Recent Advances in Autoimmune Thyroid Diseases

Won Sang Yoo; Hyun Kyung Chung

doi:10.3803/EnM.2016.31.3.379

Articles

Page Path: HOME > Endocrinol Metab > Volume 31(3); 2016 > Article

Review Article Recent Advances in Autoimmune Thyroid Diseases: Won Sang Yoo, Hyun Kyung Chung; Endocrinology and Metabolism 2016;31(3):379-385.
DOI: https://doi.org/10.3803/EnM.2016.31.3.379
Published online: August 26, 2016

Division of Endocrinology and Metabolism, Department of Internal Medicine, Dankook University College of Medicine, Cheonan, Korea.

Corresponding author: Hyun Kyung Chung. Department of Internal Medicine, Dankook University College of Medicine, 119 Dandae-ro, Dongnam-gu, Cheonan 31116, Korea. Tel: +82-41-550-3057, Fax: +82-41-556-3256, chkendo@dankook.ac.kr

• Received: July 1, 2016 • Revised: July 6, 2016 • Accepted: July 13, 2016

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

7,594 Views
134 Download
33 Web of Science
34 Crossref
34 Scopus

prev next

Full Article

Download PDF

ABSTRACT
INTRODUCTION
PATHOGENIC MECHANISMS OF AUTOIMMUNE THYROID DISEASE
CLINICAL UPDATES IN AUTOIMMUNE HYPOTHYROIDISM
CLINICAL UPDATES IN AUTOIMMUNE HYPERTHYROIDISM
CONCLUSIONS
ACKNOWLEDGMENTS
Article information
References

ABSTRACT

Autoimmune thyroid disease (AITD) includes hyperthyroid Graves disease, hypothyroid autoimmune thyroiditis, and subtle subclinical thyroid dysfunctions. AITD is caused by interactions between genetic and environmental predisposing factors and results in autoimmune deterioration. Data on polymorphisms in the AITD susceptibility genes, related environmental factors, and dysregulation of autoimmune processes have accumulated over time. Over the last decade, there has been progress in the clinical field of AITD with respect to the available diagnostic and therapeutic methods as well as clinical consensus. The updated clinical guidelines allow practitioners to identify the most reasonable and current approaches for proper management. In this review, we focus on recent advances in understanding the genetic and environmental pathogenic mechanisms underlying AITD and introduce the updated set of clinical guidelines for AITD management. We also discuss other aspects of the disease such as management of subclinical thyroid dysfunction, use of levothyroxine plus levotriiodothyronine in the treatment of autoimmune hypothyroidism, risk assessment of long-standing antithyroid drug therapy in recurrent Graves' hyperthyroidism, and future research needs.
Keywords: Autoimmune thyroid disease; Graves disease; Hashimoto disease

INTRODUCTION

Autoimmune thyroid disease (AITD) is a prototypical organ-specific autoimmune disease. The etiology of AITD is multifactorial; interactions between genetic and environmental predisposing triggers lead to dysregulation of immune tolerance. The incidence of the two main clinical presentations of AITD, Graves disease (GD) and Hashimoto's thyroiditis (HT), is estimated at 5% of the population [1]. Despite developments in effective diagnostic and therapeutic methods, there are outstanding issues in the treatment of AITD such as difficulties in treatment decision for patients with subtle changes in thyroid function and limitations in the definite treatment of hyperthyroidism without destroying or removing the thyroid gland. Therefore, it is essential to understand the etiological background of AITD and evaluate the existing clinical data to better determine the ideal management method. In this review, we focus on recent advances in understanding AITD and the controversial clinical issues.

PATHOGENIC MECHANISMS OF AUTOIMMUNE THYROID DISEASE

It has been known that there are polymorphisms in the AITD-related genes for quite some time. Among these genes, polymorphisms in the thyroid-stimulating hormone receptor (TSHR) gene contribute to susceptibility to GD [2]. Recently, a specific single-nucleotide polymorphism (SNP) in the TSHR gene related to central tolerance has been identified. Homozygosity or heterozygosity for the receptor SNP rs179247 displayed significantly decreased intrathymic expression of TSHR mRNA transcripts, which could underlie the decreased central tolerance and increased risk of GD [3]. In central tolerance, identification of the autoimmune regulator (AIRE) gene as the susceptible locus for autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) provided a new window to understand the maintenance of self-tolerance [4]. AIRE is a transcription factor regulating the expression of many proteins in medullary thymic cells; defects in the AIRE gene lead to dysregulation of central immune tolerance and multi-organ autoimmune defects. Although mutation in the APECED gene does not directly lead to AITD susceptibility, APECED patients in certain areas showed a high positive rate of thyroglobulin antibodies and a novel AIRE mutation (G228W) closely cosegregated with autoimmune thyroiditis in a family with APECED [5].

Genes regulating the immune response carry the key for the progression of AITD. Along with major histocompatibility complex (MHC) class I and II genes, cytotoxic T lymphocyte-associated factor 4 (CTLA4), CD40, CD25 (FoxP3), protein tyrosine phosphatase, non-receptor type 22 (PTPN22), and the cytokine regulatory genes have been identified as the major players in AITD [6]. CTLA4 was the first non-human leukocyte antigen (HLA) gene to be associated with GD. A recent meta-analysis of the A49G SNP in CTLA4 found an increased risk of HT in East Asians and GD in the Chinese population [7]. Previous data on PTPN22 showed contradictory results, although a meta-analysis of the C1858T polymorphism revealed an association with GD [8]. CD40 is the immune regulatory gene of the tumor necrosis factor (TNF) superfamily and is expressed on thyroid follicular cells; CD40 C/T1 polymorphism is known to correlate with GD [9]. A recent large-scale study found an association with an interleukin 1 (IL-1) receptor antagonist variable number of tandem repeats IL-1 receptor antagonist gene (IL-1 RN) variable number of tandem repeats (VNTR) polymorphism in 202 HT patients [10], and another study found an association between the rs763780 polymorphism in IL17F and HT in Chinese patients [11]. The SNP in the signal transducer and activator of transcription (STAT) family protein, which is the transcription factor regulating immune-regulatory pathways and cytokine signaling, has been found to be associated with HT as well as GD [12].

Although not specific to the thyroid, selenoprotein (SEP) is involved in the deiodination of the thyroid hormone; a recent study found a significant association with a SNP in the promoter of SEP S gene (SEPS1) in patients with HT [13]. It is not known if dietary selenium is related to the development of AITD. Previous data showed that inadequate selenium intake might exacerbate HT; however, a recent meta-analysis found that selenium supplementation in HT had no beneficial effect [14]. The ongoing the chronic autoimmune thyroiditis quality of life selenium trial (CATALYST) may further reveal the role of selenium in the pathogenesis of AITD [15]. Although how these genetic factors contribute to immune dysregulation is not yet clear, we expect that this knowledge will be extremely valuable in developing individualized and tailored therapeutic approaches for AITD.

Recent studies on the environmental triggers of AITD have identified selenium and vitamin D to be the chief dietary components. A low vitamin D level is not only an etiological factor, but is also related to the severity of AITD. A recent meta-analysis showed that patients with GD were more likely to have vitamin D deficiency [16]. However, whether vitamin D supplementation exerts any beneficial effects on the onset and pathogenesis of GD has not been determined, although the role of vitamin D in AITD is still being investigated [17]. There is strong evidence that several anticancer drugs (cytokines, interferon α, and tyrosine kinase inhibitors) can induce thyroid dysfunction [18]. After years of debate, moderate consumption of alcohol has been proven to be protective in AITD, although the exact mechanism remains unclear [18]; the role of smoking is still being investigated. Rapid industrialization and exposure to environmental toxins are also considered as causative factors of AITD. One study found an increased HT incidence among individuals residing near petrochemical complexes [19]. Climate also affects autoimmunity; women living in Siberia showed a high prevalence of thyroid peroxidase (TPO) antibodies [20]. Thus, global warming and rapid changes in the weather might contribute to the increased incidence of autoimmune diseases.

Based on genetic predisposing factors and environmental triggers, dysregulation of the immune system results in an immune attack on the thyroid. A typical finding in AITD is intrathyroidal infiltration of T and B lymphocytes which have a critical role in the pathogenesis of AITD. In cellular immunity, relatively newly identified regulatory T cells (Tregs) and follicular helper T (Tfh) cells have come into the spotlight for their roles in the pathogenic mechanism of AITD. Tregs represent 5% to 10% of CD4+ cells and express immune responses by direct cell-to-cell interaction or indirectly through cytokines such as transforming growth factor β (TGF-β) and IL-10. Altered Treg activity has been observed in patients with AITD [21]. Tfh cells exert promoter function in antigen-specific B cells through IL-21 production. Increased amounts of Tfh cells in peripheral blood have been found to correlate with thyroid-specific antibody levels in HT patients [22]. Defects in Tregs and activation of Tfh cells are generally accepted as the initiating events in AITD. In the case of cytokines, a subset of Th3, which chiefly synthesizes TGF-β, and Th17 cytokines including IL-17 and IL-22 have been identified as additional players in AITD. These cytokines have a role in the chronic inflammatory condition, particularly in HT [23]. It has been suggested that IL-22 has a role in antibody production since IL-22 levels correlate with TPO antibody levels in HT [24].

CLINICAL UPDATES IN AUTOIMMUNE HYPOTHYROIDISM

Since Hakaru Hashimoto first described AITD in 1912, significant progress has been made in our understanding of this chronic autoimmune inflammatory condition in the thyroid. Recently, "immunoglobulin G4 (IgG4) thyroiditis" has been added as a unique subtype of HT [25]. Histologically and clinically, it is characterized by fibrosis, lymphoplasmacytic infiltration, degeneration of follicular cells, rapid progression of hypothyroidism, more diffuse low echogenicity, higher antibody levels compared to non-IgG4 thyroiditis, and a lower female-to-male ratio. Although definite diagnostic criteria are not yet available, >20 IgG4-positive plasma cells per high-power field and >30% IgG4-positive/IgG-positive plasma cells have been proposed as diagnostic criteria for IgG4 thyroiditis [25]. Whether the fibrous variant of HT and Riedel's thyroiditis fall within the spectrum of systemic IgG4 diseases is still being investigated [26].

Although we have several up-to-date management guidelines for "subclinical" hypothyroidism [27], treatment decision-making is a relatively vague aspect. To begin with, the fundamental concept of "subclinical" has been questioned. Considering the progressive changes in the levels of serum TSH and free thyroxine (T4), it might be better to develop a "grading" system rather than differentiating between the "clinical" and "subclinical" forms [28]. It is not easy to determine the ideal starting point for thyroid hormone supplementation. Not all subclinical hypothyroid subjects with similar levels of TSH and free T4 develop symptoms. The majority of epidemiological and clinical data shows that thyroid hormone therapy has benefits in cardiovascular conditions, chiefly in the middle-aged group, but not in the elderly [29]. Thus, the normal range of TSH depends on patient age. Individuals may also have a narrow "normal" TSH reference range [30]; in fact, recent studies have found a risk of adverse health outcomes even within the reference range [31]. That is, the upper and lower limits of the normal TSH reference range can be marked as "unsafe" zones. Furthermore, none of the ongoing long-term randomized clinical trials are equipped to explain the benefits of treatment. Therefore, it is necessary to study the physiological and pathological mechanisms underlying functional changes in the thyroid, and there is an urgent need for the accumulation of extensive prospective clinical data on subtle thyroid dysfunction. Fortunately, the European Commission has recently initiated the thyroid hormone replacement for subclinical hypothyroidism trial (TRUST), a multicenter, double-blind, placebo-controlled, and randomized trial with 3,000 adults (≥65 years old) [32]. This trial will definitely aid in understanding the effects of levothyroxine (LT4) treatment in subclinical hypothyroidism.

Approximately 5% to 10% of hypothyroid patients complain about persistent symptoms, despite receiving LT4 treatment and having normal serum TSH levels [33]. Possible explanations of this finding include differences in individual sensitivity, combined autoimmune diseases or AITD on its own, and the inability of LT4 treatment to restore T4 and triiodothyronine (T3) concentrations to physiological levels in the serum and tissue. Recently, the European Thyroid Association (ETA) has provided a guideline for the use of LT4+levotriiodothyronine (LT3) combination therapy in hypothyroidism [34]. This guideline states that there is insufficient evidence that LT4+LT3 combination therapy is superior to T4 monotherapy, and that LT4 monotherapy should remain the standard method of treatment for hypothyroidism. LT4+LT3 combination therapy can be attempted on an experimental basis (13:1 and 20:1 dose ratio by weight) in patients with persistent complaints even with normal TSH levels. The mechanisms underlying psychological well-being and preference for LT4+LT3 combination therapy might be related to polymorphisms in thyroid hormone transporters and deiodinase [34]. Further studies on the variations in the deiodinase gene, development of other iodothyronines or their metabolites such as thyronamines [35], and graded, individualized management of hypothyroidism are warranted.

CLINICAL UPDATES IN AUTOIMMUNE HYPERTHYROIDISM

GD is traditionally treated by three methods: antithyroid drugs, radioactive iodine, and surgery, which have been used continuously since the mid-1900s. A century later, an up-to-date consensus and guidelines for the management of GD based on clinical experience and past studies have been provided by the American Thyroid Association [36], Korean Thyroid Association [37], and ETA as a survey of clinical practice patterns [38]. These guidelines indicate persistent and definite differences in the management of GD worldwide which can be attributed to the clinical decision-making attitude, individual preferences, and medical insurance system in each country. Although these recommendations help survey current practices and identify optimal methods for patient care, they still do not cover every clinical setting. For example, the existing guidelines do not have specific recommendations for atypical cases or dealing with refractory or serious side effects of antithyroid drugs. Several recent case reports presented suggested paths for the management of such rare and atypical cases. A Korean patient who was refractory to antithyroid drug treatment was successfully managed with cholestyramine [39], and serious hepatic dysfunction caused by the antithyroid drug was managed with hemodialysis [40]. The utility of potassium iodide [41] and lithium carbonate [42] as an adjuvant therapy has also been examined. Presentation of these difficult cases is vital when attempting to fill the gaps and cracks in existing knowledge and guidelines.

Subtle hyperfunctioning of the thyroid is also a controversial area. Pre-existing guidelines only provide an outline for the clinical management of patients with subclinical hyperthyroidism. Fortunately, a recent detailed guideline for subclinical hyperthyroidism has been provided separately [43]. According to this guideline, identification of endogenous thyroid disease as an etiological factor should be the first step in the management of subclinical hyperthyroidism, followed by grading based on the severity of thyroid dysfunction. Evaluation of combined risk factors (e.g., atrial fibrillation, cardiac dysfunction, and osteoporosis) is another important part of management. Although these guidelines are not supported by randomized controlled trials, data from several recent meta-analyses provide evidence that treating subclinical hyperthyroidism in patients with undetectable TSH levels can help manage the additional risks of total mortality, cardiac dysfunction, incident atrial fibrillation, and fractures [44 45]. Further research in this field should focus on the etiological basis of this mild change in thyroid function to determine if it is related to a mild form of GD, a certain stage of chronic autoimmune thyroiditis, or other types of endogenous autoimmune thyroid dysfunction. Large-scale, prospective, long-term clinical studies to evaluate the efficacy of treatment are also necessary.

Compared to other regions, Asian countries tend to choose long-term antithyroid drug treatment over radioiodine therapy, not only for first-line therapy but also in recurrent cases [36 37]. In fact, the reported overall remission rates of long-term, low-dose maintenance therapy with antithyroid drugs are fairly acceptable [46]. However, some GD patients do not attain complete remission with antithyroid drug treatment even after long-term therapy. Therefore, clinicians are interested in discriminating between groups with favorable and unfavorable responses to antithyroid drugs. History of GD, larger goiter size, and presence of TSH-stimulating antibody at the time of drug withdrawal are well-known unfavorable factors [47]. Several recent studies have identified additional correlating factors such as the course of the drug withdrawal program (slow tapering is more favorable than an abrupt end) [48], duration of low-dose maintenance therapy [46], and redevelopment of TSH-stimulating antibody during low-dose maintenance therapy [49]. Intrinsic genetic factors such as PTPN22 C/T polymorphism and the HLA subtypes DQB*01, DQA1*05, and DRB1*03 have been identified as predictors for recurrence; researchers have attempted to develop a prediction model based on the combination of clinical factors and intrinsic genetic markers [50]. In the wave of "precision medicine," evaluation of individual patients based on their genetic background could be a useful approach to develop personalized management programs [51].

Each therapeutic method of GD has its own advantages and disadvantages, but none of them constitutes a definite treatment method because they cannot completely correct the pathogenic autoimmune process. To overcome this hurdle, recent studies have focused on additional therapeutic options to permanently treat hyperthyroidism without destroying or removing the thyroid gland. The chief strategy is to develop an inhibitory factor against the stimulating antibody of the TSHR. Development of biological agents with immunomodulatory activity, such as anti-TSHR antibodies, could lead to a new drug treatment for autoimmune hyperthyroidism [52]. Small molecule inhibitors of TSHR binding and/or activation have been presented as "selective TSH receptor antagonists" [53]. In vitro data using model cell systems and primary cultures of human thyrocytes showed effective inhibitory functions of these selective TSHR antagonists [54]; in fact, the results of recent in vivo experiments are quite promising [55]. Although there are many limitations such as cost, adverse effects, and lack of remission after discontinuation of these drugs, it is clear that this new drug has the potential to open a completely new domain in the treatment of GD.

CONCLUSIONS

From subtle changes to life-threatening deteriorations, AITD contains broad spectrum thyroid dysfunctions. Recent studies have mainly focused on the consensus for general guidelines of various AITD, and also on the understanding of ideal approaches for each specific condition of AITD. Subgroup identification of Hashimoto's disease, reconsideration of long-term low dose antithyroid drug therapy in patients with Graves disease and LT4+LT3 combination therapy in hypothyroid patients are the issues with ongoing discussions. Further studies of pathophysiologic mechanisms along with genetic backgrounds of AITD will help to develop the definite and individualized therapeutic methods of AITD.

Acknowledgements

ACKNOWLEDGMENTS

This work was supported by research fund of Dankook University in 2014.

Article information

CONFLICTS OF INTEREST: No potential conflict of interest relevant to this article was reported.

References

1. Antonelli A, Ferrari SM, Corrado A, Di Domenicantonio A, Fallahi P. Autoimmune thyroid disorders. Autoimmun Rev 2015;14:174–180. Article PubMed
2. Brand OJ, Barrett JC, Simmonds MJ, Newby PR, McCabe CJ, Bruce CK, et al. Association of the thyroid stimulating hormone receptor gene (TSHR) with Graves' disease. Hum Mol Genet 2009;18:1704–1713. Article PubMed
3. Colobran R, Armengol Mdel P, Faner R, Gartner M, Tykocinski LO, Lucas A, et al. Association of an SNP with intrathymic transcription of TSHR and Graves' disease: a role for defective thymic tolerance. Hum Mol Genet 2011;20:3415–3423. Article PubMed
4. Nagamine K, Peterson P, Scott HS, Kudoh J, Minoshima S, Heino M, et al. Positional cloning of the APECED gene. Nat Genet 1997;17:393–398. Article PubMed PDF
5. Cetani F, Barbesino G, Borsari S, Pardi E, Cianferotti L, Pinchera A, et al. A novel mutation of the autoimmune regulator gene in an Italian kindred with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, acting in a dominant fashion and strongly cosegregating with hypothyroid autoimmune thyroiditis. J Clin Endocrinol Metab 2001;86:4747–4752. Article PubMed
6. Hasham A, Tomer Y. Genetic and epigenetic mechanisms in thyroid autoimmunity. Immunol Res 2012;54:204–213. Article PubMed PMC PDF
7. Ji R, Feng Y, Zhan WW. Updated analysis of studies on the cytotoxic T-lymphocyte-associated antigen-4 gene A49G polymorphism and Hashimoto's thyroiditis risk. Genet Mol Res 2013;12:1421–1430. Article PubMed PDF
8. Luo L, Cai B, Liu F, Hu X, Wang L. Association of protein tyrosine phosphatase nonreceptor 22 (PTPN22) C1858T gene polymorphism with susceptibility to autoimmune thyroid diseases: a meta-analysis. Endocr J 2012;59:439–445. Article PubMed
9. Li M, Sun H, Liu S, Yu J, Li Q, Liu P, et al. CD40 C/T-1 polymorphism plays different roles in Graves' disease and Hashimoto's thyroiditis: a meta-analysis. Endocr J 2012;59:1041–1050. Article PubMed
10. Zaaber I, Mestiri S, Marmouch H, Mahjoub S, Abid N, Hassine M, et al. Polymorphisms in TSHR and IL1RN genes and the risk and prognosis of Hashimoto's thyroiditis. Autoimmunity 2014;47:113–118. Article PubMed
11. Yan N, Yu YL, Yang J, Qin Q, Zhu YF, Wang X, et al. Association of interleukin-17A and -17F gene single-nucleotide polymorphisms with autoimmune thyroid diseases. Autoimmunity 2012;45:533–539. Article PubMed
12. Xiao L, Muhali FS, Cai TT, Song RH, Hu R, Shi XH, et al. Association of single-nucleotide polymorphisms in the STAT3 gene with autoimmune thyroid disease in Chinese individuals. Funct Integr Genomics 2013;13:455–461. Article PubMed PMC PDF
13. Santos LR, Duraes C, Mendes A, Prazeres H, Alvelos MI, Moreira CS, et al. A polymorphism in the promoter region of the selenoprotein S gene (SEPS1) contributes to Hashimoto's thyroiditis susceptibility. J Clin Endocrinol Metab 2014;99:E719–E723. Article PubMed PDF
14. Toulis KA, Anastasilakis AD, Tzellos TG, Goulis DG, Kouvelas D. Selenium supplementation in the treatment of Hashimoto's thyroiditis: a systematic review and a meta-analysis. Thyroid 2010;20:1163–1173. Article PubMed
15. Winther KH, Watt T, Bjorner JB, Cramon P, Feldt-Rasmussen U, Gluud C, et al. The chronic autoimmune thyroiditis quality of life selenium trial (CATALYST): study protocol for a randomized controlled trial. Trials 2014;15:115Article PubMed PMC PDF
16. Xu MY, Cao B, Yin J, Wang DF, Chen KL, Lu QB. Vitamin D and Graves' disease: a meta-analysis update. Nutrients 2015;7:3813–3827. Article PubMed PMC
17. D'Aurizio F, Villalta D, Metus P, Doretto P, Tozzoli R. Is vitamin D a player or not in the pathophysiology of autoimmune thyroid diseases? Autoimmun Rev 2015;14:363–369. Article PubMed
18. Carle A, Pedersen IB, Knudsen N, Perrild H, Ovesen L, Rasmussen LB, et al. Moderate alcohol consumption may protect against overt autoimmune hypothyroidism: a population-based case-control study. Eur J Endocrinol 2012;167:483–490. Article PubMed
19. Arena S, Latina A, Baratta R, Burgio G, Gullo D, Benvenga S. Chronic lymphocytic thyroiditis: could it be influenced by a petrochemical complex? Data from a cytological study in South-Eastern Sicily. Eur J Endocrinol 2015;172:383–389. Article PubMed
20. Cepon TJ, Snodgrass JJ, Leonard WR, Tarskaia LA, Klimova TM, Fedorova VI, et al. Circumpolar adaptation, social change, and the development of autoimmune thyroid disorders among the Yakut (Sakha) of Siberia. Am J Hum Biol 2011;23:703–709. Article PubMed
21. Glick AB, Wodzinski A, Fu P, Levine AD, Wald DN. Impairment of regulatory T-cell function in autoimmune thyroid disease. Thyroid 2013;23:871–878. Article PubMed PMC
22. Zhu C, Ma J, Liu Y, Tong J, Tian J, Chen J, et al. Increased frequency of follicular helper T cells in patients with autoimmune thyroid disease. J Clin Endocrinol Metab 2012;7:943–950. Article PDF
23. Figueroa-Vega N, Alfonso-Perez M, Benedicto I, Sanchez-Madrid F, Gonzalez-Amaro R, Marazuela M. Increased circulating pro-inflammatory cytokines and Th17 lymphocytes in Hashimoto's thyroiditis. J Clin Endocrinol Metab 2010;95:953–962. Article PubMed PDF
24. Bai X, Sun J, Wang W, Shan Z, Zheng H, Li Y, et al. Increased differentiation of Th22 cells in Hashimoto's thyroiditis. Endocr J 2014;61:1181–1190. Article PubMed
25. Hiromatsu Y, Satoh H, Amino N. Hashimoto's thyroiditis: history and future outlook. Hormones (Athens) 2013;12:12–18. Article PubMed PDF
26. Takeshima K, Inaba H, Ariyasu H, Furukawa Y, Doi A, Nishi M, et al. Clinicopathological features of Riedel's thyroiditis associated with IgG4-related disease in Japan. Endocr J 2015;62:725–731. Article PubMed
27. Pearce SH, Brabant G, Duntas LH, Monzani F, Peeters RP, Razvi S, et al. 2013 ETA guideline: management of subclinical hypothyroidism. Eur Thyroid J 2013;2:215–228. Article PubMed PMC
28. Wiersinga WM. Guidance in subclinical hyperthyroidism and subclinical hypothyroidism: are we making progress? Eur Thyroid J 2015;4:143–148. Article PubMed PMC
29. Collet TH, Bauer DC, Cappola AR, Asvold BO, Weiler S, Vittinghoff E, et al. Thyroid antibody status, subclinical hypothyroidism, and the risk of coronary heart disease: an individual participant data analysis. J Clin Endocrinol Metab 2014;99:3353–3362. Article PubMed PMC PDF
30. Andersen S, Pedersen KM, Bruun NH, Laurberg P. Narrow individual variations in serum T(4) and T(3) in normal subjects: a clue to the understanding of subclinical thyroid disease. J Clin Endocrinol Metab 2002;87:1068–1072. Article PubMed
31. Asvold BO, Vatten LJ, Bjoro T, Bauer DC, Bremner A, Cappola AR, et al. Thyroid function within the normal range and risk of coronary heart disease: an individual participant data analysis of 14 cohorts. JAMA Intern Med 2015;175:1037–1047. Article PubMed PMC
32. TRUST project. Thyroid hormone replacement for subclinical hypothyroidism trial (TRUST) [Internet]; TRUST project; 2012. cited 2016 Jul 24. Available from: http://www.trustthyroidtrial.com.
33. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch Intern Med 2000;160:526–534. Article PubMed
34. Wiersinga WM, Duntas L, Fadeyev V, Nygaard B, Vanderpump MP. 2012 ETA guidelines: the use of LT4 + LT3 in the treatment of hypothyroidism. Eur Thyroid J 2012;1:55–71. Article PubMed PMC
35. Piehl S, Hoefig CS, Scanlan TS, Kohrle J. Thyronamines: past, present, and future. Endocr Rev 2011;32:64–80. Article PubMed PDF
36. Bahn Chair RS, Burch HB, Cooper DS, Garber JR, Greenlee MC, Klein I, et al. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid 2011;21:593–646. Article PubMed
37. Moon JH, Yi KH. The diagnosis and management of hyperthyroidism in Korea: consensus report of the korean thyroid association. Endocrinol Metab (Seoul) 2013;28:275–279. Article PubMed PMC
38. Bartalena L, Burch HB, Burman KD, Kahaly GJ. A 2013 European survey of clinical practice patterns in the management of Graves' disease. Clin Endocrinol (Oxf) 2016;84:115–120. Article PubMed
39. Yang Y, Hwang S, Kim M, Lim Y, Kim MH, Lee S, et al. Refractory Graves' disease successfully cured by adjunctive cholestyramine and subsequent total thyroidectomy. Endocrinol Metab (Seoul) 2015;30:620–625. Article PubMed PMC
40. Min SH, Phung A, Oh TJ, Han KS, Kim MJ, Kim JM, et al. Therapeutic plasmapheresis enabling radioactive iodine treatment in a patient with thyrotoxicosis. J Korean Med Sci 2015;30:1531–1534. Article PubMed PMC
41. Okamura K, Sato K, Fujikawa M, Bandai S, Ikenoue H, Kitazono T. Remission after potassium iodide therapy in patients with Graves' hyperthyroidism exhibiting thionamide-associated side effects. J Clin Endocrinol Metab 2014;99:3995–4002. Article PubMed
42. Zheng R, Liu K, Chen K, Cao W, Cao L, Zhang H, et al. Lithium carbonate in the treatment of Graves' disease with ATD-induced hepatic injury or leukopenia. Int J Endocrinol 2015;2015:694023Article PubMed PMC PDF
43. Biondi B, Bartalena L, Cooper DS, Hegedus L, Laurberg P, Kahaly GJ. The 2015 European Thyroid Association guidelines on diagnosis and treatment of endogenous subclinical hyperthyroidism. Eur Thyroid J 2015;4:149–163. Article PubMed PMC
44. Selmer C, Olesen JB, Hansen ML, Lindhardsen J, Olsen AM, Madsen JC, et al. The spectrum of thyroid disease and risk of new onset atrial fibrillation: a large population cohort study. BMJ 2012;345:e7895Article PubMed PMC
45. Blum MR, Bauer DC, Collet TH, Fink HA, Cappola AR, da Costa BR, et al. Subclinical thyroid dysfunction and fracture risk: a meta-analysis. JAMA 2015;313:2055–2065. Article PubMed PMC
46. Konishi T, Okamoto Y, Ueda M, Fukuda Y, Harusato I, Tsukamoto Y, et al. Drug discontinuation after treatment with minimum maintenance dose of an antithyroid drug in Graves' disease: a retrospective study on effects of treatment duration with minimum maintenance dose on lasting remission. Endocr J 2011;58:95–100. Article PubMed
47. Laurberg P, Krejbjerg A, Andersen SL. Relapse following antithyroid drug therapy for Graves' hyperthyroidism. Curr Opin Endocrinol Diabetes Obes 2014;21:415–421. Article PubMed
48. Liu X, Qiang W, Liu X, Liu L, Liu S, Gao A, et al. A second course of antithyroid drug therapy for recurrent Graves' disease: an experience in endocrine practice. Eur J Endocrinol 2015;172:321–326. Article PubMed PMC
49. Liu X, Shi B, Li H. Valuable predictive features of relapse of Graves' disease after antithyroid drug treatment. Ann Endocrinol (Paris) 2015;76:679–683. Article PubMed
50. Vos XG, Endert E, Zwinderman AH, Tijssen JG, Wiersinga WM. Predicting the risk of recurrence before the start of antithyroid drug therapy in patients with Graves' hyperthyroidism. J Clin Endocrinol Metab 2016;101:1381–1389. Article PubMed
51. Ladenson PW. Precision medicine comes to thyroidology. J Clin Endocrinol Metab 2016;101:799–803. Article PubMed
52. Sanders J, Miguel RN, Furmaniak J, Smith BR. TSH receptor monoclonal antibodies with agonist, antagonist, and inverse agonist activities. Methods Enzymol 2010;485:393–420. Article PubMed
53. Gershengorn MC, Neumann S. Update in TSH receptor agonists and antagonists. J Clin Endocrinol Metab 2012;97:4287–4292. Article PubMed PMC PDF
54. van Koppen CJ, de Gooyer ME, Karstens WJ, Plate R, Conti PG, van Achterberg TA, et al. Mechanism of action of a nanomolar potent, allosteric antagonist of the thyroid-stimulating hormone receptor. Br J Pharmacol 2012;165:2314–2324. Article PubMed PMC
55. Neumann S, Nir EA, Eliseeva E, Huang W, Marugan J, Xiao J, et al. A selective TSH receptor antagonist inhibits stimulation of thyroid function in female mice. Endocrinology 2014;155:310–314. Article PubMed PDF

Figure & Data

References

Citations

Citations to this article as recorded by

A Mendelian randomization study of the effect of serum 25-hydroxyvitamin D levels on autoimmune thyroid disease
Yunfeng Yu, Xinyu Yang, Jingyi Wu, Xueli Shangguan, Siyang Bai, Rong Yu
Frontiers in Immunology.2024;[Epub] CrossRef
Therapeutic Potential of CRISPR/Cas in Hashimoto's Thyroiditis: A Comprehensive Review
Apoorva Upreti, Sayali Mukherjee
Current Gene Therapy.2024; 24(3): 179. CrossRef
The efficacy of Chinese patent medicine Xiaojin capsule in the treatment of Hashimoto's thyroiditis: A systematic review and meta-analysis
Aijing Chu, Shouyao Liu, Ying Chen, Zhongyuan Xia
European Journal of Integrative Medicine.2024; 70: 102395. CrossRef
Salenio: clinical study design
Domenico Parmeggiani, Paola Bassi, Maddalena Claudia Donnarumma, Chiara Colonnese, Vincenzo Ieluzzi, Laura Pacca, Chiara Agresti, Massimo Agresti
Endocrinology&Metabolism International Journal.2023; 11(1): 1. CrossRef
Medical Applications of Molecular Biotechnologies in the Context of Hashimoto’s Thyroiditis
Maria Trovato, Andrea Valenti
Diagnostics.2023; 13(12): 2114. CrossRef
IMMUNOHISTOCHEMICAL CHARACTERISTICS OF THYROID GLAND CHANGES IN PATIENTS WITH AUTOIMMUNE THYROIDITIS
F. G. Sadikhov
World of Medicine and Biology.2023; 19(84): 139. CrossRef
The C55A Single Nucleotide Polymorphism in CTLA-4 Gene, a New Possible Biomarker in Thyroid Autoimmune Pathology Such as Hashimoto’s Thyroiditis
Alin-Dan Chiorean, Mihaela Laura Vica, Ștefana Bâlici, Gheorghe Zsolt Nicula, Nicoleta Răcătăianu, Mădălina Adriana Bordea, Laura-Mihaela Simon, Horea Vladi Matei
Diagnostics.2023; 13(15): 2517. CrossRef
USING LASER PHOTODYNAMIC THERAPY IN THE TREATMENT OF AUTOIMMUNE THYROIDITIS
F. G. Sadikhov
World of Medicine and Biology.2023; 19(85): 166. CrossRef
Autoimmune thyroiditis in different age groups and subjects of reproductive age in Adzhariya population
N. G. Tchelidze, S. Z. Glonti, D. Sh. Baratashvili, N. O. Kedelidze, J. Yu. Ungiadze, I. I. Nakashidze
Obstetrics, Gynecology and Reproduction.2022; 16(1): 8. CrossRef
Alterations and Mechanism of Gut Microbiota in Graves’ Disease and Hashimoto’s Thyroiditis
Hong Zhao, Lijie Yuan, Dongli Zhu, Banghao Sun, Juan Du, Jingyuan Wang
Polish Journal of Microbiology.2022; 71(2): 173. CrossRef
The association of six autoimmune bullous diseases with thyroid disorders: a population‐based study
K. Kridin, F. Hübner, R. Linder, E. Schmidt
Journal of the European Academy of Dermatology and Venereology.2022; 36(10): 1826. CrossRef
Investigation of comorbid autoimmune diseases in women with autoimmune bullous diseases: An interplay of autoimmunity and practical implications
Meropi Karakioulaki, Dedee F. Murrell, Aikaterini Kyriakou, Aikaterini Patsatsi
International Journal of Women’s Dermatology.2022; 8(3): e053. CrossRef
Best Achievements in Translational and Basic Thyroidology in 2020
Sun Wook Cho, Young Joo Park
Endocrinology and Metabolism.2021; 36(1): 36. CrossRef
Incidence and Clinical Implications of Autoimmune Thyroiditis in the Development of Acne in Young Patients
Laura Endres, Delia Mirela Tit, Simona Bungau, Nicoleta Anamaria Pascalau, Laura Maghiar Țodan, Erika Bimbo-Szuhai, Gabriela Mariana Iancu, Nicoleta Negrut
Diagnostics.2021; 11(5): 794. CrossRef
Attaining Euthyroidism - Seal the Loopholes
Payel Biswas, Subhankar Chatterjee
International Journal of Thyroidology.2021; 14(1): 69. CrossRef
Cardiac Autonomic Modulation and Anti-Thyroid Peroxidase (TPO) Antibodies in Subclinical Hypothyroidism – Does Any Correlation Exist?
Manisha Mavai, Dr Bharti Bhandari , Anish Singhal, Sandeep K Mathur
Cureus.2021;[Epub] CrossRef
Sensibilidade ao glúten e tireoidite de Hashimoto: uma interação viável
Larissa Barros Pinto Franco, Fernanda Neves Pinto, Claudia Teresa Bento, Carla Viana Dendasck
Revista Científica Multidisciplinar Núcleo do Conhecimento.2021; : 110. CrossRef
Chronic urticaria and thyroid pathology
Sandra Nora Gonzalez-Diaz, Mario Sanchez-Borges, Diana Maria Rangel-Gonzalez, Rosa Ivett Guzman-Avilan, Jose Ignacio Canseco-Villarreal, Alfredo Arias-Cruz
World Allergy Organization Journal.2020; 13(3): 100101. CrossRef
Genome-Wide Analysis Identifies Two Susceptibility Loci for Positive Thyroid Peroxidase and Thyroglobulin Antibodies
Antonela Matana, Thibaud Boutin, Vesela Torlak, Dubravka Brdar, Ivana Gunjača, Ivana Kolčić, Vesna Boraska Perica, Ante Punda, Ozren Polašek, Maja Barbalić, Caroline Hayward, Tatijana Zemunik
The Journal of Clinical Endocrinology & Metabolism.2020; 105(3): 944. CrossRef
Iodine and bromine in fish consumed by indigenous peoples of the Russian Arctic
Nikita Sobolev, Andrey Aksenov, Tatiana Sorokina, Valery Chashchin, Dag G. Ellingsen, Evert Nieboer, Yulia Varakina, Elena Plakhina, Alexandra Onuchina, Magny Skinlo Thomassen, Yngvar Thomassen
Scientific Reports.2020;[Epub] CrossRef
Significance of arsenic and lead in Hashimoto's thyroiditis demonstrated on thyroid tissue, blood, and urine samples
Aleksandar Stojsavljević, Branislav Rovčanin, Jovana Jagodić, Danijela Drašković Radojković, Ivan Paunović, Marija Gavrović-Jankulović, Dragan Manojlović
Environmental Research.2020; 186: 109538. CrossRef
Prognostic Value of Caspase-1, Interleukin-1β, Tumor Necrosis Factor-α and Interleukin-18 Activity in Patients with Gastroesophageal Reflux Disease and Autoimmune Thyroiditis
T. M. Pasiieshvili, O. M. Kovaloyva, L. M. Pasiieshvili , N. M. Zhelezniakova
Ukraïnsʹkij žurnal medicini, bìologìï ta sportu.2020; 5(4): 202. CrossRef
A historical excursus of diagnostic methods for Hashimoto thyroiditis and Graves' disease
Maria Trovato
Gazzetta Medica Italiana Archivio per le Scienze Mediche.2020;[Epub] CrossRef
The value of preoperative antithyroidperoxidase antibody as a novel predictor of recurrence in papillary thyroid carcinoma
Eyun Song, Hye‐Seon Oh, Min Ji Jeon, Ki Wook Chung, Suck Joon Hong, Jin Sook Ryu, Jung Hwan Baek, Jeong Hyun Lee, Won Gu Kim, Won Bae Kim, Young Kee Shong, Tae Yong Kim
International Journal of Cancer.2019; 144(6): 1414. CrossRef
Hydatid cyst of the thyroid gland with tracheal fistula: A case report and review of the literature
Tiemin Jiang, Qiang Guo, Bo Ran, Ruiqing Zhang, Tuerganaili Aji, Yingmei Shao
Experimental and Therapeutic Medicine.2019;[Epub] CrossRef
Thyroid diseases and skin autoimmunity
Enke Baldini, Teresa Odorisio, Chiara Tuccilli, Severino Persechino, Salvatore Sorrenti, Antonio Catania, Daniele Pironi, Giovanni Carbotta, Laura Giacomelli, Stefano Arcieri, Massimo Vergine, Massimo Monti, Salvatore Ulisse
Reviews in Endocrine and Metabolic Disorders.2018; 19(4): 311. CrossRef
Does severe vitamin D deficiency impact obstetric outcomes in pregnant women with thyroid autoimmunity?
Halenur Bozdag, Esra Akdeniz
The Journal of Maternal-Fetal & Neonatal Medicine.2018; : 1. CrossRef
Constitutive Changes in Circulating Follicular Helper T Cells and Their Subsets in Patients with Graves’ Disease
Yan Liu, Xinwang Yuan, Xiaofang Li, Dawei Cui, Jue Xie
Journal of Immunology Research.2018; 2018: 1. CrossRef
Comorbidity of autoimmune thyroid disorders and psychiatric disorders during the postpartum period: a Danish nationwide register-based cohort study
V. Bergink, V. J. M. Pop, P. R. Nielsen, E. Agerbo, T. Munk-Olsen, X. Liu
Psychological Medicine.2018; 48(8): 1291. CrossRef
Spontaneous conversion from Graves’ disease to Hashimoto’s thyroiditis: a case report
Muharrem Bayrak, Kenan Çadırcı, Emine Kartal Baykan, Ünsal Aydın, Ayşe Çarlıoğlu
Ortadoğu Tıp Dergisi.2018; 10(1): 81. CrossRef
Role of T Follicular Helper (Tfh) Cells Plasticity in Autoimmune Thyroiditis among Hepatitis C Virus Infection
Helal F Hetta
Gastroenterology & Hepatology: Open Access.2017;[Epub] CrossRef
Variants of Interleukin-22 Gene Confer Predisposition to Autoimmune Thyroid Disease
Rong-hua Song, Qian Li, Wen Wang, Qiu-ming Yao, Xiao-qing Shao, Jin-an Zhang
International Journal of Endocrinology.2017; 2017: 1. CrossRef
Thyroid Involvement in Hepatitis C Virus-Infected Patients with/without Mixed Cryoglobulinemia
Clodoveo Ferri, Michele Colaci, Poupak Fallahi, Silvia Martina Ferrari, Alessandro Antonelli, Dilia Giuggioli
Frontiers in Endocrinology.2017;[Epub] CrossRef
Articles inEndocrinology and Metabolismin 2016
Won-Young Lee
Endocrinology and Metabolism.2017; 32(1): 62. CrossRef

PubReader
Cite

CITE

export Copy Format

Close

XML Download

Recent Advances in Autoimmune Thyroid Diseases