Journal Pre-proof

Hashimoto's thyroiditis: An update on pathogenic mechanisms,

diagnostic protocols, therapeutic strategies, and potential
malignant transformation

Massimo Ralli, Diletta Angeletti, Marco Fiore, Vittorio

D'Aguanno, Alessandro Lambiase, Marco Artico, Marco de
Vincentiis, Antonio Greco

PII: S1568-9972(20)30220-2
DOI: https://doi.org/10.1016/j.autrev.2020.102649
Reference: AUTREV 102649

To appear in: Autoimmunity Reviews

Received date: 15 March 2020

Accepted date: 21 March 2020

Please cite this article as: M. Ralli, D. Angeletti, M. Fiore, et al., Hashimoto's thyroiditis:
An update on pathogenic mechanisms, diagnostic protocols, therapeutic strategies, and
potential malignant transformation, Autoimmunity Reviews (2020), https://doi.org/
10.1016/j.autrev.2020.102649

This is a PDF file of an article that has undergone enhancements after acceptance, such
as the addition of a cover page and metadata, and formatting for readability, but it is
not yet the definitive version of record. This version will undergo additional copyediting,
typesetting and review before it is published in its final form, but we are providing this
version to give early visibility of the article. Please note that, during the production
process, errors may be discovered which could affect the content, and all legal disclaimers
that apply to the journal pertain.

© 2020 Published by Elsevier.

 Journal Pre-proof
Hashimoto’s thyroiditis: an update on pathogenic mechanisms,
diagnostic protocols, therapeutic strategies, and potential malignant
transformation
Massimo Ralli1,* [email protected], Diletta Angeletti1 [email protected],
Marco Fiore2 [email protected], Vittorio D’Aguanno1 [email protected], Alessandro
Lambiase1 [email protected], Marco Artico1 [email protected], Marco de
Vincentiis3 [email protected], Antonio Greco1 [email protected].
1
Department of Sense Organs, Sapienza University of Rome, Italy
2
CNR, Institute of Cell Biology and Neurobiology
3
Department of Oral and Maxillofacial Sciences, Sapienza University of Rome, Italy

of
*
Corresponding Author at. Department of Sense Organs, Sapienza University of Rome, Viale del

ro
Policlinico, 155 - 00161 Rome, Italy.
Abstract -p
Hashimoto’s thyroiditis, characterized by thyroid-specific autoantibodies, is one of the commonest
re
autoimmune disorders. Although the exact etiology has not been fully elucidated, Hashimoto’s
lP

thyroiditis is related to an interaction among genetic elements, environmental factors and epigenetic

influences. Cellular and humoral immunity play a key role in the development of the disease; thus,
na

a T and B cells inflammatory infiltration is frequently found. Histopathologic feature of the disease

includes lymphoplasmacytic infiltration, lymphoid follicle formation with germinal centers, and
ur

parenchymal atrophy. Moreover, the occurrence of large follicular cells and oxyphilic or Askanazy
Jo

cells is frequently associated to Hashimoto’s thyroiditis. Clinically, Hashimoto’s thyroiditis is

characterized mainly by systemic manifestations due to the damage of the thyroid gland, developing

a primary hypothyroidism. Diagnosis of Hashimoto’s thyroiditis is clinical and based on clinical

characteristics, positivity to serum antibodies against thyroid antigens (thyroid peroxidase and

thyroglobulin), and lymphocytic infiltration on cytological examination. The mainstream of

treatment is based on the management of the hypothyroidism with a substitution therapy. A

relationship between Hashimoto’s thyroiditis and a possible malignant transformation has been

1
 Journal Pre-proof
proposed in several studies and involves immunological/hormonal pathogenic links although

specific correlation is still debated and needs to be further investigated with prospective studies.

Keywords: Hashimoto’s Thyroiditis, Autoimmunity, Hypothyroidism, Autoimmune thyroid

disorders

of
ro
-p
re
lP
na
ur
Jo

2
 Journal Pre-proof
1. Introduction

Hashimoto Thyroiditis (HT), also called chronic lymphocytic or autoimmune thyroiditis, is an

autoimmune thyroid disease characterized by increased thyroid volume, lymphocyte infiltration of

parenchyma, and the presence of antibodies specific to thyroid antigens. HT is considered, together

with Graves’ Disease (GD), an autoimmune thyroid disorder (AITD) whose frequency has

increased considerably in the recent years [1-3]. HT is currently the leading cause of

hypothyroidism [1, 4]; moreover, patients with HT are more likely to be affected by cardiovascular

diseases and malignant neoplasms [5, 6].

of
HT was first described by a Japanese physician, Haraku Hashimoto, in 1912 [7]. He found that

ro
thyroid tissue was infiltrated by lymphocytes with increased volume of the gland, naming this

disease as “struma lymphomatosa”. Hashimoto’s struma lymphomatosa was not considered a

-p
specific clinical entity until 1931, when Allen Graham [8] described the condition as an
re
autonomous pathology. In 1956, Rose and Witebsky [9, 10] demonstrated that rabbit immunization
lP

with extracts of rabbit thyroid induced histologic modification on thyroid tissue similar to HT,

identifying anti-thyroglobulin antibodies in the serum. In the same year, Roitt, Doniach et al [11]
na

isolated anti-thyroglobulin antibodies from the serum of patients with HT and stated that patients
ur

with HT may have an immunological reaction to thyroglobulin, concluding that Hashimoto's goiter

should be considered an autoimmune disease of the thyroid gland.

Jo

2. Epidemiology

Incidence of HT rapidly increased in the last 3 decades [12]. Currently, HT is one of the most

common thyroid diseases and its incidence is 0.3-1.5 cases per 1000 people [13]. More than 10% of

women display positive antibody and around 2% show clinical manifestations [14]; men present

one-tenth of this prevalence [15] . The white race shows a higher incidence than black, while HT is

rare in Pacific Islanders [16]. Disease prevalence increases with age [16].

3
 Journal Pre-proof
Although the reasons of female gender prevalence are still unknown, possible explanations could be

found in the role of female sex hormones, as demonstrated in animal models of many autoimmune

diseases [17, 18], or following the inactivation of chromosome X and fetal microchimerism [19]. In

a recent study on 490 patients affected by HT, no significant differences in chromosome X

inactivation were observed compared to normal subjects, but four other meta-analysis showed that

chromosome X inactivation may be relevant [20]. If microchimerism played a significant role, HT

should have been more frequent in women with multiple pregnancies. However, a study of 4.6

million Danes revealed only a irrelevant increase of autoimmune diseases in women with a previous

of
pregnancy, compared to those who did not have children [21]. The pathogenesis of HT has also

ro
been associated with climate conditions, since Siberian women have higher thyroid peroxidase

(TPO) antibody title than general population [22].

-p
Last, HT may have a higher prevalence in some conditions such as myasthenia gravis (MG) and
re
systemic sclerosis. A recent meta-analysis from Song et al on 39 studies showed reliable evidence
lP

that HT, along with other thyroid disorders, have a higher prevalence in patients with MG and

identified MG as a risk factor for thyroid autoimmunity [23]. In a meta-analysis conducted on 46

na

studies by Yao et al, the authors found a considerably high prevalence of autoimmune thyroid
ur

conditions in subjects with systemic sclerosis, and that this condition is associated with increased

risks of thyroid pathologies [24]. Although the pathogenic mechanisms of the associations between
Jo

thyroid autoimmunity and these conditions are not clear, it has been hypothesized that immune

defects, hormones, genetic and environmental factors may play a central role in poly-autoimmunity

[25].

3. Etiology

Although still largely unknown, pathogenesis of HT is related to genetic influences, environmental

triggers and epigenetic effects [26].

4
 Journal Pre-proof
3.1 Genetic susceptibility

A genetic susceptibility to HT disease has been shown in epidemiological studies that focused on

familial predisposition [27]. Brix et al showed in Danish twins that monozygotic twins exhibited a

concordance rate of more than 50%, while dizygotic twins showed absence of any concordance

[28]. Moreover, data from the same study regarding thyroid autoantibodies showed an high

concordance rate for monozygotic twins that was nearly 80%, when compared to dizygotic ones

(40%) [28].

Several genes have been shown to be involved in HT pathogenesis, including genes of immune

of
response and thyroid function. Among the genes that control the immune response, a relevant role is

ro
played by those coded in the Human Leukocyte Antigen (HLA) complex; thus, it has been showed

that the HLA-B* 46:01 gene is associated with the development of HT, as demonstrated in Chinese
-p
children is a case-control and family-based study [29]. In another study of 444 Japanese patients
re
with HT, some genes (HLA-A* 02:07 and HLA-DRB4) were shown to increase the chance of illness
lP

while others favored protection [30].

Current literature established the involvement of many other immunoregulatory genes that control
na

the immune response, in addition to those in the HLA complex. Single nucleotide polymorphisms
ur

(SNPs) regarding the CTLA-4, PTPN22, CD14, CD40 and IL2R genes have been associated to the

development of HT [31]. A meta-analysis by Ji et al regarding a specific polymorphism involving

Jo

A49G in CTLA-4 gene has demonstrated an increased risk of HT for white race subjects and for

Eastern Asia population [32].

Studies have focused on possible polymorphism of the group of genes that encode for the cytokines

involved in HT pathogenesis and progression; however, no significant results have been reported so

far [33, 34]. A major study of 202 Tunisians patients with HT revealed the association with an

IL1RN VNTR polymorphism, [33] while another study of 182 Chinese patients with HT showed the

importance of the rs763780 polymorphism in IL17F[34].

5
 Journal Pre-proof
Studies regarding Graves’ disease (GD) have focused the attention on the lack of regulatory T cells

(Treg) that may induce a thyroid lymphocyte infiltration, associated with hypothyroidism in an

animal model of GD [35, 36]. This observation suggests that Treg cells in humans may determine a

natural progression from the hyperthyroidism of GD to the hypothyroidism of HT [37]. Regulatory

B cells (Breg) also seem to be involved in HT, although their role has not been completely

understood and further studies are needed [38].

Chemokines also play a role in HT and other autoimmune thyroid disorders. In a recent study,

Ferrari et al investigated the modulation of the secretion of chemokines CXCL8 and CXCL10 in

of
cell cultures of thyroid follicular cells in GD, concluding that CXCL10 could be associated with the

ro
initial phase of GD, while CXCL8 could be associated with a later chronic phase of the disease

[39].
-p
Furthermore, selenoproteins (SEP) are important for the thyroid hormone deiodination and
re
selenium deficiency could be considered a predisposing factor as dietary environmental element
lP

[40, 41], as it will be further discussed in the paragraph on environmental triggers. In a study on a

Portuguese population including 481 subjects, HT susceptibility has been associated to a

na

polymorphism in the promoter region of the selenoprotein S gene (SEPS1) [42].

ur

3.2 Environmental triggers

Jo

Environmental factors could play an important role, as demonstrate recent epidemiological changes,

and development of HT may not be only due to an innate predisposition but may be a consequence

of environmental factors that have changed rapidly. Moreover, as demonstrated in homozygous

twins, the disease only clinically accounts in about 50% of the subjects, thus in genetically

predisposed subjects some environmental factors could cause an autoimmune reaction against the

thyroid.

As observed in several autoimmune disorders, the presence of more hygienic environment without

microbial agents may be associated with an high incidence of allergic and autoimmune diseases,

6
 Journal Pre-proof
including HT [43]. Many studies have shown that the excess of iodine in the diet may determine

the onset of HT in predisposed individuals. A study of iodoprophylaxis on volunteers in a region of

Italy with iodine deficiency revealed a doubled occurrence of anti-thyroid antibodies with a

quadrupled incidence of HT during the observation period [44].

Insufficient selenium intake with diet may result in a worsening of HT. Selenium intake in Europe

showed a decrease of 50% in the last 30 years. Nevertheless, the administration of selenium

supplements did not show an improvement in thyroid morphology but only a reduction in levels of

TPO autoantibodies, as demonstrated in recent meta-analysis [45].

of
Another dietary component that could have a role in HT is vitamin D, whose serum levels are

ro
related to exposure to the sun. Although lower serum levels of vitamin D were observed in subject

with HT, these might be related to metabolic changes in hypothyroidism, especially because thyroid
-p
dysfunction is inversely related to the severity of vitamin D levels [46]. A recent study confirmed
re
that it should be taken into account in future research [47].
lP

Novel anticancer regimens such as interferon-α and tyrosine kinase inhibitors have been associated

to thyroid diseases including HT [48].

na

The role of smoking and alcohol in the etiopathogenesis of HT is still controversial and no clear
ur

evidence is available so far, although it seems that a moderate consumption of alcohol may be

protective against HT and other autoimmune diseases [49, 50].

Jo

The observation that Hepatitis C virus may cause a worsening of HT has suggested a possible

mechanism of molecular mimicry between viral and self-antigens. However, so far, all attempts to

find viruses in thyroid patients with HT did not give reliable results. Human Herpesvirus 6 has been

shown to be active in some studies in HT patients and demonstrated a strong tropism for thyroid

follicular cells (TFCs). However, these studies only included a relatively small number of patients

and require further validation [51, 52].

3.3 Epigenetics factors

7
 Journal Pre-proof
Current research has shown that genetic and environmental factors act synergically in determining

HT through modulation of epigenetic factors [53-57]. Epigenetic factors may regulate gene

expression and phenotype, resulting in the onset of disease in absence of DNA structure alterations

[58].

Epigenetic factors involved in the onset of the disease are numerous, although methylation, histone

modifications, and RNA interference through non-coding RNAs are the most frequent [58]. HT is

characterized by lymphocytic infiltration in the thyroid, followed by the infiltration of T and B cells

into the thyroid gland. It has been hypothesized that autoantibodies and B cell dysfunction represent

of
the primary immune reactions in autoimmune thyroid disorders, and aberrant functions of T cell

ro
subsets also play important roles in breaking the immune homeostasis and starting the autoimmune

cascade against thyroid tissues (Figure 1) [55].

-p
The methylation of DNA can determine the inactivation of certain genes, while some histone
re
alterations induce the activation of other genes; however, the action of these epigenetic mechanisms
lP

can be variable and influenced by environmental factors [58, 59]. Moreover, non-coding RNAs

including microRNAs can also control the expression of specific genes [60, 61].
na

Evidence suggests that female preponderance in HT may be due to X chromosome inactivation,

ur

considered a major epigenetic feature in which one X chromosome is silenced [55]. This suggests

that the functioning of the genes can be altered by epigenetic mechanisms and result in the onset of
Jo

autoimmune disorders; therefore, epigenetic factors could play a fundamental role together with

genetic and environmental factors in determining autoimmune diseases [54, 55, 62].

This growing evidence suggests that environmental factors can induce epigenetic modifications

that, in genetically susceptible individuals, may produce autoimmunity thyroid diseases including

HT [63, 64].

4. Pathogenic Mechanisms

8
 Journal Pre-proof
Pathogenesis of HT is strictly related to autoantibodies with a relevant lymphocytic infiltrate,

including of B and T cells in the thyroid tissue [65, 66]. It is believed that one of the first events in

HT pathogenesis is a functional alteration of B cells with formation of autoantibodies. In addition, T

cell dysfunction is associated with the breakdown of immune homeostasis against thyroid tissue

[65, 66]. Therefore, it could be hypothesized that cellular and humoral immunity is associated to the

pathogenesis of HT.

4.1 Cellular immunity

of
In HT patients, CD8+ T cells against thyroglobulin and TPO were found [67]. However, only a

ro
small number (2-3%) of CD8+ cells are specific to TG/TPO, so most of them are not specific to

thyroid antigens. Moreover recent studies established that cell death in autoimmune thyroiditis is
-p
not only due to cytotoxicity but also to apoptosis processes [68].
re
A specific population-specialized CD8+ cells, termed “Suppressor T cells” have been considered
lP

able to inhibit harmful immune responses. It has been hypothesized that in HT there is an alteration

in the function of T cell suppressors against specific antigens of thyroid cells [69]. Some of the
na

functions of T suppressor cells seem to be carried out by the T regulator cells (Treg) [70]. These
ur

cells can attenuate the immune response by direct or indirect contact with the production of

cytokines such as growth factor (TGF)-Beta and Interleukin 10 [70, 71]. Some studies have
Jo

demonstrated an alteration in the number and function of Treg cells in HT [72, 73].

The role of Treg cells has been focused in a recent study [36] that analyzed the rate and the

expressions of Helios and PD-1 in HT patients, exploring the relationship of these with thyroid

function and specific autoantibodies in peripheral blood mononuclear cells of HT patients and

healthy patients. In particular, Helios is considered as an important mediator for Treg cells since it

can upregulate Foxp3 expression. It has been acknowledged that Treg-coexpressing Foxp3 and

Helios phenotype exhibited a superior suppressive abilities than CD4+CD25+ Treg [74]. Moreover,

PD-1 delivers inhibitory signal to prevent immune damage when binding to its ligands PD-L1 [75].

9
 Journal Pre-proof
Helios and PD-1 may also exert vital function in regulating Treg cell peripheral tolerance and

autoimmunity. Interestingly, a recent study based on flow cytometry analysis detected the

percentage of Treg cells was remarkably lower in HT patients with an inverse correlation to thyroid

function when compared with healthy controls. The levels of Treg, aTreg, and Helios-expressing

aTreg cells were all negatively correlated with antithyroid antibodies, confirming that the deficiency

of Treg frequency and aberrant expressions of Helios and PD-1 may possibly contribute to the

immune damage to the thyroid in HT [36, 76] (Figure 2).

of
4.2 Humoral Immunity

ro
The production of specific antibodies to thyroid tissue is one of the most important features of HT.

In the great majority of HT patients, there are specific autoantibodies for TG and TPO [77]. In
-p
addition, the anti-TPO antibody assay is useful in predicting a condition of hypothyroidism [78].
re
Recently, a variant of HT called IG4 thyroiditis has been identified and is part of a systemic
lP

autoimmune disease characterized by the presence of IG4-positive cells [79].

Some studies have found an increase of serum levels of Th1 cells [80, 81] and IL-17 and IL-22
na

cytokines in HT [82]. IL-12 cytokine has been shown to be increased in 56% of patients with HT
ur

[83].

A recent study [84] suggested that circulating exosomes play an active role in the pathogenesis of
Jo

HT. Exosomes have the capability to transfer bioactive molecules into other cells thus affecting

biological activity and are involved in several cellular process as antigen presentation, inflammatory

activation, autoimmune disorders and tumor metastasis (5,6). Specific HT-exosomes might present

antigens to dendritic cells (DC) and bind TLR2/3, causing DC activation via the NFκB signaling

pathway, leading to an imbalance in CD4+ T lymphocyte differentiation and potentially

contributing to HT onset. [85] A similar process has been demonstrated in systemic lupus

erythematosus; however, further studies are required to confirm this hypothesis in patients with HT.

10
 Journal Pre-proof
HT is often associated with other autoimmune disorders, indicating a possible common poly-

autoimmune etiology. In a large prospective study on 3209 patients with GD, Ferrari et al evaluated

the association of this thyroid disorder with other autoimmune conditions. A significant percentage

(16.7%) of GD patients had another associated autoimmune disease such as vitiligo, autoimmune

gastritis, rheumatoid arthritis, polymyalgia rheumatica, multiple sclerosis, and celiac disease. In

some patients, three or more associated autoimmune disorders were diagnosed [86].

5. Histopathology

of
Histopathological characteristics of HT include lymphoplasmacytic infiltration, fibrotic tissue

ro
presence, lymphatic follicular formation, parenchyma atrophy and presence in lymphoid follicles of

large cells with eosinophilic granule in the cytoplasm called Hurtle cells [87]. Hypothyroidism is
-p
due to the destruction of thyroid cells [88].
re
Histopathological features of HT are not unique, although several different variants of HT have
lP

been identified through clinical and histologic features, such as fibrotic and atrophic [89, 90],

Riedel thyroiditis [91, 92] and IG4 thyroiditis [93, 94].

na

In the fibrous variant, thyroid tissue is completely replaced by fibrous tissue. However, fibrosis
ur

never extends beyond the thyroid capsule as is the case for malignant thyroid neoplasms [15].

In the fibrous atrophy variant, the thyroid gland is reduced in volume with large quantities of
Jo

fibrous tissue and atrophy of the thyroid tissue [88, 95]. TSH antibody receptors can be detected in

a small percentage of cases [96].

Riedel’s thyroiditis was so named by the name of its discoverer Bernhard Riedel [92], and was later

considered as a local manifestation of a systemic disease called multifocal fibrosclerosis [91]. The

main histological features are the presence of abundant fibrotic tissue extending beyond the thyroid

capsule in the absence of neoplastic cells [15].

IgG4 thyroiditis has been proposed recently as another variant of HT [94]. This variant is

characterized by high concentrations in thyroid tissue and serum of IG4. Probably, this variant

11
 Journal Pre-proof
represents a local manifestation of a systemic disease called Immunoglobulin G4-related disease

(IG4-RD) [97].

The growing interests on IG4-related disease provided recently a simplified classification [98],

where HT is divided into IgG4-positive and IgG4-negative groups, based on immunohistochemistry

for IgG4 and IgG. Patients in the IgG4-positive group were significantly younger than those in the

IgG4-negative HT group, and displayed a significantly higher degree of fibrosis of thyroid

parenchyma. Immunohistochemical expression score for TGF-b1 was higher in IgG4-positive group

than in IgG4-negative, suggesting that this new classification might have relevant clinical

of
implications for the management of HT [99].

6. Symptomatology
ro
-p
Symptomatology of HT is characterized by local and systemic manifestations. Local symptoms are
re
due to the compression of the anatomical structures of the neck, including dysphonia following the
lP

involvement of the recurrent laryngeal nerve, dyspnea due to compression of the trachea, and

dysphagia consequent to compression of the esophagus.

na

Systemic symptoms are more common and are due to primary hypothyroidism that occurs almost
ur

always in HT and involves most organs and tissues with significant variability [100], although often

preceded by subclinical manifestations [101, 102].

Jo

Non-specific rheumatic manifestations associated with undifferentiated inflammatory arthropathy

have been recently observed in patients with HT [103, 104].

Several clinical variants of HT have been described, and include painless thyroiditis, painful

thyroiditis, postpartum thyroiditis, and Hashimoto’s encephalopathy.

Painless thyroiditis is so named because the patient does not feel any pain in the neck and its main

feature is represented by a transient phase of hypothyroidism that return to euthyroidism [105].

12
 Journal Pre-proof
Painful Thyroiditis is so called because of the progressive, acute and intolerable pain in one lobe or

the whole thyroid. It is a rare variant of HT that mostly affect women with a sex ratio of 10 to 11:1

[106].

Postpartum thyroiditis is so called because it manifests six months after delivery and is clinically

identical to the painless thyroiditis. The favorable course of these two clinical forms is probably due

to transient autoimmune disorders [105].

Hashimoto’s encephalopathy is one of the most relevant clinical variants of HT [107] due to its

association with encephalopathy as first described by Brain in 1966 [108]. Later, many other

of
clinical cases were identified [109]. The most frequent symptoms include subacute cognitive

ro
deterioration, myoclonus, change in behavior, and seizures [110]. Clinically, this condition

responds well to corticosteroid therapy, and seems to be supported by alpha enolase autoantigens
-p
[107, 111-114]. The search for anti-alpha enolase antibodies is useful for the diagnosis and
re
treatment of Hashimoto's encephalopathy but does not allow a connection between thyroid and
lP

encephalic disease [115].

na

7. Diagnosis
ur

The diagnosis of HT is based on clinical symptoms, anti-thyroid antibodies and histological

features.
Jo

Serum anti-TPO antibodies are considered the most important feature of HT and are present in

about 95% of patients [100]. Instead, anti-thyroglobulin antibodies are present in a lower (60-80%)

percentage of cases and therefore are less reliable for diagnosis [116]. It appears that anti-

thyroglobulin antibodies may be the expression of an initial immune response, whereas anti-TPO

antibodies may be the result of a later immune response as if there was an immune escalation [117].

Cytological examination is not routinely performed, but only when a thyroid nodule is present with

a suspicion of malignant transformation. Moreover, HT ultrasonographic characteristics could make

difficult the nodule identification and aspiration, although not associated with non-diagnostic and

13
 Journal Pre-proof
indeterminate cytological rates [118]. The presence of lymphocytes in contact with thyroid cells is

considered the most important element to make a differential diagnosis between HT and thyroid

tumors [119] (Figure 3).

Radiologic evaluation of HT includes mainly sonographic examination, where specific features are

considered a decreased echogenicity, heterogeneity hypervascularity and presence of hypoechoic

micronodules with echogenic rim [120].

8. Treatment

of
The main purpose of HT treatment is the control of hypothyroidism and consists of oral

ro
administration of a synthetic hormone, the Levo-Thyroxine 4 (L-T4) [121], at a dosage of 1.6-1.8

micrograms per kilo. The substitution therapy must be prolonged for a lifetime to achieve normal
-p
circulating thyrotropin (TSH) levels. In selected cases, L-T4 treatment may be not required and
re
only clinical observation is needed.
lP

The role of glucocorticoids been questioned, as they may regulate the thyroiditis and acutely

improve thyroid function, although the risks associated with the high dose and long treatment are
na

considered to outweigh the benefit [122]. However, a short-term use of prednisolone may have a
ur

longer-term benefit in IgG4-disease subgroup [123].

The additional role of a specific diet for the management of HT has been questioned in recent years
Jo

[124]. It has been postulated that an excessive iodine intake induces thyroid autoimmunity by

increasing the immunogenicity of thyroglobulin in genetically predisposed subjects [125]. Thus,

an high iodine supplementation in HT should be discouraged, as possibly dangerous, although an

appropriate supplementation should be proposed in pregnancy to a total intake of 250g/day [122].

Selenium plays a key role in human thyroid hormone homeostasis, as several selenoproteins are

involved in thyroid function, although efficacy of selenium supplementation in HT patients is

debated [126]. Oral administration of selenium in the form of seleno-methionine would be

beneficial in HT patients with selenium deficiency and should protect the thyroid gland from the

14
 Journal Pre-proof
autoimmune reaction [127]. However, the literature is discordant [128]. A systematic review and

meta-analysis by Wichman et al [129] showed a reduction of serum TPO-Ab levels and serum Tg-

Ab; however, no significant correlation between the baseline selenium levels and the decrease in

serum TPO-Ab level was demonstrated. A more recent systematic review and meta-analysis

regarding the efficacy of oral administration of selenium revealed no effect of selenium

supplementation on TSH levels, health-related quality of life [130] or thyroid ultrasound, in

levothyroxine substitution-untreated individuals, and sporadic evaluation of clinically relevant

outcomes in levothyroxine substitution-treated patients [131].

of
The association between vitamin D deficiency, HT pathogenesis and thyroid hypofunction has been

ro
demonstrated in several studies [126, 132, 133]. Since the low cost and the minimal side-effect of

oral vitamin D supplementation, screening for vitamin D deficiency and supplementation may be
-p
recommended for patients with HT, with monthly monitoring of calcium and 25[OH]D levels, when
re
clinically required [126].
lP

The role of surgery for HT is limited for cases with a compression of cervical anatomical structures

or in the presence of a nodule with malignant transformation characteristics [13, 134]. However,
na

thyroidectomy performed in HT patients is burdened with a greater number of complications

ur

compared to other thyroid disorders [135]. As a future perspective, thyroid gland transplantation has

also been proposed to correct hypothyroidism but needs to be validated by further studies [136].
Jo

9. Malignant transformation

Occurrence of HT is frequently found in thyroid glands resected for a neoplastic process. The

association of HT and papillary thyroid cancer (PTC), firstly reported by Dailey in 1955 [137], has

been widely debated. Controversy exists whether HT predisposes patients to the development of

PTC, since this association may be considered a chance occurrence of two relatively common

diseases or may be indicative of a cause and effect relationship, or at least a predisposing factor.

This relationship has been postulated since chronic inflammation may lead to the development of a

15
 Journal Pre-proof
neoplastic transformation, as demonstrated for other tissues. Moreover, the prolonged elevated

levels of TSH in HT patients may stimulate follicular epithelial proliferation, thereby promoting the

development of PTC [138-140] (Figure 4).

Several studies have investigated this association; however, results are dissimilar among studies.

Interestingly, ambiguous data regarding this association may be due to a potential selection bias, as

the majority of the publications in the past decades were retrospective analyses of patients

undergoing thyroidectomy[138]. In the last years, the relationship between HT and PTC has been

achieved by fine-needle aspiration cytology (FNAC) data, that are more representative of a typical

of
population of patients with HT [138]. Data obtained from FNAC showed that the average

ro
prevalence of PTC in patients with HT was 1.20%, with an average risk ratio of 0.69, compared

with the studies based on thyroidectomy data, where the average prevalence was about 27 % and
-p
risk ratio was and 1.59 [138, 141]. These data confirmed a higher risk reported in studies of
re
thyroidectomy specimens, compared to studies of patients undergoing FNAC. Studies regarding
lP

FNAC show no significant increase of PTC in patients with HT, although FNAC specimens may be

limited by a lack of definitive histological pathology. To date, evidence favoring a causal

na

relationship between HT and PTC is inconsistent, and a validated criterion to identify HT patients at
ur

a higher risk of developing PTC is required, although a causative relationship between HT and PTC

could not be excluded.

Jo

Despite PTC, occurrence of Non-Hodgkin primary thyroid lymphoma has been strongly associated

with HT, as considered the only recognized risk factor, with a risk of about 60 times higher in

patients HT[90]. Thyroid lymphoma accounts approximately 5% of all thyroid neoplasms, with a

female predominance and histologically are mainly characterized by B cell phenotype, although a

T-cell phenotype may also occur [90].

10. Conclusions

16
 Journal Pre-proof
Although many genetic and environmental factors that could trigger an autoimmune response have

been identified, the exact pathogenic mechanisms of HT are still unknown. Recently, the

significance of epigenetic factors in HT etiopathogenesis has been highlighted, but further studies

are necessary to accurately understand their role. The treatment of HT, which currently focuses on

clinical symptoms of the disease, should in the future act on the autoimmune mechanism that causes

the destruction of the thyroid parenchyma and the consequent hypothyroidism. A better

understanding of epigenetic modifications and autoimmune pathogenic mechanisms could

contribute to a more accurate diagnosis of HT, a more adequate choice of treatment approach, and a

of
more precise prediction of treatment outcomes.

ro
Conflict of Interest of all authors

the authors report no conflict of interest

-p
Funding source
re
the authors report no funding sources for this article
lP
na
ur
Jo

17
 Journal Pre-proof

References
[1] A. Antonelli, S.M. Ferrari, A. Corrado, A. Di Domenicantonio and P. Fallahi, Autoimmune thyroid
disorders, Autoimmun Rev 14 (2015) 174-80.
[2] G.P. Leese, R.V. Flynn, R.T. Jung, T.M. Macdonald, M.J. Murphy and A.D. Morris, Increasing
prevalence and incidence of thyroid disease in Tayside, Scotland: the Thyroid Epidemiology Audit
and Research Study (TEARS), Clin Endocrinol (Oxf) 68 (2008) 311-6.
[3] D.S. McLeod and D.S. Cooper, The incidence and prevalence of thyroid autoimmunity, Endocrine 42
(2012) 252-65.
[4] S. De Leo, S.Y. Lee and L.E. Braverman, Hyperthyroidism, Lancet 388 (2016) 906-918.
[5] W.H. Chen, Y.K. Chen, C.L. Lin, J.H. Yeh and C.H. Kao, Hashimoto's thyroiditis, risk of coronary heart
disease, and L-thyroxine treatment: a nationwide cohort study, J Clin Endocrinol Metab 100 (2015)
109-14.
[6] Y.K. Chen, C.L. Lin, F.T. Cheng, F.C. Sung and C.H. Kao, Cancer risk in patients with Hashimoto's
thyroiditis: a nationwide cohort study, Br J Cancer 109 (2013) 2496-501.

of
[7] H. H, Zur Kenntniss der lymphomatösen Veränderung der Schilddrüse (Struma lymphomatosa). ,
Arch Klin Chir. (1912) 219-48.
[8] G. A., Riedel’s struma in contrast to struma lymphomatosa (Hashimoto). , West J Surg. 39 (1931)

ro
681-9.
[9] W.E. Rose NR, Studies on organ specificity. V. Changes in the thyroid glands of rabbits following
-p
active immunization with rabbit thyroid extracts. , J Immunol. 76 (1956;) 417-27.
[10] R.N. Witebsky E, Paine JR, Egan RW, Thyroid-specific autoantibodies. , Ann N Y Acad Sci. 69 (1957)
669-77.
re
[11] I.M. Roitt, D. Doniach, P.N. Campbell and R.V. Hudson, Auto-antibodies in Hashimoto's disease
(lymphadenoid goitre), Lancet 271 (1956) 820-1.
lP

[12] J. Ott, M. Meusel, A. Schultheis, R. Promberger, S.J. Pallikunnel, N. Neuhold and M. Hermann, The
incidence of lymphocytic thyroid infiltration and Hashimoto's thyroiditis increased in patients
operated for benign goiter over a 31-year period, Virchows Arch 459 (2011) 277-81.
[13] P. Caturegli, A. De Remigis, K. Chuang, M. Dembele, A. Iwama and S. Iwama, Hashimoto's
na

thyroiditis: celebrating the centennial through the lens of the Johns Hopkins hospital surgical
pathology records, Thyroid 23 (2013) 142-50.
[14] W.M. Tunbridge, M. Brewis, J.M. French, D. Appleton, T. Bird, F. Clark, D.C. Evered, J.G. Evans, R.
ur

Hall, P. Smith, J. Stephenson and E. Young, Natural history of autoimmune thyroiditis, Br Med J (Clin
Res Ed) 282 (1981) 258-62.
[15] Y. Hiromatsu, H. Satoh and N. Amino, Hashimoto's thyroiditis: history and future outlook,
Jo

Hormones (Athens) 12 (2013) 12-8.

[16] D.S. McLeod, P. Caturegli, D.S. Cooper, P.G. Matos and S. Hutfless, Variation in rates of
autoimmune thyroid disease by race/ethnicity in US military personnel, JAMA 311 (2014) 1563-5.
[17] T.P. Lee and B.L. Chiang, Sex differences in spontaneous versus induced animal models of
autoimmunity, Autoimmun Rev 11 (2012) A422-9.
[18] A. Shetty and V. Chowdappa, Cytomorphological Spectrum of Hashimoto's Thyroiditis and Its
Correlation with Hormonal Profile and Hematological Parameters, J Cytol 36 (2019) 137-141.
[19] T.H. Brix, P.S. Hansen, K.O. Kyvik and L. Hegedus, Aggregation of thyroid autoantibodies in twins
from opposite-sex pairs suggests that microchimerism may play a role in the early stages of thyroid
autoimmunity, J Clin Endocrinol Metab 94 (2009) 4439-43.
[20] M.J. Simmonds, F.K. Kavvoura, O.J. Brand, P.R. Newby, L.E. Jackson, C.E. Hargreaves, J.A. Franklyn
and S.C. Gough, Skewed X chromosome inactivation and female preponderance in autoimmune
thyroid disease: an association study and meta-analysis, J Clin Endocrinol Metab 99 (2014) E127-31.
[21] K.T. Jorgensen, B.V. Pedersen, N.M. Nielsen, S. Jacobsen and M. Frisch, Childbirths and risk of
female predominant and other autoimmune diseases in a population-based Danish cohort, J
Autoimmun 38 (2012) J81-7.

18
 Journal Pre-proof
[22] A.P. Weetman, The immunopathogenesis of chronic autoimmune thyroiditis one century after
hashimoto, Eur Thyroid J 1 (2013) 243-50.
[23] R.H. Song, Q.M. Yao, B. Wang, Q. Li, X. Jia and J.A. Zhang, Thyroid disorders in patients with
myasthenia gravis: A systematic review and meta-analysis, Autoimmun Rev 18 (2019) 102368.
[24] Q. Yao, Z. Song, B. Wang, J.A. Zhang and K. Mu, Thyroid disorders in patients with systemic
sclerosis: A systematic review and meta-analysis, Autoimmun Rev 18 (2019) 634-636.
[25] I. Lazurova and K. Benhatchi, Autoimmune thyroid diseases and nonorganspecific autoimmunity,
Pol Arch Med Wewn 122 Suppl 1 (2012) 55-9.
[26] A. Hasham and Y. Tomer, Genetic and epigenetic mechanisms in thyroid autoimmunity, Immunol
Res 54 (2012) 204-13.
[27] D. Kust and N. Matesa, The impact of familial predisposition on the development of Hashimoto's
thyroiditis, Acta Clin Belg (2018) 1-5.
[28] T.H. Brix, K.O. Kyvik and L. Hegedus, A population-based study of chronic autoimmune
hypothyroidism in Danish twins, J Clin Endocrinol Metab 85 (2000) 536-9.
[29] C.Y. Huang, T.Y. Chang, C.C. Chu, F.S. Lo, W.H. Ting, C.H. Lin, Y.L. Wu, S.Y. Chu, S.C. Chang, W.F.
Chen, C.L. Lin, W.S. Lin and Y.J. Lee, The HLA-B gene and Hashimoto disease in Han Chinese

of
children: a case-control and family-based study, Tissue Antigens 80 (2012) 431-6.
[30] S. Ueda, D. Oryoji, K. Yamamoto, J.Y. Noh, K. Okamura, M. Noda, K. Kashiwase, Y. Kosuga, K. Sekiya,
K. Inoue, H. Yamada, A. Oyamada, Y. Nishimura, Y. Yoshikai, K. Ito and T. Sasazuki, Identification of

ro
independent susceptible and protective HLA alleles in Japanese autoimmune thyroid disease and
their epistasis, J Clin Endocrinol Metab 99 (2014) E379-83.
-p
[31] X. Jia, B. Wang, Q. Yao, Q. Li and J. Zhang, Variations in CD14 Gene Are Associated With
Autoimmune Thyroid Diseases in the Chinese Population, Front Endocrinol (Lausanne) 9 (2018)
811.
re
[32] R. Ji, Y. Feng and W.W. Zhan, Updated analysis of studies on the cytotoxic T-lymphocyte-associated
antigen-4 gene A49G polymorphism and Hashimoto's thyroiditis risk, Genet Mol Res 12 (2013)
lP

1421-30.
[33] I. Zaaber, S. Mestiri, H. Marmouch, S. Mahjoub, N. Abid, M. Hassine, B. Bel Hadj Jrad-Tensaout and
K. Said, Polymorphisms in TSHR and IL1RN genes and the risk and prognosis of Hashimoto's
thyroiditis, Autoimmunity 47 (2014) 113-8.
na

[34] N. Yan, Y.L. Yu, J. Yang, Q. Qin, Y.F. Zhu, X. Wang, R.H. Song and J.A. Zhang, Association of
interleukin-17A and -17F gene single-nucleotide polymorphisms with autoimmune thyroid
diseases, Autoimmunity 45 (2012) 533-9.
ur

[35] O. Saitoh and Y. Nagayama, Regulation of Graves' hyperthyroidism with naturally occurring
CD4+CD25+ regulatory T cells in a mouse model, Endocrinology 147 (2006) 2417-22.
[36] Y. Hu, L. Zhang, H. Chen, X. Liu, X. Zheng, H. Shi, L. Jiang and D. Cui, Analysis of Regulatory T Cell
Jo

Subsets and Their Expression of Helios and PD-1 in Patients with Hashimoto Thyroiditis, Int J
Endocrinol 2019 (2019) 5368473.
[37] B. Gonzalez-Aguilera, D. Betea, L. Lutteri, E. Cavalier, V. Geenen, A. Beckers and H. Valdes-Socin,
Conversion to Graves disease from Hashimoto thyroiditis: a study of 24 patients, Arch Endocrinol
Metab 62 (2018) 609-614.
[38] M.G. Santaguida, I. Gatto, G. Mangino, C. Virili, I. Stramazzo, P. Fallahi, A. Antonelli, M. Segni, G.
Romeo and M. Centanni, BREG cells in Hashimoto's thyroiditis isolated or associated to further
organ-specific autoimmune diseases, Clin Immunol 184 (2017) 42-47.
[39] S.M. Ferrari, F. Ragusa, S.R. Paparo, F. Nasini, M. Nardi, S.S. Franceschini, P. Fallahi and A. Antonelli,
Differential modulation of CXCL8 versus CXCL10, by cytokines, PPAR-gamma, or PPAR-alpha
agonists, in primary cells from Graves' disease and ophthalmopathy, Autoimmun Rev 18 (2019)
673-678.
[40] I. Pirola, M. Rotondi, A. Cristiano, F. Maffezzoni, D. Pasquali, F. Marini, F. Coperchini, M. Paganelli,
P. Apostoli, L. Chiovato, A. Ferlin and C. Cappelli, Selenium supplementation in patients with
subclinical hypothyroidism affected by autoimmune thyroiditis: Results of the SETI study,
Endocrinol Diabetes Nutr (2019).

19
 Journal Pre-proof
[41] R. Krysiak, K. Kowalcze and B. Okopien, Selenomethionine potentiates the impact of vitamin D on
thyroid autoimmunity in euthyroid women with Hashimoto's thyroiditis and low vitamin D status,
Pharmacol Rep 71 (2019) 367-373.
[42] L.R. Santos, C. Duraes, A. Mendes, H. Prazeres, M.I. Alvelos, C.S. Moreira, P. Canedo, C. Esteves, C.
Neves, D. Carvalho, M. Sobrinho-Simoes and P. Soares, A polymorphism in the promoter region of
the selenoprotein S gene (SEPS1) contributes to Hashimoto's thyroiditis susceptibility, J Clin
Endocrinol Metab 99 (2014) E719-23.
[43] W.M. Wiersinga, Clinical Relevance of Environmental Factors in the Pathogenesis of Autoimmune
Thyroid Disease, Endocrinol Metab (Seoul) 31 (2016) 213-22.
[44] F. Aghini Lombardi, E. Fiore, M. Tonacchera, L. Antonangeli, T. Rago, M. Frigeri, A.M. Provenzale, L.
Montanelli, L. Grasso, A. Pinchera and P. Vitti, The effect of voluntary iodine prophylaxis in a small
rural community: the Pescopagano survey 15 years later, J Clin Endocrinol Metab 98 (2013) 1031-9.
[45] K.A. Toulis, A.D. Anastasilakis, T.G. Tzellos, D.G. Goulis and D. Kouvelas, Selenium supplementation
in the treatment of Hashimoto's thyroiditis: a systematic review and a meta-analysis, Thyroid 20
(2010) 1163-73.
[46] G. Tamer, S. Arik, I. Tamer and D. Coksert, Relative vitamin D insufficiency in Hashimoto's

of
thyroiditis, Thyroid 21 (2011) 891-6.
[47] P.V. Anaraki, A. Aminorroaya, M. Amini, A. Feizi, B. Iraj and A. Tabatabaei, Effects of Vitamin D
deficiency treatment on metabolic markers in Hashimoto thyroiditis patients, J Res Med Sci 22

ro
(2017) 5.
[48] F. Torino, A. Barnabei, R. Paragliola, R. Baldelli, M. Appetecchia and S.M. Corsello, Thyroid
-p
dysfunction as an unintended side effect of anticancer drugs, Thyroid 23 (2013) 1345-66.
[49] A. Carle, I.B. Pedersen, N. Knudsen, H. Perrild, L. Ovesen, L.B. Rasmussen, T. Jorgensen and P.
Laurberg, Moderate alcohol consumption may protect against overt autoimmune hypothyroidism:
re
a population-based case-control study, Eur J Endocrinol 167 (2012) 483-90.
[50] G. Effraimidis, J.G. Tijssen and W.M. Wiersinga, Alcohol consumption as a risk factor for
lP

autoimmune thyroid disease: a prospective study, Eur Thyroid J 1 (2012) 99-104.

[51] E. Caselli, M.C. Zatelli, R. Rizzo, S. Benedetti, D. Martorelli, G. Trasforini, E. Cassai, E.C. degli Uberti,
D. Di Luca and R. Dolcetti, Virologic and immunologic evidence supporting an association between
HHV-6 and Hashimoto's thyroiditis, PLoS Pathog 8 (2012) e1002951.
na

[52] S.J.R. Therese Weider, Noel G Morgan, Trond H Paulsen, Knut Dahl-Jørgensen, Sara Salehi
Hammerstad Upregulation of HLA class I and Antiviral Tissue Responses in Hashimoto’s Thyroiditis,
(2019) 30 (3), 432-442 Mar 2020.
ur

[53] C.J. Marsit, Influence of environmental exposure on human epigenetic regulation, J Exp Biol 218
(2015) 71-9.
[54] C.A. Canas, F. Canas, F. Bonilla-Abadia, F.E. Ospina and G.J. Tobon, Epigenetics changes associated
Jo

to environmental triggers in autoimmunity, Autoimmunity 49 (2016) 1-11.

[55] B. Wang, X. Shao, R. Song, D. Xu and J.A. Zhang, The Emerging Role of Epigenetics in Autoimmune
Thyroid Diseases, Front Immunol 8 (2017) 396.
[56] R. Mazzone, C. Zwergel, M. Artico, S. Taurone, M. Ralli, A. Greco and A. Mai, The emerging role of
epigenetics in human autoimmune disorders, Clin Epigenetics 11 (2019) 34.
[57] M. Ralli, A. De Virgilio, M. Artico, L. Longo, M. de Vincentiis and A. Greco, New insights into the
etiopathogenesis of Hashimoto's Thyroiditis: The role of genetics and epigenetics, Autoimmun Rev
17 (2018) 1065-1066.
[58] R. Feil and M.F. Fraga, Epigenetics and the environment: emerging patterns and implications, Nat
Rev Genet 13 (2012) 97-109.
[59] S. Dik, P.T. Scheepers and L. Godderis, Effects of environmental stressors on histone modifications
and their relevance to carcinogenesis: a systematic review, Crit Rev Toxicol 42 (2012) 491-500.
[60] M. Turner, A. Galloway and E. Vigorito, Noncoding RNA and its associated proteins as regulatory
elements of the immune system, Nat Immunol 15 (2014) 484-91.
[61] V. Ranzani, G. Rossetti, I. Panzeri, A. Arrigoni, R.J. Bonnal, S. Curti, P. Gruarin, E. Provasi, E. Sugliano,
M. Marconi, R. De Francesco, J. Geginat, B. Bodega, S. Abrignani and M. Pagani, The long intergenic

20
 Journal Pre-proof
noncoding RNA landscape of human lymphocytes highlights the regulation of T cell differentiation
by linc-MAF-4, Nat Immunol 16 (2015) 318-325.
[62] A. Hewagama and B. Richardson, The genetics and epigenetics of autoimmune diseases, J
Autoimmun 33 (2009) 3-11.
[63] Y. Tomer, Mechanisms of autoimmune thyroid diseases: from genetics to epigenetics, Annu Rev
Pathol 9 (2014) 147-56.
[64] M. Limbach, M. Saare, L. Tserel, K. Kisand, T. Eglit, S. Sauer, T. Axelsson, A.C. Syvanen, A. Metspalu,
L. Milani and P. Peterson, Epigenetic profiling in CD4+ and CD8+ T cells from Graves' disease
patients reveals changes in genes associated with T cell receptor signaling, J Autoimmun 67 (2016)
46-56.
[65] S.M. McLachlan and B. Rapoport, Breaking tolerance to thyroid antigens: changing concepts in
thyroid autoimmunity, Endocr Rev 35 (2014) 59-105.
[66] T.J. Smith and L. Hegedus, Graves' Disease, N Engl J Med 375 (2016) 1552-1565.
[67] M. Ehlers, A. Thiel, C. Bernecker, D. Porwol, C. Papewalis, H.S. Willenberg, S. Schinner, H. Hautzel,
W.A. Scherbaum and M. Schott, Evidence of a combined cytotoxic thyroglobulin and
thyroperoxidase epitope-specific cellular immunity in Hashimoto's thyroiditis, J Clin Endocrinol

of
Metab 97 (2012) 1347-54.
[68] T. Kotani, Y. Aratake, K. Hirai, Y. Fukazawa, H. Sato and S. Ohtaki, Apoptosis in thyroid tissue from
patients with Hashimoto's thyroiditis, Autoimmunity 20 (1995) 231-6.

ro
[69] J. Cardenas Roldan, J. Amaya-Amaya, J. Castellanos-de la Hoz, J. Giraldo-Villamil, G. Montoya-Ortiz,
P. Cruz-Tapias, A. Rojas-Villarraga, R.D. Mantilla and J.M. Anaya, Autoimmune thyroid disease in
-p
rheumatoid arthritis: a global perspective, Arthritis 2012 (2012) 864907.
[70] T.T. MacDonald, Suppressor T cells, rebranded as regulatory T cells, emerge from the wilderness
bearing surface markers, Gut 51 (2002) 311-2.
re
[71] E.M. Shevach, Suppressor T cells: Rebirth, function and homeostasis, Curr Biol 10 (2000) R572-5.
[72] D. Pan, Y.H. Shin, G. Gopalakrishnan, J. Hennessey and L.J. De Groot, Regulatory T cells in Graves'
lP

disease, Clin Endocrinol (Oxf) 71 (2009) 587-93.

[73] C. Mao, S. Wang, Y. Xiao, J. Xu, Q. Jiang, M. Jin, X. Jiang, H. Guo, G. Ning and Y. Zhang, Impairment
of regulatory capacity of CD4+CD25+ regulatory T cells mediated by dendritic cell polarization and
hyperthyroidism in Graves' disease, J Immunol 186 (2011) 4734-43.
na

[74] R.A. Gottschalk, E. Corse and J.P. Allison, Expression of Helios in peripherally induced Foxp3+
regulatory T cells, J Immunol 188 (2012) 976-80.
[75] S. Dai, R. Jia, X. Zhang, Q. Fang and L. Huang, The PD-1/PD-Ls pathway and autoimmune diseases,
ur

Cell Immunol 290 (2014) 72-9.

[76] G. Stassi and R. De Maria, Autoimmune thyroid disease: new models of cell death in autoimmunity,
Nat Rev Immunol 2 (2002) 195-204.
Jo

[77] A.P. Weetman, Cellular immune responses in autoimmune thyroid disease, Clin Endocrinol (Oxf) 61
(2004) 405-13.
[78] J.P. Walsh, A.P. Bremner, P. Feddema, P.J. Leedman, S.J. Brown and P. O'Leary, Thyrotropin and
thyroid antibodies as predictors of hypothyroidism: a 13-year, longitudinal study of a community-
based cohort using current immunoassay techniques, J Clin Endocrinol Metab 95 (2010) 1095-104.
[79] H. Hamano, S. Kawa, A. Horiuchi, H. Unno, N. Furuya, T. Akamatsu, M. Fukushima, T. Nikaido, K.
Nakayama, N. Usuda and K. Kiyosawa, High serum IgG4 concentrations in patients with sclerosing
pancreatitis, N Engl J Med 344 (2001) 732-8.
[80] R.A. Ajjan and A.P. Weetman, Cytokines in thyroid autoimmunity, Autoimmunity 36 (2003) 351-9.
[81] S. Trifari, C.D. Kaplan, E.H. Tran, N.K. Crellin and H. Spits, Identification of a human helper T cell
population that has abundant production of interleukin 22 and is distinct from T(H)-17, T(H)1 and
T(H)2 cells, Nat Immunol 10 (2009) 864-71.
[82] N. Figueroa-Vega, M. Alfonso-Perez, I. Benedicto, F. Sanchez-Madrid, R. Gonzalez-Amaro and M.
Marazuela, Increased circulating pro-inflammatory cytokines and Th17 lymphocytes in Hashimoto's
thyroiditis, J Clin Endocrinol Metab 95 (2010) 953-62.

21
 Journal Pre-proof
[83] R.M. Ruggeri, S. Saitta, M. Cristani, S. Giovinazzo, V. Tigano, F. Trimarchi, S. Benvenga and S.
Gangemi, Serum interleukin-23 (IL-23) is increased in Hashimoto's thyroiditis, Endocr J 61 (2014)
359-63.
[84] X. Cui, Y. Liu, S. Wang, N. Zhao, J. Qin, Y. Li, C. Fan, Z. Shan and W. Teng, Circulating exosomes
activate dendritic cells and induce unbalanced CD4+ T cell differentiation in Hashimoto thyroiditis, J
Clin Endocrinol Metab (2019).
[85] P.F. Francesca Ragusa, Giusy Elia, Debora Gonnella, Sabrina Rosaria Paparo, Claudia Giusti, Leonid
P. Churilov, Silvia Martina Ferrari, Alessandro Antonelli,, Hashimotos’ thyroiditis: Epidemiology,
pathogenesis, clinic and therapy, Best Practice & Research Clinical Endocrinology & Metabolism
(2019) 13 (6), 612-632 Aug 2018.
[86] S.M. Ferrari, P. Fallahi, I. Ruffilli, G. Elia, F. Ragusa, S. Benvenga and A. Antonelli, The association of
other autoimmune diseases in patients with Graves' disease (with or without ophthalmopathy):
Review of the literature and report of a large series, Autoimmun Rev 18 (2019) 287-292.
[87] T. Akamizu and N. Amino, Hashimoto's Thyroiditis, in: K.R. Feingold, B. Anawalt, A. Boyce, G.
Chrousos, K. Dungan, A. Grossman, J.M. Hershman, G. Kaltsas, C. Koch, P. Kopp, M. Korbonits, R.
McLachlan, J.E. Morley, M. New, L. Perreault, J. Purnell, R. Rebar, F. Singer, D.L. Trence, A. Vinik and

of
D.P. Wilson (Eds.), Endotext, South Dartmouth (MA), 2000.
[88] C. Giordano, G. Stassi, R. De Maria, M. Todaro, P. Richiusa, G. Papoff, G. Ruberti, M. Bagnasco, R.
Testi and A. Galluzzo, Potential involvement of Fas and its ligand in the pathogenesis of

ro
Hashimoto's thyroiditis, Science 275 (1997) 960-3.
[89] S.M. Katz and A.L. Vickery, Jr., The fibrous variant of Hashimoto's thyroiditis, Hum Pathol 5 (1974)
-p
161-70.
[90] R. Ahmed, S. Al-Shaikh and M. Akhtar, Hashimoto thyroiditis: a century later, Adv Anat Pathol 19
(2012) 181-6.
re
[91] J.V. Hennessey, Clinical review: Riedel's thyroiditis: a clinical review, J Clin Endocrinol Metab 96
(2011) 3031-41.
lP

[92] R. BM, Die chronische zur Bildung eisenharter Tumoren führende Entzündung der Schilddruese. ,
Verh Ges Chir. 25 (1896) 101-5.
[93] I.D. Hay, Thyroiditis: a clinical update, Mayo Clin Proc 60 (1985) 836-43.
[94] J.H. Stone, A. Khosroshahi, V. Deshpande, J.K. Chan, J.G. Heathcote, R. Aalberse, A. Azumi, D.B.
na

Bloch, W.R. Brugge, M.N. Carruthers, W. Cheuk, L. Cornell, C.F. Castillo, J.A. Ferry, D. Forcione, G.
Kloppel, D.L. Hamilos, T. Kamisawa, S. Kasashima, S. Kawa, M. Kawano, Y. Masaki, K. Notohara, K.
Okazaki, J.K. Ryu, T. Saeki, D. Sahani, Y. Sato, T. Smyrk, J.R. Stone, M. Takahira, H. Umehara, G.
ur

Webster, M. Yamamoto, E. Yi, T. Yoshino, G. Zamboni, Y. Zen and S. Chari, Recommendations for
the nomenclature of IgG4-related disease and its individual organ system manifestations, Arthritis
Rheum 64 (2012) 3061-7.
Jo

[95] K. Zaletel and S. Gaberscek, Hashimoto's Thyroiditis: From Genes to the Disease, Curr Genomics 12
(2011) 576-88.
[96] H. Tamaki, N. Amino, M. Kimura, Y. Hidaka, K. Takeoka and K. Miyai, Low prevalence of thyrotropin
receptor antibody in primary hypothyroidism in Japan, J Clin Endocrinol Metab 71 (1990) 1382-6.
[97] K. Kakudo, Y. Li, E. Taniguchi, I. Mori, T. Ozaki, E. Nishihara, F. Matsuzuka and A. Miyauchi, IgG4-
related disease of the thyroid glands, Endocr J 59 (2012) 273-81.
[98] J. Zhang, L. Zhao, Y. Gao, M. Liu, T. Li, Y. Huang, G. Lu, Y. Gao, X. Guo and B. Shi, A classification of
Hashimoto's thyroiditis based on immunohistochemistry for IgG4 and IgG, Thyroid 24 (2014) 364-
70.
[99] X.W. Yaqiong Li, Zhiyan Liu , Jiwei Ma, Xiaoyan and Y.Q. Lin , Eijun Nishihara , Akira Miyauchi ,
Kennichi Kakudo Hashimoto’s Thyroiditis with Increased IgG4‐positive Plasma Cells: Using Thyroid‐
specific Diagnostic Criteria May Identify Early‐Phase IgG4 Thyroiditis, (2019) 30 (2), 251-261 Feb
2020.
[100] P. Caturegli, A. De Remigis and N.R. Rose, Hashimoto thyroiditis: clinical and diagnostic criteria,
Autoimmun Rev 13 (2014) 391-7.
[101] B. Biondi, A.R. Cappola and D.S. Cooper, Subclinical Hypothyroidism: A Review, JAMA 322 (2019)
153-160.

22
 Journal Pre-proof
[102] E.H. Livingston, Subclinical Hypothyroidism, JAMA 322 (2019) 180.
[103] E.G.-C. Luis M Valderrama-Hinds, Evelyn Hernández, María I Agostini, Omar R Reyes-Morales,
Liliana Fung, Soham Al Snih, Martin A Rodríguez, Prevalence of undifferentiated inflammatory
arthropathy in patients with Hashimoto's thyroiditis in an endocrinology clinic, (2019) 22 (11),
1985-1989 Nov 2019.
[104] G.B. G Giuffrida, A Campennì, S Giovinazzo, K P Keller, A Alibrandi, W N Roberts, F Trimarchi, R M
Ruggeri, Non‑specific rheumatic manifestations in patients with Hashimoto’s thyroiditis: a pilot
cross‑sectional study, J Endocrinol Invest (2020) 43 (1), 87-94 Jan 2020.
[105] N. Amino, H. Tada and Y. Hidaka, Postpartum autoimmune thyroid syndrome: a model of
aggravation of autoimmune disease, Thyroid 9 (1999) 705-13.
[106] R.H.-E.C. Carol Chiung-Hui Peng, Majorie Pennant, Huei-Kai Huang, and a.K.M. Munir, A Literature
Review of Painful Hashimoto Thyroiditis: 70 Published Cases in the Past 70 Years, Endocr Soc
(2019) 4 (2), bvz008.
[107] I. Pinedo-Torres and J.L. Paz-Ibarra, Current knowledge on Hashimoto's encephalopathy: a
literature review, Medwave 18 (2018) e7298.
[108] L. Brain, E.H. Jellinek and K. Ball, Hashimoto's disease and encephalopathy, Lancet 2 (1966) 512-4.

of
[109] N. Schiess and C.A. Pardo, Hashimoto's encephalopathy, Ann N Y Acad Sci 1142 (2008) 254-65.
[110] L.S. Simone Mattozzi, Domingo Escudero, Helena Ariño, Thais Armangue, Mateus Simabukuro,
Takahiro Iizuka, Makoto Hara, Albert Saiz, Stefano Sotgiu, Josep Dalmau, and Francesc Graus,

ro
Hashimoto encephalopathy in the 21st century, (2020) 94 (2), e217-e224 2020 Jan 14.
[111] T. Ercoli, G. Defazio and A. Muroni, Cerebellar Syndrome Associated with Thyroid Disorders,
-p
Cerebellum (2019).
[112] A.M. Lascano, M.I. Vargas and P.H. Lalive, Diagnostic tools for immune causes of encephalitis, Clin
Microbiol Infect 25 (2019) 431-436.
re
[113] S. Esposito, N. Principi, P. Calabresi and D. Rigante, An evolving redefinition of autoimmune
encephalitis, Autoimmun Rev 18 (2019) 155-163.
lP

[114] R.L. Caparo Oblitas, [Autoimmune encephalitis. New diagnosis for an old condition], Medicina (B
Aires) 78 Suppl 2 (2018) 88-93.
[115] M. Yoneda, A. Fujii, A. Ito, H. Yokoyama, H. Nakagawa and M. Kuriyama, High prevalence of serum
autoantibodies against the amino terminal of alpha-enolase in Hashimoto's encephalopathy, J
na

Neuroimmunol 185 (2007) 195-200.

[116] S.M. McLachlan and B. Rapoport, Why measure thyroglobulin autoantibodies rather than thyroid
peroxidase autoantibodies?, Thyroid 14 (2004) 510-20.
ur

[117] N.R. Rose, Prediction and prevention of autoimmune disease: a personal perspective, Ann N Y Acad
Sci 1109 (2007) 117-28.
[118] Z.Y. Fengqiu Hu, Buyun Ma, Yong Jiang & Hui Huang, The impact of concurrent Hashimoto
Jo

thyroiditis on thyroid nodule cytopathology assessed by ultrasound-guided fine-needle aspiration

cytology, Postgraduate Medicine (2020) 1-6 2020 Mar 12[Online ahead of print].
[119] A.M. Harvey, L.D. Truong and D.R. Mody, Diagnostic pitfalls of Hashimoto's/lymphocytic thyroiditis
on fine-needle aspirations and strategies to avoid overdiagnosis, Acta Cytol 56 (2012) 352-60.
[120] L. Anderson, W.D. Middleton, S.A. Teefey, C.C. Reading, J.E. Langer, T. Desser, M.M. Szabunio, S.J.
Mandel, C.F. Hildebolt and J.J. Cronan, Hashimoto thyroiditis: Part 2, sonographic analysis of benign
and malignant nodules in patients with diffuse Hashimoto thyroiditis, AJR Am J Roentgenol 195
(2010) 216-22.
[121] W.M. Wiersinga, Thyroid hormone replacement therapy, Horm Res 56 Suppl 1 (2001) 74-81.
[122] D.J. Topliss, Clinical Update in Aspects of the Management of Autoimmune Thyroid Diseases,
Endocrinol Metab (Seoul) 31 (2016) 493-499.
[123] T. Watanabe, M. Maruyama, T. Ito, Y. Fujinaga, Y. Ozaki, M. Maruyama, R. Kodama, T. Muraki, H.
Hamano, N. Arakura, M. Kadoya, S. Suzuki, M. Komatsu, H. Shimojo, K. Notohara, M. Uchida and S.
Kawa, Clinical features of a new disease concept, IgG4-related thyroiditis, Scand J Rheumatol 42
(2013) 325-30.
[124] R.D. Abbott, A. Sadowski and A.G. Alt, Efficacy of the Autoimmune Protocol Diet as Part of a Multi-
disciplinary, Supported Lifestyle Intervention for Hashimoto's Thyroiditis, Cureus 11 (2019) e4556.

23
 Journal Pre-proof
[125] G. Carayanniotis, Recognition of thyroglobulin by T cells: the role of iodine, Thyroid 17 (2007) 963-
73.
[126] M.I. Liontiris and E.E. Mazokopakis, 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, Hell J Nucl Med 20 (2017) 51-56.
[127] J. Kohrle, Selenium and the thyroid, Curr Opin Endocrinol Diabetes Obes 20 (2013) 441-8.
[128] S.A. Eskes, E. Endert, E. Fliers, E. Birnie, B. Hollenbach, L. Schomburg, J. Kohrle and W.M. Wiersinga,
Selenite supplementation in euthyroid subjects with thyroid peroxidase antibodies, Clin Endocrinol
(Oxf) 80 (2014) 444-51.
[129] J. Wichman, K.H. Winther, S.J. Bonnema and L. Hegedus, Selenium Supplementation Significantly
Reduces Thyroid Autoantibody Levels in Patients with Chronic Autoimmune Thyroiditis: A
Systematic Review and Meta-Analysis, Thyroid 26 (2016) 1681-1692.
[130] A. Bruscolini, M. Sacchetti, M. La Cava, M. Nebbioso, A. Iannitelli, A. Quartini, A. Lambiase, M. Ralli,
A. de Virgilio and A. Greco, Quality of life and neuropsychiatric disorders in patients with Graves'
Orbitopathy: Current concepts, Autoimmun Rev 17 (2018) 639-643.
[131] K.H. Winther, J.E. Wichman, S.J. Bonnema and L. Hegedus, Insufficient documentation for clinical

of
efficacy of selenium supplementation in chronic autoimmune thyroiditis, based on a systematic
review and meta-analysis, Endocrine 55 (2017) 376-385.
[132] N. Roehlen, C. Doering, M.L. Hansmann, F. Gruenwald, C. Vorlaender, W.O. Bechstein, K. Holzer, K.

ro
Badenhoop and M. Penna-Martinez, Vitamin D, FOXO3a, and Sirtuin1 in Hashimoto's Thyroiditis
and Differentiated Thyroid Cancer, Front Endocrinol (Lausanne) 9 (2018) 527.
-p
[133] Y.Z. Guanqun Chao, Lizheng Fang, Correlation Between Hashimoto’s Thyroiditis–Related Thyroid
Hormone Levels and 25-Hydroxyvitamin D, Front Endocrinol (Lausanne) (2020) 11, 4 2020 Feb 14.
[134] T. Gan and R.W. Randle, The Role of Surgery in Autoimmune Conditions of the Thyroid, Surg Clin
re
North Am 99 (2019) 633-648.
[135] L.A. Mack and J.L. Pasieka, An evidence-based approach to the treatment of thyroid lymphoma,
lP

World J Surg 31 (2007) 978-86.

[136] T.F. Davies, Is thyroid transplantation on the distant horizon?, Thyroid 23 (2013) 139-41.
[137] M.E. Dailey, S. Lindsay and R. Skahen, Relation of thyroid neoplasms to Hashimoto disease of the
thyroid gland, AMA Arch Surg 70 (1955) 291-7.
na

[138] B. Jankovic, K.T. Le and J.M. Hershman, Clinical Review: Hashimoto's thyroiditis and papillary
thyroid carcinoma: is there a correlation?, J Clin Endocrinol Metab 98 (2013) 474-82.
[139] K. Mukasa, J.Y. Noh, Y. Kunii, M. Matsumoto, S. Sato, S. Yasuda, M. Suzuki, K. Ito and K. Ito,
ur

Prevalence of malignant tumors and adenomatous lesions detected by ultrasonographic screening

in patients with autoimmune thyroid diseases, Thyroid 21 (2011) 37-41.
[140] F. Boi, F. Pani and S. Mariotti, Thyroid Autoimmunity and Thyroid Cancer: Review Focused on
Jo

Cytological Studies, Eur Thyroid J 6 (2017) 178-186.

[141] O.S. Oksana Sulaieva, Dmytro Shapochka, Nataliia Belemets, Oleksandr Nechay, Yelizaveta
Chereshneva, Dibakhan Tsomartova, Marina Ivanova Hashimoto's Thyroiditis Attenuates
Progression of Papillary Thyroid Carcinoma: Deciphering Immunological Links, eliyon (2020) 6 (1),
e03077 2020 Jan 8.
[142] Y.J. Nam, B.H. Kim, S.K. Lee, Y.K. Jeon, S.S. Kim, W.J. Jung, D.H. Kahng and I.J. Kim, Co-occurrence of
papillary thyroid carcinoma and mucosa-associated lymphoid tissue lymphoma in a patient with
long-standing hashimoto thyroiditis, Endocrinol Metab (Seoul) 28 (2013) 341-5.

24
 Journal Pre-proof
Figure 1. Loss of immune tolerance results in autoimmunity during the development of
autoimmune thyroid diseases. Naive CD4+ T cells can be activated by dendritic cells (DC) or other
antigen-presenting cells and they can differentiate into various subsets which are characterized by
different cytokines and specific transcription factors. The balance of those immune cells is
necessary for the maintenance of immune homeostasis. Under normal conditions, T cell subsets
have normal functions, and there is immune homeostasis in human body, which can maintain the
immune tolerance and avoid unwarranted immune attacks to thyroid tissues. Some genetic factors
and environmental factors can result in the dysfunctions of these T cell subsets, B cells, and
antigen-presenting cells, which may break up the immune homeostasis and cause thyroid
autoimmunity. From Wang B, Shao X, Song R, Xu D, Zhang JA. The Emerging Role of Epigenetics
in Autoimmune Thyroid Diseases. Front Immunol. 2017 Apr 7;8:396 [55].

of
ro
Figure 2. Thyroid autoimmunity produces two opposite pathogenetic processes and clinical
outcomes. A: During Hashimoto’s thyroiditis, self-reactive CD4+ T lymphocytes recruit B cells and
-p
CD8+ T cells into the thyroid. Disease progression leads to the death of thyroid cells and
hypothyroidism. Both autoantibodies and thyroid-specific cytotoxic T lymphocytes (CTLs) have
re
been proposed to be responsible for autoimmune thyrocyte depletion. B: In Graves’ disease,
lP

activated CD4+ T cells induce B cells to secrete thyroid-stimulating immunoglobulins (TSI) against
the thyroid-stimulating hormone receptor (TSHR), resulting in unrestrained thyroid hormone
na

production and hyperthyroidism. From: Stassi G, De Maria R. Autoimmune thyroid disease: new
models of cell death in autoimmunity. Nat Rev Immunol 2002, 2(3):195-204 [76].
ur

Figure 3. (A) Histologic section of papillary thyroid carcinoma (left) and Hashimoto thyroiditis
Jo

background (right). (B) Hashimoto thyroiditis showing effacement of thyroid architecture by

diffuse lymphocyte infiltration and residual thyroid follicles. From: Nam YJ, Kim BH, Lee SK, Jeon
YK, Kim SS, Jung WJ, Kahng DH, Kim IJ. Co-occurrence of papillary thyroid carcinoma and
mucosa-associated lymphoid tissue lymphoma in a patient with long-standing hashimoto
thyroiditis. Endocrinol Metab 2013, 28(4):341-5 [142].

Figure 4. The relationships between Hashimoto thyroiditis (HT) and papillary thyroid carcinoma
(PTC) with their immunological/hormonal pathogenic links. The left part shows the relevance of
environmental factors and genetic background in thyroid carcinogenesis. Radiation may cause PTC
development by RET-PTC oncogene rearrangements and more rarely with point BRAF mutations.
Increased TSH levels due to nonautoimmune thyroid failure induced by radiation play an important
role both in promotion and progression of PTC. The right part displays the complex relation
25
 Journal Pre-proof
between HT and PTC. Multiple factors related to thyroid autoimmunity (serum anti-thyroid
autoantibodies, inflammatory molecules, free radicals with secondary RET/PTC rearrangements),
genetic/environmental conditions, and high TSH values (consequence of autoimmune thyroid
failure) are involved. From: Boi F, Pani F, Mariotti S. Thyroid Autoimmunity and Thyroid Cancer:
Review Focused on Cytological Studies. Eur Thyroid J. 2017 Jul; 6(4): 178–186 [140].

of
ro
-p
re
lP
na
ur
Jo

26
 Journal Pre-proof
Highlights
 Hashimoto’s thyroiditis is one of the commonest autoimmune disorders.
 Hashimoto’s thyroiditis is related to an interaction among genetic elements, environmental
factors with an epigenetic influence.
 Diagnosis of Hashimoto thyroiditis is based on clinical features, presence of serum
antibodies against thyroid antigens and cytological examination.
 The mainstream of treatment is based on the management of the hypothyroidism with a
substitution therapy.

of
ro
-p
re
lP
na
ur
Jo

27
Figure 1
Figure 2
Figure 3
Figure 4