in the form of vitamin D
2
, not vitamin D
3
. Mul-
tivitamins may contain either vitamin D
2
or vitamin D
3
, but
most companies are now reformulating their products to con-
tain vitamin D in the D
3
form [25].
There are only few natural sources of vitamin D including
cod liver oil, cheese, egg yolks, mackerel, salmon, tuna fish,
and beef liver. Because it is not easy for many individuals to
obtain adequate vitamin D intake from natural dietary sources
alone, many countries fortify foods such as orange juice, milk,
yogurt, and cereal with vitamin D. Many inexpensive supple-
mental vitamin D forms are readily available over the counter
in both vitamin D
3
and vitamin D
2
forms and with or without
calcium [26,27].
Vitamin D levels
Different cut-off values for the normal threshold of vitamin D
have been used until recently [28]. A level of 50 nmol/L has
been widely used to define 25(OH)D insufficiency, while some
studies have used 37.5 nmol/L as the lowest level of suffi-
ciency [29–31]. Further studies, however, suggest that a 25-
(OH)D level as high as 75 nmol/L or higher is needed to cover
all physiological functions of vitamin D and should therefore
be considered optimal [32–36].
Factors influencing vitamin D levels
Nutrient deficiencies are usually the result of dietary inade-
quacy, impaired absorption and use, increased requirement,
or increased excretion. Vitamin D deficiency can occur when
usual intake is lower than recommended levels over time, expo-
sure to sunlight is limited, the kidneys cannot convert
25(OH)D to its active form, or absorption of vitamin D from
the digestive tract is inadequate. Vitamin D-deficient diets are
associated with milk allergy, lactose intolerance, ovo-vegetari-
anism, and veganism [37].
Regarding the amount of vitamin D production in human
skin, it depends on several variables including environmental
factors such as geographic latitude,season, time of day,weather
conditions (cloudiness), amount of air pollution and surface
reflection which can all interfere with the amount of UVB radi-
ation reaching the skin [38–41].
Personal variations represent another group of influential
factors affecting the vitamin D production in the skin, includ-
ing age as elderly people have thinner skin, and consequently
are less capable of synthesizing vitamin D [7,38,39] and obesity
as overweight individuals have reduced vitamin D levels [42].It
is also noteworthy that skin type determines a person’s effec-
tiveness in producing vitamin D. Light skins (type I) produce
up to six fold the amount of vitamin D produced by dark skins
(type VI). In addition, clothing habits,lifestyle,workplace (e.g.,
indoor versus outdoor), and sun avoidance practices have a
strong impact on vitamin D synthesis [38–41].
The influence of some common practices as using sunblocks
or receiving sunbeds on vitamin D production is another point
of interest. Sunblocks are known to block UVB radiation
effectively. However, it is questionable whether sunscreen in
practice causes any vitamin D deficiency. Absolute full-body
coverage of sunscreen is uncommon. Some areas of the skin
are always left out. At times and locations where the sun is in-
tense and the temperature is high enough to make the popula-
tion use sunscreen, its vitamin D status is generally very
satisfactory [39–41]. On the other hand the use of sun beds is
controversial, but regardless, subjects who regularly use tan-
ning beds that emit UVB radiation are likely to have higher
25(OH)D concentrations. Nevertheless, there is a trend toward
discouraging the use of such tanning beds for fear of mela-
noma and non-melanoma skin cancer [43].
Vitamin D and the skin: What’s beyond its synthesis and
metabolism?
The skin is unique in being not only the source of vitamin D
for the body but also in being capable of responding to the ac-
tive metabolite of vitamin D, 1,25(OH)
2
D. Both 1,25(OH)
2
D
and its receptor (VDR) play essential roles in the skin.
Skin differentiation and proliferation
Both calcium and 1,25(OH)
2
D perform important and inter-
acting functions in regulating the skin differentiation process.
1,25(OH)
2
D increases the expression of involucrin, transgluta-
minase, loricrin, and filaggrin and increases keratinocyte corni-
fied envelope formation while inhibiting proliferation [44,45].
These actions are due to, at least in part, the ability of
1,25(OH)
2
D to increase intracellular calcium levels achieved
by induction of the calcium receptor [46], and the phospholi-
pase C [47] that are critical for the ability of calcium to stimu-
late keratinocyte differentiation [48,49]. Mice lacking the VDR
show defective epidermal differentiation manifesting as re-
duced levels of involucrin and loricrin and loss of keratohya-
line granules [50,51].
Cutaneous antimicrobial effects
1,25(OH)
2
D and its receptor regulate the processing of the
long chain glycosylceramides that are critical for the skin bar-
rier formation [52] which is crucial in defending the skin. Fur-
thermore, they induce toll like receptor 2 (TLR2) and its
coreceptor CD14, that initiate the innate immune response in
skin [53]. Activation of these receptors leads to the induction
of CYP27B1, which in turn induces cathelicidin resulting in
the killing of invasive organisms [53,54]. Mice lacking the
VDR or the enzyme (CYP27B1) show decreased lipid content
of the lamellar bodies leading to a defective permeability bar-
rier [52], and a defective response of the innate immune system
to invading infections [53].
Vitamin D and skin: a complex relationship 3
Please cite this article in press as: Mostafa WZ, Hegazy RA, Vitamin D and the skin: Focus on a complex relationship: A review, J Adv Res
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Vitamin D and cutaneous innate immunity
The historical link between vitamin D and innate immune
function stemmed initially from the use of cod liver oil as treat-
ment for tuberculosis (TB) [54]. More recent work has focused
on the cellular and molecular machinery that underpins the ac-
tions of vitamin D on the pathogen that causes TB, Mycobac-
terium tuberculosis (M. TB). In the first of these studies, carried
out 25 years ago, active 1,25(OH)
2
D was shown to reduce the
proliferation of M. TB in macrophages with this effect being
enhanced by the cytokine interferon c(IFNc), a known stim-
ulator of macrophages [55]. However, the major advance in
our understanding of how vitamin D directs antibacterial re-
sponses in TB arose from much more recent studies aiming
at defining the way by which monocytes and macrophages,
key cells in directing bacterial killing, respond to an encounter
with M. TB [56]. These data suggested that monocytes pro-
mote localized activation of vitamin D in response to M.
TB, with the resulting 1,25(OH)
2
D binding to endogenous
VDR. In this way, vitamin D can act to modulate gene expres-
sion in response to M. TB immune challenge – a classical intra-
crine mechanism [57,58]. Functional analyses showed that
25OHD-mediated induction of cathelicidin is coincident with
enhanced killing of M. TB in monocytes. Naturally occurring
variations in serum 25OHD have been shown to correlate with
induction of monocyte cathelicidin expression [59]. The con-
clusion from these studies was that individuals with low serum
25OHD will be less able to support monocyte induction of
antibacterial activity and may therefore be at greater risk of
infection. Conversely, supplementation of vitamin D-insuffi-
cient individuals in vivo has been shown to improve TLR-med-
iated induction of monocyte cathelicidin [60] and may
therefore help to protect against infection (Fig. 2).
Studies have shown that T-cell cytokines play a pivotal role
in both amplifying and attenuating vitamin D-mediated cath-
elicidin production [61]. Indeed, cytokine production by
monocytes themselves may be central to the intracrine metab-
olism of vitamin D in this cell type [62,63]. Thus, it seems likely
that the ability to mount an appropriate response to infection
will be highly dependent on the availability of vitamin D, with
additional tuning of this response by other components of the
normal human immune response.
Vitamin D can also influence innate immune responses to
pathogens via effects on antigen presentation by macrophages
or dendritic cells (DCs) (Fig. 2). These cells are known to ex-
press VDR [64], and treatment with 1,25(OH)
2
D has been
shown to inhibit DC maturation, suppress antigen presenta-
tion and promote a tolerogenic T-cell response [65,66].
Vitamin D and cutaneous adaptive immunity
Early studies of vitamin D and the immune system demon-
strated VDR expression in both T and B cells (Fig. 2)[67].
Notably, VDR expression by these cells was only immunolog-
ically functional in active, proliferating cells, suggesting an
antiproliferative role for 1,25(OH)
2
D on these cells [68].T
helper (Th) cells appear to be the principal target for
1,25(OH)
2
D which can suppress Th cell proliferation as well
as modulating cytokines production by these cells [69]. Activa-
tion of naive Th cells by antigen in turn leads to the generation
of Th cell subgroups with distinct cytokine profiles: Th1 (IL-2,
IFN c, tumor necrosis factor alpha) and Th2 (IL-3, IL-4, IL-5,
IL-10) that respectively support cell-mediated and humoral
immunity [70,71].
In vitro 1,25(OH)
2
D inhibits Th1 cytokines [72], while pro-
moting Th2 cytokines [73]. A third group of Th cells known to
be influenced by vitamin D are interleukin-17 (IL-17)-secreting
T cells (Th17 cells). Autoimmune disease-susceptible non obese
diabetic (NOD) mice treated with 1,25D exhibit lower levels of
IL-17 [74], and 1,25(OH)
2
D-mediated suppression of murine
retinal autoimmunity appears to involve inhibition of Th17
activity [75]. Furthermore, subsequent studies have shown that
1,25(OH)
2
D suppresses IL-17 production via direct transcrip-
tional suppression of IL-17 gene expression [76].
Another group of T cells known to be potently induced by
1,25(OH)
2
D are regulatory T cells (Tregs) [77]. Although part
of the Th cell family, Tregs act to suppress immune responses
by other T cells as part of the machinery to prevent over-
exuberant or autoimmune responses [78]. Recent studies
have underlined the importance of Tregs in mediating the
Fig. 2 A diagram illustrating the influences of vitamin D on the cutaneous innate and adaptive immunity.
4 W.Z. Mostafa and R.A. Hegazy
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immunoregulatory actions of vitamin D. Administration of
1,25(OH)
2
D systemically to patients who underwent renal
transplantation has been shown to expand circulating Treg
populations [79].
Studies of vitamin D and T-cell function have to date fo-
cused primarily on the response of these cells to active
1,25(OH)
2
D. What is less clear is the mechanism by which
variations in vitamin D status can also influence T cells, despite
reports linking serum levels of 25OHD with specific T-cell pop-
ulations [56]. For example, circulating levels of 25OHD have
been shown to correlate with Tregs activity in patients with
multiple sclerosis [80,81]. There are four potential mechanisms
by which serum 25OHD is believed to influence T-cell func-
tion; (i) direct effects on T cells mediated via systemic
1,25(OH)
2
D; (ii) indirect effects on antigen presentation to T
cells mediated via localized DC expression of CYP27B1 and
intracrine synthesis of 1,25(OH)
2
D; (iii) direct effects of
1,25(OH)
2
D on T cells following synthesis of the active form
of vitamin D by CYP27B1-expressing monocytes or DCs – a
paracrine mechanism; (iv) Intracrine conversion of 25OHD
to 1,25(OH)
2
D by T cells. As yet, it is unclear whether one
or more of these mechanisms will apply to the regulation of
specific T-cell types. For example, the effects of 1,25(OH)
2
D
on Tregs can occur indirectly via effects on DCs [82], but
may also involve direct effects on the Tregs [83]. However,
as DCs also express CYP27B1 [84] and may therefore act as
the conduit for 25OHD effects on Tregs. Interestingly, reports
have also described expression of CYP27B1 by T cells [85],
suggesting that 25OHD may also influence the function of
these cells via an intracrine mechanism, although the precise
relevance of this to specific T-cell types remains unclear [56].
Despite the fact that expression of VDR by B cells has been
recognized for many years [67], the ability of 1,25(OH)
2
Dto
suppress B-cell proliferation and immunoglobulin (Ig) produc-
tion was initially considered to be an indirect effect mediated
via Th cells [68]. However, more recent studies have confirmed
direct effects of1,25(OH)
2
D on B-cell homoeostasis [86], with
notable effects including inhibition of plasma cells and class
switched memory cells differentiation. These effects lend fur-
ther support for vitamin D’s proposed role in B-cell-related
autoimmune disorders such as systemic lupus erythematosis.
Other B-cell targets known to be modulated by for
1,25(OH)
2
D include IL-10 [87] and CCR10 [88], suggesting
that the repertoire of B-cell responses to vitamin D extends be-
yond its effects on B-cell proliferation and Ig synthesis [56].
Hair follicle cycling
In vitro studies have supported the concept that VDR may play
a vital role in the postnatal maintenance of the hair follicle.
Mesodermal papilla cells and the outer root sheath (ORS) epi-
dermal keratinocytes express VDR in varied degrees in corre-
lation with the stages of the hair cycle. In both the late
anagen and catagen stages there is an increase in VDR, which
is associated with decreased proliferation and increased differ-
entiation of the keratinocytes. These changes are thought to
promote the progression of the hair cycle [89].
Limited studies have been done in humans to elaborate the
role of vitamin D in the hair cycle. A potential application for
vitamin D is in chemotherapy-induced alopecia. Topical calci-
triol has been shown to protect against chemotherapy-induced
alopecia caused by paclitaxel and cyclophosphamide.
However, topical calcitriol failed to protect against
chemotherapy-induced alopecia caused by a combination of
5-fluorouracil, doxorubicin, and cyclophosphamide and a
combination of cyclophosphamide, methotrexate, and
5-fluorouracil. The ability of topical calcitriol to prevent
chemotherapy-induced alopecia may therefore depend on the
chemotherapy agents used. Of note, the studies in which no
effects were observed, were small and may have used doses
of vitamin D that were inadequate to protect against chemo-
therapy-induced alopecia [90].
The sebaceous gland
It has been reported that incubation of the human sebaceous
gland cell line with 1,25OH
2
D results in a dose-dependent sup-
pression of cell proliferation. Using real-time PCR, it was dem-
onstrated that key components of the vitamin D system (VDR,
25OHase, 1aOHase, and 24OHase) are strongly expressed in
such cells. It has been concluded that local synthesis or metab-
olism of vitamin D metabolites may be of importance for
growth regulation and various other cellular functions in seba-
ceous glands and that sebaceous glands represent promising
targets for therapy with vitamin D analogs or for pharmaco-
logical modulation of calcitriol synthesis/metabolism [91,92].
Photoprotection
Photodamage refers to skin damage induced by ultraviolet
(UV) light. Depending on the dose, UV light can lead
to DNA damage, inflammatory responses, skin cell apopto-
sis (programmed cell death), skin aging, and skin cancer. Some
studies, mainly in vitro (cell culture) studies [93–96] and mouse
studies where 1,25-dihydroxyvitamin D
3
was topically applied
to skin before or immediately following irradiation [93,97,98],
have found that vitamin D exhibits photoprotective effects.
Documented effects on skin cells include decreased DNA dam-
age, reduced apoptosis, increased cell survival, and
decreased erythema. The mechanisms for such effects are not
known, but one mouse study found that 1,25-dihydroxyvita-
min D
3
induced expression of metallothionein (a protein that
protects against free radicals and oxidative damage) in the
stratum basale [93]. It has also been postulated that
non-genomic actions of vitamin D contribute to the photopro-
tection [99]; such effects of vitamin D involve cell-
signaling cascades that open calcium channels [100].
Wound healing
1,25-Dihydroxyvitamin D
3
regulates the expression of cath-
elicidin (LL-37/hCAP18) [53,57], an antimicrobial protein that
appears to mediate innate immunity in skin by promot-
ing wound healing and tissue repair. One human study found
that cathelicidin expression is upregulated during early stages
of normal wound healing [58]. Other studies have shown that
cathelicidin modulates inflammation in skin [101],
induces angiogenesis [102], and improves reepithelializa-
tion (the process of restoring the epidermal barrier to re-estab-
lish a functional barrier that protects underlying cells from
environmental exposures) [103]. The active form of vitamin
D and its analogs have been shown to upregulate cathelicidin
Vitamin D and skin: a complex relationship 5
Please cite this article in press as: Mostafa WZ, Hegazy RA, Vitamin D and the skin: Focus on a complex relationship: A review, J Adv Res
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expression in cultured keratinocytes [58,104]. However, more
research is needed to determine the role of vitamin D in wound
healing and epidermal barrier function, and whether oral vita-
min D supplementation or topical treatment with vitamin D
analogs is helpful in healing surgical wounds.
Vitamin D and skin diseases
Based on the afore mentioned facts concerning the intertwined
bonding that exists between vitamin D and skin, it seems only
‘‘natural’’ to incriminate vitamin D deficiency in a long list of
cutaneous disorders including skin cancer, psoriasis, ichthyo-
sis, autoimmune skin disorders such as vitiligo, blistering dis-
orders, scleroderma and systemic lupus erythematosus, as
well as atopic dermatitis, acne, hair loss, infections and photo-
dermatoses. Nevertheless, it remains speculative whether vita-
min D deficiency primarily contributes to disease pathogenesis
or merely represents a consequential event to the inflammatory
processes involved. According to a recent systematic review
including 290 prospective cohort studies and 172 randomized
trials of major health outcomes and of physiological parame-
ters related to disease risk or inflammatory status, one solid
fact is emphasized; vitamin D deficiency appears to be a mar-
ker of ill health [105] regardless of being an actual cause or an
association. In the current review we will highlight the most
commonly studied dermatological diseases.
Skin cancer
A number of epidemiologic studies have suggested that vita-
min D may have a protective effect decreasing cancer risk
and cancer-associated mortality [106–110]. Adequate vitamin
D status has been linked to decreased risks of developing spe-
cific cancers, including cancers of the esophagus, stomach, co-
lon, rectum, gallbladder, pancreas, lung, breast, uterus, ovary,
prostate, urinary bladder, kidney, skin, thyroid, and hemato-
poietic system (e.g., Hodgkin’s lymphoma, non-Hodg-
kin’s lymphoma, multiple myeloma) [110]. With regards to
skin cancer, epidemiologic and laboratory studies have re-
ported mixed findings, with some reporting an association be-
tween higher vitamin D levels and increased skin cancer risk
[111], others showing a decreased skin cancer risk [106–109],
and still others showing no association [106]. The key findings
that point to the role of vitamin D in the prevention of the ini-
tiation and progression of lethal skin cancers are the involve-
ment of vitamin D in regulation of multiple signaling
pathways that have implications in carcinogenesis [109],
among which are the inhibition of the hedgehog signaling
pathway, the pathway underlying development of basal cell
carcinomas, and upregulation of nucleotide excision repair en-
zymes [106]. Furthermore, vitamin D induces cellular arrest,
triggers apoptotic pathways, inhibits angiogenesis, and alters
cellular adhesion [108]. Another point is that skin can-
cer metastasis depends on the tumor microenvironment,
where vitamin D metabolites play a key role in prevention of
certain molecular events involved in tumor progression [109].
The key factor complicating the association between vitamin
D and skin cancer is ultraviolet B radiation. The same spec-
trum of ultraviolet B radiation that catalyzes the production
of vitamin D in the skin also causes DNA damage that can
lead to epidermal malignancies. Overall, there is some evidence
that vitamin D may play a role in nonmelanoma skin cancer
(NMSC) including basal cell and squamous cell carcinoma as
well as melanoma prevention, although as of yet there is no di-
rect evidence to show a protective effect [106].
Psoriasis
Psoriasis is a chronic inflammatory skin disease that affects 2–
3% of the population worldwide and causes significant mor-
bidity [112]. Although the pathogenesis of psoriasis is not fully
understood, there is ample evidence suggesting that the dysreg-
ulation of the immune cells in the skin, particularly T cells,
plays a critical role in psoriasis development [113].
Several studies have focused on the possible role of vitamin
D deficiency in psoriasis [114–116]. The exact mechanism by
which vitamin D deficiency contributes in such a complex
pathogenesis is not fully understood. Several pathways have
been established including, loss of the anti-proliferative func-
tion of vitamin D, as it has been found that human cultured
keratinocytes exposed to calcitriol showed marked inhibition
of growth and accelerated maturation [117]. Moreover, as
inflammation and angiogenesis represent cornerstones in the
pathogenesis of psoriasis [118,119], the loss of the anti-inflam-
matory and anti-angiogenic activity of vitamin D [108] could
represent another explanation to the contribution of the vita-
min D deficiency in psoriasis. As 1a,25-dihydroxyvitamin D
3
is known to suppress the Th1 and Th17 cell proliferation
[69], as well as induce the Tregs [120], another proposed path-
way through which vitamin D deficiency could share in the
psoriatic predicament would be the unchecked proliferation
of Th1 and 17 cells on one hand and unchecked inhibition of
Tregs on the other hand. Topical treatment with calcipotriol
has been shown to significantly decrease cutaneous levels of
human beta defensins (HBD) 2 and HBD3 as well as IL-
17A, IL-17F and IL-8, which play significant roles in psoriasis
[121], further linking vitamin D deficiency to the pathogenesis
of psoriasis.
Owing to this postulated role played by vitamin D in the
pathogenesis of psoriasis, it is no wonder that it is one of the
most popularly prescribed topical medications for this disease,
singly or in combination with betamethasone, and numerous
studies documented the efficacy and safety of using topical cal-
cipotriol in the treatment of cases of localized plaque psoriasis
[122–126].
Acne and rosacea
Acne vulgaris is the most common skin disorder affecting mil-
lions of people worldwide. Inflammation resulting from the
immune response targeting Propionibacterium acnes (P. acnes)
has a significant role in acne pathogenesis. In a recent study, it
has been demonstrated that P. acnes is a potent inducer of
Th17, and that 1,25OH
2
D inhibits P. acnes-induced Th17 dif-
ferentiation, and thereby could be considered as an effective
tool in modulating acne [127]. Furthermore, sebocytes were
identified as 1,25OH
2
D responsive target cells, indicating
that vitamin D analogs may be effective in the treatment
of acne. In another recent study, the expression of inflamma-
tory biomarkers have been shown to be influenced by treat-
ment with vitamin D in cultured sebocytes, but not through
VDR [128].
6 W.Z. Mostafa and R.A. Hegazy
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(2014), http://dx.doi.org/10.1016/j.jare.2014.01.011

In the same spectrum of acne, another study demonstrated
relatively high serum levels of vitamin D in patients with rosa-
cea which is a common chronic skin condition affecting the
face, in comparison with controls, suggesting that
increased vitamin D levels may lead to the development of
rosacea [129].
Hair loss
The role of vitamin D in hair might be explained by the fact
that an optimal concentration of vitamin D has been suggested
to be necessary to delay the aging phenomena, including hair
loss [130]. Recently it has been shown that 1,25OH
2
D/VDR
promotes the ability of b-catenin to stimulate hair follicle dif-
ferentiation [131]. Moreover extensive data from animal mod-
els clearly show that the VDR activation plays an important
role in the hair follicle cycle, specifically anagen initiation
[132]. Interestingly, in VDR ablated mice it did not seem that
normalization of mineral ion homeostasis by a diet high in cal-
cium and phosphorous prevented alopecia suggesting that the
mechanism for alopecia is unrelated to mineral levels but
rather to the vitamin D levels [133]. Furthermore, recent data
suggested that VDR regulates directly or indirectly the expres-
sion of genes required for hair follicle cycling, including the
hedgehog signaling pathway [134].
A recent study conducted on eighty female patients demon-
strated that low serum vitamin D
2
is associated with both com-
mon types of hair loss in females namely; telogen effluvium
and androgenetic female pattern hair loss. It was suggested
that screening for vitamin D level and supplementation with
vitamin D in cases with deficiency would be beneficial in the
management of these conditions [135].
In contradistinction to the proposal of the important role
played by vitamin D in hair loss, a placebo-controlled trial
on 26 patients showed that calcipotriol did not affect the telo-
gen to anagen ratio after 6 weeks of treatment in patients with
scalp psoriasis. It is to be noted that the optimal effect of cal-
cipotriol on psoriasis was not seen until 8 weeks, thus, follow
up might have been too brief to detect an effect of calcipotriol
on hair loss [136]. Furthermore, a cross sectional study of 296
healthy men was done to explore a possible association be-
tween male pattern baldness and serum 25-hydroxyvitamin
D levels. The severity and extent of the baldness did not appear
to be associated with serum 25-hydroxyvitamin D levels [130].
This raises the speculation about the real value of vitamin D
levels in hair loss, and whether the story could be intrinsic, clo-
sely related to the receptor itself rather than to the level of vita-
min D.
Vitiligo
Vitiligo is a common pigmentary disorder characterized by
well-demarcated depigmented patches or macules of different
shapes and sizes and is caused by the destruction of functional
melanocytes in the epidermis [137].
Vitamin D protects the epidermal melanin unit and restores
melanocyte integrity via several mechanisms including control-
ling the activation, proliferation, migration of melanocytes and
pigmentation pathways by modulating T cell activation, which
is apparently correlated with melanocyte disappearance in vit-
iligo. The mechanism through which vitamin D exerts its ef-
fects on melanocytes is not yet fully understood. Vitamin D
is believed to be involved in melanocyte physiology by coordi-
nating melanogenic cytokines [most likely endothelin-3 (ET-3)]
and the activity of the SCF/c-Kit system, which is one of the
most important regulators of melanocyte viability and matura-
tion [138]. Furthermore, a proposed mechanism involving vita-
min D in the protection of vitiliginous skin is based on its
antioxidant properties and regulatory function toward the
reactive oxygen species that are produced in excess in vitiligo
epidermis [139]. Another point is that the active form of vita-
min D reduces the apoptotic activity induced by UVB in kerat-
inocytes and melanocytes [140], that has been reported to
remove melanocytes from the skin [141]. Moreover, vitamin
D might exert immunomodulatory effects by inhibiting the
expression of IL-6, IL-8, TNF-a, and TNF-c, modulate den-
dritic cell maturation, differentiation, and activation as well
as induce the inhibition of antigen presentation [65], thereby
dampen the autoimmune pathway incriminated in the patho-
genesis of vitiligo.
It is still unknown if vitamin D deficiency plays a role in
causing vitiligo, as it does in other autoimmune diseases. In
2010 Silverberg and Silverberg [142] assessed serum 25-hydrox-
yvitamin D (25(OH)D) levels in 45 patients with vitiligo and it
appeared that 55.6% were insufficient (22.5–75 nmol/L) and
13.3% were very low (<.22.5 nmo/L) a finding that was re-
demonstrated by others [143]. However, another study showed
no correlation between 25(OH)D and vitiligo [144].
Regardless the existing controversy, topical vitamin D
3
analogs are members of the armamentarium of therapeutic
modalities for vitiligo. The use of vitamin D analogs in combi-
nation with PUVAsol and topical calcipotriol for the treat-
ment of vitiligo was first reported by Parsad et al. [145].
Subsequently, a number of studies have reported on the treat-
ment of vitiligo with vitamin D analogs alone or in combina-
tion with ultraviolet light or corticosteroids to enhance
repigmentation [142,146,147] with some contradictory results
[148–150].
Pemphigus vulgaris and bullous pemphigoid
Pemphigus vulgaris and bullous pemphigoid are potentially
fatal autoimmune bullous disorders caused by keratinocyte
acantholysis as a result of pathogenic antibody production
by B cells. Vitamin D, through its participation in several im-
mune modulatory functions including B cells apoptosis, Th2
cell differentiation, apoptotic enzyme regulation and Tregs
functions, may be actively involved in the immune regulation
of such diseases. Several recent studies demonstrated that pa-
tients with pemphigus vulgaris and bullous pemphigoid have
significantly lower serum vitamin D levels in comparison with
controls regardless age, body mass index or pattern of sun
exposure [151,152]. In addition, it was suggested that this low-
er level of vitamin D might account for the increased preva-
lence of fractures in such patients and therefore should be
taken into consideration in patients who must be given cortico-
steroids [152].
Atopic dermatitis
Atopic dermatitis (AD) is a common chronic inflammatory
type of eczema. Several studies have shown initial epidermal
Vitamin D and skin: a complex relationship 7
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(2014), http://dx.doi.org/10.1016/j.jare.2014.01.011

barrier dysfunction with subsequent immune activation as the
underlying mechanism. Animal studies, case reports, and ran-
domized clinical trials have suggested that vitamin D, through
various mechanisms including immunomodulation, may allevi-
ate the symptoms of AD. The majority of these studies indicate
an inverse relationship between the severity of atopic dermati-
tis and vitamin D levels. Furthermore, studies have shown
that, in individuals with AD who are deficient in vitamin D,
repletion of vitamin D results in improvement and decreased
severity of the disease [153,154].
Should vitamin D be scripted on every prescription?
The answer to this question is still far from clear, but at least we
could clearly recommend routine evaluation of its level, with
particular focus on those who are at risk of its deficiency e.g. el-
derly, obese, lacking proper sun exposure or with malabsorption
disorders. Vitamin D supplementation could represent an
important adjuvant treatment if deficient or insufficient.
Conclusions
In conclusion one could clearly sense the unique relationship
that entangles vitamin D to dermatology. On one hand, our skin
is one source for this important vitamin and on the other hand all
available data point to its important impact on the health of our
skin and the involvement of its deficiency in the pathway of
many dermatological diseases. Several factors are responsible
for maintaining it in optimum levels; therefore sunny climates
are by far not a guarantee for providing a ‘‘comfort zone’’
regarding the possibility of this vitamin deficiency, a concern
documented by several epidemiological studies carried out in
areas close to the equator [155–158]. On the basis of currently
available data, it is clear that supplemental vitamin D should
be the preferred recommendation toward achieving its normal
serum levels, thereby avoiding the deleterious effects accompa-
nied by its deficiency. Still more research is needed to unravel
its complicated ties to dermatological diseases and create clear
guidelines and recommendations for its supplementation.
Conflict of interest
The authors have declared no conflict of interest.
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Please cite this article in press as: Mostafa WZ, Hegazy RA, Vitamin D and the skin: Focus on a complex relationship: A review, J Adv Res
(2014), http://dx.doi.org/10.1016/j.jare.2014.01.011