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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 pregnant women a higher intake of 250 mg is sug-
find it. . ... gested. Iodine is well tolerated in most individuals
Heracleitos of Ephesos, 535–475 BC up to the level of 1100 mg/daily [3]. However, in
certain susceptible individuals, high iodine intake
disrupts thyroid function and induces such disor-
INTRODUCTION ders as hyperthyroidism, particularly in regions
Homeostasis (from the Greek homeo meaning simi- where goiter is endemic, and autoimmune thyroid-
lar and stasis meaning state), the term coined in itis (AIT) where iodine is replete.
1930 by Cannon [1], denotes the tendency towards a The current review summarizes the latest scien-
relatively stable equilibrium of the internal environ- tific data highlighting the link between iodine and
ment within an organism, the disruption of which the development of AIT.
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 IODINE EXCESS AND AUTOIMMUNE
to function in an optimal manner. THYROIDITIS
The thyroid gland secretes the thyroid hor- High iodine intake reduces the synthesis of thyroid
mones, thyroxine (T4) and triiodothyronine (T3) hormones (with a transient reduction in the synthe-
that are synthesized from iodine and tyrosine and sis lasting approximately 24 h), this constituting the
control metabolic rate and protein synthesis. In so-called acute Wolff–Chaikoff effect as this was
healthy individuals, the micronutrient iodine is
rapidly and easily absorbed as iodide in the gastro-
Evgenidion Hospital, Unit of Endocrinology, Metabolism and Diabetes,
intestinal tract, whereas iodate, extensively used in
Thyroid Section, University of Athens, Greece
salt iodization, is reduced to iodide in the gut and
Correspondence to Leonidas H. Duntas, MD, Professor of Endocrinol-
almost completely absorbed in the stomach [2]. ogy and Internal Medicine, Evgenideion Hospital, Unit of Endocrinology,
Iodine, being an essential constituent of thyroid Metabolism and Diabetes, University of Athens, 20 Papadiamantopoulou
hormones, is hence involved in thyroid disease Street, Athens 11520, Greece. Tel: +30 210 674 8878;
arising from either its deficiency or its excess. For e-mail: ledunt@otenet.gr
regulation of the latter, a daily iodine intake of Curr Opin Endocrinol Diabetes Obes 2018, 25:347–352
150 mg is recommended in adults, whereas in DOI:10.1097/MED.0000000000000425
1752-296X Copyright ß 2018 Wolters Kluwer Health, Inc. All rights reserved. www.co-endocrinology.com
itis or chronic lymphocytic thyroiditis, is character- The sum total of these results provides good
ized by infiltration of the thyroid gland by evidence that the amount of iodine intake may
inflammatory cells and generation of autoantibod- influence the generation and the quantity of both
ies to thyroid-specific antigens: thyroglobulin and TPOAB and TgAB titers. Though the iodization of
thyroperoxidase (TgAB and TPOAB) [8]. It may result salt has proven to be an efficient and successful
in hypothyroidism following destruction and pro- means of tackling iodine deficiency disorders, exces-
gressive fibrosis of the follicle cells. sive iodine intake represents a public health concern
AIT is globally on the rise, and particularly in as it significantly disrupts thyroid function, thereby
regions where programs of iodization of salt have possibly inducing AIT. It is, therefore, of paramount
been adopted, thereby exposing the population to importance that thyroid functioning tests be carried
more than adequate iodine intake. This trend has out regularly in populations at risk, most particu-
been amply documented in several countries after larly in pregnant women, children and the
implementation of salt fortification programs. In elderly and in those with a positive family history
Denmark, a country with 60–70 accredited clinical of AIT.
Table 1. Nutrients, drugs and other sources of potential and maintaining peripheral tolerance, whereas the
excess iodine intake CD40, CTLA-4, and HLA genes are essential for the
Nutrients
activation of T lymphocytes as well as for antigen
Iodized salt presentation [18]. Single nucleotide polymorphisms
Seaweed (Kelp) (SNPs) in immune-modulating genes may inhibit
Seafood the development of central and peripheral tolerance
Bread, dairy (milk) and alter T-cell interactions with antigen-presenting
Drugs cells (APCs) in the immunological synapse. Basing
Amiodarone their investigation on this evidence, the authors
Nonionic iodinated contrast media showed that only Tg peptides are bound to HLA-
Povidone–iodine disinfectants
DR, suggesting that presentation of Tg peptides by
Other sources
HLA-DR to T cells may be the initial trigger of
Food preservatives
autoimmune thyroid disease (AITD). Further corrob-
Expectorants
Vitamins and supplements
orating this observation are several whole-genome
Mouthwashes screening studies demonstrating that Tg is a major
Toothpastes AITD susceptibility gene.
The effector CD4 T cells differentiate into several
Modified from [6]. subsets of Th cells: for example, Th1 cells that stim-
ulate cellular immunity and Th17 cells that activate
In addition, through intake of iodized salt, neutrophils. Th1 and Th17 cells play crucial roles in
excess iodine intake can occur via overconsumption many autoimmune diseases, including AIT [19].
of other nutrients such as seaweed and seafood [14] Meanwhile, regulatory T cells (Tregs), which are
and, most importantly, through various iodine-rich characterized by the expression of FOXP3, have a
medications and iodinated contrast agents [15] that protective role and are primarily responsible for
are liable to trigger AIT in susceptible individuals maintaining self-tolerance. In contrast, excessive
(Table 1). Th17 cell response, as compared with that of TREGs,
Amiodarone, a class-III antiarrhythmic medica- results in loss of self-tolerance.
tion containing 37% iodine by weight that has a As the nonobese diabetic (NOD.H2h4) mouse is
half-life of approximately 100 days, needs special prone to develop spontaneous AIT, this inbred strain
note. The medication is regularly prescribed at daily of mouse model has been extensively used to investi-
doses ranging from 100 to 600 mg, patients thus, gate the intriguing connection between excess iodine
receiving about 3–21 mg iodine daily per treatment. intake and the development of AIT [20]. The authors’
However, amiodarone is associated with several side finding that excess sodium iodide (NaI) intake via
effects that impact the thyroid, including hypothy- drinking water leads to increased immunogenicity
roidism, mainly in iodine-sufficient areas and in of the Tg molecule, thus triggering autoimmune dis-
patients with Hashimoto’s thyroiditis, and hyper- ease, highlights the interplay between genetic and
thyroidism, more frequently observed in iodine- dietary factors. In NOD-H-2h4 mice given either plain
deficient regions [16]. water or water with 0.05% NaI for 8 weeks, 54% of
Progress in scientific research in this area over female and 70% of male iodine-treated mice devel-
the last few decades has clearly exposed the impor- oped AIT, whereas only 1/20 of the control animals
tant role played by the quantity of iodine ingested as presented thyroiditis [21]. In the same study, a time-
well as by the time of exposure in the induction of kinetic analysis registered high TgAB in the iodine-
disease [5,17]. 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-
MECHANISMS OF DISEASE dently, a crucial step for triggering the disease, as this
AIT is a multifactorial disease generated by the was also shown by the fact that T cells from patients
interplay of genetic traits and environmental fac- with chronic thyroiditis fail to react with noniodi-
tors, the former being crucial in the loss of tolerance nated Tg [22]. Though the target epitope remains
to self-antigens and initiation of autoimmunity. unknown, it is likely that CD4þ cells are necessary
Thyroid-specific (Tg, TSHR) or immune-modulating for the development and maintenance of spontaneous
[forkhead box protein 3 (FOXP3), CD25, CD40, AIT. In the above study, it was shown that the thyro-
CTLA-4] genes, with HLA-DR3 presenting the high- globulin (Tg) T-cell epitope p2549–2560, containing
est risk, are involved. thyroxine at position 2553 (T4p2553), induces thy-
Counteracting the risks are, importantly, FOXP3 roiditis as well as strong specific T-cell and B-cell
and CD25, which play a critical role in establishing responses in NOD.H2(h4) mice [23].
1752-296X Copyright ß 2018 Wolters Kluwer Health, Inc. All rights reserved. www.co-endocrinology.com 349
In another study, NOD.H2(h4) thyrocytes cul- became hypothyroid. Serum T4 levels were reduced
tured for 24 h at very low (4–8 mmol/l) concentra- in BALB/c, but they were not altered in NOD.H2 h
tions of NaI exhibited impaired control of oxidative mice. These findings suggest that AIT-prone
stress mechanisms that was associated with an NOD.H2h4 mice may be better adapted to excess
observed high susceptibility of NOD.H2(h4) thyro- iodide intake because of escape from the Wolff–
cytes to NaI-mediated apoptosis [24]. These results Chaikoff effect. On the other hand, BALB/c mice
underscore the participation of a functioning anti- that did not develop AIT were rendered hypothyroid
oxidative stress mechanism that hinders the pro- as they failed to escape from the Wolff–Chaikoff
&
gression of the disease. effect [25 ]. The above data provide a deeper under-
Recently, in a wide spectrum of mouse strains, standing of the mechanism via, which iodide-
including thyroiditis-susceptible NOD.H2h4, and induced hypothyroidism may arise in some individ-
BALB/c, it was investigated whether a high dietary uals despite the absence of an underlying
iodide intake had any effect on serum TSH and T4 thyroid disorder.
&
levels [25 ]. Excess iodide ingestion increased serum Follicular destruction following lymphocytic
TSH levels to the same extent in both strains, yet NIS infiltration of the thyroid gland is the characteristic
messenger RNA (mRNA) levels revealed markedly hallmark of thyroiditis. The production of inflamma-
diverse responses. NOD.H2h4 mice that remained tory cytokines such as interferon-g (IFN-g), promote
euthyroid displayed a physiological NIS iodine the disease. IFN-g up-regulates certain cell surface
autoregulatory response, whereas NIS mRNA was proteins, particularly ICAM-1 on thyroidal follicle
inappropriately elevated in BALB/c mice that cells, this action mediating cell–cell interactions
Iodine Excess
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.
and therefore, enhancing the inflammatory process during childhood severely impairs somatic growth
[26]. It is of note that ICAM-1 expression is further and cognitive function. Thus, because of difficulties
increased by the elevated generation of reactive oxy- in making an accurate assessment of the mother’s
gen species (ROS), particularly anion superoxide iodine status during pregnancy, there are calls for
(O2) and hydrogen peroxide (H2O2) produced by iodine supplementation in all pregnant and breast-
the iodination of Tg. H2O2, as well as iodine, activates feeding women [2,31]. With regard to public health
transcription of ICAM-1 via the mitogen-activated in general, the implementation of universal salt
protein kinase (MAPK) pathway [27] (Fig. 1). Iodine iodization programs worldwide has proven, over
may act in synergy with ROS in inducing thyroiditis. 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-
IODINE HOMEOSTASIS ever, following recent recommendations of the
Iodine deficiency can affect people at any time WHO for a daily consumption of less than 5 g salt,
during their life and not only in the developing with the aim of reducing elevated levels of cardio-
world but, as has recently been shown in a study vascular disease because of overconsumption of salt,
from central Italy [28], also in several industrialized national programs of iodine salt fortification may be
countries. In 99 pregnant women, median urinary negatively affected [32]. Hence, the iodine status of
iodine concentration (UIC) was evaluated in spot populations undergoing salt reduction strategies
urine samples and a median UIC of 97.7 and should be frequently assessed to prevent the re-
110.3 mg/l, respectively, in control and pregnant emergence or the persistence of iodine deficiency.
women was observed. Crucially, however, the latter Monitoring of iodine supplementation may also be
observational study reveals that not only the major- needed in countries in which programs of sea water
ity of pregnant women but also their foetuses are desalination are applied that may contribute to
exposed to the detrimental consequences of iodine iodine deficiency [33].
deficiency, this principally because of the low iodine While universal salt iodization has diminished
status of their mothers, a finding that has been worldwide the incidence of such IDD as goiter, long-
corroborated by many other studies and publica- term exposure to excessive levels of iodine from
tions [28–30]. This is of critical importance, as it has underground water or inadequately monitored salt
been firmly established that iodine deficiency represent considerable risk factors for
Iodine excess
Iodine μg/L
Hypothyroidism
Autoimmune thyroiditis
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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