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Medical Applications of Molecular Biotechnologies in the Context of the Hashimoto’s Thyroiditis

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20 April 2023

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Abstract
Hashimoto’s thyroiditis (HT) is a gender autoimmune disease that is manifested by chronic inflammation of thyroid. Clinical trial studies (CTSs) use molecular biotechnologies (MB) to approach HT appearance. Aims of this study was to analyze the applications of MB in CTSs carried out in HT populations (HT-CTSs). Further, to evaluate the role of MB in the context of hygiene hypothesis (HH). From 75 HT-CTSs found at https://beta.clinicaltrials.gov/ web place, forty-five were considered for this investigation. Finally, six HT-CTSs were reported as molecular HT-CTSs (mHT-CTSs) because of these were planning to utilize MB. Two of mHT-CTSs were settled on French population to isolate DNA viral sequences. Blood, urine, and thyroid tissues biospecimens were analyzed to pick out parvo and polyoma viruses. Two mHT-CTSs carried out in China, were aimed to identify oral and fecal microbiotas by measuring PCR sequencing of 16S rRNA gene. Two mHT-CTSs were programmed in USA and Greece, respectively, for interception of DNA polymorphisms to associate with genetic susceptibility to HT. In conclusion, MB are mainly employed in HT-CTSs for infective pathogenesis and genetic fingerprinting of HT. Besides, MB don't prove the evidence of HH; however, they are useful for direct evidence of the presence of viruses.
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Subject: Medicine and Pharmacology  -   Pathology and Pathobiology

1. Introduction

Hashimoto’s thyroiditis (HT) is a chronic destructive inflammatory process that develops by autoimmune mechanisms [1]. TH falls within autoimmune thyroid diseases (AIDT) precisely because of inflammatory response to immune alterations [2,3].
Basically, morphological features of HT include four signatures such as lymphoid infiltrates, fibrosis, oxyphilic changes of follicular cells and varying degree of destruction of glandular tissue [4].
Immunological hallmarks of HT enclose serum antibodies raised against various thyroid antigens encompassing from thyroid peroxidase and antithyroglobulin to thyroid-stimulating hormone receptor [5,6]. Morphological and immunological HT traits don’t emerge concurrently. In fact, there is a small proportion of patients that show cytological features of HT whereas thyroid antibodies are low detectable in their serum [7].
Reductions of serum thyroid hormones levels are noted in HT patients: this is in case no glandular cells secrete enough thyroid hormones able to meet the needs of body. However, hypothyroidism (hy-T) is diagnosed based on serum levels of several biochemical markers such as thyroid stimulating hormone (TSH) and other thyroid hormones used to confirm the diagnosis [8,9]. HT hormonal indicators report different degree of hy-T, independently by entity of morphological damages [10]. Therefore, HT may clinically present either by prominent or mild hy-T symptoms [1]. These appear related with atypic activity of muscle and nerve fibers, alteration of glucose-lipid metabolism, cognitive and psychological disorders [11,12,13].
Currently, a biochemical “grading” system is used to identify latent hy-T forms (see Table 1 in Ref. [4]) [4]. Above of all, this system is designed for HT treatment by levothyroxine (L-T4). This system is built by confrontation between serum levels of TSH and free thyroxine (T4). At the time that L-T4 replacement was indicated as the first choice for treatment of hy-T, the method of doing this hormonal comparison became essential. In fact, since 2014 the guidelines of American thyroid Association recommend L-T4 treatment strategy for hy-T forms [14,15,16]. Further, this is in according to nationwide data from the National Health Service in the United Kingdom and European thyroid association, too [17]. However, basic science and clinical evidence are inducing to development investigations on LT4/LT3 combination therapy [18,19]. New data come up about limitations of serum TSH biochemical marker because of it partially reflects total thyroid status [20,21,22]. Lastly, 10–15% of hy-T patients voice their discontent because of L-T4 treatment outcomes [23,24]. In fact, this recent evidence urges to involve in the care of hy-T above all hy-T patients themselves [25,26].

1.1. HT biomarkers and epidemiological data

At large, HT diffusion can be reported by considering two distinct types of serum biomarkers. Firstly, HT epidemiological information can be compiled based on autoimmune biomarkers of thyroid inflammation. Secondly, to archive HT epidemiological data, HT diffusion can be related to biochemical markers of hy-T and then, to onset of hy-T symptoms.
By focusing on serum immunological biomarkers, HT is considered a gender functional disorder [27]. This is because of mechanisms underlying the appearance of autoantibodies [28,29]. In fact, the disruption of immune tolerance is genetically driven [29]. Particularly, HT autoimmune anomalies are genetically based on gender and pre-existing susceptibility individual [28,30,31]. In turns, environment plays a critical role on altered genetic background by doing influence the disease development. [27,31]. Hence, HT is reported in women 10-15 times more often than men by an incidence peak around 30-50 years [32]. Conversely, in men the HT incidence increases with aging and then, incidence peak is reached 10-15 years later [32].
When HT diffusion is related to hy-T incidence, substantial differences emerge between hy-T that spreads in endemic area of iodine deficiency and what goes accompanied by HT. Zimmermann et colleague had already observed that hy-T typically emerges in HT patient independently by iodine nutrition status [33,34]. This is because of hy-T develops even in HT patients living in area with sufficient iodine intake. Instead, when population are resident in iodine-deficient localities, it is quite common to find endemic hy-T [35].
Gender differences come up even when HT is related to onset of hy-T signs and symptoms. In fact, distinctive clinical courses and different outcomes are observed in women in respect with men. Further, difference of gender is a key determinant even in therapeutic responses to L-T4 [27,36]. Usually, hy-T symptoms include fatigue, cold intolerance, and constipation. However, there is a large variation in clinical presentation of symptoms [16].
In women, hy-T develops more frequent at a later age than HT, especially, after 60 years of age [27]. In addition, hy-T symptoms have not determinant role for identification of endocrine disorder. This is because of hy-T symptoms may occur in healthy women subjects, too. Lastly, L-T4 therapy may be associate with residual symptoms despite normal thyroid tests [18,24].
In men, hy-T symptoms that accompany overt HT are more recurrent, last longer and usually less treatable. [27]. Therefore, the presence or absence of symptoms may be contributing factors to identification of hy-T. Lastly, L-T4 therapy is less frequently accompanied by other side effects in men.

1.2. Prevalence of HT diagnoses

The methods used to diagnose HT have a long history related to description of morphological alterations of thyroid gland, recognition of autoimmune pathogenesis and identification of thyroid hormones [4]. For a proper diagnosis of HT, several methods are involved, further, different biomarkers are assessed independently or in combination with each other [4]. Mainly, serum, ultrasound and pathological examinations are considered how HT diagnostic methods [4,32]. Current research has reported the global prevalence of diagnoses of HT according to different diagnostic methods [32]. Moreover, data about the prevalence of methods useful to confirm HT diagnosis have been provided [32]. Therefore, HT is prevalently diagnosed by ultrasonography (13.2%) and pathological examination (12.5%) [32]. When serum autoantibodies profile is considered, the prevalence rate of HT diagnosed stands at 7.8% (see Figure 9 in Ref. [32]) [32]. The combination of two methods, including serum antibody titres and color Doppler ultrasound, is used for HT diagnosed with a prevalence of 10.4% [32]. This prevalence is considerably lower (4.7%) if three methods such as autoantibody titres, color Doppler ultrasonography and fine needle aspiration are associated. To confirm HT diagnosis is prevalently used thyroid tissue alone (14.1%) [32].

1.3. Molecular biotechnologies (MB) and HT

MB are the pivot for new biomedical methodologies because of their capability of revealing molecular pathogenetic pathways as well as genetic susceptibility of population to develop AIDT [6]. Above all now that use of genetic analysis is turning out to be a key tool for clinical genomic investigations owing to its high accuracy, reproducibility, and reliability of results.
The effective clinical application of MB can be assessed in accordance with the advice of qualified clinical trial studies (CTSs) [37]. These investigations are the basis of genomic screenings designed to detect viral genetic material involved in pathogenesis of diseases. That too, but especially CTSs can test how well genomic screenings work to identify susceptibility to develop diseases in subgroups of populations belonging to a specific continent.
Molecular alterations occurring in the context of HT play crucial roles to promote cellular proliferation of both lymphocytes and glandular tissue. Indeed, mucosa-associated lymphoid tissue (MALT) lymphomas can originate to the site of HT [38,39]. On the other hand, it is long since HT is reported concurrent with cancerous follicular lesions such as nodular goiter, adenoma, and carcinoma [39,40,41,42]. MB are currently employed on pathotyping of MALT lymphoma [43,44]. Further, these analyses are applied in dubious diagnoses of thyroid glandular cancerous lesions [45]. Mainly, these are part of thyroid innovative medicine that point trough biomarkers to early molecular diagnose, personalized treatment, prediction of cancerous risk and prognostic information [46].
Two were the main objectives of the study: firstly, to perform a systematic analysis of CTSs conducted on HT populations living at different geophysical latitude (HT-CTSs). This was done to establish the frequency by which these CTSs were concluded in different continents and when they were planned. Secondly, to identify samples in which MB were applied.
Therefore, wide-ranging search was conducted on CTSs provided at https://beta.clinicaltrials.gov/ web site through the files covered by “autoimmune thyroiditis Hashimoto” keywords [47]. To follow, some of these findings were selected as they were referring to HT-CTSs that planned to apply molecular technologies (mHT-CTSs).
In the context of hygiene hypothesis (HH), divergences among geographic diffusion of HT and molecular fingerprint of HT patients were also considered.
Current applications of MB for pathological practices were discussed separately. Mainly, these concerned molecular aspects for diagnosis of malignant thyroid lesions associated with HT.

2. Material and Methods

2.1. Data Sources

A systematic review of CTSs for HT was performed by surveying all results of search for terms “autoimmune thyroiditis Hashimoto” at place namely, “Condition or disease” of https://beta.clinicaltrials.gov/ web site [47].

2.2. Study Selection

A number of 75 CTSs was found for these keywords that included also three synonyms of conditions or disease such as “autoimmune thyroiditis”; “thyroiditis Hashimoto” and “Hashimoto” [47]. Mainly, 29 related terms were found of which ten pertained to “autoimmune thyroiditis” synonym (Hashimoto; thyroiditis autoimmune; Hashimoto Disease; HASHIMOTO THYROIDITIS; Hashimoto's thyroiditis; Hashimoto's Disease; chronic thyroiditis; Hashimotos Disease; Chronic lymphocytic thyroiditis; Lymphocytic thyroiditis); ten to “thyroiditis Hashimoto” (Hashimoto; Hashimoto Disease; Autoimmune Thyroiditis; HASHIMOTO THYROIDITIS; Hashimoto's thyroiditis; Hashimoto's Disease; Chronic lymphocytic thyroiditis; chronic thyroiditis; Lymphocytic thyroiditis; Hashimotos Disease) and nine to “Hashimoto” (Hashimoto Disease; Autoimmune Thyroiditis; HASHIMOTO THYROIDITIS; Hashimoto's thyroiditis; Hashimoto's Disease; Chronic lymphocytic thyroiditis; chronic thyroiditis; Lymphocytic thyroiditis; Hashimotos Disease) [47].

2.3. Inclusion criteria

Two were the inclusion criteria adopted for this investigation. The enrollment of HT patients was designed as the first criteria to select CTSs, whereas the molecular analyses were used as the second.
In the first instance, the above CTSs were scrutinized to enucleate the full set of trials carried on HT population. Secondly, to assess the effective application of MB, “Study Plan” section was analyzed for all CTSs [47]. Here, there were details on how a single CTS was planned and what the study was measuring. Specially, “Outcome Measure” sub-section provided insight into the use of molecular analysis to realize the aim of CTS.

2.4. Exclusion criteria

By reviewing and studying the 75 CTSs, 30 of them were considered irrelevant. Mainly, five CTSs were eliminated from this study because of they did not recruit participants with HT: i.e., HT was an “Medical Subject Headings” term or a collateral effect to a therapy (NCT05077865, NCT04239521, NCT04349761, NCT05680376, NCT03957616).
Twenty-four CTSs remained outside because of these concerned other autoimmune, inflammatory, or lymphocytic diseases (NCT03872284, NCT04823728, NCT05225883, NCT03993262, NCT05177939, NCT04339205, NCT04175522, NCT03530462, NCT03835728, NCT03542279, NCT03004209, NCT05198661, NCT04106596, NCT04708626, NCT01456416, NCT04875975, NCT05280600, NCT05682482, NCT05605223, NCT05503264, NCT03941184, NCT05422664, NCT05711563, NCT05772611).
One’ of CTS was omitted because of “Hashimoto” keyword indicated the location of study (NCT04339127).

2.5. Data Extraction

According to the first inclusion criteria, data extraction was performed. Basically, 45 CTSs were extracted for evaluation and included in this study because of they had effectively investigated on HT populations (Table 1). These HT-CTSs were entered into systematic analysis by evaluating seven variables such as continental and geo-location, start date, primary completion date, completion date, last verified and conclusion of study (Table 1).

2.6. Data Synthesis

According to both inclusion criteria, data were synthetized. Finally, 6 mHT-CTSs were recorded because of they had scheduled to use MB to realize their aims (Table 2). To evaluate each mHT-CTSs, six additional variables were added to previous seven. These were corresponding to: target sequences, analysis, and methods, biospecimen genetic retention and description, type and model of study, time perspective, and enrollment of subjects, respectively. Responsible party and results overview were shown, too (Table 2).

3. Results

3.1. CTSs conducted on HT population.

Forty-five CTSs enrolled HT patients. Thirty-seven of them provided information about geolocations by specifying where studies have been conducted (Table 1). In fact, there were not items in 17.7% of HT-CTSs (Table 1).
HT-CTSs were geographically assigned to four continents with different distribution. Then, 0.04% of HT-CTSs were conducted in Africa, 15.5% in America, 13.3% in Asia and 48.8% in Europe (Table 1).
In Africa, HT-CTSs were planned between 2011-2018. In America, HT populations were listened in CTSs since 2006, whereas, in Asia from 2011 onwards. In Europe, the first CTS on HT population was arranged in 2004 (Table 1).
Both HT-CTSs planned in Africa were completed (Table 1). Out of a total of 7 HT-CTSs mapped in American continent, around 85.7 per cent were completed. Conclusions were found only in one of 6 Asian HT-CTSs (16.6%) and in fourteen of 22 European HT-CTSs (63.6%) (Table 1).
These data indicate HT-CTSs specially provide large amount of information about populations living at European latitude. This is due to the hugest number of planned and concluded HT-CTSs in Europe in respect with other continents.

3.2. Clinical application of MB in HT-CTSs

In the list of mHT-CTSs, six trials were included. Two of them (33.3%) were finalized to display viral sequences. For the four remaining HT-CTSs, two were designed to identify bacteria and two to set genetic polymorphisms to associate with susceptibility for HT (Table 2).
Two DNA viruses were investigated from mHT-CTSs in the French population: these corresponded to parvo and polyoma viruses (Table 2). Both viruses were identified by polymerase chain reaction (PCR) method. Specially, genetic strands of polyomavirus were detected in different biospecimen such as blood, urine, and thyroid tissues. Based on study model, the spread of parvovirus was screened through an observational study (NCT03114267). Conversely, polyoma virus was approached by an interventional CTS (NCT03103776). A cohort model with retrospective analysis was followed for the observational study. Contrariwise, a model of parallel assignment was assigned to interventional HT-CTSs (Table 2). Consequently, both mHT-CTSs were planned to have knowledge about viral pathogenesis of HT by PCR analysis. However, NCT03114267 CTS investigated viral cause and effects by longitudinal analysis that evaluated retrospectively the outcome in HT population. Differently, NCT03103776 CTS investigated viral cause and effects on several populations affected of autoimmune diseases among which also an HT population.
The mHT-CTSs investigating bacteria aimed to identify microbiotas. Oral and fecal microbiota were examined in the Chinese population by measuring PCR sequencing of 16S rRNA gene (Table 1 and Table 2). Human feces were used to pick up microbiota genetic materials for the investigation namely NCT03390582 (Table 2). Both mHT-CTSs were observational studies; however, oral microbiota was evaluated by a case-control study whereas, fecal microbiota through a cohort study (Table 2).
Among mHT-CTSs programmed for interception of HT susceptibility, NCT00958113 investigation was performed in Colorado (USA); whereas NCT02491567 CTS was set for the Greek population (Table 1 and Table 2). DNA was examined on biospecimens such as saliva and blood leucocytes. Both mHT-CTSs pertained to observational, case-control studies with cross-sectional examination.

4. Discussion

HT may appear through different clinical and histological aspects and thus, morphological and serum diagnosis of HT are not interchangeable [4]. In addition, HT may be associated to benign and malignant follicular lesions as well as lymphomatous proliferations [39,42,43]. MB are promising surveying methods to apply on HT population.
Totally, 75 CTSs were examined in this study to assess the effective clinical use of MB for planning of trials. By examination of mHT-CTSs is emerged that MB have been employed for two unique scopes. Firstly, to reveal infective etiopathogenesis of HT; and secondly, to determine molecular fingerprinting of HT in populations. Mostly, in this investigation were isolated four trials in which clinical applications of MB served to display viral or bacterial genomes. This is demonstrating how these methos are functioned properly for exploring the complexity of infective HT pathogenesis.
Viral and bacterial infections are currently involved in HT pathogenesis, by multiple and often intertwined pathways.
Based on the old Th1/Th2 paradigm, the so-called hygiene hypothesis (HH) has been adapted to infective etiology of AIDT at the end of the last century [48,49,50,51]. Briefly, this hypothesis postulates that early infections in childhood protects against establishment of autoimmunity. [48,51,52,53,54]. Further, a reduced exposures to microbial environment in childhood is considered as element conducive to increase of autoimmune diseases in adults [55]. This is because of immune system educated by pathogens exposition may better suppress autoimmunity. However, the extension of HH to support of HT pathogenesis has not reported complete agreement [51].
Closely related to HH there are socio-demographic profiles of HT population, data come from migration survey and biographic info of HT patients.
By different concentrations, HT subjects are geographically distributed on the continental territories. A geographical map created on the bases of demographic observations reveal higher concentrations of HT subjects in Africa and Oceania (Figure 1) [32]. On the bases of socio-demographic observations, two divergent findings have been recorded. In low- and middle-income countries, the highest prevalence of HT patients is found among low-middle-income subjects (11.4%) (see Figure 8 in Ref. [32]) [32]. However, HT patients are prevalently concentrated in high-income countries. [32]. Therefore, the HH pathogenetic concepts can be applied to the last phenomena, whereas the first evidence seems limited only to infectious etiology of HT.
For over fifty years, surveys on transmigration of populations are persistently reporting that subjects migrating from a country with low incidence of autoimmune disorders develop immune-related diseases by the same frequency of the original inhabitants of the host country [52,56,57,58,59,60,61]. These data suggest an environmental effect at beginning of autoimmune diseases.
By reporting biographic info of HT patients, several investigations have focused a surprising association occurring between birth month of individuals and HT. Mostly, HT patients were born in winter and autumn [62]. This data suggests that cold weather protect against TPO-Ab development [63]. Nevertheless, this evidence is consistent with infective etiology of HT due to the abundant spread of infectious agents in winter. Further, these findings support HH because of children born in winter have early exposure to infectious agents facilitating the development of autoimmune disease. However, moving from these premises, it is possible even to affirm that incidence of HT for the individual subject may be predicted based on birthday information. Summing up these phenomena, HH seems jarring with genetic features observed in autoimmune disorders, especially in HT.
Molecular analyses have mapped on the short arm of chromosome 6 (6p) a super-region of 7.6 Mb including the extended major histocompatibility complex (eMHC) [64,65]. This region lengthens telomerically from RPL12P1 to HIST1H2AA and it is composed by six clusters and six super-clusters [65]. At 6p21.3 of eMHC are localized human leukocyte antigen (HLA) genes that are highly polymorphic. HLA expressions are strongly related to infection, immunity, and inflammation [66].
In HT, genetic polymorphisms of HLA changes depending on ethnicity [67]. This is because of different expressions of haplotypes in Caucasians (DR3, DR5, DQ7, DQB1*03, DQw7 or DRB1*04-DQB1*0301) in respect with Japanese (DRB4*0101, HLA-A2, DRw53) and Chinese (DRw9) HT patients [67]. Together, these data suggest that non-genetic factors trigger on onset of autoimmune disorders through an unidentified genetic background that is common to entire HT population. Therefore, among phases composing HT pathogenesis, genetic individual susceptibility enters at a later stage in respect with environment factors.
Genetic disparities of HLA profiles are established through use of molecular techniques. These methods have the advantage of arranging systematically HLA haplotypes by symbols. The complexity of nomenclature of HLA haplotypes has been organized by multiple molecular techniques [68]. The first molecular approach to display HLA alleles concerned application of Sanger sequencing-based typing (PCR-SBT) methods [68]. High-throughput sequencing (HTS) methods, including next-generation "short-read" (NGS) and third-generation "long-read" sequencing methods, are the natural evolution of PCR-SBT. Lastly, Oxford Nanopore Technology MinION is progressively reorganizing the number of HLA alleles [69]. Genotyping investigations on Graves’s disease (GD) have identified novel HLA alleles through high-resolution NGS [70,71]. Further, the use of methods based on machine learning are useful to predict HLA subtypes in GD [72]. These investigations suggest of matching different medical biotechnologies to better explain pathogenetic stages involving HLA haplotypes for development of autoimmune disorders.
By focusing on available molecular sources for CTSs appears that parvo and polyoma viruses were investigated from mCTSs.
The role of viruses in inducing HT has been explored but it is still not completely determined [51,73,74]. New data are coming up about roles of DNA and RNA viruses to trigger HT [75,76,77]. DNA viruses namely, parvovirus 19 (B19V), human hepatitis C virus and human herpes virus-6 have been associated to viral pathogenesis of HT [75,76,77,78,79,80]. Among RNA viruses, human immunodeficiency virus (HIV) has been related with HT as it is able to activate the immune inflammatory response through IL-6 [81,82]. Specially, in HIV patients this cytokine plays an important role by orchestrating the inflammatory cascade associated with HT [82]. The importance of IL-6 has been recognized even in animal model of DNA virus infection. In fact, IL-6 amounts are incremented in lung tissues of naïve Balb/c mice that received parvoviruses [83].
Parvoviruses are widespread in different countries of American, Europe, and Asian continent. [77]. Among DNA viruses, parvoviruses display highest levels of replication and recombination [84]. These viruses can replicate autonomously or conversely, they recombine with a helper-virus to be perpetuated [84]. The International Committee on Taxonomy of Viruses (ICTV) has reported members of Parvovirinae family as small (~20 nm in diameter), icosahedral, non-enveloped viruses that have a small single-stranded DNA of 4–6 kb [85]. In 2020, the Executive Committee of the ICTV has approved a revision for taxonomic of the family Parvoviridae [86]. Although the definition to describe these viruses remained, genetic criteria used to demark members composing this family have been updated. The proposal criteria proceed from discoveries of new members of the family Parvoviridae through application of HTS methods. Basically, the classification based on the association with host has been abandoned because of these viruses infect phylogenetically disparate hosts (see Table 1 in Ref. [86]) [86]. In this family have been incorporated infectious agents for animals showing a host range large. In fact, this is enough vast to include many phyla ranging from primates, mammals, avian species to invertebrates [86]. Beyond this, the family Parvoviridae embraces pathogens for arthropods clades, namely arachnids of Chelicerata, that molecular clock estimates go back to marine fossils of the late Cambrian period [87,88,89]. In 1975, Cossart and colleagues detected for the first-time B19V in serum sample of subject screened for hepatitis B virus [90]. Thirty years later, Allander and colleagues discovered bocavirus 1 (HBoV1) in human sample of nasopharyngeal aspirates belonging to children with respiratory tract infection [91]. B19V1 may cause a widespread and self-limiting infections in children and adults, known as erythema infectiosum or fifth disease [92]. Both, B19V and HBoV1 are pathogens for humans and have been detected in cancerous thyroid cells and HT lesions [75,76,93,94].
B19V and HBoV1 exhibit a particular tropism for nuclear compartment. The host machinery for nuclear import of viral capsid is a critical step in the early phase of infection [95,96,97]. The capsid binding protein namely, cleavage and polyadenylation specificity factor 6 plays a dominant role in directing integration to euchromatin of HBoV1 and lentivirus HIV-1, too [95,96,97]. At later stages of infection, the replication of B19V leads to morphological changes of nucleus. These are due to spatial reorganization of chromatin that appears marginalized to the nuclear periphery by super-resolution microscopic examination [98].
In this investigation, MB have proved their worth for composing the future genetic makeup of individuals suffered from HT. This is because these methodologies were employed to disclose genetic susceptibility for HT in two molecular CTSs. Currently, several microsatellites have been proposed as significant elements to build up the molecular HT phenotypes. Specially, heterozygous genotype Arg/Pro of rs 1042522 located on TP 53 gene, polymorphism of IL-23R gene rs17375018, polymorphisms of IL-6 gene promoter (-572) C/G and IL-6 rs1800795 have been associated with HT susceptibility [99,100,101,102].
With the introduction of precision medicine in 2015, MB are considered instrumental to management of cancerous lesions [103]. Molecular medicine has a key role for diagnosis and treatment of thyroid cancers associated to HT by isolating molecular alterations in histological and cytological samples. On histological fragments, the application of MB concerns the diagnosis of MALT lymphoma that develops around the primary HT alterations (see Table 1 in Ref. [104]) [104]. Genomic dissections of lymphomatous cells are employed to reveal molecular phenotypes of MALT lymphoma.

5. Conclusion

Decades of biomedical research on polymorphisms of HLA have revealed many genetic regions associated with HT. However, epidemiological evidence related to HT diffusion cannot be fully explained by HLA genetic differences. This study sheds a light on the require of new linkage between MB and production of data on demographic events such as births and migrations. This is because HH has not yet been proven, this has been widely criticized but not clearly disproved.
Besides, in HT tissues are detected DNA viruses that cause mild manifestation of inflammatory disease but produce nuclear DNA damages. Therefore, DNA viruses have relevance on HT pathogenesis and would offer important opportunities to develop antiviral strategies able also to treat HT. Mostly, viral infections should be considered in future for the development and refinement of HT therapies to use as an alternative or in conjunction with hormone replacement.
Lastly, MB have enormous potential to promote precision medicine by development of robust biomarkers to use for diagnosis and personalized therapies.

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Figure 1. Global HT prevalence; data have been extracted from reference [32].
Figure 1. Global HT prevalence; data have been extracted from reference [32].
Preprints 71435 g001
Table 1. Clinical trials studies conducted on HT population.
Table 1. Clinical trials studies conducted on HT population.
Continent Geolocation ClinicalTrials.gov
Identifier
OFFICIAL TITLE Start
Date*
Primary
Completion
Date*
Study
Completion
Date*
Last
Verified
Conclusion
Africa
(n=2)
0.04%
Egypt NCT03289403 The role of
immunomodulatory treatment
in success of ICSI in patients
with autoimmune thyroiditis
2018 2019 2019 2020 Completed
Israel NCT01270425 Sonographic and laboratory
evaluation of the thyroid gland
in patients with systemic
sclerosis
2011 2011 2012
(anticipated)
2013 Completed
American
(n=7)
15.5%
Brazil NCT01129492 Low-level laser therapy in
chronic autoimmune
thyroiditis
2006 2009 2009 2010 Completed
Brazil NCT02240563 Low level laser therapy
for autoimmune thyroiditis
2014 2016 2016 2017 Completed
Chile NCT04778865 Effect of treatment for vitamin
D deficiency on thyroid
function and autoimmunity
in Hashimoto's thyroiditis
2020 2021
(estimated)
2021
(estimated)
2021 Recruiting
USA NCT00958113 Autoimmune
thyroid disease genetic study
2009 2013 2015 2015 Completed
USA NCT01428167 Hashimotos thyroiditis and
thyroid cancer (thyroid cancer)
2011 2012 2012 2012 Completed
USA NCT01551498 Evaluating the dietary
supplement anatabloc in
thyroid health-ASAP (antabloc
supplementation autoimmune
prevention) (ASAP)
2012 2013 2013 2015 Completed
USA NCT04542278 Preoperative steroids in
autoimmune thyroid disease
2020 2022 2022 2022 Completed
Asian
(n= 6)
13.3%
China NCT03447093 The oral microbiota is
associated with autoimmune
thyroiditis
2017 2019
(estimated)
2021
(estimated)
2018 Unknown
China NCT04075851 The prevalence of serum
thyroid hormone
autoantibodies in
autoimmune thyroid diseases
2019 2022
(estimated)
2022
(estimated)
2021 Recruiting
China NCT04942769 Study on the effect of
selenium supplementation on
the structure and function
of autoimmune thyroiditis
2019 2021
(estimated)
2021
(estimated)
2021 Recruiting
China NCT03390582 Gut microbiota is associated
with autoimmune
thyroid disease
2017 2018
(estimated)
2021
(estimated)
2018 Unknown
Taiwan NCT02126683 The effect of Plaquenil on
serum inflammatory markers
and goiter in euthyroid young
women with Hashimoto's
thyroiditis
2014 2016
(estimated)
2016
(estimated)
2014 Unknown
Taiwan NCT01760421 The effect of
Hydroxychloroquine
treatment in Hashimoto's
thyroiditis
2011 2012 2013 2014 Completed
Europe
(n=22)
48.8%
Denmark NCT02013479 Selenium supplementation
in autoimmune
thyroiditis (CATALYST)
2014 2022 2022
(estimated)
2022 Active, not
recruiting
France NCT03114267 Involvement of viral infections
in the pathogenesis
of chronic lymphocytic
thyroiditis (Etude thyrovir)
2012 2015 2015 2017 Completed
France NCT03103776 Involvement of
polyomaviruses in the
pathogenesis of autoimmune
Thyroiditis and Goitrigenesis
(IPoTAIG)
2016 2018
(estimated)
2018
(estimated)
2018 Unknown
France NCT04789993 Additional
autoimmune diseases with
type 1 diabetes in pediatrics at
diabetes diagnosis and during
follow-up (AADT1D)
2021 2021
(estimated)
2021
(estimated)
2021 Enrolling
by
invitation
France NCT05544448 In vitro effect study of
Interleukin-2 muteins on
regulatory T cells of patients
with different autoimmune,
allo-immune or inflammatory
diseases (MuTreg)
2022 2023
(anticipated)
2023
(anticipated)
2022 Not yet
recruiting
Germany NCT00552487 Isolated ACTH deficiency in
patients
with Hashimoto thyroiditis
2005 NA 2006 2007 Completed
Greece NCT02491567 DNA methylation and
autoimmune
thyroid diseases (THYRODNA)
2014 2016 2018 2019 Completed
Greece NCT02644707 Selenium supplementation in
youths with autoimmune
thyroiditis (THYROSEL)
2014 2016 2018 2020 Completed
Greece NCT04693936 Metabolic biomarkers
in hashimoto's thyroiditis and
psoriasis
2021 2023
(estimated)
2024
(estimated)
2022 Recruiting
Greece NCT02725879 FGF-21 levels and RMR in
children and adolescents
with Hashimoto's
thyroiditis (THYROMETABOL)
(THYROMETABOL)
2016 2020
(estimated)
2020
(estimated)
2020 Unknown
Italy NCT03498417 Anti-insulin-like growth factor-
1 receptor (IGF-1R) Antibodies in Graves' Disease and Graves'
orbitopathy (IGF1RAbsGO)
2018 2018 2018 2018 Completed
Italy NCT01465867 Selenium supplementation in
pregnancy (Serena)
2012 2017 2018 2018 Completed
Norway NCT02319538 Hashimoto - a surgical disease.
total thyroidectomy makes
antibodies disappear and
ameliorates symptoms
2012 2017 2017 2018 Completed
Poland NCT04752202 The influence of reducing diets
on changes in thyroid
parameters in obese women
with Hashimoto's disease
2019 2019 2019 2021 Completed
Poland NCT04682340 Analysis of BPA concentration
in serum in women of
reproductive age with
autoimmune thyroid disease
2020 2021 2022 2022 Completed
Romania NCT04600349 Identity oriented
psychotrauma therapy
on Hashimoto in adults
2020 2020 2021 2021 Completed
Romania NCT04472988 Eye movement desensitization
and reprocessing
on autoimmune thyroiditis in
adults
2020 2020 2021 2021 Completed
Switzerland NCT05017142 Swiss pediatric inflammatory
brain disease registry (Swiss
Ped-IBrainD)
2020 2071
(estimated)
2071
(estimated)
2021 Recruiting
Turkey NCT01102205 Evaluation of oxidative stress
and effect of Levothyroxine
treatment on oxidative stress
in Hashimoto disease
2010 2010 2010 2013 Completed
Turkey NCT04754607 Effects of low-level laser
therapy on oxidative stress
levels, fatigue and quality of
life in patients
with Hashimoto thyroiditis
2021 2022 2022 2022 Completed
Turkey NCT00271427 Selenium treatment
in autoimmune
thyroiditis (AIT)
2004 NA 2005 2006 Completed
Turkey NCT01644318 CXCL9 and CXCL11 levels in
patients with autoimmune
thyroiditis and habitual
abortions
NA NA NA 2012 Unknown
Unknown
(n=8)
17.7%
Not
provided
NCT01884649 Fetuin A as a new marker of
inflammation
in Hashimoto thyroiditis
2012 2012 2012 2013 Completed
Not
provided
NCT02318160 Oxidative status in children
with autoimmune thyroiditis
2014 2014 2014 2014 Completed
Not
provided
NCT04613323 Management of thyroid
function in Hashimoto's
thyroiditis during pregnancy
2022
(estimated)
2022
(estimated)
2022
(estimated)
2021 Not yet
recruiting
Not
provided
NCT02190214 Thyroid disorders in Malaysia:
a nationwide multicentre
study (MyEndo-Thyroid)
2014 2016 2016 2016 Completed
Not
provided
NCT03048708 Thyroid in bariatric surgery
(ThyrBar)
2011 2013 2016 2018 Completed
Not
provided
NCT02302768 Effect of Semet (80 and 160
mcg) versus placebo in
euthyroid patients with AIT
2012 2014 2015
(estimated)
2014 Unknown
Not
provided
NCT05435547 Preoperative corticosteroids in
autoimmune thyroid disease
2022 2025
(anticipated)
2025
(anticipated)
2022 Not yet
recruiting
Not
provided
NCT05276063 A Phase 2b, study of Linsitinib
in subjects with active,
moderate to severe thyroid
eye disease (TED) (LIDS)
2022 2023
(estimated)
2025
(estimated)
2023 Recruiting
* NA: not available; Data taken from reference [47].
Table 2. Molecular clinical trials studies conducted on HT population.
Table 2. Molecular clinical trials studies conducted on HT population.
ClinicalTrials.gov identifier Target sequences Analysis and methods Biospecimen genetic retention and description Type and model of study Time perspective** Enrollment of subjects Responsible Party Results Overview
NCT03114267 Parvovirus Analysis of the viral genome by PCR*,
Analysis of the presence of capsid protein
Not provided Observational, cohort Retrospective 64 Centre Hospitalier Universitaire, Amiens No publications
available
NCT03103776 Polyoma Virus Positive PCR* Frequencies for Polyomavir us Blood, Urine and / or Thyroid Tissue Interventional, parallel assignment NA 49 Centre Hospitalier Universitaire, Amiens No publications
available
NCT03447093 Oral microbiota Measurement of microbiota by 16S rRNA gene. Not provided Observational, case control Cross-Sectional 120 First Affiliated Hospital of Harbin Medical University Publications
available
NCT03390582 Fecal microbiota Measureme nt of microbiota by 16S rRNA gene. Human feces Observational, cohort Cross-Sectional 200 First Affiliated Hospital of Harbin Medical University No publications
available
NCT00958113 HLA, CTLA4, thyroglobulin, THSR, CD40, PTPN2 and PTPN22 Map and identify genes that confer susceptibility to Autoimmune Thyroid Disease Saliva Observational, case control Cross-Sectional 199 University of Colorado, Denver, USA No publications
available
NCT02491567 CD40L, FOXP3, CTLA4, PTPN22, IL2RA, FCRL3 and HLADRB1 DNA methylatio status of CpGs within gene promoters Blood (leukocytes) Observational, case control Cross-Sectional 110 Medical School of Aristotle University of Thessaloniki Publications
available
* PCR: polymerase chain reaction; **NA: not available; Data taken from reference [47].
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