REVIEW

CURRENT
OPINION The catalytic role of iodine excess in loss of
homeostasis in autoimmune thyroiditis
Leonidas H. Duntas

Purpose of review
To review the latest developments concerning the role of iodine in the pathophysiology of autoimmune
thyroiditis.
Recent findings
Recent studies have provided evidence that in areas with excess iodine intake, increased incidence of
autoimmune thyroiditis marked by high titers of thyroid peroxidase and thyroglobulin antibodies has
occurred. Investigations in the NOD.H2h4 mouse, a strain prone to AIT, showed that they are better
adapted to the Wolff–Chaikoff effect.
Summary
To provide an overview of the studies conducted during the last few years implicating iodine in the
development and manifestation of autoimmune thyroiditis.
Keywords
autoimmune thyroiditis, homeostasis, iodine

Unless you expect the unexpected, you will not
find it. . ...
Heracleitos of Ephesos, 535–475 BC
INTRODUCTION
Homeostasis (from the Greek homeo meaning simi-
lar and stasis meaning state), the term coined in
1930 by Cannon [1], denotes the tendency towards a
relatively stable equilibrium of the internal environ-
ment within an organism, the disruption of which
stability may lead to dysfunction of the cells and
organ(s). It signifies, in other words, a state of
dynamic physiological stability enabling the body
to function in an optimal manner.
The thyroid gland secretes the thyroid hor-
mones, thyroxine (T4) and triiodothyronine (T3)
that are synthesized from iodine and tyrosine and
control metabolic rate and protein synthesis. In
healthy individuals, the micronutrient iodine is
rapidly and easily absorbed as iodide in the gastro-
intestinal tract, whereas iodate, extensively used in
salt iodization, is reduced to iodide in the gut and
almost completely absorbed in the stomach [2].
Iodine, being an essential constituent of thyroid
hormones, is hence involved in thyroid disease
arising from either its deficiency or its excess. For
regulation of the latter, a daily iodine intake of
150 mg is recommended in adults, whereas in
pregnant women a higher intake of 250 mg is sug-
gested. Iodine is well tolerated in most individuals
up to the level of 1100 mg/daily [3]. However, in
certain susceptible individuals, high iodine intake
disrupts thyroid function and induces such disor-
ders as hyperthyroidism, particularly in regions
where goiter is endemic, and autoimmune thyroid-
itis (AIT) where iodine is replete.
The current review summarizes the latest scien-
tific data highlighting the link between iodine and
the development of AIT.
IODINE EXCESS AND AUTOIMMUNE
THYROIDITIS
High iodine intake reduces the synthesis of thyroid
hormones (with a transient reduction in the synthe-
sis lasting approximately 24 h), this constituting the
so-called acute Wolff–Chaikoff effect as this was
Evgenidion Hospital, Unit of Endocrinology, Metabolism and Diabetes,
Thyroid Section, University of Athens, Greece
Correspondence to Leonidas H. Duntas, MD, Professor of Endocrinol-
ogy and Internal Medicine, Evgenideion Hospital, Unit of Endocrinology,
Metabolism and Diabetes, University of Athens, 20 Papadiamantopoulou
Street, Athens 11520, Greece. Tel: +30 210 674 8878;
e-mail: ledunt@otenet.gr
Curr Opin Endocrinol Diabetes Obes 2018, 25:347–352
DOI:10.1097/MED.0000000000000425

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Thyroid
KEY POINTS
 Optimal iodine intake is essential to prevent
thyroid disease.
 Chronic high-iodine intake may trigger autoimmune
thyroiditis in susceptible individuals.
 Autoimmune thyroiditis is the result of the interplay
between genetics and environmental factors; its
incidence increases with high intake of iodine.
 Iodine status should be frequently monitored in the
populations of countries, which following the WHO
recommendations, have introduced strategies for
reducing salt consumption or that have implemented
salination programs.
 Recent publications have presented the postulated
mechanisms underlying the induction of thyroiditis in
nonsusceptible individuals.
described in 1948 at Berkeley University [3,4].
Though the mechanism of this effect has not as
yet been completely clarified, it has been postulated
that the high iodine load leads to the generation of a
number of substances that inhibit thyroid peroxi-
dase activity, such as iodolactones and/or iodoli-
pids, as well as to decreased intrathyroidal
deiodinase activity [5,6]. However, the observation
that natrium iodide symporter (NIS) decreased at 6
and 24 h after excessive iodine administration sug-
gests that escape from the acute Wolff–Chaikoff
effect is linked to decreased synthesis of NIS, result-
ing in reduction in intrathyroidal iodine concen-
trations, and subsequently to resumption of thyroid
hormone synthesis [7]. Failure to escape from the
Wolff–Chaikoff effect may, in susceptible individu-
als, trigger AIT and hypothyroidism.
AIT is an organ-specific disease of which the
most frequent forms are Hashimoto’s thyroiditis
and Graves’ disease, the former being the most
common endocrine disorder. Hashimoto’s thyroid-
itis or chronic lymphocytic thyroiditis, is character-
ized by infiltration of the thyroid gland by
inflammatory cells and generation of autoantibod-
ies to thyroid-specific antigens: thyroglobulin and
thyroperoxidase (TgAB and TPOAB) [8]. It may result
in hypothyroidism following destruction and pro-
gressive fibrosis of the follicle cells.
AIT is globally on the rise, and particularly in
regions where programs of iodization of salt have
been adopted, thereby exposing the population to
more than adequate iodine intake. This trend has
been amply documented in several countries after
implementation of salt fortification programs. In
Denmark, a country with 60–70 accredited clinical
348 www.co-endocrinology.com
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registries, the concentrations of thyroid autoanti-
bodies were measured in two identical cross-sec-
tional population studies before [n ¼ 4649, median
urinary iodine (mui) 61 mg/l] and 4–5 years after
(n ¼ 3570, mui 101 mg/l) implementation of manda-
tory iodine fortification of salt [9,10]. Both TPOAB
and TgAB were found statistically significantly
increased, particularly in women, though at low
concentrations, after and not before the implemen-
tation of the program: TPO-Ab greater than 30 U/ml,
14.3 vs. 23.8% (P < 0.001) and Tg-Ab greater than
20 U/ml, 13.7 vs. 19.9% (P < 0.001). Of note, though
the prevalence of thyroid dysfunction and autoim-
munity in Danish pregnant women was higher after
the implementation of the Danish iodine fortifica-
tion program, no associations were found with
&
adverse obstetric outcomes [11 ].
In contrast, another population-based cross-sec-
tional study including 3813 individuals was con-
ducted in China in two areas with different levels of
iodine intake (Rongxing, mui 261 mg/l; Chengshan,
mui 145 mg/l) with the aim of analyzing the associ-
ations between more than adequate iodine-intake
levels and the development of thyroid diseases [12].
The prevalence of subclinical hypothyroidism (SCH)
and of TPOAB and TgAB levels were significantly
higher among people living in Rongxing by com-
parison with those in Chengshan. As compared with
the study in Denmark, the increase in thyroid anti-
bodies was most notable in the high concentrations
of TPOAb ( 500 IU/ml) and low concentrations of
TgAb (TgAb: 40–99 IU/ml) in Rongxing.
In a study aiming to investigate the effects of an
increased iodine intake on the prevalence of thyroid
diseases in Central and Eastern China, a total of
15 008 adults were included from 10 cities with ade-
quate (n ¼ 6) or more than adequate (n ¼ 4) iodine
intake [12]. The prevalence of SCH (16.7 vs. 3.22%),
positive TPOAb (11.5 vs. 9.81%) and positive TgAb
(12.6 vs. 9.09%) was significantly increased in the
cities, with more than adequate as compared with
those with adequate iodine intake being noted [13 ].
&
The sum total of these results provides good
evidence that the amount of iodine intake may
influence the generation and the quantity of both
TPOAB and TgAB titers. Though the iodization of
salt has proven to be an efficient and successful
means of tackling iodine deficiency disorders, exces-
sive iodine intake represents a public health concern
as it significantly disrupts thyroid function, thereby
possibly inducing AIT. It is, therefore, of paramount
importance that thyroid functioning tests be carried
out regularly in populations at risk, most particu-
larly in pregnant women, children and the
elderly and in those with a positive family history
of AIT.
Volume 25  Number 5  October 2018

Table 1. Nutrients, drugs and other sources of potential
excess iodine intake
Nutrients
Iodized salt
Seaweed (Kelp)
Seafood
Bread, dairy (milk)
Drugs
Amiodarone
Nonionic iodinated contrast media
Povidone–iodine disinfectants
Other sources
Food preservatives
Expectorants
Vitamins and supplements
Mouthwashes
Toothpastes
Modified from [6].
In addition, through intake of iodized salt,
excess iodine intake can occur via overconsumption
of other nutrients such as seaweed and seafood [14]
and, most importantly, through various iodine-rich
medications and iodinated contrast agents [15] that
are liable to trigger AIT in susceptible individuals
(Table 1).
Amiodarone, a class-III antiarrhythmic medica-
tion containing 37% iodine by weight that has a
half-life of approximately 100 days, needs special
note. The medication is regularly prescribed at daily
doses ranging from 100 to 600 mg, patients thus,
receiving about 3–21 mg iodine daily per treatment.
However, amiodarone is associated with several side
effects that impact the thyroid, including hypothy-
roidism, mainly in iodine-sufficient areas and in
patients with Hashimoto’s thyroiditis, and hyper-
thyroidism, more frequently observed in iodine-
deficient regions [16].
Progress in scientific research in this area over
the last few decades has clearly exposed the impor-
tant role played by the quantity of iodine ingested as
well as by the time of exposure in the induction of
disease [5,17].
MECHANISMS OF DISEASE
AIT is a multifactorial disease generated by the
interplay of genetic traits and environmental fac-
tors, the former being crucial in the loss of tolerance
to self-antigens and initiation of autoimmunity.
Thyroid-specific (Tg, TSHR) or immune-modulating
[forkhead box protein 3 (FOXP3), CD25, CD40,
CTLA-4] genes, with HLA-DR3 presenting the high-
est risk, are involved.
Counteracting the risks are, importantly, FOXP3
and CD25, which play a critical role in establishing
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Role of iodine excess in loss of homeostasis in AIT Duntas
and maintaining peripheral tolerance, whereas the
CD40, CTLA-4, and HLA genes are essential for the
activation of T lymphocytes as well as for antigen
presentation [18]. Single nucleotide polymorphisms
(SNPs) in immune-modulating genes may inhibit
the development of central and peripheral tolerance
and alter T-cell interactions with antigen-presenting
cells (APCs) in the immunological synapse. Basing
their investigation on this evidence, the authors
showed that only Tg peptides are bound to HLA-
DR, suggesting that presentation of Tg peptides by
HLA-DR to T cells may be the initial trigger of
autoimmune thyroid disease (AITD). Further corrob-
orating this observation are several whole-genome
screening studies demonstrating that Tg is a major
AITD susceptibility gene.
The effector CD4 T cells differentiate into several
subsets of Th cells: for example, Th1 cells that stim-
ulate cellular immunity and Th17 cells that activate
neutrophils. Th1 and Th17 cells play crucial roles in
many autoimmune diseases, including AIT [19].
Meanwhile, regulatory T cells (Tregs), which are
characterized by the expression of FOXP3, have a
protective role and are primarily responsible for
maintaining self-tolerance. In contrast, excessive
Th17 cell response, as compared with that of TREGs,
results in loss of self-tolerance.
As the nonobese diabetic (NOD.H2h4) mouse is
prone to develop spontaneous AIT, this inbred strain
of mouse model has been extensively used to investi-
gate the intriguing connection between excess iodine
intake and the development of AIT [20]. The authors’
finding that excess sodium iodide (NaI) intake via
drinking water leads to increased immunogenicity
of the Tg molecule, thus triggering autoimmune dis-
ease, highlights the interplay between genetic and
dietary factors. In NOD-H-2h4 mice given either plain
water or water with 0.05% NaI for 8 weeks, 54% of
female and 70% of male iodine-treated mice devel-
oped AIT, whereas only 1/20 of the control animals
presented thyroiditis [21]. In the same study, a time-
kinetic analysis registered high TgAB in the iodine-
treated group after 8 weeks of treatment, although
TPOAB were not detectable in the serum of any animal
[21]. The increased immunogenicity of Tg is, evi-
dently, a crucial step for triggering the disease, as this
was also shown by the fact that T cells from patients
with chronic thyroiditis fail to react with noniodi-
nated Tg [22]. Though the target epitope remains
unknown, it is likely that CD4þ cells are necessary
for the development and maintenance of spontaneous
AIT. In the above study, it was shown that the thyro-
globulin (Tg) T-cell epitope p2549–2560, containing
thyroxine at position 2553 (T4p2553), induces thy-
roiditis as well as strong specific T-cell and B-cell
responses in NOD.H2(h4) mice [23].
www.co-endocrinology.com 349
Thyroid

In another study, NOD.H2(h4) thyrocytes cul-
tured for 24 h at very low (4–8 mmol/l) concentra-
tions of NaI exhibited impaired control of oxidative
stress mechanisms that was associated with an
observed high susceptibility of NOD.H2(h4) thyro-
cytes to NaI-mediated apoptosis [24]. These results
underscore the participation of a functioning anti-
oxidative stress mechanism that hinders the pro-
gression of the disease.
Recently, in a wide spectrum of mouse strains,
including thyroiditis-susceptible NOD.H2h4, and
BALB/c, it was investigated whether a high dietary
iodide intake had any effect on serum TSH and T4
&
levels [25 ]. Excess iodide ingestion increased serum
TSH levels to the same extent in both strains, yet NIS
messenger RNA (mRNA) levels revealed markedly
diverse responses. NOD.H2h4 mice that remained
euthyroid displayed a physiological NIS iodine
autoregulatory response, whereas NIS mRNA was
inappropriately elevated in BALB/c mice that
became hypothyroid. Serum T4 levels were reduced
in BALB/c, but they were not altered in NOD.H2 h
mice. These findings suggest that AIT-prone
NOD.H2h4 mice may be better adapted to excess
iodide intake because of escape from the Wolff–
Chaikoff effect. On the other hand, BALB/c mice
that did not develop AIT were rendered hypothyroid
as they failed to escape from the Wolff–Chaikoff
&
effect [25 ]. The above data provide a deeper under-
standing of the mechanism via, which iodide-
induced hypothyroidism may arise in some individ-
uals despite the absence of an underlying
thyroid disorder.
Follicular destruction following lymphocytic
infiltration of the thyroid gland is the characteristic
hallmark of thyroiditis. The production of inflamma-
tory cytokines such as interferon-g (IFN-g), promote
the disease. IFN-g up-regulates certain cell surface
proteins, particularly ICAM-1 on thyroidal follicle
cells, this action mediating cell–cell interactions

Iodine Excess

Tg+ Th1 Th17

INF-γ
JAK/STAT TREG

ICAM-1

Thyrocyte Apoptosis

AIT
FIGURE 1. Excess iodine intake increases the iodination of thyroglobulin (Tg), a process that generates radical oxygen
species (ROS) which, via the MAPK pathway, may activate intracellular adhesion molecule-1 (ICAM-1) expression. ICAM-1 is
also activated by interferon-g via the Janus kinase (JAK) and the signal transducer and activator of transcription (STAT), JAK/
STAT pathway, thus promoting apoptosis and autoimmune thyroiditis. Decreased T regulatory cells and increased Th17 cells
accelerate the inflammatory process, thereby contributing considerably to the entire process. MAPK, mitogen-activated protein
kinase; ICAM-1, intracellular adhesion molecule-1; ROS, radical oxygen species; Tg, thyroglobulin.

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and therefore, enhancing the inflammatory process
[26]. It is of note that ICAM-1 expression is further
increased by the elevated generation of reactive oxy-
gen species (ROS), particularly anion superoxide
(O2) and hydrogen peroxide (H2O2) produced by
the iodination of Tg. H2O2, as well as iodine, activates
transcription of ICAM-1 via the mitogen-activated
protein kinase (MAPK) pathway [27] (Fig. 1). Iodine
may act in synergy with ROS in inducing thyroiditis.
IODINE HOMEOSTASIS
Iodine deficiency can affect people at any time
during their life and not only in the developing
world but, as has recently been shown in a study
from central Italy [28], also in several industrialized
countries. In 99 pregnant women, median urinary
iodine concentration (UIC) was evaluated in spot
urine samples and a median UIC of 97.7 and
110.3 mg/l, respectively, in control and pregnant
women was observed. Crucially, however, the latter
observational study reveals that not only the major-
ity of pregnant women but also their foetuses are
exposed to the detrimental consequences of iodine
deficiency, this principally because of the low iodine
status of their mothers, a finding that has been
corroborated by many other studies and publica-
tions [28–30]. This is of critical importance, as it has
been firmly established that iodine deficiency
Iodine μg/L
300
100
0
Hypothyroidism
Iodine deficiency
FIGURE 2. The homeostasis of iodine. As both excess and deficiency are associated with thyroid diseases, optimal iodine
intake should be stressed.
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Role of iodine excess in loss of homeostasis in AIT Duntas
during childhood severely impairs somatic growth
and cognitive function. Thus, because of difficulties
in making an accurate assessment of the mother’s
iodine status during pregnancy, there are calls for
iodine supplementation in all pregnant and breast-
feeding women [2,31]. With regard to public health
in general, the implementation of universal salt
iodization programs worldwide has proven, over
the past few decades, to be a cost-effective and
highly successful way to deal with the high global
prevalence of iodine deficiency diseases (IDD). How-
ever, following recent recommendations of the
WHO for a daily consumption of less than 5 g salt,
with the aim of reducing elevated levels of cardio-
vascular disease because of overconsumption of salt,
national programs of iodine salt fortification may be
negatively affected [32]. Hence, the iodine status of
populations undergoing salt reduction strategies
should be frequently assessed to prevent the re-
emergence or the persistence of iodine deficiency.
Monitoring of iodine supplementation may also be
needed in countries in which programs of sea water
desalination are applied that may contribute to
iodine deficiency [33].
While universal salt iodization has diminished
worldwide the incidence of such IDD as goiter, long-
term exposure to excessive levels of iodine from
underground water or inadequately monitored salt
represent considerable risk factors for
Iodine excess
Hypothyroidism
Autoimmune thyroiditis
www.co-endocrinology.com 351
Thyroid
hypothyroidism [34]. It is, therefore, evident that
concerted efforts must be made to establish ade-
quate and balanced levels of iodine intake in all
countries (Fig. 2), as even slight variations in this
equilibrium have the potential to adversely affect
the entire organism. In other words, the severity of
any given disorder could well be proportional to the
degree of iodine excess or deficiency.
CONCLUSION
To sum up, maintenance of the body’s homeostasis
demands the dedication and synergistic action of
public health advocates working with a well coordi-
nated agenda [35]. To achieve this aim, much work
must be done, all the time bearing in mind that
constant and committed analysis and research alone
can lead to discovery and that it is wise advice that,
at any moment, the ‘expected can rise out of the
unexpected’ (the famous saying from the quotation
attributed to the Greek philosopher, Heracleitos of
Ephesos, 535–475 BC).
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
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Volume 25  Number 5  October 2018