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

Authors:
  • The Pure North S'Energy Foundation

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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.
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Endocrine (2017) 58:563573
DOI 10.1007/s12020-017-1450-y
ORIGINAL ARTICLE
Physiological serum 25-hydroxyvitamin D concentrations are
associated with improved thyroid functionobservations 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 deciency has been associated with an
increased risk of hypothyroidism and autoimmune thyroid
disease. Our aim was to investigate the inuence 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 signicant 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 SEnergy 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. Marys 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
[24]. 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 deciency (<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 [711]. 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 [1316].
Many thyroid disorders have an autoimmune etiology,
characterized by a loss of immune system homeostasis [17].
Given the immunomodulatory and anti-inammatory 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 casecontrol
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 1.884.74) and that
AITD was more likely to develop with low serum 25(OH)D
[18]. Vitamin D deciency 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 Hashimotos thyroiditis and Graves 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 deciency [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 benet 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 [2731].
In Canada, one in ten suffer from a thyroid disorder, half
of them undiagnosed [32]. Overall, a third of Canadians are
vitamin D decient [25(OH)D<50 nmol/L] and less than
10% have levels above 100 nmol/L [33]. Vitamin D may be
an easily modiable 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 SEnergy
Foundation (Pure North), a not-for-prot 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 (NovemberApril was considered winter and
MayOctober 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 casecontrol 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 rst two digits of their postal code (to
564 Endocrine (2017) 58:563573
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
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. Marys 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, dened 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 Doctors Data Laboratory, Chicago
[DD], a fully accredited laboratory by Clinical Laboratory
Improvement Amendments (CLIA). On some occasions,
biomarker results were obtained from other certied
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: 2.55.7 pmol/L), free thyroxine (FT4; reference
range: 7.720.6 pmol/L), Thyroid Stimulating Hormone
(TSH; reference range: 0.453 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 deciency was dened as serum 25(OH)D
concentrations<50 nmol/L [35] and optimal concentrations
100 nmol/L [16]. Subclinical hypothyroidism was dened
as serum TSH concentrations >3 mlU/L, with serum con-
centrations of FT4 and FT3 within their respective refer-
ences ranges. Hypothyroidism was dened 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 [3638]. 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
dened 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) 58:563573 565
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
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 dened as
decreased levels over time in regression models. In contrast,
serum FT3 and FT4 are lower than normal and improve-
ment was dened as an increase in levels. Signicance was
dened 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
(18.524.9 kg/m
2
), 36.1% overweight (2529.9) 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
decient [<50 nmol/L], 80% below the target (<100 nmol/L)
and 92% <125 nmol/L. Serum 25(OH)D level was sig-
nicantly 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 deciency was seen in 37.5% of
these participants in winter and 23% in summer.
Participants who were vitamin D decient 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
signicantly 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 signicant
Table 1 Baseline demographics
Parameter N Percentage (%)
Age, years 11,017 48 ±16 (1895 years)
Gender 11,017
Female 6378 58
Male 4649 42
Body Mass Index, kg/m
2
10,554 27.6 ±5.7
Normal weight (18.524.99) 3730 35.3
Overweight (2529.99) 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
50100 6660 60.4
100150 1867 16.9
150200 289 2.6
200250 77 0.7
250 23 0.2
Age and BMI presented as Mean±SD
566 Endocrine (2017) 58:563573
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changes over time, except higher consumption of iodine,
magnesium and vitamin D at follow-up, as well as sig-
nicant 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 signicant
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
signicantly 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 classied 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 inammation (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 signicantly 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 signicant 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 signicantly 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 signicantly 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 signicant increase
in serum 25(OH)D levels, we found signicant 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) 58:563573 567
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
thyroid hormones for SCH (Supplementary Table 2). This
improvement was more pronounced in hypothyroid patients
rather than SCH cases.
Vitamin D, thyroid measures, and inammation
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 inammation (hs-CRP) were found to be
signicantly 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).
Inammation (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 signicantly 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 signicantly
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 casecontrol 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 rst two digits of
their postal code. Hypothyroid cases were dened 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 signicantly different between
hypothyroid and control groups. However, at baseline,
serum 25(OH)D was signicantly 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 (1.0021.029) 0.88 (0.7930.983) 0.02 1.02 (1.0031.049) 0.93 (0.8690.991) 0.03
FT4 decrease 1.56 (1.3771.773) 0.95 (0.9380.963) 0.01 1.39 (1.2921.501) 0.90 (0.8820.921) <0.001
Anti-TPO increase 1.18 (1.1581.202) 0.32 (0.2910.360) <0.001 1.60 (1.5451.653) 0.34 (0.3160.358) <0.001
Anti-TG increase 1.15 (1.1321.172) 0.37 (0.3310.409) <0.001 1.49 (1.4451.536) 0.37 (0.3520.399) <0.001
TSH increase 1.07 (1.0581.087) 0.55 (0.4950.621) <0.001 1.20 (1.1721.224) 0.57 (0.5360.615) <0.001
TG increase 1.02 (0.9981.035) 0.89 (0.7761.015) 0.08 1.04 (1.0071.071) 0.90 (0.8320.978) 0.01
hs-CRP increase 1.12 (1.0991.132) 0.43 (0.3850.479) <0.001 1.28 (1.2451.309) 0.51 (0.4770.543) <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) 58:563573
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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 signicantly
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 insufcient 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 suf-
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 decient [serum 25(OH)D<75 nmol/L] and
not taking thyroid medication with a hypothyroid control
group who were vitamin D sufcient [serum 25(OH)
D75 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-
nicantly lower and anti-TPO and anti-TG levels were
signicantly higher in hypothyroid cases who were vitamin
Ddecient compared to control group. After 1 year follow-
up, hypothyroid cases who were vitamin D decient 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 signicantly 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 (1.0071.10) 0.88 (0.7830.987) 0.03 1.13 (1.0121.25) 0.95 (0.9050.996) 0.03
Macroglossia 1.109 (1.0231.204) 0.75 (0.5710.977) 0.02 1.09 (0.8661.34) 0.97 (0.8771.07) 0.5
Low mood 1.09 (1.0421.144) 0.79 (0.6980.903) <0.001 1.2 (1.071.34) 0.92 (0.8750.972) 0.002
Unrefreshing sleep 1.09 (1.0461.14) 0.80 (0.7190.895) <0.001 1.18 (1.061.305) 0.93 (0.890.97) 0.002
Cool body temperature 0.99 (0.9471.045) 1.012 (0.9031.135) 0.8 1.00 (0.8951.13) 0.99 (0.951.05) 0.9
Weight gain 1.18 (1.121.23) 0.62 (0.5220.733) <0.001 1.27 (1.131.44) 0.89 (0.8350.95) <0.001
Low energy 1.35 (1.181.548) 0.89 (0.8550.935) <0.001 1.05 (1.011.106) 0.89 (0.7940.999) 0.05
a
Chi square test
Endocrine (2017) 58:563573 569
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Relationship between vitamin D status and thyroid function
After 1 year in program, changes in thyroid measures dif-
fered signicantly between hypothyroid cases compared to
controls (Table 5). Larger decreases in TSH, anti-TPO, and
anti-TG were found for cases. Among vitamin D-decient
cases, an increased serum 25(OH)D50 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 signicant
positive association with decreased serum TSH (β=1.135,
95% CI 1.0021.353), decreased anti-TPO (β=1.950, 95%
CI 1.3512.815), decreased anti-TG (β=1.445, 95% CI
1.0022.091) and increased FT4 (β=1.413, 95% CI
1.0062.129) levels. Moreover, serum vitamin B12
improvement had a signicant association with increased
serum FT4 (β=1.737, 95% CI 1.3872.176) and increased
FT3 (β=1.469, 95% CI 1.2031.794) levels. Serum TSH
level varied seasonably with signicantly 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% classied 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-decient 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 nding 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 signicantly following vitamin
D supplementation compared to patients receiving no vita-
min D [27,29]. In combination with these studies, our
ndings suggest that vitamin D may inuence 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-
cient (serum vitamin B12 <450 pmol/L) and improving
serum vitamin B12 status was signicantly 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 deciency 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) 58:563573
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
The current study revealed that serum TSH is sig-
nicantly 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 deciency 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 Graves
disease and Hashimotos 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
casecontrol 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., 100130 nmol/L) [16]. It
has been suggested that physiological levels should be
sustained for a considerable period of time (e.g., 23 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-
nicant 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-
nicantly affected inammation by decreasing hs-CRP
which may provide a potential reason why improving 25
(OH)D status promotes thyroid function. Given vitamin Ds
extensive roles in immune cell function and inammation,
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 casecontrol 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 signicantly
correlated with improvement in hypothyroid symptoms
assessed through thyroid assessment questionnaire and are
clinically signicant. Vitamin D decient cases experienced
greater reductions in biochemical signs of hypothyroidism
and autoimmune thyroiditis. Vitamin D deciency 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 benet.
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 100125 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 authorsresponsibilities 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 nal
manuscript.
Endocrine (2017) 58:563573 571
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Compliance with ethical standards
Conict of interest S.K. and N.M. are employed by the Pure North
SEnergy 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.
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Supplementary resource (1)

... The mechanism of acute lung injury caused by COVID-19 infection might be related to TMPRSS2-ERG (T2E) [11]. T2E is not only widely expressed in lung [12,13], but also in thyroid follicular epithelial cells [14]. Therefore, T2E related signaling pathway might also play a role in metastatic thyroid cancer. ...
... This fusion results in high expression of T2E, which is driven by the TSH response promoter of T2E gene. Compared with benign thy-roid follicular epithelial cells, these lead to an increase in invasion and migration of follicular epithelial cells and incomplete differentiation [14]. ...
... SARS-S uses ACE2 as the target receptor, and spike protein is activated by TMPRSS2 [26]. Nearly 72% of thyroid cancer patients have T2E subtypes [14], and the overexpression of ERG has been thought to drive tumor development. Frequent deletions extend the core containing the T2E promoter to the rearranged ERG allele [27,28]. ...
Article
Objective: Cancer has been shown to be an independent risk factor for 2019-nCoV. Expression of transmembrane serine protease 2 (TMPRSS2) is abnormal in many cancers. Nevertheless, system analysis of TMPRSS2-ERG (T2E) abnormalities in metastatic thyroid cancer remains to be elucidated. Method: Using genomic and chromatin data, we demonstrate a unique cis-regulatory landscape between non-T2E and T2E-positive metastatic thyroid cancers, including clusters of regulatory elements (COREs). We attempt to describe the effect of T2E silencing on the cis-regulatory structure in metastatic thyroid cancers and its phase with the obvious phenotype characteristics of T2E-positive metastatic thyroid cancers. Results: These differences were linked by the ERG (erythroblast transformation-specific related gene) co-opts of FoxA1 and HOXB13, which realized T2E specific transcription profile. The study also demonstrated the T2E-specific CORE in an ERG site of structural rearrangement, which is due to the expansion of the T2E locus and contributes to its up-expression. Ultimately, we demonstrate that T2E-specific transcription profile is the basis of vulnerability of CBF-1/RBP-Jκ pathway. In fact, CBF-1/RBP-Jκ pathway inhibits the invasion and growth of T2E-positive thyroid tumors. Conclusion: This study indicates that the overexpression of ERG co-option has a unique cis-regulatory structure in T2E positive thyroid tumors, which induces drug dependence on CBF-1/RBP-Jκ signal. Our study solved the genetic and epigenetic variation of T2E in metastatic thyroid cancer for the first time. It is worth noting that further functional and clinical validation is needed as our study is a bioinformatics analysis.
... A pilot study in Poland that looked at vitamin D status in the summer months among 133 patients on L-thyroxine treatment showed that vitamin D sufficiency is not achieved even in the summer [97]. Mirhosseini et al. documented that serum 25(OH)D values of more than 125 nmol/L were associated with a 30% decreased risk of hypothyroidism and a 32% reduced risk of elevated anti-thyroid antibodies [98]. Pezeshki et al. conducted a pilot randomized clinical trial in 2020 to investigate the efficacy of vitamin D therapy on subclinical hypothyroidism. ...
... The specific advantages of vitamin D supplementation in thyroid diseases remain elusive, and further randomized controlled studies are required to offer relevant and definite data. Table 1 gives details of some clinical studies showing the various associations between Vitamin D and thyroid [42,46,48,49,52,59,82,83,84,85,88,90,94,98,99,100,102,103,104,109], all of which are mentioned in this review. [122]. ...
Article
Hypothyroidism is a frequently encountered endocrine disorder in clinical practice. Besides its traditional role in bone health, vitamin D has been shown to have favorable effects in a variety of different systems due to its pleiotropic qualities and ubiquitous receptor expression. Over the years, researchers have been fascinated by the intricate molecular interplay between vitamin D and thyroid. In this regard, attempts have emerged to demonstrate the role of vitamin D in thyroid disorders. This article has reviewed the existing literature on the role of vitamin D in hypothyroidism. We explored studies discussing the physiological interactions between vitamin D and thyroid, as well as the clinical consequences, supplemental and prognostic relevancy of vitamin D in auto-immune thyroid disease (AITD) and hypothyroidism.
... In another scenario, Ucan et al. observed that a similar vitamin D oral supplementation to autoimmune Hashimoto's thyroiditis subjects significantly improved thyroid status concurrent with a decrease in autoimmune antibodies and an increase in free T4 (fT4) levels [41]. Mirhosseini et al. in a large cohort found that a significant fraction of subjects had an improvement in their thyroid status following vitamin D supplementation [42]. A randomized control trial by Chahardoli et al. found that vitamin D supplementation significantly reduced the levels of tropic hormone TSH and anti-Tg antibodies [43]. ...
Article
Full-text available
Purpose Many smaller studies have previously shown a significant association between thyroid autoantibody induced hypothyroidism and lower serum vitamin D levels. However, these finding have not been confirmed by large-scale studies. In this study, we evaluated the relationship between hypothyroidism and vitamin D levels using a large population-based data. Methods For this study, we used National Health and Nutrition Examination Survey (NHANES) during the years 2007–2012. We categorized participants into three clinically relevant categories based on vitamin D levels: optimal, intermediate and deficient. Participants were also split into hypothyroid and hyperthyroid. Weighted multivariable logistic regression analyses were used to calculate the odds of being hypothyroid based on vitamin D status. Results A total of 7943 participants were included in this study, of which 614 (7.7%) were having hypothyroidism. Nearly 25.6% of hypothyroid patients had vitamin D deficiency, compared to 20.6% among normal controls. Adjusted logistic regression analyses showed that the odds of developing hypothyroidism were significantly higher among patients with intermediate (adjusted odds ratio [aOR], 1.7, 95% CI: 1.5–1.8) and deficient levels of vitamin D (aOR, 1.6, 95% CI: 1.4–1.9). Conclusion Low vitamin D levels are associated with autoimmune hypothyroidism. Healthcare initiatives such as mass vitamin D deficiency screening among at-risk population could significantly decrease the risk for hypothyroidism in the long-term.
... Nine studies examined the relationship between serum levels of 25(OH) D and hypothyroidism among 372 hypothyroid patients and 802 healthy individuals [17,25,29,[32][33][34][35]61]. Vitamin D and hypothyroidism status were significantly linked (WMD − 13.43 ng/dl; 95% CI, − 26.04 to − 0.81; P = 0.03); patients with hypothyroidism presented with lower serum vitamin D compared to healthy subjects. ...
Article
Full-text available
Background The contribution of vitamin D to thyroid disorders has received paramount attention; however, results are mixed. Hence, we designed a systematic review and meta-analysis to obtain a definitive conclusion. Methods The search included PubMed, ISI Web of Science, Scopus, and Google Scholar databases up to March 2021 to collect available papers reporting the relationship between serum levels of vitamin D and thyroid disorders. The pooled effect was reported as weighted mean difference (WMD) and 95% confidence interval (CI). Results Out of 6123 datasets, 42 were eligible to get into this systematic review and meta-analysis. Serum vitamin D was markedly lower in autoimmune thyroid diseases (AITD) (WMD − 3.1 ng/dl; 95% CI, − 5.57 to − 0.66; P = 0.013; I ² = 99.9%), Hashimoto’s thyroiditis (HT) (WMD − 6.05 ng/dl; 95% CI, − 8.35 to − 3.75; P < 0.001; I ² = 91.0%) and hypothyroidism patients (WMD − 13.43 ng/dl; 95% CI, − 26.04 to − 0.81; P = 0.03; I ² = 99.5%), but not in subjects with Graves’ disease (GD) (WMD − 4.14 ng/dl; 95% CI, − 8.46 to 0.17; P = 0.06; I ² = 97.5%). Conclusions Our findings suggested lower vitamin D levels in patients with hypothyroidism, AITD, and HT compared to healthy subjects. However, the link between serum vitamin D and GD was only significant among subjects ≥40 years old.
... Specifically for HT, vitamin D levels have been inversely correlated with anti-TPO and thyroid-stimulating hormone (TSH) levels reviewed by Mele et al. [4]. Vitamin D supplementation studies have significantly decreased the risk of developing thyroid disease [9]. In addition, supplementation of HT patients resulted in a significant anti-TPO and anti-TG levels decline, suggesting a beneficial role for the thyroid gland function [10]. ...
Article
Full-text available
Hashimoto’s thyroiditis and psoriasis are inflammatory disorders that significantly impact patients’ quality of life, stressing the need for novel biomarkers of early diagnosis. This randomized clinical trial (NCT04693936) aims to identify Hashimoto’s thyroiditis’ and psoriasis’ metabolic biomarkers and to investigate the effect of environmental factors on the disease-related metabolic imprint and quality of life. Patients with Hashimoto’s thyroiditis, patients with psoriasis, and healthy individuals aged 18–60 will be recruited, enrolled according to eligibility criteria (medical history, clinical thyroid markers and the PASI score) and randomized to two groups. The intervention group will receive a combination of nutraceuticals for 6 months as part of a Mediterranean diet, and the control group will follow their usual diet. Data will be collected at baseline and the end of the study, including metabolite levels, lifestyle and anthropometric measurements, adherence to the Mediterranean diet (through the Mediterranean Diet Score) and disease-specific quality of life (through the Thyroid Patient Report Outcome for Hashimoto’s group, and the Dermatology Life Quality Index for the psoriasis group). This study will investigate metabolic biomarkers and related changes in Hashimoto’s thyroiditis and psoriasis and evaluate the association of metabolic changes with dietary factors and quality of life.
... The subjective sleep quality and gastrointestinal functioning also improved [86]. It is possible that the supplementation of vitamin D and its blood concentration increase from 36 to 50-60 ng/mL would contribute to better results [95]. In this case, however, gluten elimination did not have any positive effects. ...
Article
Introduction and objective: There is a growing interest in a gluten-free diet (GFD) in the management of various autoimmune diseases, including Hashimoto's thyroiditis (HT). Even medical professionals claim that gluten elimination may improve a patient's treatment. Some studies suggest a relationship between gluten intake and HT development or progression. The aim of the study was to analyze and describe available knowledge regarding the effect of gluten or a gluten-free diet on thyroid autoimmunity in HT with or without celiac disease. Brief description of the state of knowledge: Potentially applicable records were obtained through review and analysis of the PUBMED (MEDLINE) and Google Scholar database by using the following phrases: 'hypothyroidism gluten', 'Hashimoto gluten' and 'thyroiditis gluten'. If a record focused on the subject by title and abstrakt, the full paper was screened. Authors' scientific achievements and references of eligible records were screened for possibly omitted studies. The review was focused only on human studies. Discussion: Gluten exclusion might increase the risk of HT development because of the potential nutritional deficiencies related to the low quality of gluten-free products. Gluten intake from crops grown on selenium-depleted soil increases the risk of HT development. Only a few studies suggest that GFD would be beneficial for HT patients, even without the coexistence of CD. The strongest connection between gluten intake and thyroid destruction seems to be based on a mechanism of molecular mimicry between gut and thyroid tissue transglutaminase. Conclusions: Studies conducted so far do not support the claim that HT patients should eliminate gluten from their diet. In view of the limited number of studies, with major limitations and ambiguous results, a gluten-free diet is not recommended.
... 10 Naghmeh et al suggest that a serum 25 (OH)D level > 125 nmol/L is required for the maintenance of euthyroid functions. 11 Nevertheless, the effect of 25 (OH)D level on thyroid functions is still controversial. A population-based study using data collected by the National Health and Nutrition Examination Survey in the USA found that 25(OH)D levels were associated with neither thyroid functions nor thyroid antibody status among subjects aged 12-85 years. ...
Article
Full-text available
Purpose: Vitamin D deficiency has been linked to overt thyroid diseases. Data on the effects of vitamin D status on thyroid function in children are less examined. The goal of the present study was to explore the association between serum 25-hydroxyvitamin D [25(OH)D] levels and thyroid function parameters in early childhood. Patients and methods: This was a cross-sectional study involving record-linkage of children's data of routine health check-ups for promoting early childhood development at Guangdong Women and Children's Hospital; 2869 children aged 6-24 months were included from January 2015 to May 2017. Serum 25(OH)D, thyroid stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4) levels were measured using the electrochemiluminescence immunoassay. Results: The study population had a mean serum 25(OH)D level of 79.7 ± 28.1 nmol/L and 12.5% vitamin D deficiency and 36.0% insufficiency rates. The rates of thyroid dysfunctions detected were 2.9% hypothyroidism, 4.2% subclinical hypothyroidism, 0.9% hyperthyroidism, and 1.7% subclinical hyperthyroidism among the previously healthy children aged 6 to 24 months. Serum 25(OH)D levels had no significant correlation with TSH (r = 0.022, P = 0.236), FT3 (r = 0.014, P = 0.440) and FT4 (r = -0.059, P = 0.056) levels. No significant difference in the levels of thyroid hormones was found between the different quartiles of 25(OH)D level. Vitamin D deficiency [25(OH)D < 50 nmol/L] was associated with hypothyroidism (adjusted odds ratio = 2.16, 95% confidence interval: 1.18-3.94) but not with subclinical hypothyroidism, hyperthyroidism, and subclinical hyperthyroidism. Conclusion: Vitamin D deficiency is slightly associated with hypothyroidism. No associations were found between serum 25(OH)D levels and thyroid-related measures (TSH, FT3, and FT4) in previously healthy children aged 6-24 months.
... These findings suggest that VD is associated with the pathogenesis and development of AITD. [178][179][180][181][182][183][184][185][186][187][188] A VD deficiency has been proposed to increase the immune response through activating the production of autoimmune thyroid antibodies in T helper-2 cells (Th-2) and B cells. 189,190 Most studies have universally demonstrated that decreased VD levels are associated with T1DM through their impact on insulin sensitivity and pancreatic islet beta-cell function, indicating that VD is involved in the progression and pathogenesis of T1DM. ...
Article
Full-text available
Autoimmune thyroid disease (AITD) and type 1 diabetes mellitus (T1DM) are two common autoimmune diseases that can occur concomitantly. In general, patients with diabetes have a high risk of AITD. It has been proposed that a complex genetic basis together with multiple nongenetic factors make a variable contribution to the pathogenesis of T1DM and AITD. In this paper, we summarize current knowledge in the field regarding potential pathogenic factors of T1DM and AITD, including human leukocyte antigen, autoimmune regulator, lymphoid protein tyrosine phosphatase, forkhead box protein P3, cytotoxic T lymphocyte-associated antigen, infection, vitamin D deficiency, and chemokine (C-X-C motif) ligand. These findings offer an insight into future immunotherapy for autoimmune diseases.
Article
Full-text available
Vitamin D deficiency is becoming endemic in many parts of the world.Several studies demonstrated a relationship between vitamin D deficiency, hypocalcemia and thyroid disorders. The purpose of this study was to examine the serum level of Vitamin D in healthy adult Libyan women and the status ofserum calcium and thyroid hormones. Serum vitamin D levels were measured in 174 healthy women who are classified in groups according to the age(Mean age 34±14 years). Our results revealed that vitamin D deficiency is very common among Libyan adult females because the mean of vitamin D was 13.4 ± 6.4 (n=174). Vitamin D deficiency was considered at serum levels lower than 20 ng/ml.In addition, we evaluated serum level ofcalcium and Thyroidfunction hormones (TSH, T3 and T4) in only60participants from 174 who are included in this study.It has been previously shown that individuals with low vitamin D levels have low thyroid functionbut our results here indicated that serum thyroid hormones and calcium analysis were lay within the normal rang in most of the participants. Therefore, we strongly recommend the screening for Vitamin D deficiency in all adult Libyan females and encourage the advisability of increasing vitamin D intake combined with following up its serum level to avoid over dose.
Article
Full-text available
In spite of studying the relationship between the deficiency and the lack of vitamin D in autoimmune thyroid disorders, the effect of additional administration of the preparations of this vitamin has not been clear in such pathology. The aim of study was to investigate the effect of vitamin D on the content of thyroid peroxidase antibodies (TPO) in patients with newly diagnosed hypothyroidism on the background of autoimmune thyroiditis (AIT). Materials and methods. The study included 52 patients with newly diagnosed hypothyroidism on the background of AIT, who were randomized into two groups. Patients of the first group additionally received cholecalciferol 2000 IU/day (14 000 IU/week) and calcium preparations in a dose of 1000 mg/day for 12 weeks. Patients of the second group were administered only calcium preparations at a dose of 1000 mg/day for 12 weeks in addition to levothyroxine. A positive result of treatment was considered a reduction of antibodies to TPO of at least 25 %. Results. 94.2 % of patients with hypothyroidism had the deficiency and the lack of vitamin D. In patients with hypothyroidism, there was a significant negative correlation between the levels of 25(OH)D and the titer of antibodies to TPO (r = –0.172; p = 0.046). Vitamin D supplementation resulted in a significant decrease of the level of antibodies to TPO (–48.1 %) in patients with hypothyroidism. In general, lowering the level of antibodies to TPO by 25 % or more has been achieved in 73.1 % of patients. Administration of vitamin D contributed to a significant increase of the content of 25(OH)D in the blood serum with a corresponding reduction in the concentration of intact parathyroid hormone in patients with hypothyroidism resulted from AIT. Conclusions. The positive effect of supplemental vitamin D has been established in terms of the level of antibodies to TPO in patients with autoimmune hypothyroidism.
Article
Full-text available
Background Organic cation transporter 3 (OCT3) is an excellent transporter for metformin, which is used as first-line therapy for type 2 diabetes (T2D). OCT3 genetic variants may influence the clinical response to metformin. This study aimed to determine the genotype and allele frequency of OCT3-564G>A (rs3088442) variant and its role in the glycemic response to metformin in patients with newly diagnosed T2D. Materials and Methods Based on the response to metformin, 150 patients were classified into two groups: Sixty-nine responders (decrease in glycated hemoglobin [HbA1c] values by more than 1% from the baseline) and 81 nonresponders (decrease in HbA1c values <1% from the baseline). HbA1c levels were determined by chromatography. The variant OCT3-564G>A was genotyped using polymerase chain reaction - based restriction fragment length polymorphism. Results The genotypes frequencies were 51.3% GG, 36% AG, and 12.7% AA. Allele frequency of major allele (G) and minor allele (A) in OCT3-564G>A variant was found to be 0.69 and 0.31, respectively. Fasting glucose, HbA1c, body mass index, and lipid profile in both GG genotypes and GA + AA group decreased significantly after 3 months of metformin therapy compared with baseline (P < 0.05). In both responders and nonresponders, HbA1c and fasting glucose levels were lower in patients with the GA + AA genotype than in those with the GG genotype; however, the differences were not statistically significant (P > 0.05). Conclusion The A allele frequency (which may be a protective allele against coronary heart disease) in the Iranian diabetic patients was lower than Iranian, Caucasian and Japanese healthy populations. Metformin is useful in improving the lipid profile, in addition to its impacts in glycemic control, and these effects are regardless of OCT3-564G>A variant.
Article
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Objectives: To determine the relationship between Vitamin B12 levels and thyroid hormones in patients with multiple sclerosis (MS). Materials and Methods: One hundred and ten patients with MS were recruited for this study after Institutional Review Board approval. All patients signed a written informed consent form and donated a single blood sample. Plasma Vitamin B12 levels, triiodothyronine (T3), and thyroxine (T4) hormone levels were measured. Data were analyzed using the Statistical Package for Social Sciences (SPSS) software. Results: Analysis of Vitamin B12 levels in 110 patients with MS revealed that 65% had normal levels of Vitamin B12 (200–900 pg/ml), 30% had low levels of Vitamin B12 (<200 pg/ml), and 5% high levels of Vitamin B12 (higher than 900 pg/ml). Further analysis of patients with low levels of Vitamin B12 revealed that this cohort exhibited a significantly high number of patients with low levels of the thyroid hormones triiodothyronine (T3) and thyroxine (T4) (P < 0.005). Conclusion: This study suggests a relationship between Vitamin B12 levels and thyroid hormones. This opens the possibility that the use of therapies that increase triiodothyronine (T3) and thyroxine (T4) levels might be beneficial to patients with MS.
Article
Full-text available
Background and aims: Although Vitamin D deficiency has been linked to autoimmune thyroid disorders (AITD), the impact of Vitamin D supplementation on thyroid autoimmunity is not known. This study aimed to evaluate the impact of Vitamin D supplementation on thyroid autoimmunity (thyroid peroxidase antibody [TPO-Ab] titers) in patients with newly diagnosed AITD in a randomized controlled trial. Materials and methods: One hundred two patients with newly diagnosed AITD (TPO-Ab > 34 kIU/L and/or sonographic evidence of thyroiditis) patients were randomized into Group-1 (intervention group) and Group-2 (control group). Group-1 received cholecalciferol 60,000 IU weekly and calcium 500 mg/day for 8 weeks; Group-2 received calcium 500 mg/day for 8 weeks. Responders were defined as ≥25% fall in TPO-Ab titers. Individuals with at least 3-month follow-up were analyzed. Trial is registered at ctri.nic.in (CTRI/2015/04/005713). Results: Data from 100 AITD patients (68 with thyroid stimulating hormone [TSH] ≤10 mIU/L, 32 with TSH > 10 mIU/L), 93% having Vitamin D insufficiency, were analyzed. TPO-Ab titers were highest among patients in the lowest 25-hydroxyvitamin D quartile (P = 0.084). At 3 months follow-up, there was significant fall in TPO-Ab in Group-1 (-46.73%) as compared to Group-2 (-16.6%) (P = 0.028). Sixty-eight percentage patients in Group-1 were responders compared to 44% in Group-2 (P = 0.015). Kaplan-Meier analysis revealed significantly higher response rate in Group-1 (P = 0.012). Significantly greater reduction in TPO-Ab titers was observed in AITD with TSH ≤ 10 mIU/L compared to TSH > 10 mIU/L. Cox regression revealed Group-1 followed by TPO-Ab and free tetraiodothyronine levels to be a good predictor of response to therapy (P = 0.042, 0.069, and 0.074, respectively). Conclusion: Vitamin D supplementation in AITD may have a beneficial effect on autoimmunity as evidence by significant reductions in TPO-Ab titers.
Article
Background Vitamin D was shown to be related to autoimmune thyroid diseases (AITDs) in the previous studies. We aimed to investigate the relationship between Vitamin D and thyroid autoimmunity. Materials and Methods Eighty-two patients, diagnosed with AITD by the endocrinology outpatient clinic, were included in this prospective study. All of the patients had both AITD and Vitamin D deficiency, defined as serum values <20 ng/mL. They were randomly assigned into two groups. The first group included 46 patients and the second one included 36 patients. The first group was treated with Vitamin D for 1 month at 1000 IU/day. The second group served as the control group and was not treated with Vitamin D replacement. Serum thyroid-stimulating hormone, free T4 (fT4), thyroid peroxidase antibody (TPO-Ab), thyroglobulin antibody (TgAb), and Vitamin D levels were measured at the initiation of the study and again at 1 month in all patients. Results Two groups were similar with regard to age, sex, and type of thyroid disease. Whereas TPO-Ab (before; 278.3 ± 218.4 IU/ml and after; 267.9 ± 200.7 IU/ml) and TgAb (before; 331.9 ± 268.1 IU/ml and after; 275.4 ± 187.3 IU/ml) levels were significantly decreased by the Vitamin D replacement therapy in group 1 (P = 0.02, P = 0.03, respectively), the evaluated parameters in the control group did not significantly change (P = 0.869, P = 0.530, respectively). In addition, thyroid function tests did not significantly change with Vitamin D replacement in two groups. Conclusion Vitamin D deficiency may contribute to the pathogenesis of AITDs. Since supplementation of the Vitamin D decreased thyroid antibody titers in this study in Vitamin D deficient subjects, in the future Vitamin D may become a part of AITDs' treatment, especially in those with Vitamin D insufficiency. Further clinical and experimental studies are required to understand the effect of Vitamin D on AITD.
Chapter
Gonadal secretion of steroid hormones is episodic in men and women and is subject to neuroendocrine control by the hypothalamus and pituitary. In turn, pulsatile secretion of gonadotropin-releasing hormone (GnRH) by the hypothalamus and luteinizing hormone (LH) and follicle-stimulating hormone (FSH) by the pituitary are modulated by steroids secreted by the gonads. Current data also suggest GnRH secretion is regulated by hypothalamic catecholamines and endogenous opioids (Knobil 1980; Yen 1986; Marshall and Kelch 1986). The availability of highly sensitive and specific methods for quantitating hormone levels in small amounts of serum has allowed for sampling at short time intervals over extended periods. This and the ongoing development of new statistical methods for data analysis (Merriam and Wachter 1982; Veldhuis et al. 1986 a; Urban et al. 1988, see Chap, of Veldhuis et al.) and the detection of low-amplitude rhythms (Filicori et al. 1984; Haus et al. 1984) continue to reveal the chronobiologic complexity of the hypothalamopituitary-gonadal axes. The documentation of changes in rhythms during prepubertal development, as well as new knowledge of variations in secretion patterns associated with gonadal dysfunction and infertility in adults, has led to a better understanding of reproductive patho-physiology. In this chapter we will review the chrono-biology of normal gonadal function in men and women, prepubertal and pubertal development of these patterns and changes associated with some as-pects of reproductive pathophysiology.
Article
Objective: The aim of this study was to investigate vitamin D status by measuring serum 25(OH)D levels in euthyroid patients with Hashimoto's thyroiditis (HT) who lived and worked on the sunny island of Crete, Greece, and to evaluate whether vitamin D3 supplementation is beneficial for the management of HT patients with vitamin D deficiency. Subjects and methods: We studied 218 HT patients, euthyroid Caucasian Cretan Greek citizens: 180 females and 38 males. Among these patients, 186 (85.3%) had vitamin D deficiency defined as serum 25(OH)D levels < 30 ng/mL. The mean age of all these 218 HT patients was 35.3 ± 8.5 years. The mean age of the 186 vitamin D deficient HT patients (173 females and 13 males) was 37.3 ± 5.6 years. The 186 vitamin D deficient HT patients received vitamin D3 (cholecalciferol, CF) orally, 1200-4000 IU, every day for 4 months aiming to maintain serum 25(OH)D levels ≥ 40 ng/mL. Anthropometric characteristics (height, weight, waist circumference), systolic and diastolic blood pressure, serum concentration of 25(OH)D, thyrotropin (TSH), free thyroxine (FT4), anti-thyroid peroxidase (anti-TPO), antithyroglobulin (anti-TG), calcium and phosphorus levels and thyroid and kidney sonographic findings were recorded and measured before and after CF administration. Results: There was a significant negative correlation only between serum 25(OH)D levels and anti-TPO levels among all 218 HT patients. Also, anti-TPO levels were significantly higher in 186/218 vitamin D deficient HT patients compared to 32/218 HT patients with no vitamin D deficiency (364 ± 181IU/mL versus 115.8 ± 37.1IU/mL, P<0.0001). Supplementation of CF in 186 vitamin D deficient HT patients caused a significant decrease (20.3%) in serum anti-TPO levels. Although at the end of the 4 months period of the study body mass index (BMI), serum anti-TG and TSH levels decreased by 2.2%, 5.3% and 4% respectively, these differences were not significant. No changes in the sonographic findings were observed. Conclusion: The majority (85.3%) of the Greek Caucasian patients with HT studied who lived and worked in Crete had low serum 25(OH)D levels inversely correlated with serum anti-TPO thyroid antibodies. After 4 months of CF supplementation in the 186 HT patients with vitamin D deficiency, a significant decrease (20.3%) of serum anti-TPO levels was found. These findings suggest that vitamin D deficiency may be related to pathogenesis of HT and that its supplementation could contribute to the treatment of patients with HT.