Physiological serum 25-hydroxyvitamin D concentrations are associated with improved thyroid function—observations from a community-based program

Abstract

PurposeVitamin D deficiency has been associated with an increased risk of hypothyroidism and autoimmune thyroid disease. Our aim was to investigate the influence of vitamin D supplementation on thyroid function and anti-thyroid antibody levels. Methods
We constructed a database that included 11,017 participants in a health and wellness program that provided vitamin D supplementation to target physiological serum 25-hydroxyvitmain D [25(OH)D] concentrations (>100 nmol/L). Participant measures were compared between entry to the program (baseline) and follow-up (12 ± 3 months later) using an intent-to-treat analysis. Further, a nested case-control design was utilized to examine differences in thyroid function over 1 year in hypothyroid individuals and euthyroid controls. ResultsMore than 72% of participants achieved serum 25(OH)D concentrations >100 nmol/L at follow-up, with 20% above 125 nmol/L. Hypothyroidism was detected in 2% (23% including subclinical hypothyroidism) of participants at baseline and 0.4% (or 6% with subclinical) at follow-up. Serum 25(OH)D concentrations ≥125 nmol/L were associated with a 30% reduced risk of hypothyroidism and a 32% reduced risk of elevated anti-thyroid antibodies. Hypothyroid cases were found to have higher mean serum 25(OH)D concentrations at follow-up, which was a significant positive predictor of improved thyroid function. Conclusion
The results of the current study suggest that optimal thyroid function might require serum 25(OH)D concentrations above 125 nmol/L. Vitamin D supplementation may offer a safe and economical approach to improve thyroid function and may provide protection from developing thyroid disease.

Full text

Endocrine (2017) 58:563–573
DOI 10.1007/s12020-017-1450-y
ORIGINAL ARTICLE
Physiological serum 25-hydroxyvitamin D concentrations are
associated with improved thyroid function—observations from a
community-based program
Naghmeh Mirhosseini
1
●Ludovic Brunel
2
●Giovanna Muscogiuri
3
●
Samantha Kimball
1,4
Received: 28 June 2017 / Accepted: 4 October 2017 / Published online: 24 October 2017
© The Author(s) 2017. This article is an open access publication
Abstract
Purpose Vitamin D deficiency has been associated with an
increased risk of hypothyroidism and autoimmune thyroid
disease. Our aim was to investigate the influence of vitamin
D supplementation on thyroid function and anti-thyroid
antibody levels.
Methods We constructed a database that included 11,017
participants in a health and wellness program that provided
vitamin D supplementation to target physiological serum
25-hydroxyvitmain D [25(OH)D] concentrations (>100
nmol/L). Participant measures were compared between
entry to the program (baseline) and follow-up (12 ±
3 months later) using an intent-to-treat analysis. Further, a
nested case-control design was utilized to examine
differences in thyroid function over 1 year in hypothyroid
individuals and euthyroid controls.
Results More than 72% of participants achieved serum 25
(OH)D concentrations >100 nmol/L at follow-up, with
20% above 125 nmol/L. Hypothyroidism was detected
in 2% (23% including subclinical hypothyroidism) of
participants at baseline and 0.4% (or 6% with subclinical) at
follow-up. Serum 25(OH)D concentrations ≥125 nmol/L
were associated with a 30% reduced risk of hypothy-
roidism and a 32% reduced risk of elevated anti-thyroid
antibodies. Hypothyroid cases were found to have higher
mean serum 25(OH)D concentrations at follow-up, which
was a significant positive predictor of improved thyroid
function.
Conclusion The results of the current study suggest that
optimal thyroid function might require serum 25(OH)D
concentrations above 125 nmol/L. Vitamin D supple-
mentation may offer a safe and economical approach to
improve thyroid function and may provide protection from
developing thyroid disease.
Keywords Thyroid function ●Vitamin D ●25-
Hydroxyvitamin D ●Autoimmune thyroid ●Anti-thyroid
antibodies ●Hypothyroidism
Background
Most tissues in the body have vitamin D receptors and
thousands of genes are responsive to active vitamin D,
1-25-dihydroxyvitamin D [1,25(OH)
2
D], suggesting a role
for vitamin D in the normal physiological function of most
organ systems, including the thyroid. The thyroid is
*Samantha Kimball
Samantha.kimball@purenorth.ca
Naghmeh Mirhosseini
Naghmeh.Mirhosseini@purenorth.ca
Ludovic Brunel
Ludovic.Brunel@gmail.com
Giovanna Muscogiuri
Giovanna.muscogiuri@gmail.com
1
Pure North S’Energy Foundation, 326 11th Avenue SW, Suite
800, Calgary, AB T2R 0C5, Canada
2
Naturmend Integrative Medical Clinic, 905 1st Ave NE, Calgary,
AB T2E 2L3, Canada
3
IOS and Coleman Medicina Futura Medical Center, via Alcide De
Gasperi 107/109/111, 80011 Acerra (Napoli), Italy
4
St. Mary’s University, 14500 Bannister Road, Calgary, AB
T2X1Z4, Canada
Electronic supplementary material The online version of this article
(https://doi.org/10.1007/s12020-017-1450-y) contains supplementary
material, which is available to authorized users.
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

activated through the hypothalamus-pituitary-thyroid axis
which is remarkably prone to circadian and seasonal
changes [1]. There is seasonal variability to serum thyroid-
stimulating hormone (TSH) concentrations with the highest
levels in autumn-winter and the lowest in spring-summer
[2–4]. Vitamin D levels are also affected by seasonal
variability and serum 25 hydroxyvitamin D [25(OH)D)
levels closely correlate with sun exposure and seasonality,
with more vitamin D deficiency (<50 nmol/L) prevalent
during the colder seasons [5,6].
Evidence is increasingly indicating low vitamin D status
as a risk factor for autoimmune disease, particularly multi-
ple sclerosis, and including thyroid disease [7–11]. More-
over, TSH levels are closely associated with vitamin D
status. During the winter months when vitamin D produc-
tion is negligible and levels are at a nadir for instance,
thyroid cells are less responsive to TSH and, as a result,
thyroid hormones (T4) decrease and serum TSH levels
increase [4,12]. Vitamin D supplementation, targeted at
achieving and maintaining serum 25(OH)D levels above
100 nmol/L, may preserve normal human physiology,
decrease the risk of autoimmunity and improve immune
function in autoimmune disorders [13–16].
Many thyroid disorders have an autoimmune etiology,
characterized by a loss of immune system homeostasis [17].
Given the immunomodulatory and anti-inflammatory roles
of vitamin D, supplementation may act to suppress auto-
immune activity in thyroid disease and improve thyroid
function. A recent meta-analysis including 20 case–control
studies found that serum 25(OH)D was lower in individuals
with autoimmune thyroid disease (AITD) compared with
healthy controls (OR =2.99, 95% CI 1.88–4.74) and that
AITD was more likely to develop with low serum 25(OH)D
[18]. Vitamin D deficiency is a common feature in thyroid
disorders [19] and low serum 25-hydroxyvitamin D [25
(OH)D] concentrations are associated with the development
of both Hashimoto’s thyroiditis and Grave’s disease [20,
21]. The onset and progression of thyroid cancer has been
linked with impaired signaling of 1,25(OH)
2
D through the
vitamin D receptor and lower 25(OH)D concentrations were
associated with more severe hypothyroidism [22]. Correct-
ing serum 25(OH)D status appears to improve thyroid
function by reducing circulating thyroid-stimulating hor-
mone (TSH) [23,24].
Thyroid autoimmunity, presenting with increased thyroid
autoantibody levels, anti-thyroid peroxidase (anti-TPO)
anti-thyroglobulin (anti-TG) antibodies, is associated with
vitamin D deficiency [serum 25(OH)D<50 nmol/L] [19,
25,26]. Despite the scarcity of clinical trials investigating
vitamin D supplementation effects on thyroid function, the
available studies collectively suggest clinical benefit from
vitamin D supplementation in the treatment of autoimmune
thyroid disorders with reductions in anti-thyroglobulin
(anti-TG) and anti-thyroid peroxidase (anti-TPO) antibody
levels [27–31].
In Canada, one in ten suffer from a thyroid disorder, half
of them undiagnosed [32]. Overall, a third of Canadians are
vitamin D deficient [25(OH)D<50 nmol/L] and less than
10% have levels above 100 nmol/L [33]. Vitamin D may be
an easily modifiable risk factor for autoimmune thyroid
disease and supplementation may be used as an adjuvant for
treatment [34]. The present analysis utilized a large database
of participants in a wellness program receiving vitamin D
supplementation, with average doses of 6000 IU/d. We
investigated the association between 25(OH)D status and
thyroid function before and after treatment. We further
examine differences between hypothyroid and euthyroid
patients.
Methods
Study design and population
This database analysis is a secondary use of data collected
as part of the standard of care for participants in a health and
wellness program provided by the Pure North S’Energy
Foundation (Pure North), a not-for-profit organization in
Calgary, Alberta, Canada. In the Pure North program, par-
ticipant visits occur approximately yearly and include
gathering medical history, consultation and lifestyle
recommendations by a health care professional (medical
doctor, naturopathic doctor, or nurse practitioner), blood
work and anthropometric measurements. A dataset was
constructed to include all participant data from January 1st
2010 to December 31th, 2016 who had consented to the use
of their anonymized data for research and who met the
inclusion criteria. To be included in the dataset participants
had to have a program entry measurement for all of the
following: 25(OH)D, free T3 (FT3), and T4 (FT4), thyroid
stimulating hormone (TSH), anti-TPO, anti-TG, and high-
sensitivity C reactive protein (hs-CRP). In addition, the
following information was included if it was available:
ethnicity, gender, body mass index (BMI), season of the
observation (November–April was considered winter and
May–October as summer), medical history of thyroid dis-
orders and medications, vitamin D supplementation intake
and thyroid symptom measures (described below). To
characterize the association between serum 25(OH)D and
thyroid function, comparisons were made at baseline and
between baseline and follow-up using intent-to-treat
analyzes.
Secondly, we utilized a nested case–control design, in
which hypothyroid participants (cases, n=103) were mat-
ched in a 1:4 ratio to control participants (n=412) based on
age, sex, BMI and the first two digits of their postal code (to
564 Endocrine (2017) 58:563–573
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geographically account for some socioeconomic factors). In
this investigation, we examined the effect of serum 25(OH)
D longitudinally on thyroid function. This study was
approved by the Research Ethics Board at St. Mary’s Uni-
versity, Calgary (File # 007FA2017).
Thyroid measures
Participants were interviewed by a health care practitioner
to collect medical history, medication use (iodine, desic-
cated thyroid or armor thyroid, synthroid or levothyroxine,
or any other thyroid medications). To assess suboptimal
thyroid function a series of questions were asked during the
consultation to evaluate the most common symptoms of
hypothyroidism: brain fog, macroglossia, low mood, unre-
freshing sleep, cool body temperature, weight gain, and low
energy level. Blood work assessed thyroid function
measures.
Pure north program and vitamin D supplementation
The goal of the Pure North program is to optimize health
and prevent chronic disease. The Pure North program pro-
vides education, lifestyle advice, and nutritional supple-
ments to meet individual requirements. The goal of the
program is to achieve optimal nutritional intake with a focus
on optimizing vitamin D status, defined as serum 25(OH)D
concentrations ≥100 nmol/L. Vitamin D3 supplementation
is individualized to target an optimal 25(OH)D and doses of
vitamin D3 are often in excess of the UL (4000 IU/d) given
under medical supervision. The data collected as part of this
program provided a unique opportunity to investigate the
role of a wide range of 25(OH)D concentrations on thyroid
function and autoimmunity.
Laboratory assessments
Sample preparation and biochemical measurements were
performed mostly by Doctor’s Data Laboratory, Chicago
[DD], a fully accredited laboratory by Clinical Laboratory
Improvement Amendments (CLIA). On some occasions,
biomarker results were obtained from other certified
laboratories (Calgary Laboratory Services, Meridian Valley
Lab). All laboratory testing was validated according to
ongoing externally provided accreditation test samples.
Serum 25(OH)D was measured using liquid chromato-
graphy and tandem mass spectrometry (LC/MS-MS), with
an assay CV of 2.4%. Thyroid function parameters
including serum free triiodothyronine (FT3; reference
range: 2.5–5.7 pmol/L), free thyroxine (FT4; reference
range: 7.7–20.6 pmol/L), Thyroid Stimulating Hormone
(TSH; reference range: 0.45–3 mU/L), Thyroglobulin (TG;
reference range: M: <50 µg/L, F:<30 µg/L), anti-
peroxidase antibody (anti-TPO; reference range: <9 kIU/
L) and anti-Thyroglobulin antibody (anti-TG; reference
range: <4 kIU/L), were measured on a Beckman Coulter
automated analyzer, using chemiluminescent immu-
noassays. Inter-assay CV was 5% for TSH, 8.3% for FT3,
3.6% for FT4, 6.9% for anti-TPO antibody and 6.6% for
anti-TG antibody. High-sensitivity C reactive protein (hs-
CRP; reference range: <1.0 mg/L) was measured using the
immunoturbidimetric method with an inter-assay CV of
2.5%.
Participant subgroups
Vitamin D deficiency was defined as serum 25(OH)D
concentrations<50 nmol/L [35] and optimal concentrations
≥100 nmol/L [16]. Subclinical hypothyroidism was defined
as serum TSH concentrations >3 mlU/L, with serum con-
centrations of FT4 and FT3 within their respective refer-
ences ranges. Hypothyroidism was defined as serum TSH >
3 mlU/L with serum FT4 <10.3 pmol/L and serum FT3
either within the reference range or <2.57 pmol/L.
Several patients started thyroid replacement hormones as
a results of the testing conducted by Pure North. Partici-
pants with undiagnosed or poorly managed hypothyroidism
were referred to their family physician. In some cases
patients declined referral or follow up, refused treatment,
did not comply with medication, or their physician did not
believe that replacement hormones were needed at that time.
Any change in medication, especially when close mon-
itoring is required to reach an appropriate dose, was done
outside of the Pure North program via a primary care
practitioner.
There has been some debate on the correct upper limit of
the reference range for TSH concentrations in euthyroid
subjects [36–38]. Here we follow the 2002 recommenda-
tions of the American Association of Clinical Endocrinol-
ogists, we used the upper limit of the serum TSH euthyroid
reference range of 3 mlU/L, which represents the 95% of
normal euthyroid population [39]. Also, concentrations
above this threshold increase the odds ratio of developing
hypothyroidism over the 20 years, especially if thyroid
antibodies were elevated [40]. Thyroid autoimmunity was
defined as a serum level of anti-TPO ≥9 klU/L and/or anti-
TG was ≥4 klU/L [32].
Statistical analysis
Data were analyzed using SPSS version 23 (SPSS Inc.,
Chicago, IL). Descriptive analyzes were performed to show
the distribution of categorical data. Intent-to-treat analyzes
was used to compare measures between baseline and
follow-up. The results of per-protocol analysis are available
upon request. The follow-up average for each biomarker
Endocrine (2017) 58:563–573 565
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was inserted rather than a missing value for those partici-
pants who had the baseline value. Paired samples t-tests
were performed to evaluate changes in thyroid function
measures and other metabolic parameters over time. Inde-
pendent samples t-tests were utilized to compare mean
changes according to compliance groups. Chi-square tests
were performed to determine the association between
reported thyroid assessment parameters and serum 25(OH)
D status and vitamin D supplementation dose. Relative
Risks (RR) were calculated. Univariate analyzes were used
to compare changes in thyroid markers between cases and
controls with respect to serum 25(OH)D levels. Binary
logistic regressions were performed to look at the associa-
tion between vitamin D and B12 status with respect to
thyroid function measures and to investigate the effect of
vitamin D and/or vitamin B12 status on changes in thyroid
function over time, considering probable confounding
parameters including age, sex, BMI, season of observation,
thyroid medication or thyroid-related supplementation.
Because serum TSH, anti-TPO, anti-TG and TG levels are
higher than the reference range in hypothyroidism and
thyroid autoimmune disorders, improvement was defined as
decreased levels over time in regression models. In contrast,
serum FT3 and FT4 are lower than normal and improve-
ment was defined as an increase in levels. Significance was
defined as p<0.05.
Results
Pure north population
Baseline demographics
Baseline demographics are presented in Table 1. Mean age
was 48 ±16 years with 58% female (n=11,017). Vitamin
D supplement use was reported by 43% of participants at
baseline, greater than the estimates for Canadian of more
than 32% [33]. The BMI distribution was 35.3% normal
(18.5–24.9 kg/m
2
), 36.1% overweight (25–29.9) and 28.6%
obese (≥30) which was in agreement with Canadian popu-
lation averages [41]. Mean baseline serum 25(OH)D con-
centrations were 78 ±34 nmol/L with 19% vitamin D
deficient [<50 nmol/L], 80% below the target (<100 nmol/L)
and 92% <125 nmol/L. Serum 25(OH)D level was sig-
nificantly lower during the winter season (61 ±28 nmol/L)
compared to the summer season (70 ±26 nmol/L) in par-
ticipants who did not take vitamin D supplements at pro-
gram entry. Vitamin D deficiency was seen in 37.5% of
these participants in winter and 23% in summer.
Participants who were vitamin D deficient and did not
take any vitamin D supplement at program entry had higher
serum TSH in winter (2.54 ±2.6 mU/L) rather than summer
(2.40 ±2.3 mU/L) (p=0.1). Meanwhile, serum FT4 was
significantly lower in winter (14.2 ±2.8 pmol/L) compared
to summer (14.8 ±2.9 pmol/L) (p<0.001). We found a
negative correlation between serum TSH and 25 (OH)D
levels [Pearson r=−0.04, p=0.01], indicating that
decreased levels of serum 25(OH)D in winter were corre-
lated with increased levels of serum TSH.
Comparison between baseline and follow-up
We performed a comparison between baseline and follow-
up (12 ±3 mo) for 11,017 participants, using Intent-To-
Treat analysis. Demographics did not show any significant
Table 1 Baseline demographics
Parameter N Percentage (%)
Age, years 11,017 48 ±16 (18–95 years)
Gender 11,017
Female 6378 58
Male 4649 42
Body Mass Index, kg/m
2
10,554 27.6 ±5.7
Normal weight (18.5–24.99) 3730 35.3
Overweight (25–29.99) 3807 36.1
Obese (≥30) 3017 28.6
Medication history 4411
Desiccated thyroid (Armor
thyroid)
81 1.6
Synthroid 592 13.4
Other thyroid medications 100 2.3
Supplementation history
Iodine 1788/11,017 14.8
Magnesium 446/8926 4.9
Niacin 56/8779 0.6
Vitamin D 4694/11,016 42.6
Thyroid Assessment Questionnaire
Brain fog 3761/10,176 37.0
Low energy level 3643/6865 53.1
Macroglossia 1343/9810 13.7
Low mood 3534/10,147 34.8
Unrefreshing sleep 4993/10,329 48.3
Cool body temperature 3124/10,097 30.9
Weight gain 2715/10,004 27.1
Serum 25(OH)D status, nmol/L 11,017
<50 2101 19.1
50–100 6660 60.4
100–150 1867 16.9
150–200 289 2.6
200–250 77 0.7
≥250 23 0.2
Age and BMI presented as Mean±SD
566 Endocrine (2017) 58:563–573
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changes over time, except higher consumption of iodine,
magnesium and vitamin D at follow-up, as well as sig-
nificant improvement in thyroid symptoms like low energy
level, macroglossia, unrefreshing sleep and weight gain
(Supplementary Table 1). All thyroid measures differed
statistically between baseline and follow-up yet mean
values for FT3, FT4, TG and TSH remained within their
respective reference ranges ( ≤9kU/L for anti-TPO, ≤4kU/
L for anti-TG) (Table 2). There was a weak but significant
negative correlation between TSH and thyroid hormones
(FT3 and FT4) at both baseline (r=−0.08 for FT4, r=
−0.07 for FT3) and follow-up (r=−0.07 for FT4 and r=
−0.10 for FT3). Also, changes in thyroid hormones over
time were negatively correlated with changes in TSH level
(p<0.001). Mean anti-thyroid antibody levels were above
their respective reference ranges and were found to be
significantly lower at follow-up, with a mean change in anti-
TPO of −9.8 ±65 kU/L and anti-TG of −25.4 ±70 kU/L.
For those who had elevated anti-thyroid antibody levels, at
follow-up 77.5% were within the reference range for anti-
TG and 42.2% for anti-TPO.
Thyroid medication consumption was reported by 15.8%
of participants at program entry and another 3.3% of par-
ticipants started taking thyroid medication between entry
and follow-up. Using thyroid biomarkers, hypothyroidism
was found in 1.8% of participants at baseline, which is
similar to Canadian population estimates of 2% [32]. At
follow-up 0.4% were classified as hypothyroid. After
excluding participants who took thyroid medications at
program entry or follow-up, or thyroid medications were
initiated some times between entry and follow-up, 1.3% of
participants were hypothyroid at program entry which
decreased to 0.3% at follow-up. Subclinical hypothyroidism
(SCH) was detected in 22.1% of participants at baseline and
5.8% at follow-up. Again, after excluding participants on
thyroid medications at any point during the program, the
incidence of SCH decreased from 21.7% at baseline to 6.1%
at follow-up.
Among those participants who were hypothyroid at
baseline, 33.3% were on thyroid medications at program
entry and another 10% started taking thyroid medications at
some point during follow-up. Thyroid medication con-
sumption was reported by 21.3% of subclinical hypothyroid
participants with an additional 6.6% starting medication
later in the program. However, data for medication doses
and any change in doses over time is not available in the
current study, due to poor patient recall.
Of those with SCH, 91% had anti-TG antibody titers and
36% had anti-TPO antibody titers above the reference
range. In addition, 26% of SCH had inflammation (hs-
CRP ≥3 mg/L). Participants who presented thyroid symp-
toms like weight gain, cool body temperature, low mood,
brain fog and refreshing sleep, had significantly higher T4
levels compared to those who did not present the symptoms.
Among those participants who had high TSH levels at
baseline (≥3 mlU/L), there was a significant negative cor-
relation between T4 and the majority of hypothyroid
symptoms, revealing that with increasing T4 levels, the
incidence of presenting brain fog (r=−0.125), low mood
(r=−0.120), unrefreshing sleep (r=−0.133), cool body
temperature (r=−0.060) and weight gain (r=−0.102)
were significantly decreased.
Participants were considered at-risk for autoimmune
thyroid disease (ATD) when anti-thyroid antibody levels
were above the reference range. Considering anti-TPO, 32%
were at-risk at baseline which decreased to 20% at follow-
up. For anti-TG, 93% of participants were at-risk at baseline
down to 21% at follow-up. Concomitant high levels of anti-
TPO and anti-TG were present in 29% of participants at
baseline and 9% at follow-up. Overall, for those at-risk for
ATD at baseline, more than 60% were no longer considered
at-risk at follow-up. In contrast, for those who had normal
levels of antibodies at baseline, the chance of being at risk
for ATD at follow-up was 1%.
After 1 year in program, mean serum 25(OH)D con-
centrations significantly increased, from 78 ±34 nmol/L to
110 ±22 nmol/L, and was consistent with the increase in
vitamin D supplementation dose, from 1436 ±2543 IU/d to
4078 ±2936 IU/d at follow-up (Table 2). At follow-up
serum 25(OH)D levels ≥100 nmol/L were achieved by 86%
of participants with a mean intake of 3940 ±2660 IU/d.
Moreover, 11% had serum 25(OH)D levels ≥125 nmol/L
with a mean intake of 6164 ±4398 IU/d.
Subclinical hypothyroid cases (SCH) were investigated
in comparison with hypothyroid patients and participants
with normal thyroid function. Following significant increase
in serum 25(OH)D levels, we found significant improve-
ments in thyroid antibodies and TSH, with no change in
Table 2 Comparison of measures between baseline and one-year
follow-up
Parameter N Baseline
(mean ±SD)
Follow-up
(MEAN ±SD)
P-value
FT3 (pmol/L) 11,017 4.9 ±0.8 4.6 ±0.2* <0.001
FT4 (pmol/L) 11,017 14.8 ±2.9 13.5 ±0.9* <0.001
Anti-TPO (kU/L) 11,017 32.2 ±92.0 22.4 ±41.0* <0.001
Anti-TG (kU/L) 11,017 40.1 ±112 14.7 ±28.7* <0.001
TSH (mU/L) 110,17 2.53 ±2.1 2.13 ±0.8* <0.001
TG (µg/L) 6509 29.2 ±27.0 25.1 ±5.0* <0.001
hs-CRP (mg/L) 10,968 2.71 ±4.6 2.40 ±2.2* 0.04
25(OH)D (nmol/L) 11,017 78 ±34 110 ±22* <0.001
Vitamin D dose (IU/d) 11,017 1436 ±2543 4078 ±2936* <0.001
*p-value<0.001, Paired t-test, FT3 Free triiodothyronine, FT4 Free
thyroxine, anti-TPO anti-thyroid peroxidase antibody, anti-TG anti-
thyroglobulin, TSH thyroid stimulating hormone, TG thyroglobulin,
hs-CRP high sensitivity C-reactive protein
Endocrine (2017) 58:563–573 567
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thyroid hormones for SCH (Supplementary Table 2). This
improvement was more pronounced in hypothyroid patients
rather than SCH cases.
Vitamin D, thyroid measures, and inflammation
We examined the risk of autoimmune thyroid disease and
hypothyroidism with respect to measurable changes in 25
(OH)D levels to investigate whether thyroid measure
improvements were associated with the intervention pro-
gram. The relative risks for increased levels of anti-TPO,
anti-TG, and inflammation (hs-CRP) were found to be
significantly lower when serum 25(OH)D levels ≥125
nmol/L were achieved. Serum 25(OH)D concentrations
<125 nmol/L were associated with an increased risk of
thyroid disease, a 115% increased risk of elevated anti-TG
antibody, 118% increased risk of anti-TPO antibody and
107% increased risk of elevated TSH. Serum 25(OH)D
levels above 125 nmol/L were associated with 60 and 14%
less chance of having low levels of thyroid hormones (FT4
and FT3) (Table 3).
Inflammation (hs-CRP >3 mg/L) was present in 17% of
participants with high anti-TG, 8% with high anti-TPO and
6% of participants with both anti-TG and anti-TPO above
the reference range (Fig. 1).
Thyroid assessment questionnaire was completed by n=
3367 participants at entry to the program and again 1 year
follow-up. Both vitamin D supplementation dose and serum
25(OH)D levels were found to significantly reduce the risk
of reported hypothyroid symptoms at follow-up (Table 4).
The relative risk of reporting brain fog, low mood, unre-
freshing sleep, weight gain or low energy was significantly
higher in participants whose serum 25(OH)D level were
<125 nmol/L after 1 year in program, compared to those
with serum 25(OH)D levels ≥125 nmol/L. Vitamin D
supplementation dose ≥4000 IU/d was associated with
lower risk of reporting brain fog, low mood, unrefreshing
sleep, weight gain, and low energy.
Nested case–control study
Baseline characteristics
To examine the relationship between serum 25(OH)D status
and improved thyroid function we compared, in a 1:4 ratio,
hypothyroid cases (n=103) to euthyroid controls (n=412)
matched based on age, sex, BMI and the first two digits of
their postal code. Hypothyroid cases were defined based on
their measured thyroid biomarkers (TSH, FT3, and FT4).
Participants taking thyroid medication at program entry or
follow-up (desiccated thyroid and synthroid) were exclu-
ded. Intervention between baseline and follow-up included
vitamin D and multivitamin package. As expected hypo-
thyroid individuals had higher levels of TSH, anti-TPO, and
anti-TG, lower levels of FT3 and FT4, and more frequently
reported brain fog, unrefreshing sleep, and weight gain
(Supplementary Table 3). The reported history of vitamin
and supplement use was not significantly different between
hypothyroid and control groups. However, at baseline,
serum 25(OH)D was significantly lower in cases than
controls (68 ±32 vs. 82 ±34 nmol/L; p-value <0.001).
Biomarker changes
Serum 25(OH)D concentrations increased to a greater
extent in hypothyroid cases compared to the controls (mean
change 42 ±26 vs. 28 ±31 nmol/L, respectively, p-value
<0.001), whereas vitamin D supplementation doses were
lower at 3517 ±2620 IU/d in cases compared to 4150 ±
3321 IU/d in controls (p-value 0.05). Among hypothyroid
Table 3 Relative risk (RR) for thyroid condition worsening according to serum 25(OH)D level and vitamin D supplementation dose at one-year
follow-up
Relative risk (95% CI) based on serum 25(OH)D,
nmol/L [n=11,017]
Relative risk (95% CI) based on vitamin D supplement dose,
IU/d [n=11,017]
<125 (n=9796) ≥125 (n=1226) Pvalue
a
<4000 (n=8215) ≥4000 (n=2806) Pvalue
a
FT3 decrease 1.02 (1.002–1.029) 0.88 (0.793–0.983) 0.02 1.02 (1.003–1.049) 0.93 (0.869–0.991) 0.03
FT4 decrease 1.56 (1.377–1.773) 0.95 (0.938–0.963) 0.01 1.39 (1.292–1.501) 0.90 (0.882–0.921) <0.001
Anti-TPO increase 1.18 (1.158–1.202) 0.32 (0.291–0.360) <0.001 1.60 (1.545–1.653) 0.34 (0.316–0.358) <0.001
Anti-TG increase 1.15 (1.132–1.172) 0.37 (0.331–0.409) <0.001 1.49 (1.445–1.536) 0.37 (0.352–0.399) <0.001
TSH increase 1.07 (1.058–1.087) 0.55 (0.495–0.621) <0.001 1.20 (1.172–1.224) 0.57 (0.536–0.615) <0.001
TG increase 1.02 (0.998–1.035) 0.89 (0.776–1.015) 0.08 1.04 (1.007–1.071) 0.90 (0.832–0.978) 0.01
hs-CRP increase 1.12 (1.099–1.132) 0.43 (0.385–0.479) <0.001 1.28 (1.245–1.309) 0.51 (0.477–0.543) <0.001
FT3 Free triiodothyronine, FT4 Free thyroxine, anti-TPO anti-thyroid peroxidase antibody, anti-TG anti-thyroglobulin, TSH thyroid stimulating
hormone, TG thyroglobulin, hs-CRP high sensitivity C-reactive protein
a
Chi Square test
568 Endocrine (2017) 58:563–573
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cases optimal 25(OH)D concentrations (>100 nmol/L) were
achieved in 92% at follow-up, up from 15% at baseline,
whereas 80% of controls achieved optimal levels (up from
26%). In comparison with controls, cases had significantly
greater decreases in levels of TSH, anti-TPO, anti-TG, and
greater increase in thyroid hormones concentrations (FT4
and FT3) (Table 5). Hypothyroid cases (n=69) that were
vitamin D insufficient at baseline had greater decrease in
anti-TPO (−144 ±164 vs. −2.7 ±71), TSH (−4.0 ±4.8 vs.
0.2 ±0.7) and greater increase in FT4 (4.5 ±1.4 vs. −1.2 ±
2.9) in comparison with those who were vitamin D suffi-
cient (n=34) [anti-TPO (−68 ±103 vs. −3±71), TSH
(−2.3 ±2.9 vs. 0.2 ±0.8) and FT4 (3.4 ±1.4 vs. −0.3 ±
0.7)].
We also compared hypothyroid cases who were
vitamin D deficient [serum 25(OH)D<75 nmol/L] and
not taking thyroid medication with a hypothyroid control
group who were vitamin D sufficient [serum 25(OH)
D≥75 nmol/L] and on no medication, in a ratio of 1:4,
age-matched, sex-matched, and BMI-matched (Supple-
mentary Table 4). At program entry, serum FT4 was sig-
nificantly lower and anti-TPO and anti-TG levels were
significantly higher in hypothyroid cases who were vitamin
Ddeficient compared to control group. After 1 year follow-
up, hypothyroid cases who were vitamin D deficient had
less of a decrease in FT4 (−0.12 ±2.7 vs. −1.1 ±2.3), and
a greater decrease in anti-TPO (−28.1 ±83.9 vs. −13.1 ±
77.8) and anti-TG (−84.5 ±107 vs. −37.9 ±118.7). Fur-
ther, cases had a significantly greater increase in serum 25
(OH)D level (47.8 ±20.8 vs. 12.0 ±33.7) and greater
decrease in hs-CRP (−0.97 ±7.0 vs. −0.06 ±4.0) than
controls.
Fig. 1 Relationship between anti-thyroid antibody levels, serum 25(OH)D and C reactive protein (hs-CRP). Left Panel, anti-TPO; Right Panel,
anti-TG
Table 4 Relative risk for reported thyroid symptoms in accordance to serum 25(OH)D level and vitamin D supplementation dose at one-year
follow-up
Relative risk based on serum 25(OH)D, nmol/L (n=3367) Relative risk based on vitamin D supplement dose, IU/
d(n=3367)
<125 (n=2389) ≥125 (n=978) Pvalue
a
<4000 (n=1001) ≥4000 (n=2366) Pvalue
a
Brain fog 1.053 (1.007–1.10) 0.88 (0.783–0.987) 0.03 1.13 (1.012–1.25) 0.95 (0.905–0.996) 0.03
Macroglossia 1.109 (1.023–1.204) 0.75 (0.571–0.977) 0.02 1.09 (0.866–1.34) 0.97 (0.877–1.07) 0.5
Low mood 1.09 (1.042–1.144) 0.79 (0.698–0.903) <0.001 1.2 (1.07–1.34) 0.92 (0.875–0.972) 0.002
Unrefreshing sleep 1.09 (1.046–1.14) 0.80 (0.719–0.895) <0.001 1.18 (1.06–1.305) 0.93 (0.89–0.97) 0.002
Cool body temperature 0.99 (0.947–1.045) 1.012 (0.903–1.135) 0.8 1.00 (0.895–1.13) 0.99 (0.95–1.05) 0.9
Weight gain 1.18 (1.12–1.23) 0.62 (0.522–0.733) <0.001 1.27 (1.13–1.44) 0.89 (0.835–0.95) <0.001
Low energy 1.35 (1.18–1.548) 0.89 (0.855–0.935) <0.001 1.05 (1.01–1.106) 0.89 (0.794–0.999) 0.05
a
Chi square test
Endocrine (2017) 58:563–573 569
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Relationship between vitamin D status and thyroid function
After 1 year in program, changes in thyroid measures dif-
fered significantly between hypothyroid cases compared to
controls (Table 5). Larger decreases in TSH, anti-TPO, and
anti-TG were found for cases. Among vitamin D-deficient
cases, an increased serum 25(OH)D≥50 nmol/L was
associated with greater reductions in biochemical signs of
hypothyroidism and thyroid autoimmune disease including
an increase in FT4 and FT3, and large decrease in serum
TSH, anti-TPO, anti-TG, and TG (Supplementary Table 5).
We utilized binary logistic regression to determine the
effect of serum 25(OH)D on changes in thyroid measures
(Supplementary Table 6). Thyroid measures were corrected
for age, sex, BMI, season of observation and thyroid
medication use. Regression analysis revealed that serum 25
(OH)D improvement to above 75 nmol/L had a significant
positive association with decreased serum TSH (β=1.135,
95% CI 1.002–1.353), decreased anti-TPO (β=1.950, 95%
CI 1.351–2.815), decreased anti-TG (β=1.445, 95% CI
1.002–2.091) and increased FT4 (β=1.413, 95% CI
1.006–2.129) levels. Moreover, serum vitamin B12
improvement had a significant association with increased
serum FT4 (β=1.737, 95% CI 1.387–2.176) and increased
FT3 (β=1.469, 95% CI 1.203–1.794) levels. Serum TSH
level varied seasonably with significantly lower levels
during the winter season. These changes were independent
of changes affecting FT3 and FT4.
Discussion
Approximately 2% of participants in this health and well-
ness program were found to be hypothyroid at program
entry, with an additional 22% classified as subclinical
hypothyroid. High incidence of subclinical hypothyroidism
in this study population might explain 15.8% of participants
that reported thyroid medication use. Like other studies [25,
42,43], we found that hypothyroid individuals were three
times more likely (27%) and subclinical hypothyroidism
nearly twice as likely (17%) to be vitamin D-deficient than
euthyroid individuals (10%). Supplementation with vitamin
D resulted in an overall reduction in TSH and in the
detection of hypothyroidism (down 58% at follow-up).
Most intriguing was the finding that subclinical hypothyr-
oidism was reduced by 72% at follow-up. It is well accepted
that subclinical hypothyroidism is a mild, early form of
thyroid failure [44]. Achieving serum 25(OH)D concentra-
tions above 125 nmol/L reduced the risk for high TSH as
well as symptoms of low thyroid function (brain fog, weight
gain, low mood, unrefreshing sleep and low energy).
These results are consistent with clinical trials centered on
patients with autoimmune thyroid diseases showing that
thyroid antibodies decreased significantly following vitamin
D supplementation compared to patients receiving no vita-
min D [27,29]. In combination with these studies, our
findings suggest that vitamin D may influence thyroid
function and that supplementation may be used as an
intervention to help prevent hypothyroidism. We also found
that 76% of hypothyroid patients were vitamin B12 insuf-
ficient (serum vitamin B12 <450 pmol/L) and improving
serum vitamin B12 status was significantly associated with
increased thyroid hormones (FT3 and FT4). Replacement of
B12 might lessen hypothyroid symptoms. Jabbar et al. [45]
and Al-Khamis [46] previously showed that there is a
high prevalence of vitamin B12 deficiency in hypothyroid
patients and replacing vitamin B12 improves their
symptoms.
Table 5 Comparison of thyroid measures over time between cases and controls
Serum parameter Case Control Between groups
comparison (P-value)
a
NBaseline
(mean ±SD
Follow-up
(mean ±SD)
NBaseline
(mean ±SD)
Follow-up
(mean ±SD)
FT3 (pmol/L) 103 4.34 ±0.6 4.57 ±0.2
b
412 4.85 ±0.7 4.30 ±0.5
b
<0.001
FT4 (pmol/L) 103 9.06 ±1.1 13.4 ±1.0
b
412 14.7 ±2.8 13.5 ±1.0
b
<0.001
Anti-TPO (kU/L) 103 162.8 ±120 43.4 ±116
b
412 21.5 ±54.8 18.8 ±26.7 <0.001
Anti-TG (kU/L) 103 51.8 ±33.7 17.6 ±27.2
b
412 32.0 ±61.3 14.5 ±30.7
b
0.05
TSH (mlU/L) 103 5.97 ±4.2 2.50 ±1.1
b
412 1.78 ±0.7 1.98 ±0.6
b
<0.001
TG (µg/L) 31 43.1 ±39.4 25.6 ±4.0
b
244 28.2 ±26.3 25.4 ±5.9 0.003
hs-CRP (mg/L) 103 2.05 ±2.2 2.52 ±1.4 412 2.35 ±3.1 2.41 ±1.9 0.2
25(OH)D (nmol/L) 103 68 ±32 110 ±14
b
412 82 ±34 110 ±27
b
0.001
Vitamin D dose (IU/day) 103 1243 ±2606 3517 ±2620
b
412 1824 ±2770 4150 ±3321
b
0.9
a
Independent samples T-test (between groups comparison)
b
P<0.05 paired samples T-test (within group comparison)
570 Endocrine (2017) 58:563–573
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The current study revealed that serum TSH is sig-
nificantly affected by season and is the highest in winter,
when average serum 25(OH)D concentrations were at their
lowest. Moreover, this association was independent of
thyroid hormones and yet was dependent on improve-
ments in serum 25(OH)D status. Considering the high
prevalence of vitamin D deficiency worldwide and the high
incidence of undiagnosed subclinical hypothyroidism
in the general population (as we found in Canadians), the
existence of the association between TSH and vitamin D
status is of high importance and makes vitamin D supple-
mentation a potential asset for patients already taking
thyroid medications.
Autoimmune thyroid disease (AITD), including Grave’s
disease and Hashimoto’s thyroiditis, are prevalent auto-
immune disorders affecting an estimated 5% of the popu-
lation [47]. A link between hypovitaminosis D and thyroid
autoimmunity has been established [23] and a review of 20
case–control studies revealed that lower levels of 25(OH)D
were prevalent in autoimmune thyroid diseases [18]. We
found elevated anti-thyroid antibodies, both anti-TPO and
anti-TG, in 29% of the population considered at-risk for
developing autoimmune thyroid disease, over 80% of
whom did not have optimal 25(OH)D levels (>100 nmol/L)
at baseline.
Proper thyroid function requires appropriate physiologi-
cal levels of serum 25(OH)D (i.e., 100–130 nmol/L) [16]. It
has been suggested that physiological levels should be
sustained for a considerable period of time (e.g., 2–3 years)
for the goal of chronic disease prevention or treatment
achieved [48]. In accordance, we also found that of the
subjects who achieved serum 25(OH)D above 100 nmol/L
at follow-up, roughly 1 year after program entry, only 8.8%
were still considered at-risk of AITD. Given that AITD is
the main cause of thyroid dysfunction in Canada [49], the
remarkable decrease in thyroid autoantibodies following
improved serum 25(OH)D status might explain the sig-
nificant decrease in the prevalence of hypothyroidism (from
2 to 0.4%) and this is likely to attributable to the immu-
noregulatory role of vitamin D rather than a direct effect of
vitamin D on thyroid function. Short duration of supple-
mentation and low serum 25(OH)D levels (rather than the
physiological levels) are likely reasons why the effects of
vitamin D on thyroid function were not recovered in other
studies [27]. Improved serum 25(OH)D status also sig-
nificantly affected inflammation by decreasing hs-CRP
which may provide a potential reason why improving 25
(OH)D status promotes thyroid function. Given vitamin D’s
extensive roles in immune cell function and inflammation,
these results are not surprising. Supplementation with
vitamin D has been found to induce tolerance [50,51] and
reduce auto reactivity in other autoimmune conditions such
as multiple sclerosis [15,52].
We utilized a nested case–control study design to further
investigate the associations between thyroid function and
vitamin D. Hypothyroid cases not taking thyroid medication
had reduced TSH levels by 58% with a mean level that was
within the reference range at follow-up. Large reductions in
anti-thyroid antibody levels were found in cases with
decreases in anti-TG by 66% and anti-TPO by 73%.
Changes in thyroid hormones and TSH were significantly
correlated with improvement in hypothyroid symptoms
assessed through thyroid assessment questionnaire and are
clinically significant. Vitamin D deficient cases experienced
greater reductions in biochemical signs of hypothyroidism
and autoimmune thyroiditis. Vitamin D deficiency appeared
to be a relevant risk factor for hypothyroidism and auto-
immune thyroid disease, in addition to which supple-
mentation with vitamin D provided measurable benefit.
The limitations of the study include the retrospective
nature of the analyzes. Because the sample was drawn from
a community-based program there is a selection bias to
contend with, yet the extremely large sample size (over
11,000) must be considered a strength. Some risk factors
associated with thyroid disease, such as cigarette smoking,
were not available for all participants. The main strength of
this study lies in the large number of thyroid function tests
that were analyzed longitudinally to investigate the rela-
tionship between serum 25(OH)D status and these
parameters.
Conclusion
Overall, the results of the current study suggest that for
normal thyroid function an optimal 25(OH)D concentration
above 100–125 nmol/L may be required. Although
improving other nutrient status, like vitamin B12, should
also be taken into consideration. Of concern, recommended
daily intakes for vitamin D are aimed at achieving serum 25
(OH)D concentrations of 50 nmol/L and targeted at bone
health alone. Vitamin D offers a safe and economical
approach to improve thyroid function and may provide
protection from developing thyroid disease.
Acknowledgements We wish to thank Mr. Ken Fyie for his
expertize preparing the dataset for this study and Dr. Brian Rankin for
reviewing this manuscript.
Author contributions The authors’responsibilities were as follows:
N.M., L.B., G.M. and S.K. designed the study; N.M. organized the
data and performed for the statistical analysis; S.K., N.M., G.M and L.
B. wrote the manuscript. All authors read and approved the final
manuscript.
Endocrine (2017) 58:563–573 571
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Compliance with ethical standards
Conflict of interest S.K. and N.M. are employed by the Pure North
S’Energy Foundation. The remaining authors declare that they have no
competing interests.
Informed consent Informed consent was obtained from all indivi-
dual participants included in the study.
Open Access This article is distributed under the terms of the
Creative Commons Attribution 4.0 International License (http://crea
tivecommons.org/licenses/by/4.0/), which permits unrestricted use,
distribution, and reproduction in any medium, provided you give
appropriate credit to the original author(s) and the source, provide a
link to the Creative Commons license, and indicate if changes were
made.
References
1. C.H. Blomquist, J.P. Holt, Chronobiology of the Hypothalamic-
Pituitary-Gonadal Axis in Men and Women. Biological Rhythms
in Clinical and Laboratory Medicine. (Springer, Berlin), 1992)
2. M. Maes, K. Mommen, D. Hendrickx, D. Peeters, P. D’Hondt, R.
Ranjan, F. De Meyer, S. Scharpe, Components of biological
variation, including seasonality, in blood concentrations of TSH,
TT3, FT4, PRL, cortisol and testestrone in healthy volunteers.
Clin. Endocrinol. 46, 587–598 (1997)
3. M. Simoni, A. Velardo, V. Montanini, M. Faustini, S. Seghedoni,
P. Marrama, Circannual rhythm of plasma thyrotropin in middle-
aged and old euthyroid subjects. Horm. Res. 33, 184–189 (1999)
4. I. Barchetta, M.G. Baroni, F. Leonetti, M. De Bernardinis, L.
Bertoccini, M. Fontana, E. Mazzei, A. Fraioli, M.G. Cavallo, TSH
levels are associated with vitamin D status and seasonality in an
adult population of euthyroid adults. Clin. Exp. Med. 15, 389–396
(2015). https://doi.org/10.1007/s10238-014-0290-9
5. Y. Wang, E.J. Jacobs, M.L. McCullough, C. Rodriguez, M.J.
Thun, E.E. Calle et al. Comparing methods for accounting for
seasonal variability in a biomarker when only a single sample is
available: insights from simulations based on serum 25-
hydroxyvitamin D. Am. J. Epidemiol. 170,88–94 (2009)
6. A. Nanri, L.H. Foo, K. Nakamura, A. Hori, K. Poudel-Tandukar,
Y. Matsushita, T. Mizoue, Serum 25-hydroxyvitamin D con-
centrations and season-specific correlates in Japanese adults. J.
Epidemiol. 21, 346–353 (2011)
7. F. Baeke, T. Takiishi, H. Korf, C. Gysemans, C. Mathieu, Vitamin
D: modulator of the immune system. Curr. Opin. Pharmacol. 10,
482–496 (2010)
8. C.D. Marques, A.T. Dantas, T.S. Fragoso, A.L. Duarte, The
importance of vitamin D levels in autoimmune diseases. Rev.
Bras. Reumatol. 50,67–80 (2010)
9. K.L. Munger, L.I. Levin, J. Massa, R. Horst, T. Orban, A.
Ascherio, Preclinical serum 25-hydroxyvitamin D levels and risk
of type 1 diabetes in a cohort of US military personnel. Am. J.
Epidemiol. 177, 411–419 (2013)
10. J. Mitri, M.D. Muraru., A.G. Pittas, Vitamin D and type 2 dia-
betes: a systematic review. Eur. J. Clin. Nutr. 65, 1005–1015
(2011)
11. M.F. Holick, Vitamin D: extraskeletal health. Endocrinol. Metab.
Clin. N. Am. 39, 381–400 (2010)
12. J.P. Berg, G. Sornes, P.A. Torjesen, E. Haug, Cholecalciferol
metabolites attenuate cAMP production in rat thyroid cells
(FRTL-5). Mol. Cell. Endocrinol. 76, 201–206 (1991)
13. E. Vanoirbeek, A. Krishnan, G. Eelen, L. Verlinden, R. Bouillon,
D. Feldman, A. Verstuyf, The anti-cancer and anti-inflammatory
actions of 1,25(OH)2D3. Best Pract. Res. Clin. Endocrinol.
Metab. 25, 593–604 (2011)
14. M.F. Holick, Vitamin D deficiency. N. Engl. J. Med. 357,
266–281 (2007)
15. S. Kimball, R. Vieth, H.M. Dosch, A. Bar-Or, R. Cheung, D.
Gagne, P. O’Connor, C. D’Souza, M. Ursell, J.M. Burton, Cho-
lecalciferol plus calcium suppresses abnormal PBMC reactivity in
patients with multiple sclerosis. J. Clin. Endocrinol. Metab. 96,
2826–2834 (2011). https://doi.org/10.1210/jc.2011-0325
16. R.P. Heaney, Toward a physiological referent for the vitamin D
requirement. J. Endocrinol. Invest. 37, 1127–1130 (2014)
17. G.A. Brent, Environmental exposure and autoimmune thyroid
disease. Thyroid J. 20, 755–761 (2010)
18. J. Wang, S. Lv, G. Chen, Gao Ch, J. He, H. Zhong, Y. Xu, Meta-
analysis of the association between Vitamin D and autoimmune
thyroid disease. Nutrients 7, 2485–2498 (2015)
19. S. Kivity, N. Agmon-Levin, M. Zisappl, Y. Shapira, E.V. Nagy,
K. Dankó, Z. Szekanecz, P. Langevitz, Y. Shoenfeld, Vitamin D
and autoimmune thyroid diseases. Cell. Mol. Immunol. 8,
243–247 (2011)
20. G. Tamer, S. Arik, I. Tamer, D. Coksert, Relative vitamin D
insufficiency in Hashimoto’s thyroiditis. Thyroid J. 21, 891–896
(2011)
21. T. Yasuda, Y. Okamoto, N. Hamada, K. Miyashita, M. Takahara,
F. Sakamoto, Serum vitamin D levels are decreased and associated
with thyroid volume in female patients with newly onset Graves’
disease. Endocrine 42, 739–741 (2012)
22. I. Clinckspoor, L. Verlinden, C. Mathieu, R. Bouillon, A.
Verstuyf, B. Decallonne, Vitamin D in thyroid tumorigenesis
and development. Prog. Histochem. Cytochem. 48,65–98
(2013)
23. A.M.H. Mackawy, B. Al-Ayed, B.M. Al-rashidi, Vitamin D
deficiency and its association with thyroid disease. Int. J. Health
Sci. 7, 267–275 (2013)
24. L. Chailurkit, W. Aekplakom, B. Ongphiphadhanakul, High
vitamin D status in younger individuals is associatedwith low
circulating thyrotropin. Thyroid J. 23,25–30 (2013)
25. Q.Q. Zhang, M. Sun, Z.X. Wang, Q. Fu, Y. Shi, F. Yang, S.
Zheng, J.J. Xu, X.P. Huang, X.Y. Liu, D. Cui, T. Yang,
Relationship between serum 25-hydroxy vitamin D and
thyroid autoimmunity among middle-aged and elderly individuals.
Acta Universitatis Medicinalis Nanjung 34, 486–489 (2014)
26. D.Y. Shin, K.J. Kim, D. Kim, S. Hwang, E.J. Lee, Low serum
vitamin D is associated with anti-thyroid peroxidase antibody in
autoimmune thyroiditis. Yonesi Med. J. 55, 476–481 (2014)
27. S. Chaudhary, D. Dutta, M. Kumar, S. Saha, S.A. Mondal, A.
Kumar, S. Mukhopadhyay, Vitamin D supplementation reduces
thyroid peroxidase antibody levels in patients with autoimmune
thyroid disease: an open-labeled randomized controlled trial.
Indian J. Endocrinol. Metab. 20, 391–398 (2016)
28. E.E. Mazokopakis, M.G.. Papadomanolaki, K.C. Tsekouras, A.D.
Evangelopoulos, D.A. Kotsiris, A.A. Tzortzinis, Is vitamin D
related to pathogenesis and treatment of Hashimoto’s thyroiditis?
Hell J. Nucl. Med. 18, 222–227 (2015)
29. Y. Simsek, I. Cakir, M. Yetmis, O.S. Dizdar, O. Baspinar, F.
Gokay, Effects of vitamin D treatment on thyroid autoimmunity.
J. Res. Med. Sci. 21, 92 (2016)
30. P. De Remigis, L. Vianale, A. De Remingis, G. Napolitano,
Vitamin D and autoimmune thyroid disease (at): preliminary
results. Thyroid J. 23, A81–A82 (2013)
31. I.V. Pankiv, Impact of vitamin D supplementation on the level of
thyroid peroxidase antibodies in patients with autoimmune
hypothyroidism. Int. J. Endocrinol. (2016)
572 Endocrine (2017) 58:563–573
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

32. J.R. Garber, R.H. Cobin, H. Gharib, J.V. Hennessey, I. Klein, J.I.
Mechanick, R. Pessah-Pollack, P.A. Singer, K.A. Woeber, Clin-
ical practice guidelines for hypothyroidism in adults. Endocr.
Pract. 18, 988–1028 (2012)
33. T. Janz, C. Pearson, Vitamin D blood levels of Canadians. Stat.
Can. 82-624-X (2011)
34. G. Muscogiuri, G. Tirabassi, G. Bizzaro, F. Orio, S.A. Paschou,
A. Vryonidou, G. Balercia, Y. Shoenfeld, A. Colao, Vitamin D
and thyroid disease: to D or not to D? Eur. J. Clin. Nutr. 69,
291–296 (2015)
35. Institute of Medicine, Food and Nutrition Board. Dietary Refer-
ence Intakes for Calcium and Vitamin D. National Academy
Press, Washington, DC (2010)
36. L. Wartofsky, R.A. Dickey, The evidence for a narrower thyro-
tropin reference range is compelling. J. Clin. Endocrinol. Metab.
90, 5483–5488 (2005)
37. M.I. Surks, G. Goswami, G.H. Daniels, The thyrotopin reference
range should remain unchanged. J. Clin. Endocrinol. Metab. 90,
5489–5496 (2005)
38. B. Biondi, The normal TSH reference range: what has changed
in the last decade? J. Clin. Endocrinol. Metab. 98, 3584–3587
(2013)
39. L.M. Demers, C.A. Spencer, Laboratory Medicine Practice
Guidelines: Laboratory Support for the Diagnosis and Monitoring
of Thyroid Disease. Clin. Endocrinol. 58, 138–140 (2003)
40. V. Fatourechi, G.G. Klee., S.K. Grebe et al. Effects of reducing
the upper limit of normal TSH values. JAMA 290, 3195–3196
(2003)
41. T. Navaneelan T, T. Janz, Adjusting the scales: Obesity in the
Canadian population after correcting for respondent bias. Stat.
Can. 82-624-X (2012)
42. N.C. Bozkurt, B. Karbek, B. Ucan, M. Sahin, E. Cakal, M. Ozbek,
T. Delibasi, The association between severity of vitamin D
deficiency and Hashimoto’s thyroiditis. Endocr. Pract. 19,
479–484 (2013). https://doi.org/10.4158/EP12376
43. O.M. Camurdan, E. Doger, A. Bideci, N. Celik, P. Cinaz, Vitamin
D status in children with Hashimoto thyroiditis. J. Pediatr.
Endocrinol. Metab. 25, 467–470 (2012)
44. D.S. Cooper, B. Biondi, Subclinical thyroid disease. Lancet 379,
1142–1154 (2012)
45. A. Jabbar, A. Yawar, S. Waseem, N. Islam, N. Ul Haque, L.
Zuberi, A. Khan, J. Akhter, Vitamin B12 deficiency common in
primary hypothyroidism. J. Pak. Med. Assoc. 58, 258–261 (2008)
46. F.A. Al-Khamis, Serum Vitamin B12 and thyroid hormone levels
in Saudi patients with multiple sclerosis. J. Fam. Community
Med. 23, 151–154 (2016)
47. A. Antonelli, S. Ferrari, A. Corrado, A. Di Domenicantonio, P.
Fallahi, Autoimmune thyroid disorders. Autoimmun. Rev. 14,
174–180 (2015). https://doi.org/10.1016/j.autrev.2014.10.016
48. Y. Zheng, J. Zhu, M. Zhou, L. Cui, W. Yao, Y. Liu, Meta-analysis
of long-term vitamin D supplementation on overall mortality.
PLoS One 8, e82109 (2013)
49. L.M. Demers, Thyroid disease: pathophysiology and diagnosis.
Clin. Lab. Med. 24,19–28 (2004)
50. R.F. Chun, P.T. Liu, R.L. Modlin, J.S. Adams, M. Hewison,
Impact of vitamin D on immune function: lessons learned from
genome-wide analysis. Front. Physiol. 5, 151 (2014). https://doi.
org/10.3389/fphys.2014.00151
51. M. Hewison, Vitamin D and innate and adaptive immunity.
Vitam. Horm. 86,23–62 (2011). https://doi.org/10.1016/B978-0-
12-386960-9.00002-2
52. J. Smolders, E. Peelen, M. Thewissen, J.W. Cohen Tervaert, P.
Menheere, R. Hupperts, J. Damoiseaux, Safety and T cell mod-
ulating effects of high dose vitamin D3 supplementation in mul-
tiple sclerosis. PLoS One 5, e15235 (2010). https://doi.org/10.
1371/journal.pone.0015235
Endocrine (2017) 58:563–573 573
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