European Journal of Clinical Nutrition (2014), 1–6

© 2014 Macmillan Publishers Limited All rights reserved 0954-3007/14

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MINI REVIEW
Vitamin D and thyroid disease: to D or not to D?
G Muscogiuri1, G Tirabassi2, G Bizzaro3, F Orio4, SA Paschou5, A Vryonidou5, G Balercia2, Y Shoenfeld3,6 and A Colao1

The main role of vitamin D is to maintain calcium and phosphorus homeostasis, thus preserving bone health. Recent evidence has
demonstrated that vitamin D may also have a role in a variety of nonskeletal disorders such as endocrine diseases and in particular
type 1 diabetes, type 2 diabetes, adrenal diseases and polycystic ovary syndrome. Low levels of vitamin D have also been associated
with thyroid disease, such as Hashimoto’s thyroiditis. Similarly, patients with new-onset Graves’ disease were found to have
decreased 25-hydroxyvitamin D concentrations. Impaired vitamin D signaling has been reported to encourage thyroid
tumorigenesis. This review will focus on the role of vitamin D in thyroid diseases, both autoimmune diseases and thyroid cancer,
and will summarize the results of vitamin D supplementation studies performed in patients with thyroid disorders. Although
observational studies support a beneficial role of vitamin D in the management of thyroid disease, randomized controlled trials are
required to provide insight into the efficacy and safety of vitamin D as a therapeutic tool for this dysfunction.

European Journal of Clinical Nutrition advance online publication, 17 December 2014; doi:10.1038/ejcn.2014.265

INTRODUCTION analogues. However, the administration of 1,25(OH)2D3 for 3 days

The most important role of vitamin D is to maintain calcium and
phosphorus homeostasis and to preserve bone health.1 However,
animal and human studies have demonstrated that vitamin D may
also have a role in a variety of nonskeletal disorders. There is an
increasing prevalence of hypovitaminosis D that gives rise to an
emerging public health problem. In particular, a prevalence of
vitamin D deficiency has been estimated ranging from 20 to 100%
of American, Canadian and European elderly men and women.2–4
The same prevalence has been reported in children and young
and middle-aged adults worldwide.5,6 Vitamin D has been
involved in the pathogenesis of several endocrine conditions
such as type 1 diabetes,7 type 2 diabetes,8 adrenal diseases9 and
polycystic ovary syndrome.10 The involvement of vitamin D in
thyroid disease has been suggested by pioneering studies
performed in the eighties. In particular, McDonnell et al.11 found
a strong homology between the molecular structure of vitamin D3
receptor and the receptor for thyroid hormone, which was due to
two regions that they have in common: the first is a 70 amino acid,
cysteine-rich sequence and the second region is a 62 amino acid
one located towards the carboxyl terminus of the proteins.
Later, Lamberg Allardt et al.12 demonstrated the existence of a
functional 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] receptor in rat
thyroid follicular cells (FRTL-5). The incubation of FRTL-5 with 1,25
(OH)2D3 inhibited thyrotropin (TSH)-stimulated iodide uptake in a
dose-dependent manner, indicating that 1,25(OH)2D3 has an
effect on the physiological function of rat thyroid follicular cells in
culture. These results were further confirmed by Berg et al.13 who
reported a decrease in TSH stimulated production of the
intracellular signalling molecule 3′,5′-cyclic adenosine mono-
phosphate (cAMP), iodide uptake and cell growth of FRTL-5 when
they were incubated with 1,25(OH)2D3 or with cholecalciferol
in rats was found not to have any effect on serum triiodothyronine
(T3), thyroxine (T4) or TSH concentrations.14 These intriguing
results laid the basis and encouraged the recent research on
vitamin D and thyroid disease.
In particular, low vitamin D concentrations, certain vitamin D
receptor (VDR) gene polymorphisms and pathologies of vitamin
D-binding proteins and of their gene may favor the development
of Hashimoto’s thyroiditis (HT).15 Women with new onset Graves’
disease (GD) have a reduced 25-hydroxyvitamin D [25(OH)D]
serum concentration, which also correlates with thyroid volume
measured with ultrasonography.16 Furthermore, impaired 1,25
(OH)2D3-VDR signaling has been reported to be associated with
the onset and progression of thyroid cancer.17
The present review will focus on the association of vitamin D
with autoimmune thyroid disease and thyroid cancer and the
potential role for vitamin D supplementation in the therapy of
thyroid disease.
VITAMIN D AND THYROID AUTOIMMUNE DISEASES
In vitro evidence
The molecular mechanism by which vitamin D exerts its action
seems to be mediated by its binding to VDR, an intracellular
receptor belonging to the steroid/thyroid nuclear receptor family,
expressed by human immune cells, such as macrophages,
dendritic cells and T and B lymphocytes. Vitamin D central target
are dendritic cells (DCs).18 In particular, it has been shown that
1,25(OH)2D3 and calcifediol impair T-cell-stimulatory capacities of
murine DC.19 DCs isolated from VDR knockout mice were not
impaired in their T-cell-activating potential, demonstrating that
the inhibitory effect of these vitamin D metabolites was

1
Department of Clinical Medicine and Surgery, Section of Endocrinology, University ‘Federico II’, Naples, Italy; 2Division of Endocrinology, Department of Clinical and Molecular
Sciences, Umberto I Hospital, School of Medicine, Polytechnic University of Marche, Ancona, Italy; 3The Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center,
Tel-Hashomer, Israel; 4Department of General Surgery and Transplantation Unit ‘San Giovanni di Dio e Ruggi D’Aragona’ University Hospital, Scuola Medica Salernitana, Salerno, Italy;
5
Department of Endocrinology and Diabetes, Hellenic Red Cross Hospital, Athens, Greece and 6Incumbent of the Laura Schwarz-Kip Chair for Research of Autoimmune Diseases,
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Correspondence: Dr G Muscogiuri, Department of Clinical Medicine and Surgery, Section of Endocrinology,
University ‘Federico II’, Via Sergio Pansini, 5, Naples I-80131, Italy.
E-mail: giovanna.muscogiuri@gmail.com
Received 8 May 2014; revised 16 October 2014; accepted 18 November 2014
 Vitamin D and thyroid disease
G Muscogiuri et al
2
dependent on the presence of VDR.19 In particular, 1,25(OH)2D3
inhibited DC maturation as well as production of DC-derived
cytokines, such as interleukin (IL)-12 and IL-23. In this way, 1,25
(OH)2D3 alters the Th balance and causes the differentiation of
the T cells in a T-helper 2 phenotype, rather than in T helper 1
(Th1) and Th17 phenotype. DC-derived IL-10 release was
enhanced, promoting its tolerogenic properties.20 Moreover, 1,25
(OH)2D3 decreased the production of inflammatory Th1 cytokines
such as IL-2 and interferon-γ, which promote cell-mediated
cytotoxicity leading to thyroid destruction in HT.21 In this regard,
it is worth mentioning that the suppression of Th1 response by
Vitamin D may counteract the onset of GD, as Th1 dominance
seems to be involved in the induction of the disease.22 Finally, 1,25
(OH)2D3 inhibits Th17-derived cytokines IL-17 and IL-21 produc-
tion, promoting the induction of regulatory rather than effector
T cells.21
Many studies point to a role of vitamin D in the development of
thyroid autoimmune diseases (AITD), which has been also
demonstrated in animal models. In particular, vitamin D has been
reported to modulate hyperthyroidism induced in BALB/c mice by
immunization with adenovirus, encoding thyrotropin receptor or
its A-subunit.23 In fact, hyperthyroid BALB/mice fed with a diet
deprived of vitamin D showed fewer splenic B cells, decreased
interferon-γ responses to mitogen and lack of memory T-cell
responses to A-subunit protein. In addition, vitamin D-deprived
animals developed persistent hyperthyroidism induced by ade-
novirus expressing the human TSHR_A subunit, demonstrating a
clear role of vitamin D in modulating thyroid function in this
animal model.23
Human clinical studies
Regarding the association of vitamin D levels with antithyroid
antibodies, lower 25(OH)D levels were found in subjects with
higher levels of antithyroid antibodies compared with those who
were negative for thyroid autoimmunity.24,25 Vitamin D deficiency
has been diagnosed more frequently in AITD subjects, especially
in those affected by HT, than in healthy subjects.24 In a study
conducted by Tamer et al.,15 25(OH)D insufficiency (o 30 ng/ml)
was found to be more common in subjects with HT than in
controls. The association between hypovitaminosis D and thyroid
autoimmunity has also been reported in a Chinese population by
Choi et al.26 In particular the association between thyroid
peroxidase antibody (TPOAb) and levels of 25(OH)D was found
only in Chinese premenopausal women, but not in post-
menopausal women or in men, thus suggesting that vitamin D
may modulate thyroid autoimmunity through estrogens. More-
over, in female patients with newly onset GD, a significant
relationship of low levels of 25(OH)D with increased thyroid
volume was observed, suggesting that vitamin D status may be
involved in the pathogenesis of the disease.16
On the other hand, some studies failed to find an association
between vitamin D deficiency and AITD. Chailurkit et al.27 did not
find any relationship between 25(OH)D status and thyroglobulin
antibody (TgAb) and TPOAb. Furthermore, an Asian Indian
community-based survey found a significant but weak inverse
correlation between serum 25(OH)D values and TPOAb titers, with
an R2 value of only 0.006, indicating that only 0.6% variation in
thyroid autoimmunity was determined by 25(OH)D levels in the
population.28 An inverse correlation between TPOAb production
de novo and 25(OH)D levels was missing in a longitudinal study
conducted on a Dutch female population.29 In addition, in the
same population the Authors compared subjects with genetic
susceptibility to AITD with healthy subjects. In both groups, 25
(OH)D levels were not lower in the cases than in the controls,
showing that low vitamin D levels are not associated with thyroid
autoimmunity in the early stages of the disease.29
European Journal of Clinical Nutrition (2014) 1 – 6
Regarding thyroid function, hypothyroid subjects showed both
low 25(OH)D and serum calcium levels; interestingly, the degree
and the severity of hypothyroidism were significantly associated
with vitamin D levels.30 Yasuda et al.16 failed to find any
association between thyroid function and vitamin D in subjects
with GD. In addition, high 25(OH)D values were observed to be
independently associated with low circulating TSH levels in
middle-aged and elderly Chinese males with negative thyroid
autoimmunity, independently of free T3 and free T4. Conversely,
this association was not found in women.31
Some studies evaluated the association between functional
polymorphism in the VDR gene or vitamin D binding proteins and
AITD risk. However, results are still ambiguous and inconclusive.
A meta-analysis of eight studies, analyzing mainly females of various
ethnicities (European, Asian and African) and including about 1000
cases and 1000 controls for each polymorphism studied, indicated
that the BsmI or TaqI VDR polymorphism was significantly
associated with AITD risk, whereas the ApaI or FokI polymorphism
was not.32 Allele analyses demonstrated that in BsmI polymorph-
ism the b allele was more associated with AITD risk than the
B allele. However, statistically significant heterogeneity was
detected for BsmI polymorphism only when all the eligible studies
were pooled in a meta-analysis. After a subgroup analysis by
ethnicity, Europeans showed a strong decrease in heterogeneity,
indicating that the genetic background might contribute to the
observed heterogeneity. Regarding TaqI, no heterogeneity was
detected in the subgroup analysis. Polymorphisms of the CYP27B1
gene that encodes the 1-α-hydroxylase enzyme, responsible for
converting 25(OH)D to active 1,25(OH)2D3, were linked to
autoimmune thyroid disease supporting the hypothesis of a link
between vitamin D and AITD.33
Section remarks
Most of the above data indicate a primary role of vitamin D
deficiency in the pathogenesis of AITD. Vitamin D is able to trigger
both innate and adaptive immune responses and to switch the
immune system in a tolerogenic sense, avoiding the autoimmune
response. However, further studies are needed to determine
whether hypovitaminosis D is a key factor in the pathogenesis of
AITD or, rather, a consequence of the disease.
VITAMIN D AND THYROID TUMORIGENESIS
Histochemical and in vitro evidence
The molecular basis of the hypothesized antitumoral effect of
Vitamin D relies on the biological actions of 1,25(OH)2D3 through
binding to the VDR, a nuclear hormone receptor, that is present,
although variably, in benign and malignant thyroid tissue.17 The
expression of VDR and 1-α-hydroxylase, that is, the activating
enzyme of Vitamin D (also named CYP27B1), was found to be
increased in papillary thyroid carcinoma (PTC) compared with
normal thyroid tissue; in addition, VDR was significantly lower in
lymph node PTC metastases compared with both normal thyroid
tissue and primary PTC. These findings suggest that the increased
local action of vitamin D may be associated with differentiation,
reduced proliferation and a generally favorable prognosis in PTC.34
Similar results, indicating a local antitumor response of 1,25(OH)
2D3 in early cancer stages, were later confirmed by Clinckspoor
et al. who found an increased expression of VDR, CYP27B1 and
CYP24A1, that is, the enzyme catabolizing vitamin D, in follicular
adenoma and differentiated thyroid cancer compared with the
normal thyroid. These data suggest an increase in the local 1,25
(OH)2D3 metabolism in tumoral tissue compared with the normal
one. Moreover, the Authors, comparing well-differentiated malig-
nant thyroid tumours with benign tumours, observed significantly
higher VDR, lower CYP24A1 and similar CYP27B1 expression,
suggesting a stronger antitumor response in differentiated thyroid
© 2014 Macmillan Publishers Limited
 Vitamin D and thyroid disease
G Muscogiuri et al
3
cancer, which results in an increase in the local availability of 1,25 strongly suggesting that growth arrest was only because of the
(OH)2D3. In addition, these Authors reported decreased VDR antiproliferative effects.17
and CYP24A1 expression in PTC with lymph node metastasis,
compared with nonmetastasized PTC; also in addition, in In vivo evidence
anaplastic thyroid cancer, VDR expression was often lost, whereas
In vivo evidence on the antineoplastic activity of vitamin D3 is
CYP27B1/CYP24A1 expression was comparable to DTC. Further-
quantitatively more limited. In 2005, some scientists investigated
more, in anaplastic thyroid cancer with high Ki67 expression or
the pattern of xenografted thyroid cancer cells in severe
distant metastases at diagnosis, increased negative VDR/CYP24A1/
combined immunodeficient mice and found that tumor weight
CYP27B1 staining was evident.35 Of note, some Authors have
and volume were reduced by 50% and 22%, respectively, after
suggested that the vitamin D system may also have a role in
1,25(OH)2D3 treatment. In addition, they reported that in
tumoral cell growth by affecting estrogen receptor expression,
fibronectin-downregulated cells the effect of the treatment was
which is in turn involved in estrogen-induced cell growth in an
lesser, suggesting a role for fibronectin in mediating vitamin D3
estrogen receptor-type-specific manner. In fact, they found that a
actions on neoplastic cell growth.49 Another group, which
Vitamin D analog (JK 1624 F2-2) in three human thyroid cancer
implanted 5 × 106 WRO cells, derived from human thyroid
lines, that is, anaplastic, papillary and follicular carcinoma, was
follicular carcinoma, in the neck of 4- to 5-week-old female severe
able to up- and downregulate, not only VDR receptor and 1,25
combined immunodeficient mice, found that animals receiving
(OH)2D3, but also ERβ.36
Several preclinical studies have reported that vitamin D and 1,25(OH)2D3 exhibited a smaller mean tumor volume than the
some analogs have antiproliferative effects on different thyroid vehicle-treated ones. Furthermore, they confirmed the ability of
cancer cell lines. In this regard, the effects of 1,25(OH)2D3 and of Vitamin D3 to restore p27 accumulation in thyroid carcinoma
the superagonistic analog CD578 have been evaluated in various cells.41
cell lines of thyroid cancer, such as anaplastic, undifferentiated
and differentiated follicular thyroid cancer cells. Clear effects on Human clinical studies
growth arrest were observed, and absolute cell counts demon- Vitamin D deficiency has been reported in various types of
strated a reduction in all cell lines after treatment with 1,25(OH) cancer;17 however, clinical data are few and inconsistent in the
2D3. Growth inhibition was evident even after treatment with a case of thyroid cancer (Table 1). A recent retrospective cohort
1000-fold lower concentration of analog CD578.37 Similarly, study from Canada demonstrated an association between 25(OH)
another group found that 1,25(OH)2D3 and its noncalciomimetic D deficiency and the rate of diagnosis for well-differentiated
analog EB1089 exhibited antiproliferative effects in a dose- thyroid cancer in patients undergoing thyroidectomy, with an
dependent manner on thyroid carcinoma cell growth, specifically increase in the malignancy rate from 37.5 to 75%, when
on well- and poorly differentiated papillary, well-differentiated comparing vitamin-deficient (n = 12) and vitamin-sufficient
follicular carcinoma and anaplastic cell lines; interestingly, this (n = 88) subjects, respectively, corresponding to a relative risk of
report also showed that administration of 1,25(OH)2D3 increased 2.0 (P = 0.03, 95% confidence interval 1.07–2.66).50 A different
the expression of p27, a tumor suppressor protein that has a group from Turkey also observed decreased levels of 25(OH)D and
critical role in the pathogenesis and prognosis of several human higher prevalence of 25(OH)D deficiency in 344 patients with
malignancies.38 This antiproliferative tendency was consistent papillary thyroid cancer compared with 116 healthy controls.51 Of
with the findings both of Suzuki et al.,39 who demonstrated, in the note, in this work cases and controls differed greatly in number,
thyroid anaplastic carcinoma cell line, the effectiveness of 22- but, at the same time, were matched for two confounding factors,
oxacalcitriol, a vitamin D3 analog, in inhibiting tumoral cell growth such as age and body mass index. Another small study from
and with the recent results of Bennett et al.,40 who observed cell Poland showed reduced levels only of 1,25(OH)2D3 in peripheral
growth inhibition by 25(OH)D3 or 1,25(OH)2D3 in cancerous blood from patients with thyroid cancer compared with normal
(papillary, follicular and anaplastic carcinoma) and in SV40- controls, without any significant differences in the levels of 25(OH)
immortalized follicular cell lines. D.52 Other researchers, however, by evaluating in total more than
However, a certain degree of inconsistency is present regarding seven hundred subjects, did not find any associations between
the effect of 1,25(OH)2D3 on redifferentiation of thyroid cancer
cells. As far as thyroglobulin is concerned, Liu et al.38 did not find
any change, whereas other Authors reported an increase in this
marker after 1,25(OH)2D3 treatment.37,41 Conversely, sodium Table 1. Main clinical studies evaluating the relationship between
iodide symporter mRNA levels were found to modestly increase vitamin D levels and thyroid diseases
after 1,25(OH)2D3 in two different studies;37,42 furthermore, one of
these showed no change in thyroid-stimulating hormone receptor Study Number of studied subjects Primary end point
or thyroperoxidase mRNA expression.37 Kivity et al.24 92 AITD
As far as the antitumorigenic activity of vitamin D on C cells is Shin et al.25 304 AITD
concerned, findings are more controversial. Although consistent Choi et al.26 6685 AITD
data report a decreasing effect of 1,25(OH)2D3 on calcitonin Chailurkit et al.27 2582 AITD
secretion and synthesis by C cell line derived from medullary Goswami et al.28 642 AITD
thyroid carcinoma,43,44 findings on antiproliferative activity are Effraimidis et al.29 790 AITD
very contradictory. In this regard, Zabel et al.45 demonstrated that Mackawy et al.30 60 AITD
Zhang et al.31 1424 AITD
1,25-(OH)2D3 and two analogs (PRI-1906 and PRI-2191) weakly Roskies et al.50 100 Thyroid cancer
inhibited proliferation of human and rat thyroid medullary Sahin et al.51 460 Thyroid cancer
carcinoma cells. On the contrary, other reports even identified a Stepien et al.52 110 Thyroid cancer
role for 1,25(OH)2D3 in stimulating the growth and proliferation of Jonklaas et al.53 65 Thyroid cancer
the same cell line,46,47 whereas yet another found that the growth Laney et al.54 111 Thyroid cancer
rate of cells treated with 1,25(OH)2D3 or 24,25-dihydroxyvitamin Mack et al.55 584 Thyroid cancer
D3 did not differ significantly from control-treated cells.48 Ron et al.56 62 Thyroid cancer
Finally, it is also worth noting that in vitro studies did not prove Abbreviation: AITD, autoimmune thyroid disease.
an effect of 1,25(OH)2D3 on the apoptosis of thyroid cancer cells,

© 2014 Macmillan Publishers Limited European Journal of Clinical Nutrition (2014) 1 – 6

 Vitamin D and thyroid disease
G Muscogiuri et al
4
the levels of 25(OH)D or the percentage of 25(OH)D deficiency and
the rate of diagnosis or the stage of differentiated thyroid
cancer.53–55 Only one isolated study, carried out on 30 cases and
32 controls, reported a positive association between vitamin D
supplements and thyroid cancer, mostly because of a fourfold risk
of medullary carcinoma.56
VITAMIN D SUPPLEMENTATION IN THYROID DISEASES
Vitamin D supplementation is currently recommended for the
treatment of hypovitaminosis D conditions. In particular, vitamin D
deficiency is defined by the US Endocrine Society guideline as 25
(OH)D less than 20 ng/ml (50 nmol/l), vitamin D insufficiency as 25
(OH)D between 21 and 29 ng/ml, and the upper cutoff to
minimize the risk of adverse effects as 25(OH)D equal to
100 ng/ml (250 nmol/l).57 The 25(OH)D levels recommended
as ‘cutoffs’ differ in the US Institute of Medicine report, where
a 25(OH)D concentration greater than 20 ng/ml (50 nmol/l)
covers the requirements of the majority (⩾97.5%) of the
population, and 50 ng/ml (125 nmol/l) is the upper safety margin
for hypercalcemia.58 25(OH)D is considered as the best indicator
for monitoring vitamin D levels. This is the major circulating form
of vitamin D, with a half-life of 2–3 weeks. 1,25(OH)2D3 does not
reflect vitamin D status, as its half-life is ~ 4 h only, its peripheral
levels are 1000 times lower than 25(OH)D, and is tightly regulated
by PTH, calcium and phosphate.57 Regarding screening for vitamin
D deficiency, the US Endocrine Society guideline recommends it in
individuals with specific conditions, who are at risk for this
deficiency. None of potential thyroid diseases are included in the
list of these conditions.57
According to the US Endocrine Society guideline, all adults
require at least 600–800 IU daily dietary intake of vitamin D. In the
case of deficiency or insufficiency, supplementation is needed and
either vitamin D2 or vitamin D3 can be used. Adults who are
vitamin D-deficient should be treated with 50 000 IU of vitamin D2
or vitamin D3 once a week for 8 weeks or its equivalent of 6000 IU
of vitamin D2 or vitamin D3 daily to achieve a blood level of 25
(OH)D above 30 ng/ml. Supplementation should be continued by
a maintenance therapy of 1500–2000 IU daily.57
Although vitamin D has been shown to have a potential
beneficial role in the treatment of various autoimmune diseases,59
the debate surrounding recommendations for vitamin D supple-
mentation in autoimmune disease is still open. Evidence is even
less clear as far as autoimmune thyroid disease is concerned.
Supplementation studies in animals
There is a real lack of vitamin D supplementation studies in the
literature regarding autoimmune thyroid disease. The beneficial
effect of supplementation with vitamin D on treatment or
prevention of autoimmune thyroid disease has been demon-
strated in experimental animal studies only.60,61 In the first study,
daily treatment with cyclosporin or 1,25(OH)2D3 alone resulted in
a reduction of up to 26% of the severity of histological lesions in
mice with experimental autoimmune thyroiditis. When mice were
treated simultaneously with low doses of both cyclosporin and
1,25(OH)2D3, the outcome included a lower incidence of thyroid
autoimmune pathology and a significantly milder clinical disease
compared with the control group, without any changes in the
levels of thyroid autoantibodies.60
In a more recent study, the incidence of experimental
autoimmune thyroiditis in mice, after administration of low dose
of cyclosporine and 1,25(OH)2D3, decreased by 44.44% in the
group studied for prevention and by 37.50% in the group studied
for treatment. When severe autoimmune disease was examined,
the incidence in the two groups decreased by 71.43% and 60.32%,
respectively.61
Section remarks
Considering the current available data along with the minimal side
effects (that is, possible hypercalcemia after overtreatment, potential
interactions with other drugs62), careful vitamin D supplementation
could be considered as a potential tool for the treatment of patients
with autoimmune thyroid disease. However, this recommendation is
not included in the US Endocrine Society guideline,57 obviously due
to the lack of clinical trials performed in humans. Similarly to thyroid
autoimmune disease, no clinical trials exist regarding the effect of
vitamin D supplementation on thyroid cancer.
GENERAL REMARKS
Evidence on this issue deriving from clinical association studies
must be taken with great caution. In fact, there are many
confounding factors able to influence vitamin D concentration
that have not always been properly considered in the relevant
works and that can affect the relationship between vitamin D
levels and thyroid diseases.
As known, vitamin D metabolism may be influenced by
exposure to sunlight, use of sunscreen, naturally dark skin tone,
season, geographic latitude, clothing and institutionalization.57,63
Variability of vitamin D can be due also to physiological factors
(for example, age, body mass index, extracellular volume and
vitamin D binding globulin concentration and affinity).63 More-
over, other pathological or pharmacological causes of vitamin D
deficiency, such as fat malabsorption syndromes, nephrotic
syndrome, lymphomas, primary hyperparathyroidism and use of
anticonvulsants and medications to treat AIDS/HIV, must be
considered.57,63
It is also worth mentioning that racial differences in vitamin D
metabolism make total 25(OH)D not always the best parameter to
truly indicate vitamin D deficiency. In fact, the mean levels of total 25
(OH)D are usually lower in blacks than in whites, with the former
having also lower levels of vitamin D binding globulins than the latter,
thus resulting in similar concentrations of bioavailable 25(OH)D.64
Moreover, there are several methods to measure vitamin D.
The most widely used one for determining 25(OH)D is Diasorin
RIA that recognizes both 25(OH)D2 and 25(OH)D3, although

Table 2. Summary of available evidence that links vitamin D to thyroid disease

Diseases Potential mechanisms Observational studies Clinical trials

Hashimoto’s thyroiditis Vitamin D promotes a Th2 phenotype while suppressing Th1 activity, and inhibits !! !! !! !! No
cytokine production, which is important in the development of Hashimoto’s thyroiditis
Graves’ disease Vitamin D seems to inhibit inflammatory responses in human thyroid cells and T-cell !! !! !! No
production of cytokine leading to the production of TSH receptor autoantibodies
Thyroid cancer Vitamin D, through binding to its receptor, seems to increase the expression of p27, a !! !! No
tumor suppressor protein that has a critical role in several human malignancies
Abbreviations: Th1, Th1 helper cells; Th2, Th2 helper cells. Number of !! denotes degree of available evidence (from low (!!) to very high (!! !! !! !! !!)).

European Journal of Clinical Nutrition (2014) 1 – 6 © 2014 Macmillan Publishers Limited


the calibration curves are constructed with 25(OH)D3.65
High-performance liquid chromatography methods are less
common and the main limitations for its use are represented by
its laborious prepurification steps and the use of normal phase
chromatography.66 However, mass spectrometry is considered to
be the most accurate of all methods because of its ability to
separate and accurately quantify both 25(OH)D2 and 25(OH)D3.
However, the main limit of this method is represented by the
frequent issues with ion suppression, which could affect the
measurements of small quantities of analytes.67,68
In view of these considerations, future protocols must rigorously
consider all these aspects in order to clarify the real existence of
this association.
CONCLUSION
Although several findings support the role of vitamin D in the
pathogenesis of thyroid diseases (Table 2), no guidelines are
currently available for or against recommending vitamin D
supplementation in the prevention or therapy of thyroid disease,
outside the current recommendations made by the Endocrine
Society. However, because of the paucity of intervention studies,
further clinical trials are needed before evidence-based recom-
mendations can be made.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
DISCLAIMER
No external funding, apart from the support of the authors' institution, was
available for this article.
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