Hashimoto’s thyroiditis and coexisting disorders in correlation with HLA status—an overview

Hashimoto’s thyroiditis (HT), also known as chronic lymphocytic thyroiditis or Hashimoto’s disease, was first described by the Japanese physician Hakaru Hashimoto in 1912 as an enlarged thyroid with a chronic lymphatic infiltration. This form of HT is also frequently referred to as the hypertrophic or goitrous form of HT. After many years the thyroid typically shrinks in size, leading to a secondary atrophic form of HT. A thyroid gland of normal or reduced size at diagnosis with a lymphatic infiltration is called Ord thyroiditis. However, in clinical practice, these different forms of HT are usually summarized under the term Hashimoto’s thyroiditis (HT). If not otherwise mentioned, this article will in general refer to both forms of HT (hypertrophic and atrophic), as in most papers the different forms of HT are considered as one disease with different presentations in thyroid sized?>

The frequency of HT is increasing among Caucasians and its prevalence in the population is estimated at approximately 5% [1]. HT is caused by autoimmune-trigged lymphocytic infiltration and destruction of the thyroid gland. Excessively stimulated T CD4+ cells and their differentiated cells (ThH1, Th2, Th17, Treg) and different proinflammatory cytokines such as interferon and interleukin (IL)-17 play an important role in the pathogenesis of HT [1, 2]. The underlying background of the pathological autoimmune reaction towards the thyroid gland is regarded as being multifactorial [3], with environmental influences such as the extent of iodine supply, infections, and stress as triggers of immune modulation [2, 4‐6]. Also, the gut microbiota has been discussed as a further possible cause of influencing thyroid immunity and the development of HT [7]. Different studies have shown a changed intestinal microbiota composition in patients with HT as compared to healthy controls, thus possibly having an influence on the reactivity of the immune system and the development of HT [8‐11]. However, further studies on this topic have to be awaited to determine whether gut dysbiosis may have an impact on the development of HT [7, 8, 12]. In addition, genetic factors in association with the human leucozyte antigen (HLA) gene, different immunoregulatory genes (CD25, CD40, FOXP3, CTLA4, PTPN22), and thyroid-specific genes (thyroid stimulating hormone receptor, thyroglobulin) also play a key role.

With the progressive destruction of the organ by activated macrophages and cytotoxic lymphocytes, the thyroid gland shrinks in size, thus commonly leading to hypothyroidism in the long term. Consequently, therapy of HT is mainly focused on managing the thyroid dysfunction by oral substitution of L‑thyroxine. However, patients with HT often complain about a broad spectrum of symptoms, with some of them hardly explained solely by HT itself. Several other disorders are frequently seen with HT, assuming an association with this thyroid disorder. In clinical practice this necessitates a broad view on HT itself and the spectrum of other disorders related to HT, in order to diagnose and manage all disease aspects.

This paper will provide an overview of diseases related to HT, including their correlation to certain HLA patterns. With this presentation, a broader view on HT and its related disorders will be presented, facilitating detailed examination and management of patients with HT and its associated disorders.

Although the background and cause of HT is multifactorial [3], including environmental influences such as iodine supply, infections, and stress as triggers of immune modulation [2, 4, 6], it became evident that HT is also based on genetic changes and the HLA status. Already in 1978 was HLA-DRw3 suspected to be more frequent in HT [13], and in 1981, Farid et al. [14] found a higher occurrence of HLA-DR5 in goitrous thyroiditis, whereas HLA-DR3 was more frequent in atrophic thyroiditis. Tandon et al. [15] could confirm the association of HT with HLA-DR3, but a difference between HLA-DR5 and HLA-DR3 in their association to goitrous or atrophic HT variations could not be seen in their study. In 2001, the HLA haplotype DRB1*04-DQB1*0301 was found to increase the risk of developing HT [16]. Another potential connection to HT was seen with genetic changes at the HLA-DR pocket, in particular the exchange of the neutral amino acids Ala or Gln for arginine at position beta 74 [17]. In contrast, the association of HT with the HLA-DR3 family could not be supported in another study from 2002 [18].

There are also other genetic aberrations which may increase the risk for HT. The CTLA4 gene plays a role in T‑cell activation and is located on chromosome 2q33. In a meta-analysis [19] it could be demonstrated that two frequent single nucleotide polymorphisms (SNPs) of the cytotoxic T-lymphocyte-associated protein 4 (CTLA4) gene (+49A/G and CT 60) are associated with HT. Additional sequential analysis showed that the +49A/G polymorphisms may be candidate biomarkers for HT. The risk for HT with +49A/G was higher in the subgroup of Asians as compared to Caucasians. The CT 60 showed no significant association in the Caucasian subgroup [19]. The Forkhead box P3 (FoxP3) gene plays a relevant role for regulatory T‑cells concerning development and function. The -2383CC polymorphism of FoxP3 was found more frequent in severe HT forms than in less severe ones [20]. The ZFAT ex9b-SNP10 polymorphism, especially the TT genotype and T allele, showed a significant higher frequency in patients with severe HT compared with less severe HT patients (p = 0.0029 and p = 0.0049, respectively) [21].

To date, the controversial discussion about the associations of HT with HLA-DR and many other gene aberrations is still ongoing. HT is considered a multifactorial disease caused not only by genetic predisposition, but also by other different non-genetic factors, which all increase the risk of developing HT [3].

The paper provides a summary of diseases related to HT. The associated disorders will be elucidated from two different points of view. Firstly, as pointed out above, HT is associated with polymorphisms in the HLA-DR gene locus [3]. Several other diseases are also associated with changes in the HLA-DR gene locus, which thus makes a simultaneous occurrence of these disorders possible. For this, the HLA-DR gene was searched in PubMed in terms of its coexistence with HT. Secondly, disorders known to be associated with HT were searched in PubMed and evaluated from a clinical point of view as well. The associated diseases were grouped according to the affected organ systems (Fig. 1).

Thyroid function may be normal or even slightly hyperthyroid at the beginning of HT, whereas in later stages of HT the thyroid function may remain either euthyroid or becomes hypothyroid. Sonographic features can vary depending on the phase and severity of HT. During the initial phase, the thyroid gland may be either normal in size or diffusely enlarged with a heterogeneous echotexture. Hypoechoic micronodules (1–6 mm) with surrounding echogenic septations are also considered to have a relatively high positive predictive value for HT. This sonographic pattern may be described as a pseudonodular or giraffe pattern. In later stages of HT the thyroid gland progressively decreases in size and the sonographic appearance of the thyroid gland finally shows a diffusely hypoechogenic pattern. Color Doppler studies usually show a normal or decreased flow, although in some cases, hypervascularity, not representing thyrotoxicosis, can be present. Besides sonography, the evaluation of thyroid antibodies is essential for diagnosis of HT. TgAb are found in approximately 70% and TPOAb in 90–95% of cases. A small portion of patients reveal negative thyroid antibodies, although sonography and the clinical presentation indicate HT (antibody-negative HT). All in all, it may be difficult to diagnose HT at an early stage of the disease, whereas the diagnosis of a clinically evident HT is usually an easy task, putting together the clinical presentation with signs of hypothyroidism, the hypoechogenic sonographic appearance, and usually positive thyroid antibodies. With the diagnosis of HT, these patients may need L‑thyroxine medication in case of hypothyroidism, whereas euthyroid HT patients will not need thyroid medication as long as they remain euthyroid, These HT patients will only require frequent sonographic follow-up controls due to the higher prevalence of PTC in HT.

With a diagnostic and therapeutic procedure focused only on the thyroid gland, most of the patients with HT can be diagnosed and managed sufficiently, ensuring normal thyroid function and surveillance of possibly growing thyroid nodules (Fig. 2, points a–c). However, a small proportion of patients with HT continue to complain about symptoms even after normalization of thyroid function. In these cases, diseases concomitantly occurring with HT, as presented above, should be considered (Fig. 2, point d) or even other disorders not associated with HT (Fig. 2, point e). The question is how to proceed in clinical practice in order to broadly evaluate possible concomitant disorders. At first, a detailed clinical and physical examination, not only focused on the thyroid gland, should be performed in these cases and, in particular, symptoms seen in HT-associated disorders should be checked (Fig. 2). By this, some disorders may be diagnosed at a glance, such as vitiligo or urticaria. Others will need further investigations including imaging (e.g., abdominal sonography, computed tomography, magnetic resonance imaging) and further specific laboratory parameters to diagnose these additional autoimmune disorders (Fig. 2). Furthermore, the coexistence of HT with other autoimmune disorders, as pointed out above, has also to be seen from another viewpoint. Those patients having autoimmune disorders with a known association to HT should also be screened for HT (Fig. 2, point f), as outlined by different authors in their conclusions [35‐37, 44, 57, 63, 67, 86, 89, 90, 93]. In all of those disorders with a documented increased OR for coexistence with HT, a clinical evaluation for HT, even in case of any clinical symptoms indicative for HT, should be included into the diagnostic work-up of these disorders. This would include sonography of the thyroid gland and laboratory evaluation with TSH, TPOAb, and TgAb. By this, even the early subclinical presence of possible coexisting HT could be diagnosed, thus optimizing treatment of the affected patient. All in all, this evolves into a complex diagnostic work-up of patients with HT and possibly other autoimmune disorders and of patients with other autoimmune disorders which are known to show associations with HT, thus needing thyroid screening. Finally, iron (particularly in menstruating women) and vitamin D should be regularly evaluated in patients with HT to correct any deficiency, as thyroid function is dependent on iron and vitamin D status, as pointed out above [87, 90].

In certain cases, the HLA status may also be of interest. Evaluation of the HLA status in patients with HT and additional clinical symptoms not explained by HT itself could provide an approach to evaluate additional autoimmune disorders or a possibly increased risk for certain autoimmune disorders. The association of HLA-DR with HT and the published studies was rated according to the quality and quantity of data published (Tab. 1).

In case of certain HLA subtypes known to be more frequently associated with certain disorders, a closer surveillance of these patients may be additionally implemented in their follow-up controls.

In summary, this approach of a broader and multidisciplinary view on HT and associated autoimmune disorders would broaden and improve clinical management of patients with HT, with a better handling of their various complaints.