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Trovato, M.C.; Valenti, A. Medical Applications of Molecular Biotechnologies in Hashimoto’s Thyroiditis. Encyclopedia. Available online: https://encyclopedia.pub/entry/46204 (accessed on 27 July 2024).
Trovato MC, Valenti A. Medical Applications of Molecular Biotechnologies in Hashimoto’s Thyroiditis. Encyclopedia. Available at: https://encyclopedia.pub/entry/46204. Accessed July 27, 2024.
Trovato, Maria Concetta, Andrea Valenti. "Medical Applications of Molecular Biotechnologies in Hashimoto’s Thyroiditis" Encyclopedia, https://encyclopedia.pub/entry/46204 (accessed July 27, 2024).
Trovato, M.C., & Valenti, A. (2023, June 29). Medical Applications of Molecular Biotechnologies in Hashimoto’s Thyroiditis. In Encyclopedia. https://encyclopedia.pub/entry/46204
Trovato, Maria Concetta and Andrea Valenti. "Medical Applications of Molecular Biotechnologies in Hashimoto’s Thyroiditis." Encyclopedia. Web. 29 June, 2023.
Medical Applications of Molecular Biotechnologies in Hashimoto’s Thyroiditis
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This entry is adapted from the peer-reviewed paper 10.3390/diagnostics13122114

Hashimoto’s thyroiditis (HT) is a gender autoimmune disease that is manifested by chronic inflammation of the thyroid. Clinical trial studies (CTSs) use molecular biotechnologies (MB) to approach HT appearance. 

Hashimoto’s thyroiditis molecular biotechnologies

1. Introduction

Hashimoto’s thyroiditis (HT) is a chronic destructive inflammatory process that develops by autoimmune mechanisms [1]. HT falls within autoimmune thyroid diseases (AIDT) precisely because of the 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 receptors [5][6]. Morphological and immunological HT traits do not emerge concurrently. In fact, there is a small proportion of patients that show cytological features of HT, whereas thyroid antibodies are lowly detectable in their serum [7].
Reductions of serum thyroid hormone levels are noted in HT patients: this is in case no glandular cells secrete enough thyroid hormones able to meet the needs of the 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 degrees of hy-T, independently according to the existence of morphological damage [4]. Therefore, HT may clinically present either with prominent or mild hy-T symptoms [1]. These appear related to the atypic activity of muscle and nerve fibers, the alteration of glucose-lipid metabolism, and cognitive and psychological disorders [10][11][12].
Currently, a biochemical “grading” system is used to identify latent hy-T forms (see Table 1 in Ref. [4]) [4]. Above all, this system is designed for HT treatment by levothyroxine (L-T4). This system is built by the confrontation between serum levels of TSH and free thyroxine (T4). At the time that L-T4 replacement was indicated as the first choice for the treatment of hy-T, the method of performing this hormonal comparison became essential. In fact, since 2014, the guidelines of the American Thyroid Association have recommended the L-T4 treatment strategy for hy-T forms [13][14][15][16]. Further, this is in accordance with nationwide data from the National Health Service in the United Kingdom and the European thyroid association [17]. However, basic science and clinical evidence are inducing the development of investigations on LT4/LT3 combination therapy [18][19]. New data has come up regarding the limitations of serum TSH biochemical markers because they partially reflect the patient’s total thyroid status [20][21][22][23][24]. Lastly, 10–15% of hy-T patients voiced their discontent because of L-T4 treatment outcomes [22][23]. In fact, this recent evidence urges the involvement, in the care of hy-T, above all, of hy-T patients themselves [22][23][24][25].

1.1. HT Biomarkers and Epidemiological Data

Overall, 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 the onset of hy-T symptoms.
By focusing on serum immunological biomarkers, HT is considered a gender-functional disorder [26]. This is because of the mechanisms underlying the appearance of autoantibodies [27][28]. In fact, the disruption of immune tolerance is genetically driven [29][30]. Particularly, HT autoimmune anomalies are genetically based on gender and pre-existing individual susceptibility [27][29][30]. In turn, the environment plays a critical role in altering genetic backgrounds by influencing disease development [26][30]. Hence, HT is reported in women 10–15 times more often than in men, with an incidence peak at around 30–50 years of age [31]. Conversely, in men, the HT incidence increases with aging and the incidence peak is reached 10–15 years later [31].
When HT diffusion is related to hy-T incidence, substantial differences emerge between hy-T that spreads in endemic areas of iodine deficiency and that which is accompanied by HT. Zimmermann and colleagues previously observed that hy-T typically emerges in HT patients independently according to iodine nutrition status [32][33]. This is because hy-T develops even in HT patients living in areas with sufficient iodine intake. Moreover, when populations are resident in iodine-deficient localities, it is quite common to find endemic hy-T [34].
Gender differences come up even when HT is related to the onset of hy-T signs and symptoms. In fact, distinctive clinical courses and different outcomes are observed in women compared to men. Further, differences in gender are a key determinant even of therapeutic responses to L-T4 [26][35]. Usually, hy-T symptoms include fatigue, cold intolerance, and constipation. However, there is a large variation in the clinical presentation of symptoms [15].
In women, hy-T develops more frequently at a later age than HT, especially after 60 years of age [26]. In addition, hy-T symptoms have no determinant role in the identification of endocrine disorders. This is because hy-T symptoms may occur in healthy female subjects, too. Lastly, L-T4 therapy may be associated with residual symptoms despite normal thyroid tests [17][24].
In men, hy-T symptoms that accompany overt HT are more recurrent, last longer, and are usually less treatable [26]. Therefore, the presence or absence of symptoms may be contributing factors in the 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 the description of morphological alterations of the thyroid gland, the recognition of autoimmune pathogenesis, and the 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 HT diagnostic methods [4][31]. Current research has reported the global prevalence of diagnoses of HT according to different diagnostic methods [31]. Moreover, data about the prevalence of methods useful to confirm HT diagnoses have been provided [31]. Therefore, HT is prevalently diagnosed by ultrasonography (13.2%) and pathological examination (12.5%) [31]. When the serum autoantibody profile is considered, the prevalence rate of HT diagnosis stands at 7.8% (see Figure 9 in Ref. [31]) [31]. The combination of two methods, including serum antibody titers and color Doppler ultrasound, is used for HT diagnosed with a prevalence of 10.4% [31]. This prevalence is considerably lower (4.7%) if three methods, such as autoantibody titers, color Doppler ultrasonography, and fine needle aspiration, are combined. To confirm HT diagnosis, thyroid tissue alone is prevalently used (14.1%) [31].

1.3. Molecular Biotechnologies (MB) and HT

MB are pivotal for new biomedical methodologies because of their capability to reveal molecular pathogenetic pathways as well as the genetic susceptibility of populations to develop AIDT [6]. Above all, now the 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) [36]. These investigations are the basis of genomic screenings designed to detect viral genetic material involved in the pathogenesis of diseases. Not only this, but CTSs can especially 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 in promoting the cellular proliferation of both lymphocytes and glandular tissue. Indeed, mucosa-associated lymphoid tissue (MALT) lymphomas can originate at the site of HT [37][38]. On the other hand, for a considerable time, HT was reported concurrent with cancerous follicular lesions such as nodular goiter, adenoma, and carcinoma [38][39][40][41]. MB are currently employed for the classification of MALT lymphoma [42][43]. Further, these analyses are applied in dubious diagnoses of thyroid glandular cancerous lesions [44]. Mainly, these are part of innovative thyroid medicine that aims through biomarkers to early molecular diagnosis, personalized treatment, the prediction of cancerous risk, and prognostic information [45].

2. Medical Applications of Molecular Biotechnologies in Hashimoto’s Thyroiditis

HT may appear through different clinical and histological aspects, and thus, morphological and serum diagnoses of HT are not equivalent [4]. In addition, HT may be associated with benign and malignant follicular lesions as well as lymphomatous proliferations [38][41][42]. The exact etiology of HT still remains incompletely elucidated. Mainly, it has been related to interactions of different elements, such as genetic alterations, environmental and epigenetic factors [30][46][47]. MB are promising surveying methods to apply to the HT population. 

Viral and bacterial infections are currently involved in HT pathogenesis via multiple and often intertwined pathways.
Based on the old Th1/Th2 paradigm, the so-called hygiene hypothesis (HH) has been adapted to the infective etiology of AIDT at the end of the last century [48][49][50][51]. Briefly, this hypothesis postulates that early infections in childhood protect against the establishment of autoimmunity [48][51][52][53][54]. Further, reduced exposure to microbial environments in childhood is considered an element conducive to the increase of autoimmune diseases in adults [55]. This is because an immune system educated by pathogen exposition may better suppress autoimmunity. However, the extension of HH to support HT pathogenesis has not reported a complete agreement [51].
Closely related to HH are the socio-demographic profiles of the HT population, data from migration surveys 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 reveals higher concentrations of HT subjects in Africa and Oceania (Figure 1) [31]. On the basis 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. [31]) [31]. However, HT patients are prevalently concentrated in high-income countries [31]. Therefore, the HH pathogenetic concepts can be applied to the last phenomena, whereas the first evidence seems limited only to the infectious etiology of HT.
/media/item_content/202306/649d49e1f3c61diagnostics-13-02114-g001.png
Figure 1. Global HT prevalence. Data has been extracted from reference [31].
For over 50 years, surveys on the transmigration of populations are persistently reporting that subjects migrating from a country with a low incidence of autoimmune disorders develop immune-related diseases with the same frequency as the original inhabitants of the host country [52][56][57][58][59][60][61]. These data suggest an environmental effect at the beginning of autoimmune diseases.
By reporting the biographic info of HT patients, several investigations have focused on the surprising association occurring between the birth month of individuals and HT. Mostly, HT patients were born in winter and autumn [62]. This data suggests that cold weather protects against TPO-Ab development [63]. Nevertheless, this evidence is consistent with the infective etiology of HT due to the abundant spread of infectious agents in winter. Further, these findings support HH because children born in winter have early exposure to infectious agents, facilitating the development of autoimmune diseases. However, moving from these premises, it is even possible to affirm that the incidence of HT for the individual subject may be predicted based on their date of birth. 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 of six clusters and six super-clusters [65]. At 6p21.3 of eMHC, human leukocyte antigen (HLA) genes are localized, which are highly polymorphic [65]. HLA expressions are strongly related to infection, immunity, and inflammation [66].
In HT, genetic polymorphisms of HLA change 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) with respect to Japanese (DRB4*0101, HLA-A2, DRw53) and Chinese (DRw9) HT patients [67]. Together, this data suggests that non-genetic factors trigger the onset of autoimmune disorders through an unidentified genetic background that is common to the entire HT population. Therefore, among phases composing HT pathogenesis, individual genetic susceptibility enters at a later stage than environmental factors.
Genetic disparities in HLA profiles are established through the use of molecular techniques. These methods have the advantage of systematically arranging HLA haplotypes using symbols. The complexity of the nomenclature of HLA haplotypes has been organized using multiple molecular techniques [68]. The first molecular approach to displaying HLA alleles concerned the 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, methods based on machine learning are useful for predicting HLA subtypes in GD [72]. These investigations suggest matching different medical biotechnologies to better explain pathogenetic stages involving HLA haplotypes for the development of autoimmune disorders.
By focusing on available molecular sources for CTSs, it appears that the parvo and polyoma viruses were investigated in the mCTSs.
The role of viruses in inducing HT has been explored, but it is still not completely determined [51][73][74]. New data is becoming available regarding the roles of DNA and RNA viruses in triggering HT [75][76]. DNA viruses, namely, parvovirus 19 (B19V), human hepatitis C virus, and human herpes virus-6, have been associated with the viral pathogenesis of HT [75][76][77][78][79]. Among RNA viruses, human immunodeficiency virus (HIV) has been related to HT as it is able to activate the inflammatory immune response through IL-6 [80][81]. Particularly in HIV patients, this cytokine plays an important role by orchestrating the inflammatory cascade associated with HT [81]. The importance of IL-6 has been recognized even in animal models of DNA virus infection. In fact, IL-6 amounts are incremented in lung tissues of naïve Balb/c mice that received parvoviruses [82].
Parvoviruses are widespread in different countries on the American, European, and Asian continents [76]. Among DNA viruses, parvoviruses display the highest levels of replication and recombination [83]. These viruses can replicate autonomously or, conversely, recombine with a helper virus to be perpetuated [83]. The International Committee on Taxonomy of Viruses (ICTV) has reported members of the Parvoviridae family as small (~20 nm in diameter), icosahedral, non-enveloped viruses that have a small single-stranded DNA of 4–6 kb [84]. In 2020, the Executive Committee of the ICTV approved a revision for the taxonomy of the Parvoviridae family [85]. 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 Parvoviridae family through the application of HTS methods. Basically, the classification based on the association with the host has been abandoned because these viruses infect phylogenetically disparate hosts (see Table 1 in Ref. [85]) [85]. In this family, infectious agents for animals have been incorporated, showing a large host range. In fact, this is vast enough to include many phyla ranging from primates, mammals, and avian species to invertebrates [85]. Beyond this, the Parvoviridae family embraces pathogens for arthropod clades, namely the arachnids of the Chelicerata, that the molecular clock estimates go back to marine fossils of the late Cambrian period [86][87][88]. In 1975, Cossart and colleagues detected for the first-time B19V in serum samples of subjects screened for hepatitis B virus [89]. Thirty years later, Allander and colleagues discovered bocavirus 1 (HBoV1) in human samples of nasopharyngeal aspirates belonging to children with respiratory tract infections [90]. B19V1 may cause a widespread and self-limiting infection in children and adults, known as erythema infectiosum or fifth disease [91]. Both B19V and HBoV1 are pathogens for humans and have been detected in cancerous thyroid cells and HT lesions [75][92][93][94].
B19V and HBoV1 exhibit a particular tropism for the 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 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]. During the later stages of infection, the replication of B19V leads to morphological changes in the nucleus. These are due to the spatial reorganization of chromatin that appears marginalized to the nuclear periphery by super-resolution microscopic examination [98].

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Subjects: Endocrinology & Metabolism
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Maria Concetta Trovato
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Andrea Valenti
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