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Does vitamin D play a role in autoimmune endocrine disorders?
A proof of concept
Barbara Altieri
1
&Giovanna Muscogiuri
2
&Luigi Barrea
2
&Chantal Mathieu
3
&
Carla V. Vallone
4
&Luca Mascitelli
5
&Giorgia Bizzaro
6
&Vincenzo M. Altieri
7
&
Giacomo Tirabassi
8
&Giancarlo Balercia
8
&Silvia Savastano
9
&Nicola Bizzaro
10
&
Cristina L. Ronchi
11
&Annamaria Colao
9
&Alfredo Pontecorvi
1
&Silvia Della Casa
1
#Springer Science+Business Media New York 2017
Abstract In the last few years, more attention has been given
to the Bnon-calcemic^effect of vitamin D. Several observa-
tional studies and meta-analyses demonstrated an association
between circulating levels of vitamin D and outcome of many
common diseases, including endocrine diseases, chronic dis-
eases, cancer progression, and autoimmune diseases. In par-
ticular, cells of the immune system (B cells, T cells, and anti-
gen presenting cells), due to the expression of 1α-hydroxylase
(CYP27B1), are able to synthesize the active metabolite of
vitamin D, which shows immunomodulatory properties.
Moreover, the expression of the vitamin D receptor (VDR) in
these cells suggests a local action of vitamin D in the immune
response. These findings are supported by the correlation be-
tween the polymorphisms of the VDR or the CYP27B1 gene
and the pathogenesis of several autoimmune diseases.
Currently, the optimal plasma 25-hydroxyvitamin D concentra-
tion that is necessary to prevent or treat autoimmune diseases is
still under debate. However, experimental studies in humans
have suggested beneficial effects of vitamin D supplementation
in reducing the severity of disease activity. In this review, we
summarize the evidence regarding the role of vitamin D in the
pathogenesis of autoimmune endocrine diseases, including type
1 diabetes mellitus, Addison’s disease, Hashimoto’s thyroiditis,
Graves’disease and autoimmune polyendocrine syndromes.
Furthermore, we discuss the supplementation with vitamin D
to prevent or treat autoimmune diseases.
Keywords Vitamin D .Autoimmunity .Type 1 diabetes
mellitus .Addison’sdisease .Hashimoto’s thyroiditis .
Graves’disease .Autoimmune polyendocrine syndromes .
Environment .Lifestyle
1 Introduction
Vitamin D
3
(cholecalciferol) is a steroid hormone precursor
synthesized within skin under the photochemical reaction in-
fluenced by ultraviolet B radiation of sunlight. Dietary intake
of vitamin D is generally limited to oily fish and eggs.
Cholecalciferol is biologically inert and requires two succes-
*Barbara Altieri
altieri.barbara@gmail.com
1
Division of Endocrinology and Metabolic Diseases, Institute of
Medical Pathology, Catholic University of the Sacred Heart,
Rome, Italy
2
Ios and Coleman Medicina Futura Medical Center, University
Federico II, Naples, Italy
3
Clinical and Experimental Endocrinology, KU Leuven,
Leuven, Belgium
4
Emergency Department, Fondazione Poliambulanza Istituto
Ospedaliero, Brescia, Italy
5
Comando Brigata Alpina Julia/Multinational Land Force, Medical
Service, Udine, Italy
6
TSEM med Swiss SA, Lugano, Switzerland
7
Department of Urology, Bolognini Hospital, Seriate, Italy
8
Division of Endocrinology, Department of Clinical and Molecular
Sciences, Umberto I Hospital, Polytechnic University of Marche,
Ancona, Italy
9
Department of Clinical Medicine and Surgery, University BFederico
II^, Naples, Italy
10
Laboratory of Clinical Pathology, San Antonio Hospital,
Tol mezzo , Ita ly
11
Division of Endocrinology and Diabetes, Department of Internal
Medicine I, University Hospital of Wuerzburg, Wuerzburg, Germany
Rev Endocr Metab Disord
DOI 10.1007/s11154-016-9405-9
sive hydroxylation reactions for activation. The first hydrox-
ylation occurs in the liver to form the 25-hydroxyvitamin D
3
[25(OH)D
3
or calcidiol], which is converted in the kidney to
the biologically active compound 1,25-dihydroxyvitamin D
3
[1,25(OH)
2
D
3
or calcitriol] by the 1α-hydroxylase
(CYP27B1), an enzyme which is stimulated by parathyroid
hormone (PTH) [1]. Calcitriol acts through binding the nucle-
ar vitamin D receptor (VDR) that mediates the transcription of
several target genes [2].
The main physiologic role of vitamin D is the regulation of
mineral and bone metabolism. Nowadays, the expression of
both 1α-hydroxylase and VDR beyond tissues involved in
classical endocrine pathway, including colon, breast, pancre-
as, malignant cells and immune cells, suggests that also other
tissues, different from kidney, are able to synthesize the active
form of vitamin D [3,4]. Thus, vitamin D has pleiotropic
effects and may act in paracrine or autocrine manner in addi-
tion to its endocrine function. This suggests an important im-
pact of vitamin D in the pathogenesis and outcome of many
common diseases, including endocrine diseases [5], chronic
diseases [6] and cancer progression [7,8].
Particularly, cells of the immune system (B cells, T cells
and antigen presenting cells), due to the expression of 1α-
hydroxylase [9], are able to synthesize the active metabolite
of vitamin D, which shows immunomodulatory properties
similar to locally active cytokines [10]. Moreover, differently
to what happens in the kidney, the 1α-hydroxylase presented
on macrophages and dendritic cells is not regulated by PTH,
calcium and 1,25(OH)
2
D
3
, but is predominantly regulated
by interferon (IFN)-γand lipopolysaccharides [11].
Recently, Hossein-nezhad et al. demonstrated that vitamin
D supplementation in vivo significantly regulated the expres-
sion of 291 genes in white blood cells, which interfere with
more than 160 distinct pathways linked to cancer, autoim-
mune disorders and cardiovascular diseases [12]. However,
the pathway associated with immunological responses seems
to have a prominent position, demonstrating that vitamin D
is an important immune regulator, both to the innate and
adaptive immune responses [12].
According to this, several observational studies and meta-
analyses demonstrated an association between circulating
levels of vitamin D and autoimmune disorders, including type
1 diabetes mellitus, Addison’s disease, autoimmune thyroid
disease, rheumatoid arthritis, multiple sclerosis, inflammatory
bowel disease, systemic lupus erythematosus [5,13,14]and
infectious disease [15]. Many observational studies and meta-
analyses have demonstrated strong associations between low
circulating concentrations of vitamin D and non-skeletal dis-
ease and their outcomes [16].
Our review focuses on the reported association between
vitamin D status and autoimmune endocrine disease and the
role of vitamin D supplementation to reduce autoimmune dis-
ease risk by modulating the immune system.
2 Methods: search strategy and selection criteria
Relevant literature was searched in multiple databases, includ-
ing PubMed/Medline, EMBASE, and the Cochrane Library
up to October 2016. The following specific keywords were
used alone or in combination for the search: vitamin D, cho-
lecalciferol, calcidiol, calcitriol, 25-hydroxyvitamin D, 1,25-
dihydroxyvitamin D, autoimmunity, type 1 diabetes mellitus,
Addison’s disease, Hashimoto’s thyroiditis, Graves’disease,
autoimmune polyendocrine syndromes. Boolean operators
(AND, OR, NOT) were also used to increase the sensitivity
of the search. Studies in non-English languages, as well as
letters to the editor, conference abstracts and editorials, were
excluded. Studies were evaluated by title, abstract relevance,
and importance and availability of the full text. Additionally,
the reference lists of original articles and reviews were cross-
referenced to find further eligible articles. All full texts of the
included studies were successively screened and discussed by
the panel of authors until a general consensus was reached.
Manuscripts not focused on the topic were excluded, and the
full text of the remaining selected studies was reviewed in this
paper.
3 Vitamin D and autoimmune diseases: clinical
and basic evidence
Autoimmune diseases are characterized by a loss of immune
homeostasis resulting in failure of self-recognition followed
by the destruction of body tissue by autoreactive immune
cells. A combination of genetic predisposition, epidemiologic
risk factors and environmental contributors may lead to the
development of autoimmune disease [14,17]. Among the
mechanisms contributing to the development of autoimmuni-
ty, one important factor could be represented by insufficient
vitamin D levels, as mounting epidemiologic evidence sug-
gestsanassociationbetweenvitaminDdeficiencyanda
higher incidence of autoimmune diseases.
Vitamin D has been found to play a significant role in the
function of the immune system, in both innate and adaptive
immunity [18]. Indeed, many immune cells express vitamin D
receptors. Besides VDR, immune cells also express the 1α-
hydroxylase, which converts 25(OH)D into its active form
1,25(OH)
2
D
3
. Thus, all these cells are capable of responding
not only to the active vitamin D metabolite but also to its
precursors, and possess a mechanism to convert vitamin D
[19].
Vitamin D is an important mediator of innate immune re-
sponses enhancing the antimicrobial properties of immune
cells, such as monocytes and macrophages. The historical link
between vitamin D and innate immune function relies on the
use of cod liver as treatment for tuberculosis [20]. In fact,
1,25(OH)
2
D
3
intensifies the antimicrobial peptide activity in
Rev Endocr Metab Disord
monocytes, neutrophils and other cell lines [21]. In particular,
vitamin D has been found to modulate gene expression in
response to a Mycobacterium tuberculosis’immune chal-
lenge. Potential targets for this response include the antibiotic
protein cathelicidin that represents a direct transcriptional tar-
get for the 1,25(OH)
2
D
3
–VDR complex. The vitamin D-
mediated induction of cathelicidin has been found to enhance
the killing of Mycobacterium tuberculosis in monocytes [20].
Beyond cathelicidin, vitamin D stimulates the expression of
other potent antimicrobial peptides, such as βdefensin 2 [22],
which exist in neutrophils, monocytes, natural killer cells and
epithelial cells lining the respiratory tract.
These findings may be of particular interest considering
that autoimmune responses can be triggered by infectious
agents [23] and an association has been found between low
levels of vitamin D and many infections [24]. Of note, Epstein
Barr virus, one of the most compelling infectious agents,
while considering induction of autoimmunity, also shows an
association with vitamin D levels, as it leads to a down-
regulation of VDR expression [25].
Vitamin D has important effects on both monocytes and
dendritic cells (DC) [21]. It inhibits monocyte production of
inflammatory cytokines such as interleukin (IL)-1, IL-6, IL-8,
IL-12 and tumor necrosis factor (TNF)-α. Additionally, it in-
hibits DC differentiation and maturation with preservation of
an immature phenotype as evidenced by a decreased expres-
sion of major histocompatibility complex (MHC) class II mol-
ecules, co-stimulatory molecules and IL-12 [1](Fig.1).
Moreover, vitamin D is also involved in the humoral response
indirectly causing suppression of T cell proliferation, resulting
in a shifting from a T-helper (Th)1 to a Th2 phenotype [26].
Influencing the phenotype and function of DC, with the con-
sequent inhibition of their differentiation and maturation, the
final effect of vitamin D is a reduction of the number of
antigen-presenting cells that stimulate T cells, thus favoring
T-cell tolerance.
Inhibition of DC differentiation and maturation is partic-
ularly important in the context of autoimmunity and the
abrogation of self-tolerance. Indeed, antigen presentation to
a T cell by a mature DC facilitates an immune response
against that antigen, whereas antigen presentation by an im-
mature DC facilitates tolerance. Interestingly, self-antigens
are abundant in the normal state from physiologic cell death
and turnover; however, presentation of these self-antigens is
usually driven by immature DC so that tolerance to self is
maintained [1]. In particular, 1,25(OH)
2
D
3
affects T cell
maturation with a skewing away from the inflammatory
Th17 phenotype. These effects result in a decreased produc-
tion of inflammatory cytokines such as IL-17 with increased
production of anti-inflammatory cytokines such as IL-10;
furthermore, vitamin D facilitates the induction of T regula-
tory cells (Tregs) (Fig. 1). Tregs function to decrease the
immune response by regulating the activity of other T cells
through a diverse array of mechanisms including secretion
of anti-inflammatory cytokines, and consumption of the T-
cell growth and survival factor, IL-2 [27]. Tregs may also
induce direct cytolysis of target cells and impair the capacity
of antigen presenting cells to prime adaptive immune re-
sponse. Through such mechanisms, vitamin D is thought
to modulate cell-mediated immune responses and regulate
inflammatory T cell activity. Of note, recent data show
that Th17 cells also participate in pregnancy-related pathol-
ogies, including recurrent spontaneous abortion and pre-
eclampsia, and imbalances between Th1/Tregs/Th17 subsets
in both circulation and uterus have been reported [28].
Interestingly, it has been shown that the odds of developing
pre-eclampsia and eclampsia may increase by up to 5-fold in
women with vitamin D insufficiency [29].
Fig. 1 The immunomodulatory
effects of the vitamin D on
immune cells. Effects of vitamin
D on monocytes and dendritic
cells include inhibition of
inflammatory cytokine
production by monocytes and
inhibition of dendritic cell
differentiation and maturation,
which in turn leads to suppression
of T cell proliferation and results
in a shift from a T-helper (Th)1 to
a Th2 phenotype. Vitamin D
affects T cell maturation with a
skewing away from the
inflammatory Th17 phenotype
and facilitates the induction of T
regulatory cells (Tregs)
Rev Endocr Metab Disord
However, also B cells express VDR, and the differentiation
into plasma cells and post-switch memory B cells has been
found to be inhibited in the presence of 1,25(OH)
2
D
3
[30].
Therefore, vitamin D can also modulate immunoglobulin pro-
duction and exert direct effects on B cell homeostasis.
In summary, vitamin D activity may enhance the innate
immune system and regulate the adaptive immune system,
promoting immune tolerance and acting to the decrease the
likelihood of developing autoimmune disease.
4 Vitamin D and type 1 diabetes mellitus
Conflicting data exist on a role for the vitamin D system in
type 1 diabetes mellitus (T1DM). Although some studies sug-
gest a linkage between polymorphisms of the VDR, others
failed to do so. A large meta-analysis found an association
between BsmI polymorphism and T1DM risk in the Asian
population, with a 30% increased risk for carriers [31]. A
study by Ban et al. revealed an association between FokI
polymorphism and glutamic acid decarboxylase autoanti-
bodies (GAD65) positivity in a Japanese population [32].
However, the Type I Diabetes Genetics Consortium did not
find any association of VDR SNPs with T1DM in the overall
sample set, or in any of the subgroups analyses of the parent-
of-origin, sex of offspring, and the human leukocyte antigen
(HLA) risk [33]. Nevertheless, the FokI polymorphism of the
VDR could have functional implications, altering ligand-
mediated gene expression in beta-cells or the immune system
[34]. Similar confusing data exist for linkage between T1DM
and polymorphisms in the genes encoding enzymes with cen-
tral roles in vitamin D metabolism, like CYP27B1 or vitamin
D binding protein (DBP).
In childhood diabetes, several epidemiologic studies de-
scribe a north-south gradient in the incidence of T1DM as well
as a seasonal pattern of disease onset [35]. Dietary vitamin D
supplementation is often recommended for pregnant women
and children to prevent vitamin D deficiency, but studies on
correlations between levels of vitamin D or even vitamin D
supplementation in early life are confusing, with some show-
ing a protective correlation with vitamin D supplementation or
higher serum levels [36,37], but others not [38]. A meta-
analysis of four case-control studies and one cohort-study re-
vealed that the risk of T1DM in later life was significantly
reduced (29% reduction) in infants who were supplemented
with vitamin D compared with unsupplemented controls [39].
Preclinical data point to a role for the vitamin D system in
the pathogenesis of T1DM, as receptors for 1,25(OH)
2
D
3
are found both in beta-cells and most cells of the immune
system. Wolden-Kirk et al. showed that 1,25(OH)
2
D
3
could
almost completely prevent cell death induced by IL-1βand
IFN-γin human and mouse whole islets, while it restored
impaired insulin secretion. Moreover, this protection was
accompanied by alterations in gene expression of genes in-
volved in chemotaxis, cell death and beta-cell function [40].
When studying islets from a vitamin D-sufficient donor, how-
ever, no improvement of insulin secretion is observed by in-
cubating these islets with higher doses of vitamin D in vitro
[41]. As previously said, effects of vitamin D on the immune
system in vitro and in animal models of T1DM indicate that
1,25(OH)
2
D
3
is a potent immune modulator, with shifting of
the cytokine profile of Tcells towards a Th2 profile, induction
of tolerance-inducing DC and induction of regulator T cells,
both via direct effect on T cells and indirect effects on DC
[39]. When high doses of vitamin D, 1,25(OH)
2
D
3
or vitamin
D analogs are administered in an animal model of type 1
diabetes, the NOD mouse, these immune alterations can be
picked up in vivo and diabetes can be prevented or its progres-
sion arrested [39].
Until now, clinical intervention studies using vitamin D or
1,25(OH)
2
D
3
(-analogs) in the prevention of T1DM or in peo-
ple already affected with the disease have been disappointing.
A small intervention trial in which new-onset diabeticchildren
were given a small dose of 1,25(OH)
2
D
3
(0.25 μg/2d) or nic-
otinamide (25 mg/kg/d) showed that they had no improve-
ments of C-peptide levels, although insulin requirements de-
creased in the 1,25(OH)
2
D
3
-treated group [42]. Even when
the dose was increased to 0.25 μg 1,25(OH)
2
D
3
daily for
2 years, given to recent-onset diabetic patients with high basal
C-peptide levels, no protective effect was observed on HbA1c
and insulin requirement. In a small prospective trial, 12 high-
risk children with type 1 diabetes autoantibodies were treated
with oral calcitriol (0.25 μg/d) for 1–3 years. Here,
1,25(OH)
2
D
3
was able to decrease serum autoantibody levels
against GAD65 and insulin in all participants, suggesting some
immune modulating effect [43]. The study was, however, too
small to allow clinical conclusions. Patients with latent auto-
immune diabetes in adults (LADA) who received 1α(OH)D
3
,
the synthetic precursor of 1,25(OH)
2
D
3
, exhibited a partial
preservation of beta-cell function in comparison to patients
treated with insulin alone [44]. An open study in recent-onset
diabetic patients with 1,25(OH)
2
D
3
(0.25 μg daily for
9 months,the maximum tolerable dose) revealed no significant
safety issues as a result of the therapy but the treatment failed to
induce preservation of beta-cell function [45]. No differences
in area under the curve (AUC) of C-peptide, peak C-peptide,
and fasting C-peptide levels between the treatment and placebo
groups were observed at 9 and 18 months after study entry.
Moreover, HbA
1c
and daily insulin requirement were compa-
rable between control and 1,25(OH)
2
D
3
-treated patients
throughout the study follow-up period.
At present, the advice to individuals at high genetic risk for
developing T1DM should be to avoid vitamin D deficiency
with adequate vitamin D supplementation, but at present data
to advise higher supplements of vitamin D or interventions
with high doses of 1,25(OH)
2
D
3
are lacking. Thus, clinical
Rev Endocr Metab Disord
studies indicating that the beneficial effects observed in ani-
mal models can be safely reproduced in humans are needed.
5 Vitamin D and Addison’sdisease
Addison’s disease (AD) is a rare disorder characterized by
autoimmune-mediated selective destruction ofthe adrenal cor-
tex, which can be isolated (40% of patients) or associated with
autoimmune polyendocrine syndromes (APS) (60% of pa-
tients) type 1, 2, or 4 [46]. The etiology of AD still remains
largely elusive. Several genes, of which the HLA haplotypes
are the most strongly associated, interact with environmental
factors to confer disease susceptibility [47]. However, poly-
morphisms of VDR as well other genes involved in vitamin D
metabolism are associated with AD [48–51]. A study by Pani
et al. on distribution of four VDR polymorphisms (FokI, BsmI,
ApaI, and TaqI) in 95 patients with AD in comparison to 220
healthy controls, demonstrated that the Bff^genotype of FokI
and the Btt^genotype of TaqI were significantly more frequent
in patients than in control group (13.7% versus 5.5%, OR) =
2.75 for Bff^genotype and 28.4% versus 14.1%, OR = 2.42
for Btt^genotype) [48]. They did not observe any difference in
the other studied polymorphisms between patients and con-
trols. The authors concluded that the Bff^and the Btt^geno-
type of the VDR gene may be associated with susceptibility of
AD [48]. Another component of the vitamin D metabolism,
the cytochrome P450 27B1 (CYP27B1), is associated with
AD. The CYP27B1 encodes the 1α-hydroxylase, the mito-
chondrial enzyme that catalyzes the conversion of
25(OH)D
3
to 1,25(OH)
2
D
3
. In particular, three different stud-
ies demonstrated a significant association between the
CYP27B1 promoter C(-1260)A polymorphisms and AD in
German (OR 1.53, 95% CI 1.07–2.20) [49], British (OR
1.71, 95% CI 1.20–2.44) [51], and Polish population (OR
1.18, 95% CI 0.86–1.62) [50]. In the more recent of these
studies, Fichna et al. performed also a meta-analysis of these
three European cohorts, including a total of 325 patients af-
fected by AD and 925 healthy controls. The meta-analysis
showed in AD patients an overall OR of 1.44 (95% CI:
1.18–1.75) for the C(-1260)A allele [50]. Therefore, it was
demonstrated that patients with APS associated with AD pre-
sented an increased frequency of the C(-1260) allele [52].
These results highlighted a potential role of CYP27B1 poly-
morphisms with a favorable genetic background for various
autoimmune disorders. Little is known about the role of this
C(-1260)A allele; however, it seems that it may affect the
CYP27B1 transcription that causes a decrease of the availabil-
ity of the active form of vitamin D [51].
Only few observational studies investigated the link be-
tween vitamin D plasma levels and AD. A record-linkage
study by Ramagopalan et al. showed in a large cohort of
patients admitted to a UK hospital for vitamin D deficiency,
significantly elevated rates of AD (rate ratio = 7.0, 95% CI:
3.6–12.3) and of other autoimmune diseases [53].
Accordingly, Bellastella et al. demonstrated that patients with
APS presented lower levels of 25(OH)D in comparison to
healthy controls (P < 0.001)[54]. Moreover, they showed that
the vitamin D status was not different in patients with single or
multiple autoimmune diseases, but it changed depending on
the type of autoimmune disease. The authors concluded that
the presence of other autoimmune diseases, which could im-
pair the absorption or the metabolic steps of vitamin D in the
skin, liver, or kidney, may influence vitamin D levels more
than AD [54].
It is important to note that in AD, the glucocorticoid defi-
ciency may lead to suppression of the PTH–vitamin D axis
[55]. In a small randomized trial involving nine patients with
primary adrenal insufficiency, of whom eight were affected by
AD, the authors showed that those patients who underwent all
different schedules of glucocorticoid replacement therapy did
not present suppressed levels of vitamin D [56].
At present, evidence regarding the association of vitamin D
and AD is largely based on few observational studies. These
preliminary results suggest that vitamin D may influence the
genetic susceptibility of AD by modifying the immune re-
sponse. However, further intervention studies are necessary
to confirm or refute the correlation between vitamin D levels
and AD.
6 Vitamin D and Hashimoto’s thyroiditis
Several studies in the last few years have led to presume a link
between vitamin D deficiency and autoimmune thyroid dis-
eases, including Hashimoto’s thyroiditis (HT) and Graves’
disease (GD) [57]. A recent meta-analysis investigated the
association between vitamin D level and autoimmune thyroid
disease (AITD) through an accurate systematic literature re-
view [58] concluded that serum 25(OH)D was lower in AITD
patients compared with healthy control individuals (OR =
2.99, 95% CI: 1.88–4.74) and AITD was more likely to de-
velop in individuals who showed low levels of serum
25(OH)D, thus suggesting that vitamin D deficiency may play
a role in the pathologic process of AITD. This result was
confirmed by several recent studies, which showed that vita-
min D deficiency is more common in AITD patients, whether
children [59]orelderly[60], both at low [61] and high latitude
[62]. Moreover, a randomized controlled trial has recently
found that vitamin D supplementation in AITD patients was
correlated with significant reduction in anti-thyroperoxidase
antibody (TPO-Ab) titers, leading to the idea that giving vita-
min D to AITD patient can induce an improvement of the
disease [63].
Other studies failed to establish a firm correlation.
Effraimidis et al. [64] showed how vitamin D deficiency is
Rev Endocr Metab Disord
not associated with early stages of thyroid autoimmunity,
while an Asian Indian community-based survey found only
a weak inverse correlation between serum 25(OH)D values
and TPO-Ab titers [65]. A further study showed, by measur-
ing 25(OH)D level in a HT group and in a control group, that
the mean 25(OH)D level for the female HT group (30.8 ±
7.5 ng/mL) was significantly higher than in the female control
group (27.6 ± 8.1). In contrast with many other studies, it was
observed that female HT subjects had both a higher rate of
vitamin D sufficiency (51.7% versus 31.1%) and a lower rate
of insufficiency (48.3% versus 68.9%). Of note, however, is
that this difference may have been due to potentially increased
vitamin D supplementation in HT females [66].
Growing evidence shows that the VDR polymorphisms are
associated with an increased incidence of AITD.One study
investigated the distribution of VDR alleles in a group of 111
Turkish patients with HTand 159 healthy controls. It showed
that VDR gene TaqI TT and FokI FF genotypes were associ-
ated with increased risk of HT; BbAaTtFf genotype seemed to
be protective for HT disease in the same population [67].
In another study, it was tested if the functional VDR poly-
morphisms (TaqI rs731236, ApaI rs7975232, FokI
rs2228570, and BsmI rs1544410) are involved in the patho-
genesis of AITD [68]. Using polymerase chain reaction-
restriction fragment length polymorphism, 139 Graves’dis-
ease patients, 116 HT patients, and 76 control subjects were
genotyped. The frequency of the TT genotype for the TaqI
polymorphism was higher in GD patients than in HT patients
(P = 0.0147). The frequency of the C allele for the ApaI poly-
morphism was higher in AITD patients than in control sub-
jects (P = 0.0349). Focusing on HT, the frequency of the CC
genotype for the FokI polymorphism was higher in HT pa-
tients than in control subjects (P = 0.0174). Because the C
allele was also associated with a higher production of IL-12,
which induces Th1 differentiation and thyroid destruction in
HD patients [34], the CC genotype may be associated with the
induction of autoimmune thyroid destruction. No differences
were found in the frequencies of the genotypes and alleles of
the BsmI polymorphism between the control subjects and the
HT patients. Except for BsmI polymorphism, this experiment
showed how genetic differences in the VDR gene may be
involved in the development of AITD. Conflicting evidence
was observed in a meta-analysis of eight studies, in which the
result indicates that both BsmI and TaqI polymorphisms are
significantly associated with AITD risk (Pz = 0.001 for B ver-
sus b; Pz = 0.010 for t versus T), but not the ApaI or FokI
polymorphisms. In the subgroup analysis in Europeans, the
decreased risk of AITD remained for the B or t variant [69].
This gene-based analysis indicates that based on current evi-
dence from published studies, the cumulative effect of BsmI
or TaqI polymorphisms in VDR is significantly associated
with AITD [69]. This result was not confirmed by
Giovinazzo et al. [70], who observed that the genotype
distribution of the VDR single nucleotide polymorphisms
(SNPs) was not different between HT patients and healthy
individuals (BsmI P = 0.783;ApaIP = 0.512;TaqIP=
0.471). However, even if the VDR locus does not appear to
be involved in conditioning the genetic susceptibility of HT,
vitamin D deficiency may likely contribute to the disease de-
velopment and progression, acting as an environmental trigger.
Thus, controversial opinions on vitamin D role in AITD
onset are expressed by the scientific community. Several co-
factors may affect the results of epidemiologic studies, such as
sun exposure, obesity, sedentary life, leading to contradicting
results. However, the growing evidence of a correlation be-
tween low levels of vitamin D and AITD suggests the advis-
ability of supplementation.
7 Vitamin D and Graves’disease
Current evidence suggested that vitamin D deficiency might
cause the onset and/or development of different organ-specific
and systemic autoimmune diseases [71]. GD is one of the
most frequent diseases among autoimmune disorders, with
an annual incidence of approximately 14 per 100,000 [72].
GD is an autoimmune thyroid disease in which thyroid-
stimulating hormone (TSH) receptor autoantibodies cause hy-
perthyroidism [73]. Besides thyrotoxicosis, the clinical mani-
festations of GD include several extra-thyroidal signs, such as
ophthalmopathy, dermopathy, and acropathy [74].
Experimental and clinical evidence supports that GD results
from complex interactions between genetic and environmen-
tal factors that lead to the loss of immune tolerance to thyroid
antigens and the initiation of an immune reaction [75,76]. GD
occurs with the infiltration of T cells in the thyroid gland. In
particular, TH cells elaborate various cytokines, including
IFN-γ, which induce in thyrocytes the expression of HLA-
DR antigens. The expression of HLA-DR antigens on thyroid
follicular cells triggers an autoimmune process and renders
them susceptible to immunologic attack [77].
Although vitamin D is commonly included among the en-
vironmental factors responsible for the immunopathogenesis
of AITD, the association between vitamin D status and GD is
not so straight forward [78]. Two recent meta-analyses ad-
dressed the association between vitamin D and GD. Besides
the above-mentioned systematic review of Wang et al. [58],
Xu et al. [79] in a meta-analysis including 26 studies showed
that low vitamin D status may increase the risk of GD. In
particular, patients with GD were more likely to be deficient
in vitamin D compared with the controls (OR = 2.24, 95% CI:
1.31–3.81) [79]. Nevertheless, it should be noted that this
association, even supported by a stronger statistical signifi-
cance compared with previous studies, does not necessarily
imply a causal relationship between vitamin D status and GD
[80].
Rev Endocr Metab Disord
Choi et al. [81] reported that serum 25(OH)D
3
levels
were significantly lower in premenopausal women with
TPO-Ab than in women without TPO-Ab, with a preva-
lence of 21.2%, 15.5%, and 12.6% in women with vita-
min D deficiency, insufficiency, and sufficiency, respec-
tively. However, a prospective study performed within the
Amsterdam AITD cohort, in which controls were matched
to cases for age, body mass index, smoking, estrogen use,
season, and duration of follow-up did not confirm these
data, in that 25(OH)D
3
and serum 1,25(OH)
2
D
3
concen-
trations were not different between cases (defined as those
subjects in whom TPO-Ab developed de novo during fol-
low-up) and controls, neither at baseline nor at the time of
the occurrence of TPO-Ab [64].
The issue of the relationships between vitamin D and
GD may become even more complicated by the finding
that, as above mentioned, particular polymorphisms in the
VDR gene are associated with AITD [69]. Human immune
cells, including macrophages, dendritic cells, T and B
lymphocytes, are known to express the vitamin D-
activating enzyme CYP27B1 and the VDR, an intracellu-
lar receptor belonging to the steroid/thyroid nuclear recep-
tor family [58,82]. Thus, altered activities of polymorphic
variants of VDR may affect immune cells interaction with
vitamin D. Similarly to what was found in the
Hashimoto’s thyroiditis, specific VDR gene polymor-
phisms were found to be associated with susceptibility
to GD in a number of different investigations, but the
statistical power of most studies was very low. A compre-
hensive meta-analysis by Zhou et al. analyzed the associ-
ations among four polymorphisms of the VDR gene
(ApaI, TaqI, BsmI, and FokI) and susceptibility to GD
in a total of 1820 GD patients and 2066 controls from
Caucasian and Asian populations [83]. ApaI, BsmI, and
FokI polymorphisms in the VDR gene resulted associated
with susceptibility to GD in Asian populations, whereas
ApaI, BsmI, TaqI, and FokI polymorphisms were not as-
sociated with GD in Caucasian populations. Thus, associ-
ations or linkage of VDR gene polymorphisms with GD
found in same reports have been difficult to replicate in
other populations and the mechanisms by which these
variants associate with the disease susceptibility remain
largely elusive.
In conclusion, an association between low vitamin D
levels and thyroid autoimmunity is likely. However,
whether vitamin D deficiencyplaysacausativerolein
the onset of the disease needs to be unravelled. In addi-
tion, so far there have been no definitive studies to eval-
uate the effect of vitamin D supplementation on thyroid
autoimmunity. To confirm any causality link between vi-
tamin D and GD, more cohort or intervention studies are
needed to evaluate whether vitamin D supplementation
decreases the risk of thyroid autoimmunity [78].
8 Vitamin D and autoimmune polyendocrine
syndromes
The APS include different conditions characterized by the
coexistence of at least two endocrine or non-endocrine auto-
immune-mediated diseases [84].
According to the accepted criteria of classification, APS are
distinguished in four main types. APS-1, characterized by the
presence of chronic candidiasis, chronic hypoparathyroidism
and AD, is a very rare syndrome that affects young subjects
and is caused by different mutations of the autoimmune regu-
lator (AIRE) gene localized on chromosome 21 [85]. APS-2,
characterized by the presence of AD (always present), auto-
immune thyroid diseases, and/or T1DM, is also a rare syn-
drome affecting particularly adult females and is associated to
a genetic pattern of HLA DR3/DR4. Autoimmune thyroid
diseases associated to other autoimmune diseases (excluding
AD and/or hypoparathyroidism) are the main characteristics
of APS-3. The different clinical combinations of autoimmune
diseases not included in the previous groups are characteristics
of APS-4 [84].
However, only one study has evaluated whether the asso-
ciation of APS affects the vitamin D status [54]. As already
discussed above, this study reported that a higher prevalence
of low vitamin D status was observed in those with APS-3. In
addition, lower vitamin D concentrations were found among
patients either with a single autoimmune disease, such as
T1DM, or with APS including T1DM, compared with control
subjects. This finding suggested that the kind of autoimmune
disease rather than the association of several autoimmune dis-
eases, as happens in APS, may influence negatively vitamin D
status of affected patients, likely linked to an impairment of
the absorption or the metabolic steps of this vitamin at the
skin, liver, or kidney level [54].
In conclusion, further prospective studies are needed to
clarify if impaired vitamin D status is a causal factor in the
pathogenesis of APS or a consequence of them.
9 The role of vitamin D supplementation
inthepreventionofautoimmunediseases
Blood concentration of 25(OH)D is the biomarker usually
used by clinicians and researchers to determine vitamin D
status [4]. At this time there is no international consensus on
the optimal concentration of vitamin D to prevent deleterious
consequences in non-classic vitamin D pathways. The
Institute of Medicine (IOM) guideline and the National
Osteoporosis Society guideline consider 20 ng/mL
(50 nmol/L) a sufficient concentration of total vitamin D
(25OHD) to achieve appropriate bone health. Vitamin D defi-
ciency is defined as 25OHD level less than 12 ng/mL
(30 nmol/L) [86,87]. The Endocrine Society derived different
Rev Endocr Metab Disord
thresholds, recognizing sufficient 25-OH vitamin D levels
greater than 30 ng/mL (75 nmol/L), insufficient levels ranging
from 20 to 29.9 ng/mL (52–72 nmol/L), and deficient vitamin
D levels less than 20 ng/mL (50 nmol/L) [88]. The differences
between these guidelines are explained by the investigated
target population; particularly, the IOM guidelines are based
largely on vitamin D effects on bone and mineral homeostasis
in the general healthy population, whereas the Endocrine
Society guidelines are based on observational and clinical
trials on populations with high risk for vitamin D deficiency.
Therefore, the optimal 25(OH)D levels to prevent the onset of
autoimmune diseases are still under debate [3,86,88].
However, authors suggest vitamin D levels higher than
30 ng/mL might be needed in order to reach positive effects
[88,89].
Similar to what has been reported for optimal vitamin D
levels, there also is no consensus for the optimal amount of
vitamin D supplementation. In vivo studies on animal models
showed that the administration of vitamin D3 arrested immu-
nologic progression and prevented the clinical onset of auto-
immune diseases such as T1DM [90]. Moreover, experimental
studies in humans showed beneficial effects of vitamin D sup-
plementation in reducing the risk of developing autoimmune
disease [39] and in reducing the severity of disease activity
[91].
Nevertheless, oral vitamin D intake in many of the studied
populations could be too low to produce significant effects;
further, variability in administration may reduce positive ef-
fects. In the evaluated observational studies, the difference
between the higher and the lower oral doses of vitamin D
administration is mostly 400 IU/d (10 μg/d). It is important
to note that the achievement of optimal 25(OH)D levels de-
pends on both the baseline serum level and the chosen target
level [92]. Heaney et al. reported a linear correlation between
serum 25(OH)D levels and vitamin D dosing with a coeffi-
cient of determination of 0.7 nmol/L [92]. For example, to
reach and maintain a sufficient serum 25(OH)D level of
80 nmol/L from a vitamin D deficiency baseline of 60 nmol/
L, one would need an additional intake of 29 μg (1160 IU)
daily of vitamin D, whereas from a deficiency baseline
25(OH)D level of 40 nmol/L, one would need a supplemen-
tation of about 55 μg (2200 IU) daily of vitamin D [93].
However, there is a steeper rise in serum 25(OH)D levels
when vitamin D administration dosing is less than 1000 IU/
d; a slower, more flattened response is seen when doses of
1000 IU/d or higher are administered. Thus, when the supple-
mentation dose of vitamin D is ≥1000 IU/d, the rise in serum
25(OH)D is approximately 1 nmol/L (0.4 ng/mL) for each
40 IU of intake, whereas when the dose is ≤600 IU/d, the rise
is serum 25(OH)D is approximately 2.3 nmol/L for each 40 IU
[92]. Thus, when the ingested dose of vitamin D is more than
1000 IU per day, a difference between the various dosages
reported from the studies of 10 μg(400IU)perday
corresponds to a difference in 25(OH)D levels of only
10 nmol/L (4 ng/mL) [94,95]. This increase in serum
25(OH)D levels of 10 nmol/L observed among different stud-
ies might be too low to achieve the expected outcome. Indeed,
it is necessary to reach 25(OH)D levels greater than 75 nmol/L
to obtain health benefits [88]. Thus, it is often required to
ingest vitamin D dosages of at least 20–25 μg (800–
1000 IU) per day for patients with insufficient 25(OH)D levels
at baseline [94,96–98]. The Endocrine Society guidelines
suggest a high intake of 50,000 IU of vitamin D once a week
for 8 weeks (6000 IU) per day to reach sufficient 25(OH)D
blood levels, followed by maintenance administration of
1500–2000 IU (37.5–50 μg) per day in all adults who are
vitamin D deficient [88,99].
Most studies suggest an acute vitamin D intoxication for
serum 25(OH)D levels >150 ng/mL, characterized by hypercal-
cemia, hypercalciuria and calcifications in different organs [3,
100–102]. However, the great majority of vitamin D intoxica-
tion cases are due to a prolonged intake of >40,000 IU/d [103].
The IOM suggests a supplementation of vitamin D of maxi-
mum 4000 IU/d [86], whereas the Endocrine Society recom-
mends a maximum supplementation of 10,000 IU/d. [88].
Because of the potential side effect of activated vitamin D,
cholecalciferol is the preferred form for supplementation. In
comparison to the other inactive forms of vitamin D (vitamin
D
2
or ergocalciferol), cholecalciferol has a longer plasma half-
life [104] and a higher tissue bioavailability [105].
It appears necessary to evaluate through controlled ran-
domized studies both the best kind of vitamin D compound
and the appropriate dose to prevent insufficient vitamin D
levels, in order to control the autoimmune mechanisms [91].
10 Conclusion
In the last few years, more attention has been given to the
Bnon-calcemic^effects of vitamin D. Several observational
studies and meta-analyses demonstrated an association be-
tween circulating levels of vitamin D with autoimmune endo-
crine disorders, including T1DM, AD, AITD, including HT
and GD, and autoimmune polyendocrine syndromes [5].
These findings are supported by the expression of the 1α-
hydroxylase and the VDR in cells of the immune system [9].
The expression of the enzyme involved in the activation of the
vitamin D suggests a local action of vitamin D, which presents
immunomodulatory properties. Thus, it is possible that vita-
min D insufficiency or deficiency may unsettle the normal
immune response, predisposing to the development of the
autoimmune diseases. Moreover, the association between
both VDR and CYP27B1 polymorphisms and a higher risk
of T1DM, AD, and AITD [34,48,50,68] strengthens the
potential role of vitamin D in the pathogenesis of autoimmune
endocrine diseases.
Rev Endocr Metab Disord
Currently, the optimal plasma 25(OH)D concentration that
is necessary to prevent or treat autoimmune diseases is still
under debate. However, experimental studies in humans have
indicated the beneficial effects of vitamin D supplementation
in reducing the severity of disease activity [91]. Similarly,
studies on animal models showed that the administration of
vitamin D could prevent the development of autoimmune dis-
eases [91].
It is important to note that the described association be-
tween low levels of vitamin D and autoimmune endocrine
diseases is mostly derived from in vivo animal models or ob-
servational studies, which could present several bias.
Therefore, the observed low levels of vitamin D could be
caused by inflammatory state and/or less time spent outdoors
by the individuals because of their underlying disease. Further
randomized controlled trials with a long period of follow-up
are necessary to establish causality between vitamin D and
autoimmune endocrine diseases and to provide information
about the potential role of vitamin D supplementation in the
prevention of these autoimmune diseases.
Authors contribution B.A. and G.M. designed the study. B.A., G.M.,
L.B., C.M.,C.V.V., L.M. and G.B. participated in the literature search and
performed the selection of studies. B.A. wrote the Introduction, Methods
and the Conclusion of the review, as well as the paragraphs on Addison’s
disease and on vitamin D supplementation. C.V.V. supported B.A. in
writing the Introduction and the paragraphs on vitamin D supplementa-
tion. G.M., S.S., N.B. and C.L.R. collaborated to the preparation of the
manuscript providing relevant suggestions and corrections according to
their long-lasting expertise in different research fields. L.B. wrote the
paragraph on Grave’s disease and autoimmune polyendocrine syn-
dromes. C.M. wrote the paragraph on diabetes mellitus. L.M. prepared
the figure and wrote the paragraph on clinical and basic evidence. G.B.
wrote the paragraph on Hashimoto thyroiditis. V.M.A., G.T. and G.B.
contributed to the final version of the manuscript. A.C., A.P. and S.D.C.
coordinated and supervised the preparation of the manuscript. All the
authors reviewed and approved the final version of the manuscript.
Conflict of interest The authors declare that they have no conflict of
interest.
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