A concise review of Hashimoto thyroiditis (HT) and the importance of iodine, selenium, vitamin D and gluten on the autoimmunity and dietary management of HT patients.Points that need more investigation

Abstract

Hashimoto's thyroiditis (HT) is a chronic autoimmune thyroid disease caused by an interaction between genetic factors and environmental conditions, both of which are yet to be fully understood. The management of HT depends on its clinical manifestations, commonly including diffuse or nodular goiter with euthyroidism, subclinical hypothyroidism and permanent hypothyroidism. However, in most cases of patients with HT, lifelong levothyroxine substitution is required. The additional role of diet for the management of HT is usually overlooked. A literature search regarding the importance and the influence of iodine, selenium, vitamin D and gluten on HT was conducted. In HT careful supplementation of possible deficiencies is recommended for the dietary management of these patients. The use of a diet low in gluten among HT patients with or without celiac disease (CD) is discussed.

Full text

93
Hellenic Journal of Nuclear Medicine January-April 2017
•
www.nuclmed.gr
Michael I. Liontiris, MD,
Elias E. Mazokopakis MD, PhD
Department of Internal Medicine,
Naval Hospital of Crete, Chania,
Greece
Keywords: Hashimoto's thyroiditis 
Diet - Iodine - Selenium - Vitamin-D
- Gluten - Autoimmunity
- Clinical course
Corresponding author:
K. Mitsotaki 36, Chania,
73 132, Crete, Greece.
Tel.: (+30) 2821 0 82754,
Fax: (+30) 2821 0 82510.
emazokopakis@yahoo.gr
Receved:
10 January 2017
Accepted revised :
27 February 2017
A concise review of Hashimoto thyroiditis (HT) and
the importance of iodine, selenium, vitamin D and
gluten on the autoimmunity and dietary management
of HT patients.Points that need more investigation
Abstract
Hashimoto's thyroiditis (HT) is a chronic autoimmune thyroid disease caused by an interaction between ge-
netic factors and environmental conditions, both of which are yet to be fully understood. The management
of HT depends on its clinical manifestations, commonly including diuse or nodular goiter with euthyro-
idism, subclinical hypothyroidism and permanent hypothyroidism. However, in most cases of patients with
HT, lifelong levothyroxine substitution is required. The additional role of diet for the management of HT is
usually overlooked. A literature search regarding the importance and the inuence of iodine, selenium, vita-
min D and gluten on HT was conducted. In HT careful supplementation of possible deciencies is recom-
mended for the dietary management of these patients. The use of a diet low in gluten among HT patients
with or without celiac disease (CD) is discussed.
Hell J Nucl Med 2017; 20(1): 51-56 Epub ahead of print: 20 March 2017 Published online: 20 April 2017
Introduction
Hashimoto's thyroiditis (HT), also called chronic lymphocytic or autoimmune thy-
roiditis (AITD), is part of the spectrum of chronic autoimmune thyroid diseases
and is associated with various degrees of thyroid hypofunction, with thyroid au-
toantibodies production like the most common, thyroid peroxidase antibodies (TPO-Ab)
and thyroglobulin antibodies (Tg-Ab)], and with lymphocytic inltration [1-5]. Its preva-
lence depends on age (more frequently appears between 45-55 years), gender (4-10 ti-
mes more frequent in females than in males) and race (more common in whites than in
blacks, hispanics and asians) [3, 6, 7]. Aside from smoking, which decreases the risk for HT,
other factors like alcohol, stress, pregnancy and drug use e.g. iodine, interferon-, immu-
nomodulatory agents such as ipilimumab, pembrolizumab, nivolumab, and the huma-
nised monoclonal antibody to CD52 alemtuzumab may in genetically predisposed indi-
viduals, initiate the development of HT [8, 9]. Although the exact mechanism of prog-
ressive thyroid tissue destruction is not clear, HT is regarded as a disorder of T cell-medi-
ated immunity, caused by an interaction between susceptibility genes and environ-men-
tal factors, the research of which is still inconclusive [5]. In most cases of patients with HT,
lifelong levothyroxine (LT4) substitution, adjusting the dose to achieve normal circu-
lating thyrotropin ( TSH) levels, is required [4, 9, 10]. In addition, the coexistence of HT
with other organ specic diseases [e.g. pernicious anemia, vitiligo, celiac disease (CD), ty-
pe 1 diabetes mellitus, autoimmune liver disease, primary biliary cirrhosis, myasthenia
gravis, alopecia areata, sclerosis multiplex, Addison's disease], and non-specic [e.g. rhe-
umatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjögren syndrome, systemic
sclerosis, mixed connective tissue disease], non-endocrine autoimmune diseases should
be evaluated [11, 12]. Nuclear medicine contributes to the diagnosis of HT and hypothy-
roidism and to dierential diagnosis of HT with other diseases. Many of the tests for the
evaluation of thyroid gland function and structure and for other diseases coexisting with
HT are nuclear medicine tests.
The purpose of this article was to present an update about HT and the impor-tance of
iodine, selenium (Se), vitamin D and gluten in autoimmunity of HT and also the role of
diet in the clinical course of HT.
51
Review Article

Hashimoto's thyroiditis and iodine
Iodine is an essential micronutrient of the diet required for
thyroid function and synthesis of thyroid hormones [13].
The recommended adult daily iodine intake is 150g, inc-
reasing to 250g in pregnancy and lactation [14]. Main diet
iodine sources are seafood (e.g. seaweed, scallops, cod, sar-
dines, shrimps, salmon and tuna), animal products (yoghurt,
cow's milk, eggs) and fruits (cranberries and strawberries).
Iodine deciency causes several consequences and mani-
fests with a wide clinical range: from goiter to cretinism [15].
he problem of iodine deciency in many countries world-
wide was solved with iodized salt (IS) programs, and nowa-
days about two thirds of the world's population (71%) uses IS
[16]. In iodine-replete areas, most persons with thyroid di-
sorders have AITD ranging from primary atrophic hypothy-
roidism, HT to thyrotoxicosis caused by Graves' disease [17].
Other studies revealed the inuence of dietary iodine intake
on the epidemiology of thyroid dysfunction [17]. Studies on
the incidence of AITD have only been conducted in a small
number of developed countries. Autoimmune hypothyro-
idism and thyroid antibodies (TAb) are more common in iodi-
ne replete areas than in iodine decient areas [8, 18]. Hypo-
thyroidism induced by iodine in AITD may be due to a persis-
tent inhibitory eect of iodine on thyroid hormone synthesis
and secretion, i.e., a pathologically persistent Wol-Chaiko
eect [9, 19]. Cases of HT may have inadequate thyroid hor-
mone synthesis, may be unable to escape from the acute Wo-
lf Chaiko eect, and can develop iodine-induced hypothy-
roidism. A number of studies indicated that moderate or mild
iodine excess (median urinary iodine 220µg per 24 hours)
is associated with a more frequent occurrence of hypothy-
roidism, especially in elderly subjects, the exact mechanism
of which has not been claried [20]. In the longitudinal, po-
pulation-based DanThyr study [21] subjects were examined
at baseline in 1997 to 1998 and re-examined 11 years later in
2008 to 2010 after initiation of a mandatory programme of
salt iodization. Even small dierences in the level of iodine in-
take between otherwise com-parable populations were as-
sociated with considerable dierences in serum TSH at the
eleventh year of follow-up [21]. Furthermore, a cross-sec-
tional study from south China showed that high iodine intake
was likely to lead to the occurrence of thyroid diseases, such
as HT, nodular goiter, and hyperthyroidism, through a long-
term process [22].
Even small increases in iodine intake are associated with
an increased prevalence of thyroid autoimmunity [15]. Pe-
dersen et al. [23] found an increased prevalence of TAb, 4-5
years after a cautious salt iodization programme, suppor-
ting the view that even a small increase in iodine supple-
mentation may be associated with increased thyroid auto-
immunity. The underlying mechanism for this association is
yet to be elucidated. A recent study [24] suggested that the
apoptosis of thyroid follicular cells seen in HT development
is likely caused by suppression of autophagy activity, which
is induced by iodine excess. This process is mediated thro-
ugh transforming growth factor-1 downregulation, activa-
tion of the Akt/mTOR signaling pathway and enhanced
reactive oxygen species (ROS) production. Another poten-
tial mechanism could be that iodine excess increases intra-
thyroid inltrating Th17 cells and inhibits T regulatory ( TR-
EG) cells development, while it triggers an abnormal expres-
sion of tumor necrosis factor related apoptosis-inducing li-
gand (TRAIL) in thyrocytes, thus inducing apoptosis and pa-
renchymal destruction [25]. The fact that excessive iodine
plays a signicant role in inducing thyroid autoimmunity is
also strongly supported in genetically predisposed animals
by increasing the immunogenicity of thyroglobulin (TG)
[26]. This phenomenon may be explained by the fact that TG
is the only self-antigen that undergoes post-translational
modication as a consequence of the environmental supply
of iodine, with the exposure of previously hidden epitopes
[27-31].
Considering the above, high iodine supplementation in
HT should be discouraged, as not benecial and possibly
harmful. Discouraging iodine over-supplementation must
not preclude its appropriate supplementation in pregnancy
to a total intake of 250g/day [9].
Hashimoto's thyroiditis and selenium
Selenium (Se) is an essential micronutrient of diet with many
pleiotropic eects ranging from antioxidant and anti-inam-
matory to increasing active thyroid hormone production [32-
36]. The thyroid is the organ with the highest Se content per
gram of tissue. Among at least 30 selenoproteins, the seleno-
enzymes such as glutathione peroxidases (GPX), thioredoxin
reductases (TR), iodothyronine deiodinases and seleno-
protein P, seem to play a unique role in human thyroid func-
tion and thyroid hormone homeostasis [2, 32, 33]. Selenium
supplementation in patients with AITD, including HT, seems
to modify the inammatory and immune responses, probably
by enhancing plasma GPX and TR activity and by decreasing
toxic concentrations of hydrogen peroxide (H2O2) and lipid
hydroperoxides, resulting from thyroid hormone synthesis [2,
33, 34]. When Se intake is adequate, the intracellular GPX and
TR systems protect thyrocyte from these peroxides, as oxida-
tive stress induces TR1 and GPX [4]. This article points out that
type 1 and 2 iodothyronine deiodinases (D1 and D2) which
support the conversion of peripheral T4 to T3 via outer (5')-
ring deiodination of the pro-hormone T4, are selenoproteins
and thus this conversion is susceptible to Se deciency [37].
For that reason Se-decient individuals have mildly elevated
serum T4 and T4 to T3 ratios, but normal TSH [37].
Selenium is present in soil and enters the food chain thro-
ugh plants. So, the Secontent of plants and animals depends
on whether the soil where plants grow is seleniferous or not;
therefore the amount of Se in the soil is vital. The current re-
commended dietary intake of Se in adults, in order to achi-
eve the maximal activity of GPX in plasma or in erythrocytes
is between 55 and 75g per day [2, 38-40]. Foods rich in Se
are Brazil nuts [40], oysters, tuna, whole-wheat bread, sun-
ower seeds, most kinds of meat (pork, beef, lamb, turkey,
93
Hellenic Journal of Nuclear Medicine January-April 2017
• www.nuclmed.gr
52
9
Review Article

chicken), mushrooms and rye. In a study conducted in the
north-west part of Greece the total daily average intake of Se
from the food was 39.3g per person [41].
Studies have shown dierent results regarding the e-
cacy of Se supplementation in HT patients [42-45]. Three
meta-analyses have conrmed a suppressive eect of Se sup-
plementationon serum TPO-Ab and Tg-Ab levels in HT pati-
ents [42-44]. Particularly, the recently (2016) published sys-
tematic review and meta-analysis of Wichman et al. (2016)
[44] showed that Se supplementation eectively reduces se-
rum TPO-Ab levels at 3, 6, and 12 months and serum Tg-Ab at
12 months in LT4-treated populations, but not in non treated
ones. However, no signicant correlation between the base-
line serum Se and the decrease in serum TPO-Ab level was
demonstrated in LT4-treated patients. This meta-analysis also
showed a signicant decrease in serum TPO-Ab levels in the
patients groups receiving 200g selenomethionine, but not
in those receiving 200g sodium selenite. The dierence
might lie on the fact that the absorption of selenite is appro-
ximately two-thirds of the absorption of selenomethionine
[3, 44]. However, another meta-analysis in the Cochrane lib-
rary concluded that the evidence to support or refute the ef-
cacy of Se supplementation in patients with HT is insuf-
cient [45].
Inhomogeneity in various groups studied, like dierences
in the duration of illness, variations in baseline serum Se and/
or iodine, the duration of the study and the dierent Se com-
pounds applied appear to play a role in the divergence of the
results [44, 46]. A most recent study from south Italy showed
that the 6 months long supplementation with L-seleno-
methionine had no eect on TPO-Ab [47]. Other Italian [48]
and a Greek [2] studies have shown that a 12 months long Se
supplementation decreased TPO-Ab. The Greek study also
showed that the patients group after ceased receiving Se,
after 6 months had a 4.8% increase in the mean serum TPO-
Ab concentrations.  recent population-based study in Chi-
na [49] provided us with potent circumstantial evidence that
low Se intake is associated with thyroid autoimmunity be-
cause showed that the prevalence of thyroid diseases (ex-
cept hyperthyroidism, Graves' and nodular disease) was hig-
her in a region of low Se intake (serum Se < 69g/L) compa-
red to a region of adequate Se intake (serum Se 69g/L) [49].
Previous evidence about the relationship between Se sup-
plementation and type 2 diabetes mellitus (T2DM) has been
conicting [50-54]. In a meta-analysis of ve studies (13.460
participants) a signicantly higher prevalence of T2DM was
conrmed in patients with relatively low (97.5g/L) or high
serum Se levels (132.50g/L), revealing a U-shaped non-
linear dose-response relationship between serum selenium
and T2DM [53]. Jablonska et al. (2016) demonstrated that in
76 non-diabetics, daily supplementation with 200g Se in
the form of Se yeast for 6 weeks was associated with a signi-
cantly decreased level of HbA1c and hardly aected fasting
plasma glucose or down-regulation of seven genes involved
in dierent steps of glucose metabolism (INSR, ADIPOR1,
LDH, PDHA, PDHB, MYC, HIF1 inhibitor) [55]. Decreased ex-
pression of mRNA levels for these receptors has been linked
to insulin resistance and diabetes in humans and animals
[56-58].
Chronic ingestion of large quantities of Se may have ad-
verse eects in human health [59-64]. Consumption of ap-
proximately 330g of Se per day could be toxic not only for
growth hormones and insulin-like growth factor 1 meta-
bolism but also in the synthesis of thyroid hormones [59, 60].
Possible major side eects include nail and hair loss, ano-
rexia, diarrhea, depression, hemorrhage, liver and kidney
necrosis, blindness, ataxia and respiratory disturbances [60,
61]. There have also been instances of dermatitis and CNS
disorders in an area with high Se content in Enshi, China [62].
These signs and symptoms of Se toxicity are known as sele-
nosis. A Se intake of 50-400g/d is considered a safe range
for adults, while 850-900g could be allowed as minimum
for Se toxicity [65]. In case of Se deciency, the excessive
amounts of HO generated lead to immoderate production
of T4 and damage of thyroid cells. Selenium deciency also
increases the weight of the thyroid [66] and, combined with
iodine deciency, may lead to a further increase of thyroidal
weight. In addition, a phenomenon that has not been stu-
died with sucient experimental data is that Se deciency
causes accelerated iodine depletion [67]. This may be a pro-
tective adaptation against thyroid damage, when Se is de-
cient and iodine is adequate. Supplementing an HT patient
who is decient in both elements with either Se or iodine
would be ineective and, in certain cases, could cause com-
plications. This explains the deterioration of thyroid function
which was observed after Se administration to iodine-de-
cient people in northern Zaire, a region of endemic goiter,
suggesting that the reduction in D1 activity during Se de-
ciency might be protective against iodine deciency, presu-
mably by reducing the deiodination of T4, T3, or T3 sulfate
[37, 68, 69]. In order to predict whether a patient with HT wo-
uld benet from Se supplementation, the clinician should
rst investigate the patient's iodine status [59]. This is pos-
sible by determining the urinary iodine excretion (UIE) test
in a 24h urine collection. It should be noted that excessive
iodine may indicate dietary excess intake [70], recent con-
trast media exposure or use of drugs containing iodine (e.g.
amiodarone). The eect of iodine-containing antiseptic so-
lutions suggested by healthcare professionals appears to be
negligible [71, 72].
In summary, Se supplementation in the form of selenome-
thionine would be benecial in HT patients with Se deci-
ency and adequate iodine intake. Careful Se supplemen-
tation is required among HT patients with T2DM, but chroni-
c ingestion of large quantities of Se may have adverse eects
in human health.
Hashimoto's thyroiditis and vitamin D
Despite the fact that it was initially described as a vitamin'',
vitamin D is now considered as both a fat-soluble vitamin
and a steroid hormone that plays a central role in the regu-
lation of calcium/phosphate homeostasis and bone inten-
sity [73]. It is synthesized within the body via two routes: skin
exposure to sunlight and dietary intake [5]. The natural sour-
93
Hellenic Journal of Nuclear Medicine January-April 2017
•
www.nuclmed.gr 53
Review Article

ces that provide humans with large amounts of vitamin D3
are sh (cod liver oil, wild fresh salmon, sardines) and dairy
products [5]. Its serum normal range is between 30 and 80ng
/mL and levels below 30ng/mL are considered by most scho-
lars indicative of vitamin D insuciency [5].
Several studies have shown the correlation between vita-
min D deciency and thyroid autoimmunity [5, 74-78], such
as the fact that this association applies for all ages [75, 76]
and that cholecalciferol supplements are eective in redu-
cing TPO-Ab among HT patients with vitamin D deciency
[78, 79]. What is still unclear, however, is whether the low
25[OH ]D levels observed in HT patients are the result of the
disease itself or actually part of its cause. Aside from its cal-
cium/phosphate homeostasis functions, vitamin D is con-
sidered to be one of the natural immune modulators and a
regulator of various immune-mediated processes [5]. The
mechanisms underlying the assumption that vitamin D is
linked with autoimmunity are not clear but are probably as-
sociated with its anti-inammatory and immunomodu-
latory functions. The Endocrine Society of USA guidelines
armed that daily vitamin D intakes of 1500-2000IU are ne-
eded to raise the blood level of 25(OH) D constantly above
30ng/mL [80], whilst the Institute of Medicine of USA
reported that the tolerable upper intake level, dened as the
maximum daily intake above which the potential for adverse
health eects may increase after chronic use, is 4000IU per
day [81]. Levels of 25(OH) D between 30 and 40ng/mL, that
are adequate for avoiding metabolic and autoimmune di-
sorders [82], in more than 97% of the population, can be ac-
hieved by an optimal dosage of approximately 2000IU cho-
lecalciferol daily, regardless of increased exposure to UVB
[83]. The main side eect of vitamin D overtreatment is hy-
percalcemia (calcium serum levels above 11mg/dL) and
nephrolithiasis. To avoid coronary artery calcication, which
is an important predictor of cardiovascular disease (CVD),
concomitant use of cholecalciferol with vitamin K2 (mena-
quinones) may be necessary [84]. Patients with renal disease
cannot convert 25[OH]D to active 1,25[OH]D2 and need to
receive calcitriol instead of cholecalciferol. In addition, we
must consider the potential interactions of some drugs with
vitamin D supplements [5, 85]. Apart from cholecalciferol or
calcitriol, a regular exposure to sunlight could contribute to
the prevention and management of vitamin D deciency in
HT patients. It is obvious that excessive sun exposure and
sunburn should be avoided because of the high risk of skin
cancer (particularly melanoma) [86].
In summary, the presented data demonstrate the asso-
ciation of vitamin D deciency with HT pathogenesis, thy-
roid hypofunction and autoimmunity in general. Taking into
consideration the low cost and the minimal side eects of
vitamin D supplementation, screening for vitamin D de-
ciency and careful vitamin D supplementation with monthly
monitoring calcium and 25[OH]D levels, when required, may
be recommended for patients with HT [5, 73].
Hashimoto's thyroiditis and gluten
Celiac disease (CD) is an immune-mediated disease charac-
terized by chronic inammation and destruction of the vil-
lous structure of the small intestine [87, 88]. It is triggered by
the ingestion of gluten, a protein complex found in wheat
and related grains, such as barley, rye and oat. Celiac disease
has increasingly become considered as a multi-organ disor-
der, often presenting with diarrhea, malabsorption synd-
rome and weight loss, and has been linked to a number of
diseases including autoimmune disorders [87-90].
According to the international medical bibliography, AI-
TD and CD are clearly associated [12, 90-92]. This might be
explained partly by the increased immunosensitivity of CD
patients, as part of an autoimmune polyglandular synd-
rome (APS), by the deciency of key elements such as Se and
iodine due to malabsorption [93, 94] or due to antibodies
that aect both target-tissues [95]. According to a most re-
cent meta-analysis, all patients with AITD should be scre-
ened for CD, given the increased prevalence of the coexis-
tence of these two disorders [96]. This study advocates that
patients with HT must undergo celiac serological tests [se-
rum IgA and IgG gliadin antibodies (AGA-IgA, AGA-IgG), IgA
transglutaminase antibodies (TGA), and serum IgA endo-
mysium antibodies (EMA)], and that if any of the celiac sero-
logical tests is positive, the patients must be investigated
with gastroduodenoscopy and duodenal biopsy [96]. It
must be considered that positive thyroid and celiac tests
might represent an epiphenomenon, because serum auto-
antibodies generally do not reect per se a clinical autoim-
mune disease [97].
In summary, whereas it is not yet clear whether a gluten-
free diet can prevent autoimmune diseases, it is worth men-
tioning that HT patients with or without CD benet from a
diet low in gluten as far as the progression and the potential
disease complications are concerned [98]. Still, a lifelong
gluten-free diet is not easy to maintain, it could be very cos-
tly and the subject's quality of life may deteriorate [99].
In conclusion, present evidence indicates the benecial
role of diet in the autoimmune status and the clinical course
of HT patients. Serum levels of iodine, Se and vitamin D, in
HT patients are necessary, and a careful supplementation in
case of deciency of these agents is recommended. Due to
the increasing coexistence of HT with CD and other autoim-
mune diseases, a low gluten diet is important.
The authors declare that they have no conicts of interest
Bibliography
1. Caturegli P, De Remigis A, Rose NR. Hashimoto thyroiditis: clinical and
diagnostic criteria. Autoimmun Rev 2014; 13: 391-7.
2. Mazokopakis E, Papadakis JA, Papadomanolaki MG et al. Eects of 12
months treatment with L-selenomethionine on serum anti-TPO levels
in patients with Hashimoto's thyroiditis. Thyroid 2007; 17: 609-12.
3. Mazokopakis EE, Tzortzinis AA, Dalieraki-Ott EI et al. Coexistence of
Hashimoto's thyroiditis with papillary thyroid carcinoma. A retros-
pective study. Hormones (Athens) 2010; 9: 312-7.
4. Mazokopakis EE, Chatzipavlidou V. Hashimoto's thyroiditis and the ro-
le of selenium. Current concepts. Hell J Nucl Med 2007; 10: 6-8.
5. Mazokopakis EE, Kotsiris DA. Hashimoto's autoimmune thyroiditis and
vitamin D deciency. Current aspects. Hell J Nucl Med 2014; 17: 37-40.
93
Hellenic Journal of Nuclear Medicine January-April 2017
• www.nuclmed.gr
54
9
Review Article

6. McLeod DS, Cooper DS. The incidence and prevalence of thyroid auto-
immunity. Endocrine 2012; 42: 252-65.
7. McLeod DS, Caturegli P, Cooper DS et al. Variation in rates of auto-
immune thyroid disease by race/ethnicity in US military personnel.
JAMA 2014; 311: 1563-5.
8. Eraimidis G, Wiersinga WM. Mechanisms in endocrinology: auto-
immune thyroid disease: old and new players. Eur J Endocrinol 2014;
170: R241-52.
9. Topliss DJ. Clinical update in aspects of the management of auto-
immune thyroid diseases. Endocrinol Metab (Seoul) 2016; 31: 493-9.
10. Pearce SH, Brabant G, Duntas LH et al. 2013 ETA guideline: manage-
ment of subclinical hypothyroidism. Eur Thyroid J 2013; 2: 215-28.
11. Dilas LT, Icin T, Paro JN, Bajkin I. Autoimmune thyroid disease and other
non-endocrine autoimmune diseases. Med Pregl 2011; 64: 183-7.
12. Boelaert K, Newby PR, Simmonds MJ et al. Prevalence and relative risk
of other autoimmune diseases in subjects with autoimmune thyroid
disease. Am J Med 2010; 123: 183.e1-9.
13. Rohner F, Zimmermann M, Jooste P et al. Biomarkers of nutrition for
development-iodine review. J Nutr 2014; 144: 1322S-42S.
14. Zimmermann MB, Boelaert K. Iodine deciency and thyroid disorders.
Lancet Diabetes Endocrinol 2015; 3: 286-95
15. Pearce EN, Andersson M, Zimmermann MB. Global iodine nutrition:
where do we stand in 2013? Thyroid 2013; 23: 523-8.
16. Zimmermann MB. Iodine deciency. Endocr Rev 2009; 30: 376-408.
17. Vanderpump MPJ. The epidemiology of thyroid diseases. Br Med Bull
2011; 99: 39-51.
18. Laurberg P, Pedersen KM, Hreidarsson A et al. Iodine intake and the
pattern of thyroid disorders: a comparative epidemiological study of
thyroid abnormalities in the elderly in Iceland and in Jutland,
Denmark. J Clin Endocrinol Metab 1998; 83: 765-9.
19. Markou K, Georgopoulos N, Kyriazopoulou V, Vagenakis AG. Iodine-
Induced hypothyroidism. Thyroid 2001; 11: 501-10.
20. Laurberg P, Bulow Pedersen I, Knudsen N et al. Environmental iodine
intake aects the type of nonmalignant thyroid disease. Thyroid 2001;
11: 457-69.
21. Bjergved L, Jorgensen T, Perrild H et al. Predictors of change in serum
TSH after iodine fortication: an 11-year follow-up to the DanThyr
study. J Clin Endocrinol Metab 2012; 97: 4022-9.
22. Zhao H, Tian Y, Liu Z et al. Correlation between iodine intake and thy-
roid disorders: a cross-sectional study from the South of China. Biol
Trace Elem Res 2014; 162: 87-94.
23. Pedersen IB, Knudsen N, Carle A et al. A cautious iodization program
bringing iodine intake to a low recommended level is associated with
an increase in the prevalence of thyroid autoantibodies in the popu-
lation. Clin Endocrinol (Oxf ) 2011; 75: 120-6.
24. Xu C, Wu F, Mao C et al. Excess iodine promotes apoptosis of thyroid
follicular epithelial cells by inducing autophagy suppression and is as-
sociated with Hashimoto thyroiditis disease. J Autoimmun 2016; 75:
50-57.
25. Duntas LH. The role of iodine and selenium in autoimmune thyroiditis.
Horm Metab Res 2015; 47: 721-6.
26. Carayanniotis G: Recognition of thyroglobulin by T cells: the role of io-
dine. Thyroid 2007; 17: 963-73.
27. Dai YD, Rao VP, Carayanniotis G. Enhanced iodination of thyroglobulin
facilitates processing and presentation of a crypticpathogenic
peptide. J Immunol 2002; 168: 5907-11.
28. Li HS, Jiang HY, Carayanniotis G. Modifying eects of iodine on the im-
munogenicity of thyroglobulin peptides. J Autoimmun 2007; 28: 171-6.
29. Jiang HY, Li HS, Carayanniotis K, Carayanniotis G. Variable inuences of
iodine on the T-cell recognition of a single thyroglobulin epitope.
Immunology 2007; 121: 370-6.
30. Shi L, Bi M, Yang R et al. Defective expression of regulatory B cells in
iodine-induced autoimmune thyroiditis in non-obese diabetic H-
2(h4) mice. J Endocrinol Invest 2014; 37: 43-50.
31. Fiore E, Latrofa F, Vitti P. Iodine, thyroid autoimmunity and cancer. Eur
Thyroid J 2015; 4: 26-35.
32. Brown KM, Arthur JR. Selenium, selenoproteins and human health: a
review. Public Health Nutr 2001; 4: 593-9.
33. Beckett GJ, Arthur JR. Selenium and endocrine systems. J Endocrinol
2005; 184: 455-65.
34. Duntas LH. The role of selenium in thyroid autoimmunity and cancer.
Thyroid 2006; 16: 455-60.
35. Schomburg L. Dietary selenium and human health. Nutrients 2016; 9:
E22.
36. Rayman MP. Selenium and human health. Lancet 2012; 379: 1256-68.
37. Maia AL, Goemann IM, Meyer EL, Wajner SM. Deiodinases: the balance
of thyroid hormone: type 1 iodothyronine deiodinase in human physi-
ology and disease. J Endocrinol 2011; 209: 283-97.
38. Rayman MP. The importance of selenium to human health. Lancet 20-
00; 356: 233-41.
39. Institute of Medicine. Dietary Reference Intakes for Vitamin C, Vitamin
E, Selenium, and Carotenoids. Washington (DC): National Academic
Press (US) 2000, pp 284-319.
40 Mazokopakis EE, Protopapadakis EE. Recommended dietary selenium
intakes and selenium concentrations in nuts. Hell J Nucl Med 2007; 10:
34.
41. Pappa EC, Pappas AC, Surai PF. Selenium content in selected foods
from the Greek market and estimation of the daily intake. Sci Total En-
viron 2006; 372: 100-8.
42. Toulis KA, Anastasilakis AD, Tzellos TG et al. Selenium supplement-
ation in the treatment of Hashimoto's thyroiditis: a systematic review
and a meta-analysis. Thyroid 2010; 20: 1163-73.
43. Fan Y, Xu S, Zhang H et al. Selenium supplementation for autoimmune
thyroiditis: a systematic review and meta-analysis. Int J Endocrinol
2014; 2014: 904573.
44. Wichman J, Winther KH, Bonnema SJ, Hegedüs L. Selenium sup-
plementation signicantly reduces thyroid autoantibody levels in
patients with chronic autoimmune thyroiditis: a systematic review
and meta-analysis. Thyroid 2016; 26: 1681-92.
45. van Zuuren EJ, Albusta AY, Fedorowicz Z et al. Selenium Supplemen-
tation for Hashimoto's thyroiditis: Summary of a Cochrane systematic
review. Eur Thyroid J 2014; 3: 25-31.
46. Duntas LH, Benvenga S. Selenium: an element for life. Endocrine 2015;
48: 756-75.
47. Esposito D, Rotondi M, Accardo G et al. Inuence of short term sele-
nium supplementation on the natural course of Hashimoto's thyro-
iditis: clinical results of a blinded placebo-controlled randomized
prospective trial. J Endocrinol Invest 2017; 40: 83-9.
48. Nacamulli D, Mian C, Petricca D et al. Inuence of physiological dietary
selenium supplementation on the natural course of autoimmune
thyroiditis. Clin Endocrinol (Oxf ) 2010; 73: 535-9.
49. Wu Q, Rayman MP, Lv H et al. Low population selenium status is associ-
ated with increased prevalence of thyroid disease. J Clin Endocrinol
Metab 2015; 100: 4037-47.
50. Joshi U, Raut P, Agrawal S et al. Evaluation of serum selenium level in
patients with uncomplicated diabetes mellitus, Raipur, India. J Clin
Diagn Res 2011; 5: 70-3.
51. Lu CW, Chang HH, Yang KC et al. High serum selenium levels are associ-
ated with increased risk for diabetes mellitus independent of central
obesity and insulin resistance. BMJ Open Diabetes Res Care 2016; 4:
e000253.
52. Su LQ, Jin YL, Unverzagt FW et al. Nail selenium level and diabetes in
older people in rural China. Biomed Environ Sci 2016; 29: 818-24.
53. Wang XL, Yang TB, Wei J et al. Association between serum selenium
level and type 2 diabetes mellitus: a non-linear dose-response meta-
analysis of observational studies. Nutr J 2016; 15: 48.
54. Stranges S, Marshall JR, Natarajan R et al. Eects of long-term selenium
supplementation on the incidence of type 2 diabetes: a randomized
trial. Ann Intern Med 2007; 147: 217-23.
55. Jablonska E, Reszka E, Gromadzinska J et al. The eect of selenium
supplementation on glucose homeostasis and the expression of ge-
nes related to glucose metabolism. Nutrients 2016; 8: 772.
56. Kadowaki T, Yamauchi T, Kubota N et al. Adiponectin and adiponectin
receptors in insulin resistance, diabetes, and the metabolic syndrome.
J Clin Investig 2006; 116: 1784-92.
57. Foti D, Chiefari E, Fedele M et al. Lack of the architectural factor HMGA1
causes insulin resistance and diabetes in humans and mice. Nat Med
2005; 11: 765-73.
58. Boucher J, Kleinridders A, Kahn CR. Insulin receptor signaling in nor-
mal and insulin-resistant states. Cold Spring Harb Perspect Biol 2014; 6:
a009191.
59. Kaprara A, Krassas GE. Selenium and thyroidal function; the role of
immunoassays. Hell J Nucl Med 2006; 9: 195-203.
60. Vinceti M, Wei ET, Malagoli C et al. Adverse health eects of selenium in
9
93
Hellenic Journal of Nuclear Medicine January-April 2017
•
www.nuclmed.gr 55
Review Article

humans. Rev Environ Health 2001; 16: 233-51.
61. Fan AM, Kizer KW. Selenium. Nutritional, toxicologic and clinical
aspects. West J Med 1990; 153: 160-7.
62. Yang GQ, Wang SZ, Zhou RH et al. Endemic selenium intoxication of
humans in China. Am J Clin Nutr 1983; 37: 872-81.
63. Vinceti M, Bonvicini F, Bergomi M, Malagoli C. Possible involvement of
overexposure to environmental selenium in the etiology of amy-
otrophic lateral sclerosis: a short review. Ann Ist Super Sanita 2010; 46:
279-83.
64. Aldosary BM, Sutter ME, Schwartz M, Morgan BW. Case series of sele-
nium toxicity from a nutritional supplement. ClinToxicol (Phila) 2012;
50: 57-64.
65. Parekh PP, Khan AR, Torres MA, Kitto ME. Concentrations of selenium,
barium, and radium in Brazil nuts. J Food Compost Anal 2008; 21: 332-5.
66. Rasmussen LB, Schomburg L, Köhrle J et al. Selenium status, thyroid
volume, and multiple nodule formation in an area with mild iodine
deciency. Eur J Endocrinol 2011; 164: 585-90.
67. Wu HY, Xia YM, Chen XS. Selenium deciency and thyroid hormone
metabolism and function. Sheng Li Ke Xue Jin Zhan 1995; 26: 12-6 (Ar-
ticle in Chinese).
68. Contempre B, Dumont JE, Ngo B et al. Eect of selenium supplemen-
tation in hypothyroid subjects of an iodine and selenium decient
area: the possible danger of indiscriminate supplementation of iodi-
ne-decient subjects with selenium. J Clin Endocrinol Metab1991; 73:
213-5.
69. Contempre B, Duale NL, Dumont JE et al. Eect of selenium supple-
mentation on thyroid hormone metabolism in an iodine and selenium
decient population. Clin Endocrinol (Oxf ) 1992; 36: 579-83.
70. Katagiri R, Asakura K, Uechi K et al. Iodine excretion in 24-hour urine
collection and its dietary determinants in healthy Japanese adults. J
Epidemiol 2016; 26: 613-21.
71. Michalaki M, Pylioti A, Loutas V et al. Absence of dierences in urinary
iodine excretion and thyroid function tests in operating room sta
members using or not using iodine-containing antiseptic solutions.
Thyroid 2013; 23: 1659-60.
72. Markou KB, Koukkou EG. The Greek population is iodine sucient and
not at risk of iodine-induced hyperthyroidism. J Nutr 2012; 142: 1611;
authors reply 1612.
73. Caprio M, Infante M, Calanchini M et al. Vitamin D: not just the bone.
Evidence for benecial pleiotropic extraskeletal eects. Eat Weight
Disord 2016.
74. Kivity S, Agmon-Levin N, Zisappl M et al. Vitamin D and autoimmune
thyroid diseases. Cell Mol Immunol 2011; 8: 243-7.
75. Sönmezgöz E, Ozer S, Yilmaz R et al. Hypovitaminosis D in children with
Hashimoto thyroiditis. Rev Med Chil 2016; 144: 611-6.
76. Muscogiuri G, Mari D, Prolo S et al. 25 Hydroxyvitamin D deciency and
its relationship to autoimmune thyroid disease in the elderly. Int J En-
viron Res Public Health 2016; 13: 850.
77. Bozkurt NC, Karbek B, Ucan B et al. The association between severity of
vitamin D deciency and Hashimoto's thyroiditis. Endocr Pract 2013;
19: 479-84.
78. Mazokopakis EE, Papadomanolaki MG, Tsekouras KC et al. Is vitamin D
related to pathogenesis and treatment of Hashimoto's thyroiditis? Hell
J Nucl Med 2015; 18: 222-7.
79. Chaudhary S, Dutta D, Kumar M et al. Vitamin D supplementation redu-
ces thyroid peroxidase antibody levels in patients with autoimmune
thyroid disease: An open-labeled randomized controlled trial. Indian J
Endocrinol Metab 2016; 20: 391-8.
80. Holick MF, Binkley NC, Bischo-Ferrari HA et al. Evaluation, treatment,
and prevention of vitamin D deciency: an Endocrine Society clinical
practice guideline. J Clin Endocrinol Metab 2011; 96: 1911-30.
81. Institute of Medicine. Dietary Reference Intakes for Calcium and
Vitamin D. Editors: A Catharine Ross, Christine L Taylor, Ann L Yaktine,
and Heather B Del Valle; Washington (DC): National Academic Press
(US) 2011.
82. Holick MF. Vitamin D deciency. N Engl J Med 2007; 357:266-81.
83. Heaney RP. The case for improving vitamin D status. J Steroid Biochem
Mol Biol 2007; 103:635-41.
84. Beulens JW, Booth SL , van den Heuve l EG et al. The role of
menaquinones (vitamin K) in human health. Br J Nutr 2013; 110: 1357-
68.
85. Robien K, Oppeneer SJ, Kelly JA et al. Drug-vitamin D interactions: a
systematic review of the literature. Nutr Clin Pract 2013; 28: 194-208.
86. van der Rhee HJ, de Vries E, Coebergh JW. Regular sun exposure bene-
ts health. Med Hypotheses 2016; 97: 34-7.
87. Green PH, Cellier C. Celiac disease. N Engl J Med 2007; 357: 1731-43.
88. Tonutti E, Bizzaro N. Diagnosis and classication of celiac disease and
gluten sensitivity. Autoimmun Rev 2014; 13: 472-6.
89. Kaukinen K, Collin P, Mykkanen AH et al. Celiac disease and auto-
immune endocrinologic disorders. Dig Dis S ci 1999; 44: 1428-33.
90. Freeman HJ. Endocrine manifestations in celiac disease. World J
Gastroenterol 2016; 22: 8472-9.
91. Hadithi M, de Boer H, Meijer JW et al. Coeliac disease in Dutch patients
with Hashimoto's thyroiditis and vice versa. World J Gastroenterol 20-
07; 13: 1715-22.
92. Tuhan H, Ik S, Abac A et al. Celiac disease in children and adolescents
with Hashimoto Thyroiditis. Turk Pediatri Ars 2016; 51: 100-5.
93. Stazi AV, Trinti B. Selenium deciency in celiac disease: risk of auto-
immune thyroid diseases. Minerva Med 2008; 99: 643-53.
94. Stazi AV, Trinti B. Selenium status and over-expression of interleukin-
15 in celiac disease and autoimmune thyroid diseases. Ann Ist Super
Sanita 2010; 46: 389-99.
95 Naiyer AJ, Shah J, Hernandez L et al. Tissue transglutaminase anti-
bodies in individuals with celiac disease bind to thyroid follicles and
extracellular matrix and may contribute to thyroid dysfunction. Thy-
roid 2008; 18: 1171-8.
96. Roy A, Laszkowska M, Sundström J et al. Prevalence of celiac disease in
patients with autoimmune thyroid disease: a meta-analysis. Thyroid
2016; 26: 880-90.
97. Volta U, De Franceschi L, Molinaro N et al. Organ-specic autoantibo-
dies in coeliac disease: do they represent an epiphenomenon or the
expression of associated autoimmune disorders? Ital J Gastroenterol
Hepatol 1997; 29: 18-21.
98. Lundin KE, Wijmenga C. Coeliac disease and autoimmune disease-
genetic overlap and screening. Nat Rev Gastroenterol Hepatol 2015; 12:
507-15.
99. Collin P. Should adults be screened for celiac disease? What are the be-
nets and harms of screening? Gastroenterology 2005; 128: S104-S108.
93
Hellenic Journal of Nuclear Medicine January-April 2017
• www.nuclmed.gr
56
9
Review Article