Hashimoto thyroiditis: clinical and diagnostic criteria.
Caturegli P,De Remigis A,Rose N R
Hashimoto thyroiditis (HT), now considered the most common autoimmune disease, was described over a century ago as a pronounced lymphoid goiter affecting predominantly women. In addition to this classic form, several other clinico-pathologic entities are now included under the term HT: fibrous variant, IgG4-related variant, juvenile form, Hashitoxicosis, and painless thyroiditis (sporadic or post-partum). All forms are characterized pathologically by the infiltration of hematopoietic mononuclear cells, mainly lymphocytes, in the interstitium among the thyroid follicles, although specific features can be recognized in each variant. Thyroid cells undergo atrophy or transform into a bolder type of follicular cell rich in mitochondria called Hürthle cell. Most HT forms ultimately evolve into hypothyroidism, although at presentation patients can be euthyroid or even hyperthyroid. The diagnosis of HT relies on the demonstration of circulating antibodies to thyroid antigens (mainly thyroperoxidase and thyroglobulin) and reduced echogenicity on thyroid sonogram in a patient with proper clinical features. The treatment remains symptomatic and based on the administration of synthetic thyroid hormones to correct the hypothyroidism as needed. Surgery is performed when the goiter is large enough to cause significant compression of the surrounding cervical structures, or when some areas of the thyroid gland mimic the features of a nodule whose cytology cannot be ascertained as benign. HT remains a complex and ever expanding disease of unknown pathogenesis that awaits prevention or novel forms of treatment.
Mechanisms of autoimmune thyroid diseases: from genetics to epigenetics.
Annual review of pathology
Recent advances in our understanding of genetic-epigenetic interactions have unraveled new mechanisms underlying the etiology of complex autoimmune diseases. Autoimmune thyroid diseases (AITDs) are highly prevalent, affecting 1% to 5% of the population. The major AITDs include Graves disease (GD) and Hashimoto's thyroiditis (HT); although these diseases contrast clinically, their pathogenesis involves shared immunogenetic mechanisms. Genetic data point to the involvement of both shared and unique genes. Among the shared susceptibility genes, HLA-DRβ1-Arg74 (human leukocyte antigen DR containing an arginine at position β74) confers the strongest risk. Recent genome-wide analyses have revealed new putative candidate genes. Epigenetic modulation is emerging as a major mechanism by which environmental factors interact with AITD susceptibility genes. Dissecting the genetic-epigenetic interactions underlying the pathogenesis of AITD is essential to uncover new therapeutic targets.
Influence of cigarette smoking on thyroid gland--an update.
Sawicka-Gutaj Nadia,Gutaj Paweł,Sowiński Jerzy,Wender-Ożegowska Ewa,Czarnywojtek Agata,Brązert Jacek,Ruchała Marek
Many studies have shown that cigarette smoking exerts multiple effects on the thyroid gland. Smoking seems to induce changes in thyroid function tests, like decrease in TSH and increase in thyroid hormones. However, these alterations are usually mild. In addition, tobacco smoking may also play a role in thyroid autoimmunity. Many studies have confirmed a significant influence of smoking on Graves' hyperthyroidism and particularly on Graves' orbitopathy. Here, smoking may increase the risk of disease development, may reduce the effectiveness of treatment, and eventually induce relapse. The role of smoking in Hashimoto's thyroiditis is not as well established as in Graves' disease. Nonetheless, lower prevalence of thyroglobulin antibodies, thyroperoxidase antibodies and hypothyroidism were found in smokers. These findings contrast with a study that reported increased risk of hypothyroidism in smokers with Hashimoto's thyroiditis. Moreover, cigarette smoking increases the incidence of multinodular goitre, especially in iodine-deficient areas. Some studies have examined cigarette smoking in relation to the risk of thyroid cancer. Interestingly, many of them have shown that smoking may reduce the risk of differentiated thyroid cancer. Furthermore, both active and passive smoking during pregnancy might modify maternal and foetal thyroid function. This review evaluates the current data concerning the influence of cigarette smoking on thyroid gland, including hormonal changes, autoimmunity and selected diseases. These findings, however, in our opinion, should be carefully evaluated and some of them are not totally evidence-based. Further studies are required to explain the effects of smoking upon thyroid pathophysiology.
Mechanisms in endocrinology: autoimmune thyroid disease: old and new players.
Effraimidis Grigoris,Wiersinga Wilmar M
European journal of endocrinology
The last 10 years have seen some progress in understanding the etiology of autoimmune thyroid disease (AITD). The female preponderance can now be explained - at least in part - by fetal microchimerism and X-chromosome inactivation. The number of identified susceptibility genes for AITD is increasing (among others now including TSHR, TG, HLA, CTLA4, PTPN22, CD40, FCRL3, IL2RA, and FOXP3), but these genes together probably do not explain more than about 10% of the heritability of AITD. As twin studies indicate that genes contribute for 70% of AITD, it follows that there must be many more loci, each of them contributing a little. While the genetic studies have clarified why various autoimmune diseases so often cluster in the same patient, the molecular mechanism of action of these genetic polymorphisms (frequently located in introns) has hardly been explained. Polymorphisms in AITD susceptibility genes may become helpful in clinical practice, e.g. in assessing risk of recurrent Graves' hyperthyroidism (GH) after a course of antithyroid drugs. Moderate alcohol intake decreases the risk on overt GH and overt Hashimoto's hypothyroidism. Current smokers - as well known - are at increased risk for Graves' disease, but - surprisingly - at diminished risk for Hashimoto's thyroiditis. Low selenium and low vitamin D levels might increase the risk of developing AITD, but data are still inconclusive. Current options for preventive interventions in subjects at risk to develop AITD are very limited.
Erythrovirus B19 and autoimmune thyroid diseases. Review of the literature and pathophysiological hypotheses.
Page Cyril,Duverlie Gilles,Sevestre Henri,Desailloud Rachel
Journal of medical virology
Erythrovirus B19 (EVB19) has been incriminated, over recent years, in the onset and/or pathogenesis of many diseases, especially autoimmune thyroid diseases. This review of the literature (published over the last 40 years using Pubmed and Science Direct search engines) was designed to define the role of EVB19, particularly in autoimmune thyroid diseases.Two cases of subacute thyroiditis, one case of Graves' disease (associated with type 1 diabetes and rheumatoid arthritis), and one case of Hashimoto's thyroiditis following acute EVB19 infection were reported. A retrospective case-control study in a pediatric population demonstrated the role of EVB19 in Hashimoto's thyroiditis. Four retrospective studies of pathology slides (including PCR, immunohistochemistry or in situ hybridization) and a prospective case-control study on pathology slides demonstrated the presence of EVB19 in thyroid tissue of patients with benign multinodular goiter, Graves' disease, autoimmune thyroiditis (including Hashimoto's thyroiditis), and thyroid cancer. EVB19 can be demonstrated in the thyroid gland in a wide range of diseases. Although acute EVB19 infection could theoretically trigger autoimmune thyroid disease, there is currently no evidence that EVB19 plays a specific role in the pathophysiology of autoimmune thyroid diseases.
The role of the immune system and cytokines involved in the pathogenesis of autoimmune thyroid disease (AITD).
Mikoś Hanna,Mikoś Marcin,Obara-Moszyńska Monika,Niedziela Marek
Autoimmune thyroid disease (AITD) is the most common organ-specific autoimmune disorder. AITD development occurs due to loss of immune tolerance and reactivity to thyroid autoantigens: thyroid peroxidase (TPO), thyroglobulin (TG) and thyroid stimulating hormone receptor (TSHR). This leads to infiltration of the gland by T cells and B cells that produce antibodies specific for clinical manifestations of hyperthyroidism in Graves' disease (GD) and chronic autoimmune thyroiditis (cAIT). In addition, T cells in Hashimoto's thyroiditis induce apoptosis in thyroid follicular cells, leading ultimately to the destruction of the gland. Cytokines are involved in the pathogenesis of thyroid diseases working in both the immune system and directly targeting the thyroid follicular cells. They are involved in the induction and effector phase of the immune response and inflammation, playing a key role in the pathogenesis of autoimmune thyroid disease. The presence of multiple cytokines has been demonstrated: IL-1alpha, IL-1b, IL-2, IL-4 , IL-6, IL-8, IL-10, IL-12, IL-13, IL-14, TNF-alpha and IFN-gamma within the inflammatory cells and thyroid follicular cells. Finally, cytokines derived from T cells can directly damage thyroid cells, leading to functional disorders and may also stimulate the production of nitric oxide (NO) and prostaglandin (PG), thus increasing the inflammatory response in AITD. Immunological mechanisms involved in the pathogenesis of AITD are strongly related to each other, but differences in the image of cAIT and GD phenotype are possibly due to a different type of immune response observed in these two counteracting clinical thyroid diseases. This article describes the potential role of cytokines and immune mechanisms in the pathogenesis of AITD.
Is Hashimoto's thyroiditis a risk factor for medullary thyroid carcinoma? Our experience and a literature review.
Zayed Ayman A,Ali Moaath K Mustafa,Jaber Omar I,Suleiman Moh'd J,Ashhab Ashraf A,Al Shweiat Wajdi Mohammed,Momani Munther Suliaman,Shomaf Maha,AbuRuz Salah Mohammed
The etiology of medullary thyroid carcinoma remains unknown. The aim of this study was to determine whether there is a significant association between medullary thyroid carcinoma and Hashimoto's thyroiditis in the histopathologic material of thyroidectomized patients. Retrospective cross-sectional study. In this study, we reviewed the medical records of all patients who underwent total thyroidectomy for different thyroid-related complaints between January 2000 and January 2012 at Jordan University Hospital-Amman, Jordan. To highlight relevant previously published studies addressing this topic, a literature search was conducted for English language studies reporting "medullary thyroid carcinoma" or "C-cell hyperplasia" in patients with Hashimoto's thyroiditis. Of the 863 patients with a mean age of 47.2 ± 12.3 years who underwent total thyroidectomy during the study period, 78 (9.04 %) were diagnosed with Hashimoto's thyroiditis, and 15 (1.74 %) had medullary thyroid carcinoma, 3 (20 %) of whom had coexistent Hashimoto's thyroiditis. A total of 683 (79.1 %) patients had benign thyroid disease, 67 (9.8 %) of whom had Hashimoto's thyroiditis. The difference between these rates was not statistically significant (p = 0.19). When examined by gender, 9 females had medullary thyroid carcinoma, 3 (33.3 %) of whom had coexistent Hashimoto's thyroiditis; by contrast, of 560 females with benign thyroid disease, 62 (11.1 %) had Hashimoto's thyroiditis (p = 0.04). Although this study population represents a small and single-institution experience, our results suggest that there might be an association between Hashimoto's thyroiditis and medullary thyroid carcinoma only in female patients who undergo total thyroidectomy.
Obesity in autoimmune diseases: not a passive bystander.
Versini Mathilde,Jeandel Pierre-Yves,Rosenthal Eric,Shoenfeld Yehuda
In the last decades, autoimmune diseases have experienced a dramatic increase in Western countries. The involvement of environmental factors is strongly suspected to explain this rise. Particularly, over the same period, obesity has followed the same outbreak. Since the exciting discovery of the secretory properties of adipose tissue, the relationship between obesity and autoimmunity and the understanding of the underlying mechanisms have become of major interest. Indeed, the fat tissue has been found to produce a wide variety of "adipokines", involved in the regulation of numerous physiological functions, including the immune response. By conducting a systematic literature review, we extracted 329 articles regarding clinical, experimental and pathophysiological data on the relationship between obesity, adipokines - namely leptin, adiponectin, resistin, visfatin - and various immune-mediated conditions, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), multiple sclerosis (MS), type-1 diabetes (T1D), psoriasis and psoriatic arthritis (PsA), and thyroid autoimmunity (TAI), especially Hashimoto thyroiditis (HT). The strongest levels of evidence support an increased risk of RA (OR=1.2-3.4), MS (OR=2), psoriasis and PsA (OR=1.48-6.46) in obese subjects. A higher risk of IBD, T1D and TAI is also suggested. Moreover, obesity worsens the course of RA, SLE, IBD, psoriasis and PsA, and impairs the treatment response of RA, IBD, psoriasis and PsA. Extensive clinical data and experimental models demonstrate the involvement of adipokines in the pathogenesis of these autoimmune diseases. Obesity appears to be a major environmental factor contributing to the onset and progression of autoimmune diseases.
[The importance of selenium in Hashimoto's disease].
Zagrodzki Paweł,Kryczyk Jadwiga
Postepy higieny i medycyny doswiadczalnej (Online)
The aim of this study was to present the current state of knowledge on the role of selenium in the treatment of Hashimoto's disease. In recent years, the number of cases of autoimmune Hashimoto's thyroiditis - a chronic disease that usually leads to hypothyroidism - has increased. Most patients have elevated levels of anti-TPO antibodies. The presence of these antibodies has an effect on subsequent thyroid damage. So far we have not developed an effective, standard therapy of this disease. However, more attention is being paid to the relationship between supplementation of selenium deficiency and inhibition of production of anti-TPO antibodies in patients with Hashimoto's thyroiditis. Therefore, selenium supplementation may be an effective option in the treatment of this disease.
Wiersinga Wilmar M
Autoimmune thyroid disease (AITD) is a multifactorial disease in which autoimmunity against thyroid antigens develops against a particular genetic background facilitated by exposure to environmental factors. Immunogenicity of the major thyroid antigens thyroid peroxidase, thyroglobulin (TG) and thyrotropin receptor (TSHR) is increased by genetic polymorphisms, a high number of antigenic peptides available for binding to human leukocyte antigen (HLA), and a high degree of glycosylation. Antigens bound to HLA are presented by antigen-presenting cells to T cell receptors. Further interaction between both cells is required via binding of CD40 ligand to CD40 and of B7-1/2 to CD28 for activation of T cells. Complex regulatory mechanisms serve to prevent an immune response directed against 'self'-antigens in the thymus (central tolerance) and in peripheral tissues (peripheral tolerance) with the help of regulatory T cells. Breakdown of tolerance to thyroid antigens can result in thyroid autoimmunity, which may happen in subjects who have the wrong genes and who are exposed to the wrong environment. Polymorphisms in thyroid genes (TG, TSHR) and immunoregulatory genes (HLA, CTLA4, PTPN22, CD40, FCRL3, IL2RA, FOXP3) would contribute for about 70% to AITD, and environmental exposures (like iodine, smoking, infections, parity) for the remaining 30%. Thyroid-infiltrating activated T cells may lead to cell-mediated immunity, thyroid injury and eventually hypothyroidism, whereas humoral immunity via TSHR-stimulating antibodies may give rise to hyperthyroidism. Pediatric Hashimoto's and Graves' disease are less prevalent than in adults, and the female preponderance is also less marked in children. The discrepancy is probably due to relatively less involvement of environmental insults in children, whereas the prevalence of risk alleles in AITD children is higher than in AITD adults.
Clinical aspects of Hashimoto's thyroiditis.
Hashimoto's thyroiditis (HT) is one of the commonest autoimmune endocrine diseases in the paediatric age group. It is considered a typical, organ-specific, autoimmune disease, characterized by autoimmune-mediated destruction of the thyroid gland. The diagnosis is suggested by a typical ultrasound pattern and by the presence of antithyroid antibodies. Attention must be taken with obese children as they may have an echographic pattern very similar to that observed in patients with HT, without being affected. HT is frequently associated with other autoimmune diseases such as alopecia, vitiligo, coeliac disease and type 1 insulin-dependent diabetes. Thyroid function at presentation may be variable, ranging from a transient hyperthyroid phase to frank hypothyroidism. Treatment with L-thyroxine should be started promptly in the presence of frank hypothyroidism while more debated is the optimal management of patients without symptoms and a normal free thyroxine but with a slightly elevated thyroid-stimulating hormone (TSH) between the upper reference level and 10 µU/ml. Since there is no convincing evidence to show negative effects on growth and cognitive function, a suggestion would be to avoid treatment with L-thyroxine unless TSH remains constantly above 10 µU/ml. More evidence is needed before treatment with selenium may be recommended.
Genetic variants of interleukin-4 gene in autoimmune thyroid diseases: an updated meta-analysis.
Shen Xiaokun,Yan Xingqiang,Xie Bojian,Xu Dong,Wang Kuifeng,Zhu Jiansheng,Li Jichen,Zhang Xiaohua,Cao Feilin
Autoimmune thyroid diseases (AITDs) including Graves' disease (GD) and Hashimoto's thyroiditis (HT) are common autoimmune endocrine disorders. Interleukin-4 (IL-4), a cytokine secreted by T cells, plays a critical role in antigen-specific Th2 responses. The IL-4 gene is highly polymorphic and it has been reported that the polymorphism at -590 (T/C, rs2243250) in the promoter region of IL-4 may contribute to the development of AITDs. Recently, several case-control studies have examined the association of genetic variants of IL-4 with AITDs. However, the results of these studies remain conflicting. To systematically study the role of IL-4 in the pathogenesis of AITDs, we conducted a meta-analysis including 11 eligible studies (1847 cases and 2068 healthy controls). Fixed-effect or random-effect models were used to calculate pooled odds ratios (ORs) with corresponding 95% confidence intervals (CIs). Our results revealed a significant association between the IL-4 genetic variant (-590, T/C, rs2243250) and the risk of developing AITDs (TC + TT versus TT genotype: OR = 1.83, 95% CI = 1.083-3.091, p = 0.024). These findings demonstrate that the IL-4 rs2243250 genetic variant might play a key role in the development of AITDs.
Hashimoto's thyroiditis and papillary thyroid cancer: are they immunologically linked?
Ehlers Margret,Schott Matthias
Trends in endocrinology and metabolism: TEM
Hashimoto's thyroiditis (HT) is the most common autoimmune disease in humans frequently leading to hypothyroidism. HT is characterized by a cellular immune response with lymphatic infiltration of the thyroid gland by T and B cells, as well as by a humoral immune response leading to specific antibody production. The synchronous appearance of HT and papillary thyroid cancer (PTC) indicates an immunological link between the two entities. Three different pathomechanisms may be postulated, including preexisting autoimmunity leading to malignancy due to inflammation, immunity towards preexisiting tumor cells leading to specific autoimmunity, and immune tolerance leading to malignancy despite (auto)immunity. In this article we review data describing these potential mechanisms that might lead to the synchronous appearance of HT and PTC.
Is vitamin D a player or not in the pathophysiology of autoimmune thyroid diseases?
D'Aurizio Federica,Villalta Danilo,Metus Paolo,Doretto Paolo,Tozzoli Renato
1,25-Dihydroxyvitamin D is a steroid hormone derived from vitamin D, playing an important role in maintaining an adequate serum level of calcium and phosphorus. It is now clear that vitamin D exerts an endocrine action on the cells of the immune system, generating anti-inflammatory and immunoregulatory effects. The mechanisms underlying the role of vitamin D in autoimmunity are not completely understood. Lower vitamin D levels have been found in several autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, type 1 diabetes mellitus, multiple sclerosis, inflammatory bowel diseases, autoimmune thyroid diseases (i.e. Hashimoto's thyroiditis and Graves' disease) and autoimmune gastritis. Several genetic studies have demonstrated an association between thyroid autoimmunity susceptibility and gene polymorphisms of vitamin D receptor, vitamin D binding protein, 1-alpha-hydroxylase and 25-hydroxylase. Of note, some papers do not confirm this connection. With regard to the role of vitamin D in autoimmune thyroid diseases, available data remain controversial. Only few reports have analyzed the supposed association between autoimmune thyroid diseases and vitamin D concentration with inconclusive results. In our experience, low serum levels of vitamin D do not correlate either with Hashimoto's thyroiditis or with Graves' disease. The inability to achieve an unambiguous conclusion is in part due to the limitations in study design. In fact, most of the studies are cross-sectional surveys with a small number of subjects. In addition, the heterogeneity of the study population, seasonal variation of blood sampling, inter-method analytical variability of vitamin D assays and different definitions of vitamin D deficiency/insufficiency contribute to contradicting results. Therefore, further randomized, controlled, prospective trials are needed in order to demonstrate the causality of vitD in AITD and consequently the role of vitamin D supplementation in prevention or improvement of AITD, providing also information on the best formulation, dose and timing of supplementation.
Association of Hashimoto's thyroiditis and thyroid cancer.
Noureldine Salem I,Tufano Ralph P
Current opinion in oncology
PURPOSE OF REVIEW:The association of Hashimoto's thyroiditis and thyroid cancer remains an active focus of research and controversy. Since it was first proposed in 1955, numerous studies have explored the epidemiology and etiology of these concurrent disease processes. RECENT FINDINGS:The lymphocytic infiltration of Hashimoto's thyroiditis is frequently encountered in thyroid glands resected for a neoplasm. The most frequent association is noted with papillary thyroid cancer. Several recent studies performed on patients undergoing thyroidectomy with coexisting Hashimoto's thyroiditis report an increased prevalence of papillary thyroid cancer, with a favorable disease profile and an improved prognosis, particularly in women. Conversely, some population-based studies using fine-needle aspiration biopsy data report no linkage between serologic Hashimoto's thyroiditis and thyroid cancer, yet they are limited by the lack of definitive pathology. On the other hand, the significantly increased incidence of primary thyroid lymphomas in patients with Hashimoto's thyroiditis strongly suggests a pathogenetic link between this autoimmune disorder and malignant thyroid lymphoma. SUMMARY:The lymphocytic infiltration of Hashimoto's thyroiditis is frequently associated with papillary thyroid cancer and may indeed be a risk factor for developing this type of cancer. Nonetheless, a pathogenesis linking these diseases remains unclear. The relationship between thyroid lymphoma and Hashimoto's thyroiditis appears to be well established.
Autoimmune thyroid disorders.
Antonelli Alessandro,Ferrari Silvia Martina,Corrado Alda,Di Domenicantonio Andrea,Fallahi Poupak
Autoimmune thyroid diseases (AITD) result from a dysregulation of the immune system leading to an immune attack on the thyroid. AITD are T cell-mediated organ-specific autoimmune disorders. The prevalence of AITD is estimated to be 5%; however, the prevalence of antithyroid antibodies may be even higher. The AITD comprise two main clinical presentations: Graves' disease (GD) and Hashimoto's thyroiditis (HT), both characterized by lymphocytic infiltration of the thyroid parenchyma. The clinical hallmarks of GD and HT are thyrotoxicosis and hypothyroidism, respectively. The mechanisms that trigger the autoimmune attack to the thyroid are still under investigation. Epidemiological data suggest an interaction among genetic susceptibility and environmental triggers as the key factor leading to the breakdown of tolerance and the development of disease. Recent studies have shown the importance of cytokines and chemokines in the pathogenesis of AT and GD. In thyroid tissue, recruited T helper 1 (Th1) lymphocytes may be responsible for enhanced IFN-γ and TNF-α production, which in turn stimulates CXCL10 (the prototype of the IFN-γ-inducible Th1 chemokines) secretion from the thyroid cells, therefore creating an amplification feedback loop, initiating and perpetuating the autoimmune process. Associations exist between AITD and other organ specific (polyglandular autoimmune syndromes), or systemic autoimmune disorders (Sjögren's syndrome, rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, cryoglobulinemia, sarcoidosis, psoriatic arthritis). Moreover, several studies have shown an association of AITD and papillary thyroid cancer. These data suggest that AITD patients should be accurately monitored for thyroid dysfunctions, the appearance of thyroid nodules, and other autoimmune disorders.
Vitamin D and thyroid disease: to D or not to D?
Muscogiuri G,Tirabassi G,Bizzaro G,Orio F,Paschou S A,Vryonidou A,Balercia G,Shoenfeld Y,Colao A
European journal of clinical nutrition
The main role of vitamin D is to maintain calcium and phosphorus homeostasis, thus preserving bone health. Recent evidence has demonstrated that vitamin D may also have a role in a variety of nonskeletal disorders such as endocrine diseases and in particular type 1 diabetes, type 2 diabetes, adrenal diseases and polycystic ovary syndrome. Low levels of vitamin D have also been associated with thyroid disease, such as Hashimoto's thyroiditis. Similarly, patients with new-onset Graves' disease were found to have decreased 25-hydroxyvitamin D concentrations. Impaired vitamin D signaling has been reported to encourage thyroid tumorigenesis. This review will focus on the role of vitamin D in thyroid diseases, both autoimmune diseases and thyroid cancer, and will summarize the results of vitamin D supplementation studies performed in patients with thyroid disorders. Although observational studies support a beneficial role of vitamin D in the management of thyroid disease, randomized controlled trials are required to provide insight into the efficacy and safety of vitamin D as a therapeutic tool for this dysfunction.
Selenium: an element for life.
Duntas Leonidas H,Benvenga Salvatore
This review aims to illustrate the importance of selenium (Se) for maintenance of overall health, especially for the thyroid, immunity, and homeostasis. Furthermore, it outlines the role of Se in reproduction and in virology and discusses the effects of Se supplementation in critical illness. The multifaceted aspects of this essential nutrient have attracted worldwide clinical and research interest in the last few decades. Se exerts its activity in the form of the aminoacid selenocysteine incorporated in selenoproteins. The impact of Se administration should be considered in relation to its apparent U shaped effects, i.e., exhibiting major advantages in Se-deficient individuals but specific health risks in those with Se excess. Addition of selenium to the administration of levothyroxine may be useful in patients with low Se intake and with mild-form or early-stage Hashimoto's thyroiditis (HT). Serum Se concentration (possibly also at tissue level) decreases in inflammatory conditions and may vary with the severity and duration of the inflammatory process. In such cases, the effect of Se supplementation seems to be useful and rational. Meanwhile, Se's ability to improve the activity of T cells and the cytotoxicity of natural killer cells could render it effective in viral disease. However, the evidence, and this should be stressed, is at present conflicting as to whether Se supplementation is of benefit in patients with HT, though there are indications that it is advantageous in cases of mild/moderate Graves' Orbitopathy. The role of Se in type 2 diabetes mellitus (T2DM) is ambiguous, driven by both Se intake and serum levels. The evidence that insulin and glycaemia influence the transport and activity of Se, via regulatory activity on selenoproteins, and that high serum Se may have a diabetogenic effect suggests a 'Janus-effect' of Se in T2DM. Though the evidence is not as yet clear-cut, the organic form (selenomethionine), due to its pharmacokinetics, is likely to be more advantageous in long-term prevention, and supplementation efforts, while the inorganic form (sodium selenite) has proven effective in an acute, e.g., sepsis, clinical setting. Recent data indicate that functional selenoprotein single-nucleotide polymorphisms (SNPs) may interfere with Se utilization and effectiveness.
Autoimmune thyroid disease: mechanism, genetics and current knowledge.
Dong Y H,Fu D G
European review for medical and pharmacological sciences
Recent epidemiological studies recognized a steady increase in the incidence of different autoimmune endocrine disorders, including autoimmune thyroid disease (AITD). The etiology of AITD is multifactorial and involves genetic and environmental factors and apparently with a strong preponderance in females. There are mainly two types of AITD, Graves' disease and Hashimoto's disease and both of these show strong association in age groups above 45-50 years. Among environmental factors smoking and alcohol have significant effects, both protective as well as for aggravating the disease, even though the precise nature of these effects are not clearly known. There are elevated levels of circulating antibodies against the thyroid proteins, mainly thyroid oxidase, thyroglobulin and thyroid stimulating hormone receptor, in patients with Graves' disease or Hashimoto's disease. Linkage and association studies in AITD identified several major genes that are relevant for the onset of AITD, including the thyroid-specific genes, thyroglobulin and thyroid-stimulating hormone receptor and also many immune-regulatory genes. In this review we addressed many aspects of AITD including disease mechanisms, involved thyroid antigens, environmental factors and genetic factors.
Interleukin 35-Producing B Cells (i35-Breg): A New Mediator of Regulatory B-Cell Functions in CNS Autoimmune Diseases.
Egwuagu Charles E,Yu Cheng-Rong
Critical reviews in immunology
Neuroinflammation contributes to neuronal deficits in neurodegenerative CNS (central nervous system) autoimmune diseases, such as multiple sclerosis and uveitis. The major goal of most treatment modalities for CNS autoimmune diseases is to limit inflammatory responses in the CNS; immune-suppressive drugs are the therapy of choice. However, lifelong immunosuppression increases the occurrence of infections, nephrotoxicity, malignancies, cataractogenesis, and glaucoma, which can greatly impair quality of life for the patient. Biologics that target pathogenic T cells is an alternative approach that is gaining wide acceptance as indicated by the popularity of a variety of Food and Drug Administration (FDA)-approved anti-inflammatory compounds and humanized antibodies such as Zenapax, Etanercept, Remicade, anti-ICAM, rapamycin, or tacrolimus. B cells are also potential therapeutic targets because they provide costimulatory signals that activate pathogenic T cells and secrete cytokines that promote autoimmune pathology. B cells also produce autoreactive antibodies implicated in several organ-specific and systemic autoimmune diseases including lupus erythematosus, Graves' disease, and Hashimoto's thyroiditis. On the other hand, recent studies have led to the discovery of several regulatory B-cell (Breg) populations that suppress immune responses and autoimmune diseases. In this review, we present a brief overview of Breg phenotypes and in particular, the newly discovered IL35-producing regulatory B cell (i35-Breg). We discuss the critical roles played by i35-Bregs in regulating autoimmune diseases and the potential use of adoptive Breg therapy in CNS autoimmune diseases.
Immune disorders in Hashimoto's thyroiditis: what do we know so far?
Pyzik Aleksandra,Grywalska Ewelina,Matyjaszek-Matuszek Beata,Roliński Jacek
Journal of immunology research
This review of literature attempts to identify the factors that are involved in the pathogenesis of Hashimoto thyroiditis, an immune defect in an individual with genetic susceptibility accompanied with environmental factors. The frequency of Hashimoto's disease is a growing trend and among Caucasians it is estimated at approximately 5%. The dysfunction of the gland may be clinically evident (0.1-2% of the population) or subclinical (10-15%). The pathology is diagnosed five to ten times more often in women than men and its incidence increases with the age (the peak of the number of cases is between 45 and 65); however, it can also be diagnosed in children. The pathogenesis of Hashimoto's thyroiditis is still not fully comprehended. In the etiology of Hashimoto thyroiditis excessively stimulated T CD4+ cells are known to play the most important role. Recent research has demonstrated an increasing role of newly discovered cells such as Th17 (CD4+IL-17+) or T regulatory cells (CD4+CD25+(high)FoxP3+) in the induction of autoimmune disorders. The process of programmed cell death also plays an equally important role in the pathogenesis and the development of hypothyroidism.
Vitamin D in thyroid disorders.
Kmieć P,Sworczak K
Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association
Vitamin D's canonical role are its effects exerted on the musculoskeletal system. In the last decades the importance of this hormone has been studied in the context of extraskeletal health. Hypovitaminosis D and several polymorphic variants of genes coding proteins crucial in the transport, metabolism and effects of vitamin D have been associated with negative health outcomes.In this review the current state of knowledge on the role of vitamin D in thyroid disorders is presented. The review is based on a literature search of the PubMed database performed in December 2014. The following search terms were used in conjunction with 'vitamin D': thyroid cancer, Graves', Hashimoto, thyroiditis, autoimmune thyroid, AITD, nodules, hyperthyroidism, and hypothyroidism.Currently, similarly to other extraskeletal health outcomes, a clear role of vitamin D has not been demonstrated in thyroid disorders. Further research is necessary to fully elucidate the importance of vitamin D in case of thyroid disease.
Immunogenetics of autoimmune thyroid diseases: A comprehensive review.
Lee Hanna J,Li Cheuk Wun,Hammerstad Sara Salehi,Stefan Mihaela,Tomer Yaron
Journal of autoimmunity
Both environmental and genetic triggers factor into the etiology of autoimmune thyroid disease (AITD), including Graves' disease (GD) and Hashimoto's thyroiditis (HT). Although the exact pathogenesis and causative interaction between environment and genes are unknown, GD and HT share similar immune-mediated mechanisms of disease. They both are characterized by the production of thyroid autoantibodies and by thyroidal lymphocytic infiltration, despite being clinically distinct entities with thyrotoxicosis in GD and hypothyroidism in HT. Family and population studies confirm the strong genetic influence and inheritability in the development of AITD. AITD susceptibility genes can be categorized as either thyroid specific (Tg, TSHR) or immune-modulating (FOXP3, CD25, CD40, CTLA-4, HLA), with HLA-DR3 carrying the highest risk. Of the AITD susceptibility genes, FOXP3 and CD25 play critical roles in the establishment of peripheral tolerance while CD40, CTLA-4, and the HLA genes are pivotal for T lymphocyte activation and antigen presentation. Polymorphisms in these immune-modulating genes, in particular, significantly contribute to the predisposition for GD, HT and, unsurprisingly, other autoimmune diseases. Emerging evidence suggests that single nucleotide polymorphisms (SNPs) in the immunoregulatory genes may functionally hinder the proper development of central and peripheral tolerance and alter T cell interactions with antigen presenting cells (APCs) in the immunological synapse. Thus, susceptibility genes for AITD contribute directly to the key mechanism underlying the development of organ-specific autoimmunity, namely the breakdown in self-tolerance. Here we review the major immune-modulating genes that are associated with AITD and their potential functional effects on thyroidal immune dysregulation.
Selenium and the thyroid.
Current opinion in endocrinology, diabetes, and obesity
PURPOSE OF REVIEW:This article provides an update on the role of the essential trace element selenium and its interaction with the other trace elements iodine and iron that together contribute to adequate thyroid hormone status. Synthesis, secretion, metabolism and action of thyroid hormone in target tissues depend on a balanced nutritional availability or supplementation of these elements. Selenium status is altered in benign and malignant thyroid diseases and various selenium compounds have been used to prevent or treat widespread diseases such as goiter, autoimmune thyroid disease or thyroid cancer. RECENT FINDINGS:Several studies, most with still too low numbers of cases, indicate that selenium administration in both autoimmune thyroiditis (Hashimoto thyroiditis) and mild Graves' disease improves clinical scores and well-being of patients and reduces thyroperoxidase antibody titers. However, published results are still conflicting depending on basal selenium status, dose, time and form of selenium used for intervention. Evidence for sex-specific selenium action, lack of beneficial effects in pregnancy and contribution of genetic polymorphisms (selenoprotein S) has been presented. SUMMARY:Adequate nutritional supply of selenium that saturates expression of circulating selenoprotein P, together with optimal iodine and iron intake, is required for a healthy and functional thyroid during development, adolescence, adulthood and aging.
The Pathogenesis of Hashimoto's Thyroiditis: Further Developments in our Understanding.
Ajjan R A,Weetman A P
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme
Hashimoto's thyroiditis (HT) is part of a spectrum of thyroid autoimmune conditions and this review provides an update on the latest developments in the field. HT has a genetic predisposition with a number of immune-related and thyroid-specific genes conferring disease susceptibility. However, disentangling genes with protective and predisposing effect is a complex process that requires further work. The recent increase in the incidence of HT implicates environmental factors in disease pathogenesis including improved hygiene, increased dietary iodine intake, new treatment modalities and chemical agents. Additional unmodifiable predisposing factors include stress, climate, age and gender. Both cellular and humoral immunity play a role in HT pathogenesis. Defects in T regulatory cells and increased activation of follicular helper T cells may have a role in disease initiation/perpetuation. Infiltrating lymphocytes can be directly cytotoxic to thyroid follicular cells (TFC) or may affect cell viability/function indirectly through cytokine production, which alters TFC integrity and modulates their metabolic and immune function. Thyroid peroxidase and thyroglobulin antibodies are present in the majority of HT patients and help with management decisions. Antibodies against the sodium iodide symporter and pendrin are present in a minority with little known about their clinical relevance. In addition to immune cells, recent work has identified DNA fragments, generated following cell death, and micro RNA as potential factors in HT pathogenesis. Despite the large number of studies, the mechanistic pathways in HT are still not fully understood and further work is required to enhance our knowledge and identify novel preventative and therapeutic clinical targets.
The Role of Iodine and Selenium in Autoimmune Thyroiditis.
Duntas L H
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme
Iodine and selenium (Se) are both essential elements to thyroid hormone economy, while they represent key players in the development of autoimmune thyroiditis.Chronic high iodine intake has been associated in various studies with increased frequency of autoimmune thyroiditis. In susceptible individuals, iodine excess increases intra-thyroid infiltrating Th17 cells and inhibits T regulatory (TREG) cells development, while it triggers an abnormal expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in thyrocytes, thus inducing apoptosis and parenchymal destruction. As was shown in a mouse model, high iodine supply leads to changes in the immunogenicity of the thyroglobulin molecule, upregulation of vascular intercellular adhesion molecule-1 (ICAM-1), and reactive oxygen species (ROS) generation in the thyrocytes. Serum Se levels were found decreased in Hashimoto thyroiditis and especially in Graves' disease as well as in thyroid-associated ophthalmopathy patients, the levels being related to the pathogenesis and outcome. Selenium is strongly involved, via the variable selenoproteins, in antioxidant, redox, and anti-inflammatory processes. Selenium enhances CD4+/CD25 FOXP3 and T regulatory cells activity while suppressing cytokine secretion, thus preventing apoptosis of the follicular cells and providing protection from thyroiditis. Selenium supplementation may be useful in autoimmune thyroid diseases, though, while usually well-tolerated, it should not be universally recommended, and it is also likely to be helpful for those with low Se status and autoimmunity. Broadly speaking, the achievement and maintenance of "selenostasis" as well as adequate urinary iodine excretion are mandatory to control disease, while, putatively, they may additionally be critical to preventing disease.
In children with Hashimoto's thyroiditis the evolution over time of thyroid status may differ according to the different presentation patterns.
Zirilli Giuseppina,Velletri Maria Rosa,Porcaro Federica,Candela Gilberto,Maisano Pina,La Monica Giuseppina
Acta bio-medica : Atenei Parmensis
AIM:to report the salient literature news concerning the relationships between thyroid function presenting patterns and subsequent biochemical evolution of Hashimoto's thyroiditis (HT) in pediatric age. DESIGN:the most recent reports from pediatric literature concerning biochemical thyroid function patterns at HT presentation and their spontaneous changes over time were analyzed and shortly commented. RESULTS:from the analysis of pediatric literature on this theme, it emerges that HT in children may present with a very heterogeneous biochemical picture ranging from overt hypothyroidism to overt hyperthyroidism. The presenting biochemical pattern may also condition its subsequent evolution over time. CONCLUSIONS:a) the most common biochemical pattern at HT diagnosis in children is euthyroidism, followed by overt hypothyroidism, subclinical hypothyroidism (SH) and hyperthyroidism; b) the association with HT negatively affects the evolution over time of SH; c) in the cases with either Turner syndrome or Down syndrome the evolution over time of SH is more severe than in those without these chromosomopathies.
The role of natural killer cells in pathogenesis of autoimmune diseases.
Popko Katarzyna,Górska Elżbieta
Central-European journal of immunology
There is growing evidence that NK cell-mediated immunoregulation plays an important role in the control of autoimmunity. NK cells are a subset of lymphocytes that generally contribute to innate immunity but have also a great impact on the function of T and B lymphocytes. The major role of NK cells is cytotoxic reaction against neoplastic, infected and autoreactive cells, but they regulatory function seems to play more important role in the pathogenesis of autoimmune diseases. Numerous studies suggested the involvement of NK cells in pathogenesis of such a common autoimmune diseases as juvenile rheumatoid arthritis, type I diabetes and autoimmune thyroid diseases. The defects of NK cells regulatory function as well as cytotoxic abilities are common in patients with autoimmune diseases with serious consequences including HLH hemophagocytic lymphocytosis (HLH) and macrophage activation syndrome (MAS). The early diagnosis of NK cells defect responsible for the loss of the protective abilities is crucial for the prevention of life-threatening complications and implementation of necessary treatment.
Novel Therapies for Thyroid Autoimmune Diseases.
Fallahi Poupak,Ferrari Silvia Martina,Elia Giusy,Nasini Francesco,Colaci Michele,Giuggioli Dilia,Vita Roberto,Benvenga Salvatore,Ferri Clodoveo,Antonelli Alessandro
Expert review of clinical pharmacology
C-X-C chemokine receptor (CXCR)3 and its interferon(IFN)γ-dependent chemokines (CXCL10, CXCL9, CXCL11) are implicated in the immune-pathogenesis of autoimmune thyroiditis (AT), Graves disease (GD) and Graves Ophthalmopathy (GO). In tissue, recruited Th1 lymphocytes produce IFNγ, enhancing the tissue secretion of IFNγ-inducible chemokines, initiating and perpetuating the autoimmune process. Patients with AT (with hypothyroidism), and with GO and GD, particularly in the active phase, have high IFNγ-inducible chemokines. Peroxisome proliferator-activated receptor (PPAR)γ or -α agonists and methimazole exert an immune-modulation on CXCR3 chemokines in AT, GD and GO. Other studies are ongoing to evaluate new molecules acting as antagonists of CXCR3, or blocking CXCL10, in Hashimoto thyroiditis (HT), GD and GO. Recently, novel molecules targeting the various agents involved in the pathogenesis of GO, such as rituximab, have been proposed as an alternative to corticosteroids. However, randomized and controlled studies are needed to generalize these interesting results.
Ultrasonography in the diagnosis of Hashimoto's thyroiditis.
Wu Guihua,Zou Dazhong,Cai Haiyun,Liu Yajun
Frontiers in bioscience (Landmark edition)
Hashimoto's thyroiditis is a type of autoimmune thyroid disease with an increasing prevalence in past decades. Its diagnosisis mostly based on ultrasonography. Ultrasonography is a useful and essential tool to make this diagnosis based on the characteristics of the disease. In the differential diagnosis of thyroid nodules, ultrasound-guided fine-needle biopsy is an effective method to distinguish Hashimoto's thyroiditis from other thyroid disorders. One exciting and recent advance is that non-invasive ultrasound-based methods have supplemented fine-needle aspiration to diagnose Hashimoto's thyroiditis under more complex conditions. In this review, we discuss the recent advantages of ultrasonography in the diagnosis of Hashimoto's thyroiditis.
Recent Advances in Autoimmune Thyroid Diseases.
Yoo Won Sang,Chung Hyun Kyung
Endocrinology and metabolism (Seoul, Korea)
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.
The mutual cooperation of blood platelets and lymphocytes in the development of autoimmune thyroid diseases.
Tomczyńska Małgorzata,Saluk-Bijak Joanna
Acta biochimica Polonica
Autoimmune thyroid diseases include several distinct clinical entities, mainly Graves' disease and Hashimoto's thyroiditis. An incompetent immune response directed against the body's own tissues, and the production of antibodies against specific cell antigens accompanied by chronic inflammation, all occur in autoimmune thyroid diseases. The autoimmune process is induced by genetic and environmental factors that are difficult to identify and generates the development of concomitant diseases in other systems. Leukocyte activation and overproduction of inflammatory mediators, as well as improper levels of thyroid hormones, play an essential role in the chronic course of these diseases. The development of autoimmune thyroid diseases results from the impairment of the regulatory and suppressor functions of T-cells or NK cells and activation of B cells, or from the changes in the number of those cells. Many reports have shown the significant role of platelet-leukocyte interaction in inflammation. Autoantibodies react with target antigens in different kinds of cells, including blood platelets, and autoimmune processes can modulate the mutual cooperation of blood platelets and lymphocytes. The activity of blood platelets and lymphocytes is reciprocally regulated. It has been suggested that blood platelets can influence lymphocyte function by direct contact with receptors, and indirectly via soluble mediators. The interactions of platelet-immune cells (neutrophils, monocytes, lymphocyte and dendritic cells) can have a potent enhancing effect on immune cells functions.
Untangling thyroid autoimmunity through modeling and simulation.
Merrill Stephen J,Pandiyan Balamurugan
Frontiers in bioscience (Landmark edition)
Thyroid autoimmunity is characterized by a large number of identified factors, and determining the relative importance of genetics and environment, for instance, can be difficult. In addition, the definition and progression of the individual diseases can also be challenging, and questions such as "when to begin treatment" or even "should treatment be begun" can be problematic. One approach to handling situations in which there are many factors is utilizing mathematical modeling. In a model, quantities that are clinically measurable are related through equations, based on known and inferred relationships between the systems involved. ations where these relationships are complicated, the resulting simulations can provide information not previous recognized as logically resulting from those relationships. One advantage of this approach is that patient-specific parameter estimates can be used to personalize disease monitoring and treatment. In this paper, models involving Hashimoto's (autoimmune) thyroiditis, Graves' disease, and the roles of leptin, vitamin D, and adipose tissue are described. In the case of Hashimoto's, a model consisting of a system of differential equations is presented which allows a patient specific description of the progression of the disease. The conditions leading to Hashitoxicosis are also described through that model. The patient specific model of the treatment of Graves' disease is also described. Finally, the roles of the inflammatory adipokines, especially leptin, and vitamin D is explored as it relates to the initiation of thyroid autoimmunity. The result of this approach is an enhanced view of the initiation and progression of autoimmunity in the thyroid.
The pathogenesis of thyroid autoimmune diseases: New T lymphocytes - Cytokines circuits beyond the Th1-Th2 paradigm.
Li Qian,Wang Bin,Mu Kaida,Zhang Jin-An
Journal of cellular physiology
Autoimmune thyroid disease (AITD) is one of the most common organ-specific autoimmune disorders. It mainly manifests as Hashimoto's thyroiditis (HT) and Graves' disease (GD). HT is characteristic of hypothyroidism resulting from the destruction of the thyroid while GD is characteristic of hyperthyroidism due to excessive production of thyroid hormone induced by thyrotropin receptor-specific stimulatory autoantibodies. T lymphocytes and their secretory cytokines play indispensable roles in modulating immune responses, but their roles are often complex and full of interactions among distinct components of the immune system. Dysfunction of these T cells or aberrant expressions of these cytokines can cause the breakdown of immune tolerance and result in aberrant immune responses during the development of AITDs. This review summarizes recently identified T subsets and related cytokines and their roles in the pathogenesis of AITDs with the hope to provide a better understanding of the precise roles of notably identified T subsets in AITDs and facilitate the discovery of functional molecules or novel immune therapeutic targets for AITDs.
The Role of Surgery in Autoimmune Conditions of the Thyroid.
Gan Tong,Randle Reese W
The Surgical clinics of North America
The two most common autoimmune conditions of the thyroid include chronic lymphocytic (Hashimoto's) thyroiditis and Graves' disease. Both conditions can be treated medically, but surgery plays an important role. Hashimoto's thyroiditis and Graves' disease are mediated by autoantibodies that interact directly with the thyroid, creating inflammation and impacting thyroid function. Patients may develop large goiters with compressive symptoms or malignancy requiring surgical intervention. In addition, there are several surgical indications specific to Hashimoto's and Graves' Disease.
Sunshine vitamin and thyroid.
Nettore Immacolata Cristina,Albano Luigi,Ungaro Paola,Colao Annamaria,Macchia Paolo Emidio
Reviews in endocrine & metabolic disorders
Vitamin D exerts its canonical roles on the musculoskeletal system and in the calcium/phosphorus homeostasis. In the last years, increasing evidences suggested several extra-skeletal actions of this hormone, indicating that vitamin D may produce effects in almost all the body tissues. These are mediated by the presence of vitamin D receptor (VDR) and thanks to the presence of the 1-α-hydroxylase, the protein that converts the 25-hydroxyvitamin (calcidiol) to the active form 1,25-dihydroxyvitamin (calcitriol). Several studies evaluated the possible role of vitamin D in the pathogenesis of thyroid diseases, and this review will focus on the available data of the literature evaluating the association between vitamin D and thyroid function, vitamin D and autoimmune thyroid diseases, including Hashimoto's thyroiditis, Graves' disease and post-partum thyroiditis, and vitamin D and thyroid cancer.
Immunoglobulin G4-Related Thyroid Diseases.
Kottahachchi Dulani,Topliss Duncan J
European thyroid journal
Immunoglobulin G4-related disease (IgG4-RD) is a new disease category involving many organ systems, including the endocrine system in general and the thyroid in particular. Since an initial association was made between hypothyroidism and autoimmune (IgG4-related) pancreatitis, more forms of IgG4-related thyroid disease (IgG4-RTD) have been recognized. Four subcategories of IgG4-RTD have so far been identified: Riedel thyroiditis (RT), fibrosing variant of Hashimoto thyroiditis (FVHT), IgG4-related Hashimoto thyroiditis, and Graves disease with elevated IgG4 levels. Although a male predominance is seen for IgG4-RD in general, RT and FVHT have a female preponderance. The pathogenesis of IgG4-RD is not completely understood; however, genetic factors, antigen-antibody reactions, and an allergic phenomenon have been described. Diagnosis of IgG4-RD requires a combination of clinical features, serological evidence, and histological features. Histology is the mainstay of diagnosis, with IgG4 immunostaining. Although serum IgG4 levels are usually elevated in IgG4-RD, raised serum IgG4 is neither necessary nor adequate for diagnosis. Imaging supports the diagnosis and is a useful tool in disease monitoring. Management of IgG4-RTD is both medical and surgical. Steroids are the first-line treatment and may produce a swift response. Tamoxifen and rituximab are second-line agents used in steroid-resistant patients. Surgical debulking is carried out in RT solely as a procedure to relieve obstruction. Other endocrine associations described with IgG4-RD are hypophysitis and Hashimoto encephalopathy. IgG4-RTD is an uncommon disease entity, and prompt diagnosis and treatment can improve outcomes.
Multiple Nutritional Factors and the Risk of Hashimoto's Thyroiditis.
Hu Shiqian,Rayman Margaret P
Thyroid : official journal of the American Thyroid Association
BACKGROUND:Hashimoto's thyroiditis (HT) is considered to be the most common autoimmune disease. It is currently accepted that genetic susceptibility, environmental factors, and immune disorders contribute to its development. With regard to nutritional factors, evidence implicates high iodine intake and deficiencies of selenium and iron with a potential relevance of vitamin D status. To elucidate the role of nutritional factors in the risk, pathogenesis, and treatment of HT, PubMed and the Cochrane Library were searched for publications on iodine, iron, selenium, and vitamin D and risk/treatment of HT. SUMMARY:Chronic exposure to excess iodine intake induces autoimmune thyroiditis, partly because highly iodinated thyroglobulin (Tg) is more immunogenic. Recent introduction of universal salt iodization can have a similar, though transient, effect. Selenoproteins are essential to thyroid action. In particular, the glutathione peroxidases protect the thyroid by removing excessive hydrogen peroxide produced for Tg iodination. Genetic data implicate the anti-inflammatory selenoprotein S in HT risk. There is evidence from observational studies and randomized controlled trials that selenium/selenoproteins can reduce thyroid peroxidase (TPO)-antibody titers, hypothyroidism, and postpartum thyroiditis. Iron deficiency impairs thyroid metabolism. TPO, the enzyme responsible for the production of thyroid hormones, is a heme (iron-containing) enzyme which becomes active at the apical surface of thyrocytes only after binding heme. HT patients are frequently iron deficient, since autoimmune gastritis, which impairs iron absorption, is a common co-morbidity. Treatment of anemic women with impaired thyroid function with iron improves thyroid-hormone concentrations, while thyroxine and iron together are more effective in improving iron status. Lower vitamin D status has been found in HT patients than in controls, and inverse relationships of serum vitamin D with TPO/Tg antibodies have been reported. However, other data and the lack of trial evidence suggest that low vitamin D status is more likely the result of autoimmune disease processes that include vitamin D receptor dysfunction. CONCLUSIONS:Clinicians should check patients' iron (particularly in menstruating women) and vitamin D status to correct any deficiency. Adequate selenium intake is vital in areas of iodine deficiency/excess, and in regions of low selenium intake a supplement of 50-100 μg/day of selenium may be appropriate.
A concise review of Hashimoto thyroiditis (HT) and the importance of iodine, selenium, vitamin D and gluten on the autoimmunity and dietary management of HT patients.Points that need more investigation.
Liontiris Michael I,Mazokopakis Elias E
Hellenic journal of nuclear medicine
Hashimoto's thyroiditis (HT) is a chronic autoimmune thyroid disease caused by an interaction between genetic factors and environmental conditions, both of which are yet to be fully understood. The management of HT depends on its clinical manifestations, commonly including diffuse or nodular goiter with euthyroidism, subclinical hypothyroidism and permanent hypothyroidism. However, in most cases of patients with HT, lifelong levothyroxine substitution is required. The additional role of diet for the management of HT is usually overlooked. A literature search regarding the importance and the influence of iodine, selenium, vitamin D and gluten on HT was conducted. In HT careful supplementation of possible deficiencies is recommended for the dietary management of these patients. The use of a diet low in gluten among HT patients with or without celiac disease (CD) is discussed.
Painful Hashimoto's thyroiditis: myth or reality?
Rotondi M,Capelli V,Locantore P,Pontecorvi A,Chiovato L
Journal of endocrinological investigation
Neck pain is a common complain, being in most cases due to non-thyroidal causes. However, a minority of patients suffer from painful thyroid diseases. Among them, sub-acute thyroiditis (SAT) is the most frequent one. Rare thyroid-related causes of neck pain include hemorrhage within a thyroid nodule as well as Riedel's thyroiditis and suppurative thyroiditis. In the last 30 years, a few cases of a painful variant of Hashimoto's thyroiditis (HT) have been described. Biochemical, ultrasound, and histologic features were clearly suggestive for HT in all of the published cases and definitely ruled out the diagnosis of SAT. While sound descriptions of painful HT are present in the literature, it is important to emphasize that only 20 cases were reported from the year 2000 until now. The condition, however, is clinically relevant because neck pain was reported to be refractory both to steroids and to other analgesic drugs, being thyroidectomy the only effective treatment for pain relief in these patients. This short review analyzes currently available data supporting a role for HT as a rare cause of neck pain.
The Emerging Role of Epigenetics in Autoimmune Thyroid Diseases.
Wang Bin,Shao Xiaoqing,Song Ronghua,Xu Donghua,Zhang Jin-An
Frontiers in immunology
Autoimmune thyroid diseases (AITD) are a group of both B cell- and T cell-mediated organ-specific autoimmune diseases. Graves' disease and Hashimoto thyroiditis are the two main clinical presentations of AITD. Both genetic and environmental factors have important roles in the development of AITD. Epigenetics have been considered to exert key roles in integrating those genetic and environmental factors, and epigenetic modifications caused by environmental factors may drive genetically susceptibility individuals to develop AITD. Recent studies on the epigenetics of AITD have provided some novel insights into the pathogenesis of AITD. The aim of this review is to provide an overview of recent advances in the epigenetic mechanisms of AITD, such as DNA methylation, histone modifications, and non-coding RNAs. This review highlights the key roles of epigenetics in the pathogenesis of AITD and potential clinical utility. However, the epigenetic roles in AITD are still not fully elucidated, and more researches are needed to provide further deeper insights into the roles of epigenetics in AITD and to uncover new therapeutic targets. Although there are many studies assessing the epigenetic modifications in AITD patients, the clinical utility of epigenetics in AITD remains poorly defined. More studies are needed to identify the underlying epigenetic modifications that can contribute to accurate diagnosis of AITD, adequate choice of treatment approach, and precise prediction of treatment outcomes.
Thyroid Autoimmunity: Role of Anti-thyroid Antibodies in Thyroid and Extra-Thyroidal Diseases.
Fröhlich Eleonore,Wahl Richard
Frontiers in immunology
Autoimmune diseases have a high prevalence in the population, and autoimmune thyroid disease (AITD) is one of the most common representatives. Thyroid autoantibodies are not only frequently detected in patients with AITD but also in subjects without manifest thyroid dysfunction. The high prevalence raises questions regarding a potential role in extra-thyroidal diseases. This review summarizes the etiology and mechanism of AITD and addresses prevalence of antibodies against thyroid peroxidase, thyroid-stimulating hormone receptor (TSHR), and anti-thyroglobulin and their action outside the thyroid. The main issues limiting the reliability of the conclusions drawn here include problems with different specificities and sensitivities of the antibody detection assays employed, as well as potential confounding effects of altered thyroid hormone levels, and lack of prospective studies. In addition to the well-known effects of TSHR antibodies on fibroblasts in Graves' disease (GD), studies speculate on a role of anti-thyroid antibodies in cancer. All antibodies may have a tumor-promoting role in breast cancer carcinogenesis despite anti-thyroid peroxidase antibodies having a positive prognostic effect in patients with overt disease. Cross-reactivity with lactoperoxidase leading to induction of chronic inflammation might promote breast cancer, while anti-thyroid antibodies in manifest breast cancer might be an indication for a more active immune system. A better general health condition in older women with anti-thyroid peroxidase antibodies might support this hypothesis. The different actions of the anti-thyroid antibodies correspond to differences in cellular location of the antigens, titers of the circulating antibodies, duration of antibody exposure, and immunological mechanisms in GD and Hashimoto's thyroiditis.
C Cell and Follicular Epithelial Cell Precursor Lesions of the Thyroid.
Archives of pathology & laboratory medicine
CONTEXT:- The identification of precursor or dysplastic lesions in the thyroid is difficult. Pathology of the C cell has been extensively studied, and the preneoplastic nature of C-cell hyperplasia in the setting of familial medullary thyroid carcinomas is well established. However, the distinction between neoplastic and physiologic/reactive C-cell hyperplasia remains a challenge. Unlike C cells, the existence of a precursor lesion of follicular cell-derived tumors is less well established, and a dysplastic or preneoplastic follicular lesion has not been well defined. OBJECTIVE:- To discuss putative precursor lesions in the thyroid arising from C cells and follicular epithelial cells. DATA SOURCES:- Data were obtained from a review of the pertinent peer-reviewed literature. CONCLUSIONS:- Although the preneoplastic nature of C-cell hyperplasia in the setting of familial medullary thyroid carcinoma is well recognized, the preneoplastic nature/malignant potential of reactive/physiologic C-cell hyperplasia and its role in the development of sporadic, medullary thyroid carcinoma is still unclear. Current data suggest that benign follicular lesions may have malignant potential, and there may be a multifocal progression from benign to malignant. Atypical follicular lesions in the background of chronic lymphocytic thyroiditis may represent dysplastic or premalignant lesions.
Autoimmune Thyroiditis and Myasthenia Gravis.
Lopomo Angela,Berrih-Aknin Sonia
Frontiers in endocrinology
Autoimmune diseases (AIDs) are the result of specific immune responses directed against structures of the self. In normal conditions, the molecules recognized as "self" are tolerated by immune system, but when the self-tolerance is lost, the immune system could react against molecules from the body, causing the loss of self-tolerance, and subsequently the onset of AID that differs for organ target and etiology. Autoimmune thyroid disease (ATD) is caused by the development of autoimmunity against thyroid antigens and comprises Hashimoto's thyroiditis and Graves disease. They are frequently associated with other organ or non-organ specific AIDs, such as myasthenia gravis (MG). In fact, ATD seems to be the most associated pathology to MG. The etiology of both diseases is multifactorial and it is due to genetic and environmental factors, and each of them has specific characteristics. The two pathologies show many commonalities, such as the organ-specificity with a clear pathogenic effect of antibodies, the pathological mechanisms, such as deregulation of the immune system and the implication of the genetic predisposition. They also show some differences, such as the mode of action of the antibodies and therapies. In this review that focuses on ATD and MG, the common features and the differences between the two diseases are discussed.
Thyroid Autoimmunity and Thyroid Cancer: Review Focused on Cytological Studies.
Boi Francesco,Pani Fabiana,Mariotti Stefano
European thyroid journal
The association between Hashimoto thyroiditis (HT) and papillary thyroid carcinoma (PTC) has been originally suggested by retrospective pathological studies and has recently been re-evaluated and proposed on the basis of several fine-needle aspiration cytology (FNAC) studies. In FNAC studies, the association between HT and PTC is based on the comparison of anti-thyroid autoantibodies (ATA) (anti-thyroperoxidase [TPOAb] and anti-thyroglobulin [TgAb]), thyroid function (TSH), and cytology with histology of thyroid nodules and lymphocytic thyroid infiltration (LTI) of operated thyroid glands. Most of the pathological studies found a high prevalence rate of PTC in HT. In most FNAC studies, the risk ratio of PTC in HT patients was evaluated using multivariate statistical analysis: increased TSH levels represented the main and common independent risk factor of malignancy, although it resulted not consistently related to HT. On the other hand, several studies provided a positive relationship between ATA and PTC, particularly with TgAb. Two recent FNAC studies from the same referral center clearly demonstrated an independent risk for thyroid malignancy conferred by both TPOAb and TgAb, confirming the role of increased TSH levels, and found a significant association between PTC and ATA and diffuse LTI at histology. These studies are consistent with the hypothesis that autoimmune thyroid inflammation and increased serum TSH concentration may be involved in thyroid tumor growth. The complex relationship between HT and PTC, which involves immunological/hormonal pathogenic links, needs to be further investigated with prospective studies.
The Role of Vitamin D in Thyroid Diseases.
International journal of molecular sciences
The main role of vitamin D is regulating bone metabolism and calcium and phosphorus homeostasis. Over the past few decades, the importance of vitamin D in non-skeletal actions has been studied, including the role of vitamin D in autoimmune diseases, metabolic syndromes, cardiovascular disease, cancers, and all-cause mortality. Recent evidence has demonstrated an association between low vitamin D status and autoimmune thyroid diseases such as Hashimoto's thyroiditis and Graves' disease, and impaired vitamin D signaling has been reported in thyroid cancers. This review will focus on recent data on the possible role of vitamin D in thyroid diseases, including autoimmune thyroid diseases and thyroid cancers.
Autoimmune endocrine diseases.
Ruggeri Rosaria M,Giuffrida Giuseppe,Campennì Alfredo
The endocrine system is interested by several autoimmune diseases, characterized by different impact and severity, according to the organs involved. Autoimmune thyroid disorders (i.e. Hashimoto's thyroiditis and Graves' disease) and type 1 diabetes mellitus are the most common autoimmune endocrine disorders, while hypophysitis, adrenalitis (90% of cases of primary hypocortisolism or Addison's disease), POF and hypoparathyroidism represent quite rare conditions. Autoimmune endocrine diseases can also coexist in the same individuals and cluster in families. Some of these associations are nosologically codified in the so-called autoimmune polyglandular syndromes, but autoimmune endocrinopathies can also be accompanied by other non-endocrine autoimmune disorders (i.e. connective tissue, skin or gastrointestinal diseases). Pathophysiology generally results from a complex interplay among genetic predisposition and environmental/endogenous factors. In the diagnostic process, measurement of organ-specific autoantibodies, both with a causative role or as an epiphenomenon, is often fundamental and integrates the assessment of hormone axes and the targeted imaging studies.
Recent advances in understanding autoimmune thyroid disease: the tallest tree in the forest of polyautoimmunity.
Bliddal Sofie,Nielsen Claus Henrik,Feldt-Rasmussen Ulla
Autoimmune thyroid disease (AITD) is often observed together with other autoimmune diseases. The coexistence of two or more autoimmune diseases in the same patient is referred to as polyautoimmunity, and AITD is the autoimmune disease most frequently involved. The occurrence of polyautoimmunity has led to the hypothesis that the affected patients suffer from a generalized dysregulation of their immune system. The present review summarizes recent discoveries unravelling the immunological mechanisms involved in autoimmunity, ranging from natural autoimmunity to disease-specific autoimmunity. Furthermore, the clinical grounds for considering AITD in a setting of polyautoimmunity are explored. A better understanding of these may pave the way for designing new treatment modalities targeting the underlying immune dysregulation when AITD appears in the context of polyautoimmunity.
Hypothalamic-pituitary-thyroid (HPT) axis functioning in anxiety disorders. A systematic review.
Fischer Susanne,Ehlert Ulrike
Depression and anxiety
Depression has repeatedly been linked to subclinical hypothyroidism, and thyroid hormones have successfully been used to augment antidepressant treatment. By contrast, the extent of thyroid dysfunction in anxiety disorders remains less clear. This is surprising, given that anxiety-related symptoms (e.g., nervousness, palpitations, increased perspiration) are highly prevalent in hyperthyroidism. The present study was undertaken to synthesize the literature on hypothalamic-pituitary-thyroid (HPT) axis functioning in anxiety disorders. The PubMed and PsycINFO databases were systematically searched. Three types of studies were included: (1) "comorbidity studies" assessing the prevalence of thyroid disorders in individuals with anxiety disorders, (2) "case-control studies" comparing HPT parameters between patients and controls, and (3) "correlational studies" assessing self-reported anxiety levels and HPT parameters. Risk of bias was assessed via a standardized quality rating. Twenty studies were eligible. Nearly all found the comorbidity between anxiety and thyroid disorders was significant. Half of the studies additionally supported the notion of subtle thyroid dysfunction in that thyroid-stimulating hormone (TSH) responses to the administration of thyrotropin-releasing hormone (TRH) were blunted and an inverse relationship was observed between self-reported anxiety levels and TSH. Overall, HPT assessments were well conducted, but several studies failed to adjust their analyses for smoking, body mass index (BMI), and depression. The findings resonate well with clinical recommendations to routinely screen for thyroid disorders in patients with anxiety disorders, and with what is known from basic research about thyroid-brain interactions. The results of the risk of bias assessment underscore the importance of further high-quality experimental and longitudinal epidemiological research.
Infections, genetic and environmental factors in pathogenesis of autoimmune thyroid diseases.
Shukla Sanjeev Kumar,Singh Govind,Ahmad Shahzad,Pant Prabhat
In Autoimmune disease a combination of infection, genetic and environmental factors causes an autoimmune response to the thyroid gland (characterized by lymphocytic infiltrations), thyroid stimulating hormone receptor (TSHR) and different thyroid antigens. Graves' and Hashimoto disease are autoimmune disorders with genetic predisposition. CD40 that stimulates the proliferation and differentiation of lymphocytes is an essential immunomodulatory component for follicular cells in the thyroid and the cell that present the antigen. CD40, PTPN22 and thyroid-specific genes are immunomodulating genes for the TSH receptor and thyroglobulin. CD40 used to be associated with Graves's disease as positional candidate on the basis of Graves' disease linkage study connecting with 20q11 genome chromosomal region. The PTPN22 gene gives rise to a substantial risk of specific autoimmune phenotypes and frequent disease mechanisms. Infections have been implicated in the pathogenesis of AITD including Coxsackie virus, Yersinia enterocolitica, Borrelia burgdorferi, Helicobacter pylori and retroviruses (HTLV-1, HFV, HIV and SV40). Infectious hepatitis C agents are the strongest proof supporting an affiliation with AITD. The essential environmental triggers of AITD are iodine, drugs, infection, smoking and perhaps stress. Autoimmune disease provide important facts on genetic mechanisms that influence the prognosis and treatment of the disease and by recent molecular techniques through gene expression study by quantitative Real Time-PCR and microarray, we can identify novel genes which are responsible for Graves' and Hashimoto disease.
Thyroid Autoimmunity: An Interplay of Factors.
Merrill Stephen J,Minucci Sarah B
Vitamins and hormones
The literature on thyroid autoimmunity has identified many potential factors at play for the initiation and progression of autoimmune thyroid diseases. These factors include genetic susceptibility, environmental factors, some drugs, iodine and selenium, infection, molecular mimics, and immune system defects. The sheer number of feasible factors makes sorting out the necessary agents from the fellow travelers difficult. In addition, many of these factors have the capability to interact-further confusing the picture. Another difficulty in interpreting these data is that most proposed mechanisms are not able to accomplish the triggering event in which the tolerance to self-antigens is actually overcome. In addition, some findings may be describing the conditions present after a disease is diagnosed and may be consequences of the disease rather than a cause. Recent description of the role of adipokines, which include leptin, tumor necrosis factor-alpha, and interleukin-6, in contributing to the inflammatory environment of the thyroid, along with the presence of thyroid Toll-like receptors for pathogen-associated patterns have the potential to deliver that necessary adjuvant signal to break tolerance, seen as necessary in animal autoimmune models. An additional factor, vitamin D, due to its interaction both with white adipose tissue (WAT) and the immune system, has a complicated and somewhat controversial story with respect to thyroid autoimmunity. Conflicting results can result when not all factors are considered together. AIMS:To describe the many factors at play in thyroid autoimmunity and how they interact. CONCLUSION:Thyroid autoimmunity is the result of an interplay of factors, with adipokines produced by WAT and vitamin D providing immune modulating signals external to the thyroid, while thyrocyte innate responses to environmental conditions provide the necessary adjuvant signal. Shaping the response to be reactive to particular self-antigens and likelihood of a response are due to genetics and molecular mimics.
Association of Depression and Anxiety Disorders With Autoimmune Thyroiditis: A Systematic Review and Meta-analysis.
Siegmann Eva-Maria,Müller Helge H O,Luecke Caroline,Philipsen Alexandra,Kornhuber Johannes,Grömer Teja Wolfgang
Importance:With a prevalence of 4% to 13% in the United States, autoimmune thyroiditis (AIT) is a major health problem. Besides somatic complications, patients with AIT can also experience psychiatric disorders. The extent of these organic psychiatric diseases in patients with AIT, however, is so far not commonly known. Objective:To provide meta-analytic data on the association of depression and anxiety with AIT. Data Sources:Google Scholar, the EBSCO Host databases, the Web of Knowledge, and PubMed were searched from inception through December 5, 2017. Articles identified were reviewed and reference lists were searched manually. Study Selection:Case-control studies that reported the association between AIT and either depression or anxiety disorders or both were included. Data Extraction and Synthesis:Data extraction was performed by multiple observers following the PRISMA guidelines. Two univariate random-effects meta-analyses were performed, and moderators were tested with Bonferroni-corrected meta-regression analysis. Heterogeneity was assessed with the I2 statistic. Sensitivity analyses tested the robustness of the results. Small study effects were assessed with funnel plots and the Egger test. Main Outcomes and Measures:The odds ratio of patients with AIT and depression compared with a healthy control group, as well as the odds ratio of patients with AIT and anxiety disorders compared with a healthy control group. Results:Nineteen studies comprising 21 independent samples were included, with a total of 36 174 participants (35 168 for depression and 34 094 for anxiety). Patients with AIT, Hashimoto thyroiditis, or subclinical or overt hypothyroidism had significantly higher scores on standardized depression instruments, with an odds ratio of 3.56 (95% CI, 2.14-5.94; I2 = 92.1%). For anxiety disorders, patients with AIT, Hashimoto thyroiditis, or subclinical or overt hypothyroidism had an odds ratio of 2.32 (95% CI, 1.40-3.85; I2 = 89.8%). Funnel plot asymmetry was detected for studies of depression. Study quality assessed with the Newcastle-Ottawa Scale for case-control studies (mean [SD] score: anxiety, 5.77 [1.17]; depression, 5.65 [1.14]; of a possible maximum score of 9) and proportion of females did not modulate the meta-analytic estimate, whereas mean age did. Conclusions and Relevance:This meta-analysis establishes the association between AIT and depression and anxiety disorders. Patients with AIT exhibit an increased chance of developing symptoms of depression and anxiety or of receiving a diagnosis of depression and anxiety disorders. This finding has important implications for patients and could lead to the choice of early treatment-and not only psychotherapeutic treatment-of the organic disorder.
Selenoproteins in human body: focus on thyroid pathophysiology.
Valea Ana,Georgescu Carmen Emanuela
Hormones (Athens, Greece)
Selenium (Se) has a multilevel, complex and dynamic effect on the human body as a major component of selenocysteine, incorporated into selenoproteins, which include the selenocysteine-containing enzymes iodothyronine deiodinases. At the thyroid level, these proteins play an essential role in antioxidant protection and hormone metabolism. This is a narrative review based on PubMed/Medline database research regarding thyroid physiology and conditions with Se and Se-protein interferences. In humans, Se-dependent enzyme functions are best expressed through optimal Se intake, although there is gap in our knowledge concerning the precise mechanisms underlying the interrelation. There is a good level of evidence linking low serum Se to autoimmune thyroid diseases and, to a lesser extent, differentiated thyroid cancer. However, when it comes to routine supplementation, the results are heterogeneous, except in the case of mild Graves' orbitopathy. Autoimmune hypothyroidism is associated with a state of higher oxidative stress, but not all studies found an improvement of thyroid function after Se was introduced as antioxidant support. Meanwhile, no routine supplementation is recommended. Low Se intake is correlated with an increased risk of developing antithyroid antibodies, its supplementation decreasing their titres; there is also a potential reduction in levothyroxine replacement dose required for hypothyroidism and/or the possibility that it prevents progression of subclinical hypothyroidism, although not all studies agree. In thyroid-associated orbitopathy, euthyroidism is more rapidly achieved if the micronutrient is added to traditional drugs, while controls appear to benefit from the microelement only if they are deficient; thus, a basal assay of Se appears advisable to better select patients who need substitution. Clearly, further Se status biomarkers are required. Future introduction of individual supplementation algorithms based on baseline micronutrient levels, underlying or at-risk clinical conditions, and perhaps selenoprotein gene polymorphisms is envisaged.
Genome-Wide Association Studies of Autoimmune Thyroid Diseases, Thyroid Function, and Thyroid Cancer.
Hwangbo Yul,Park Young Joo
Endocrinology and metabolism (Seoul, Korea)
Thyroid diseases, including autoimmune thyroid diseases and thyroid cancer, are known to have high heritability. Family and twin studies have indicated that genetics plays a major role in the development of thyroid diseases. Thyroid function, represented by thyroid stimulating hormone (TSH) and free thyroxine (T4), is also known to be partly genetically determined. Before the era of genome-wide association studies (GWAS), the ability to identify genes responsible for susceptibility to thyroid disease was limited. Over the past decade, GWAS have been used to identify genes involved in many complex diseases, including various phenotypes of the thyroid gland. In GWAS of autoimmune thyroid diseases, many susceptibility loci associated with autoimmunity (human leukocyte antigen [HLA], protein tyrosine phosphatase, non-receptor type 22 [PTPN22], cytotoxic T-lymphocyte associated protein 4 [CTLA4], and interleukin 2 receptor subunit alpha [IL2RA]) or thyroid-specific genes (thyroid stimulating hormone receptor [TSHR] and forkhead box E1 [FOXE1]) have been identified. Regarding thyroid function, many susceptibility loci for levels of TSH and free T4 have been identified through genome-wide analyses. In GWAS of differentiated thyroid cancer, associations at FOXE1, MAP3K12 binding inhibitory protein 1 (MBIP)-NK2 homeobox 1 (NKX2-1), disrupted in renal carcinoma 3 (DIRC3), neuregulin 1 (NRG1), and pecanex-like 2 (PCNXL2) have been commonly identified in people of European and Korean ancestry, and many other susceptibility loci have been found in specific populations. Through GWAS of various thyroid-related phenotypes, many susceptibility loci have been found, providing insights into the pathogenesis of thyroid diseases and disease co-clustering within families and individuals.
Coexistence of sarcoidosis and Hashimoto thyroiditis.
Semiz H,Yalcin M,Kobak S
Sarcoidosis is a chronic, inflammatory disease with unknown cause characterized by non-caseating granuloma formations. It can present with bilateral hilar lymphadenopathy, skin lesions, eye involvement and locomotor system findings. Hashimoto thyroiditis is an organ-specific autoimmune disease characterized by increased autoantibody synthesis. Sarcoidosis can involve different endocrine glands. Thyroid gland involvement may lead to increased thyroid function disorders and autoantibodies. Herein, we report an 80-year-old female patient with sarcoidosis and Hashimoto coexistence.
Richard-Eaglin Angela,Smallheer Benjamin A
The Nursing clinics of North America
Autoimmune disorders are a category of diseases in which the immune system attacks healthy cells as a result of a dysfunction of the acquired immune system. Clinical presentation and diagnosis are disease specific and often correspond with the degree of inflammation, as well as the systems involved. Treatment varies based on the specific disease, its stage of presentation, and patient symptoms. The primary goal of treatment is to decrease inflammation, minimize symptoms, and lessen the potential for relapse. Graves disease, Hashimoto thyroiditis, rheumatoid arthritis, Crohn disease, ulcerative colitis, systemic lupus erythematosus, and multiple sclerosis are discussed in this article.
Multiple nutritional factors and thyroid disease, with particular reference to autoimmune thyroid disease.
Rayman Margaret P
The Proceedings of the Nutrition Society
Hashimoto's thyroiditis (HT) and Graves' disease (GD) are examples of autoimmune thyroid disease (AITD), the commonest autoimmune condition. Antibodies to thyroid peroxidase (TPO), the enzyme that catalyses thyroid-hormone production and antibodies to the receptor for the thyroid-stimulating hormone, are characteristic of HT and GD, respectively. It is presently accepted that genetic susceptibility, environmental factors, including nutritional factors and immune disorders contribute to the development of AITD. Aiming to investigate the effect of iodine, iron and selenium in the risk, pathogenesis and treatment of thyroid disease, PubMed and the Cochrane Library were searched for relevant publications to provide a narrative review. Iodine: chronic exposure to excess iodine intake induces autoimmune thyroiditis, partly because highly-iodinated thyroglobulin (Tg) is more immunogenic. The recent introduction of universal salt iodisation can have a similar, although transient, effect. Iron: iron deficiency impairs thyroid metabolism. TPO is a haem enzyme that becomes active only after binding haem. AITD patients are frequently iron-deficient since autoimmune gastritis, which reduces iron absorption and coeliac disease which causes iron loss, are frequent co-morbidities. In two-thirds of women with persistent symptoms of hypothyroidism despite appropriate levothyroxine therapy, restoration of serum ferritin above 100 µg/l ameliorated symptoms. Selenium: selenoproteins are essential to thyroid action. In particular, the glutathione peroxidases remove excessive hydrogen peroxide produced there for the iodination of Tg to form thyroid hormones. There is evidence from observational studies and randomised controlled trials that selenium, probably as selenoproteins, can reduce TPO-antibody concentration, hypothyroidism and postpartum thyroiditis. Appropriate status of iodine, iron and selenium is crucial to thyroid health.
Thyrotropin Receptor Blocking Antibodies.
Diana Tanja,Olivo Paul D,Kahaly George J
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme
Autoantibodies (Ab) against the thyroid-stimulating hormone receptor (TSHR) are frequently found in autoimmune thyroid disease (AITD). Autoantibodies to the TSHR (anti-TSHR-Ab) may mimic or block the action of TSH or be functionally neutral. Measurement of anti-TSHR-Ab can be done either via competitive-binding immunoassays or with functional cell-based bioassays. Antibody-binding assays do not assess anti-TSHR-Ab functionality, but rather measure the concentration of total anti-TSHR binding activity. In contrast, functional cell-based bioassays indicate whether anti-TSHR-Ab have stimulatory or blocking activity. Historically bioassays for anti-TSHR-Ab were research tools and were used to study the pathophysiology of Graves' disease and Hashimoto's thyroiditis. In the past, bioassays for anti-TSHR-Abs were laborious and time-consuming and varied widely in performance from laboratory to laboratory. Recent advances in the development of cell-based assays, including the application of molecular engineering, have led to significant improvements that have enabled bioassays to be employed routinely in clinical laboratories. The prevalence and functional significance of TSHR blocking autoantibodies (TBAb) in autoimmune hypothyroidism has been less well investigated compared to TSHR stimulating Ab. There is an increasing body of data, however, that demonstrate the clinical utility and relevance of TBAb, and thus the importance of TBAb bioassays, in the diagnosis and management of patients with AITD. In the present review, we summarize the different methods used to measure TBAb, and discuss their prevalence and clinical relevance.
Selenium and Selenoproteins in Immune Mediated Thyroid Disorders.
Santos Liliana R,Neves Celestino,Melo Miguel,Soares Paula
Diagnostics (Basel, Switzerland)
Selenium is an essential micronutrient that is required for the synthesis of selenocysteine-containing selenoproteins, processing a wide range of health effects. It is known that the thyroid is one of the tissues that contain more selenium. The "selenostasis" maintenance seems to contribute to the prevention of immune mediated thyroid disorders. Prospective, observational studies, randomized, controlled studies evaluating selenium supplementation, and review articles that are available in Medline and PubMed have undergone scrutiny. The differences concerning methodology and results variability have been analyzed. Several authors support the idea of a potential efficacy of selenium (mainly selenomethionine) supplementation in reducing antithyroperoxidase antibody levels and improve thyroid ultrasound features. In mild Graves' orbitopathy, selenium supplementation has been associated with a decrease of the activity, as well as with quality of life improvement. Future research is necessary to clearly understand the selenium supplementation biologic effects while considering the basal selenium levels/biomarkers, selenoprotein gene polymorphisms that may be involved, underlying comorbidities and the major clinical outcomes.
Reflections on Thyroid Autoimmunity: A Personal Overview from the Past into the Future.
Rapoport Basil,McLachlan Sandra M
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme
After investigating thyroid autoimmunity for more than 40 years, we present a personal perspective on the field. Despite effective therapies for Graves' hyperthyroidism and Hashimoto's thyroiditis, cures are elusive. Novel forms of therapy are being developed, such as small molecule inhibitors of the TSH receptor (TSHR), but cure will require immunotherapy. This goal requires advances in understanding the pathogenesis of thyroid autoimmunity, the 'keys' for which are the thyroid antigens themselves. Presently, however, greater investigative focus is on non-thyroid specific immune cell types and molecules. Thyroid autoantigens are the drivers of the autoimmune response, a prime example being the TSHR. In our view, the TSHR is the culprit as well as the victim in Graves' disease because of its unique structure. Unlike the closely related gonadotropin receptors, the TSHR cleaves into subunits and there is strong evidence that its shed extracellular A-subunit, not the holoreceptor, is the major antigen driving pathogenic thyroid stimulating autoantibodies (TSAb) development. There is no Graves' disease of the gonads. Studies of potential antigen-specific immunotherapies require an animal model. Such models have been developed in which TSAb can be induced or, more importantly, arise spontaneously. Not appreciated until recently by thyroid investigators is that B cell surface autoantibodies are highly efficient 'antigen receptors' and the epitope to which an autoantibody binds influences antigen processing and which peptide is presented to T cells. These animal models and recombinant human autoantibodies cloned from Graves' and Hashimoto's B cells (plasma cells) are available for study by future generations.
Thyroid Peroxidase as an Autoantigen in Hashimoto's Disease: Structure, Function, and Antigenicity.
Williams Daniel E,Le Sarah N,Godlewska Marlena,Hoke David E,Buckle Ashley M
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme
Human thyroid peroxidase (TPO), is an important enzyme responsible for the biosynthesis of thyroid hormones and is a major autoantigen in autoimmune thyroid diseases (AITDs) such as the destructive Hashimoto's thyroiditis. Although the structure of TPO has yet to be determined, its extracellular domain consists of three regions that exhibit a high degree of sequence similarity to domains of known three-dimensional structure: the myeloperoxidase (MPO)-like domain, complement control protein (CCP)-like domain, and epidermal growth factor (EGF)-like domain. Homology models of TPO can therefore be constructed, providing some structural context to its known function, as well as facilitating the mapping of regions that are responsible for its autoantigenicity. In this review, we highlight recent progress in this area, in particular how a molecular modelling approach has advanced the visualisation and interpretation of epitope mapping studies for TPO, facilitating the dissection of the interplay between TPO protein structure, function, and autoantigenticity.
Resistance to thyroid hormone β in autoimmune thyroid disease: a case report and review of literature.
Wu Di,Guo Rui,Guo Huiling,Li Yushu,Guan Haixia,Shan Zhongyan
BMC pregnancy and childbirth
BACKGROUND:Resistance to thyroid hormone beta (RTHβ) results in symptoms of both increased and decreased thyroid hormone action. The effect of thyroid hormone changes in different types of autoimmune thyroid disease (AITD) in RTHβ is dynamic. CASE PRESENTATION:A 25-year-old Asian female had a RTHβ Y321C mutation with Hashimoto's thyroiditis and type 2 diabetes mellitus. She was followed-up through gestation and two years postpartum, revealing development of postpartum thyroiditis (PPT) with characteristic wide fluctuations in serum thyrotropin levels, and of spontaneous recovery from an episode of transient hypothyroidism. The presence of RTHβ did not prolong thyroiditis duration nor progressed toward permanent hypothyroidism. Prenatal genetic analysis was not performed on the unaffected fetus, and did not result in congenital hypothyroidism, possibly because maternal free thyroxine (FT4) levels were mildly elevated at less than 50% above the reference range in early gestation and gradually decreased to less than 20% after the 28th gestational week. CONCLUSION:In RTHβ patients with autoimmune thyroid disease, episodes of thyroid dysfunction can significantly alter thyrotropin levels. During pregnancy, mildly elevated maternal free thyroxine levels less than 20% above the upper limit may not be harmful to unaffected fetuses. Unnecessary thyroid hormone control and fetal genetic testing was avoided during the gestational period with monthly follow-up.
Thyroid peroxidase as a dual active site enzyme: Focus on biosynthesis, hormonogenesis and thyroid disorders of autoimmunity and cancer.
Godlewska Marlena,Banga Paul J
Thyroid peroxidase (TPO) is the key enzyme involved in thyroid hormone synthesis. Autoantibodies to TPO (TPOAbs) are a hallmark of autoimmune thyroid disease (AITD). Here, we highlight recent progress over several years in understanding TPO biochemistry and function in various pathologies. TPO undergoes complex post-translational modifications as a dimer in endoplasmic reticulum during secretory pathway to apical membrane of thyrocytes. In silico modelling of TPO dimer has provided new information into the two enzyme active site regions and autoantigenic determinants. TPO and hydrogen peroxide generating DUOX and caveolin-1 form a complex known as thyroxisome to bring together in close proximity the components of hormone synthesis in apical membrane. Autoimmunity to TPO is characterised by autoantibodies and T cell reactivity in Hashimoto's disease and Graves' disease. TPOAbs are directed predominantly to two immunodominant determinants (IDR) termed IDR-A and IDR-B regions, with the latter antibodies more predominant in autoimmune disease. Strong genetic risk has been shown to be associated with TPOAbs for AITD development. A different antibody with unusual features of bispecificity for both TPO and thyroglobulin may play protective role in Hashimoto's disease. In the context of TPO biology in human cancer, thyroid tumor tissue and breast cancer differ in TPO expression and isoform composition. In thyroid cancer, TPO expression is decreased partly by the BRAF(V600E) mutation, with direct impact on significant hormone production. TPOAbs may play a protective role in breast cancer development. An understanding of TPO and its unique two enzymatic active sites and autoantigenic determinants continues to add new knowledge on the biochemistry and immunology of this enzyme.
DIAGNOSIS OF ENDOCRINE DISEASE: IgG4-related thyroid autoimmune disease.
Rotondi Mario,Carbone Andrea,Coperchini Francesca,Fonte Rodolfo,Chiovato Luca
European journal of endocrinology
IgG4-related disease (IgG4-RD) is fibro-inflammatory, immune-mediated, systemic disease recognized as a defined clinical condition only in 2001. The prevalence of IgG4-RD is 6/100 000, but it is likely to be underestimated due to insufficient awareness of the disease. The diagnostic approach is complex because of the heterogeneity of clinical presentation and because of rather variable diagnostic criteria. Indeed, high concentrations of IgG4 in tissue and serum are not a reliable diagnostic marker. The spectrum of IgG4-RD also includes well-known thyroid diseases including Riedel's thyroiditis, Hashimoto's thyroiditis and its fibrotic variant, Graves' disease and Graves' orbitopathy. Results from clinical studies indicate that a small subset of patients with the above-mentioned thyroid conditions present some features suggestive for IgG4-RD. However, according to more recent views, the use of the term thyroid disease with an elevation of IgG4 rather than IgG4-related thyroid diseases would appear more appropriate. Nevertheless, the occurrence of high IgG4 levels in patients with thyroid disease is relevant due to peculiarities of their clinical course.
Thyroid autoimmune disorders and cancer.
Ferrari Silvia Martina,Fallahi Poupak,Elia Giusy,Ragusa Francesca,Ruffilli Ilaria,Paparo Sabrina Rosaria,Antonelli Alessandro
Seminars in cancer biology
In the last decades, many studies conducted in vitro, and in vivo, have shown that thyroid autoimmunity and thyroid cancer (TC) (mainly papillary TC) can be concomitant, even if the exact mechanisms at the basis of this association are still not clear. Growing incidence of TC coincides with increased registration of autoimmune thyroid disorders (AITD) suggesting an association between those pathologies. Elevated TSH levels and thyroid autoimmunity were defined as independent risk factors for TC. However a lot of evidence suggests that autoimmunity and inflammation, per se, are risk factors for TC. The link between inflammation and TC involves multiple components of the immune system, extracellular matrix, stroma, and adipose tissue, with pro-tumoral activity of inflammation being opposed to anti-inflammatory effects, favoring protection against cancer progression. Within the tumor microenvironment, inflammatory cells, belonging both to innate (macrophages) and adaptive (lymphocytes) immune responses, are interconnected with fibroblasts, endothelial cells, adipocytes, and extracellular matrix through cytokines, chemokines and adipocytokines. Under the influence of transcriptional regulators (such as Nuclear Factor-kappa B, mitogen-activated protein kinases, or Phosphoinositide-3 kinase/protein kinase-B), oncogenes connected to the different subtypes of TC promote their farthermost proliferative effect on the tumor microenvironment. Future studies will be necessary to understand the connections between thyroid autoimmunity and cancer, also in order to design a tailored therapy for TC patients with AITD.
Microbiota and Thyroid Interaction in Health and Disease.
Fröhlich Eleonore,Wahl Richard
Trends in endocrinology and metabolism: TEM
The microbiota has been identified as an important factor in health and in a variety of diseases. An altered microbiota composition increases the prevalence of Hashimoto's thyroiditis (HT) and Graves' disease (GD). Microbes influence thyroid hormone levels by regulating iodine uptake, degradation, and enterohepatic cycling. In addition, there is a pronounced influence of minerals on interactions between host and microbiota, particularly selenium, iron, and zinc. In manifest thyroid disorders, the microbiota may affect L-thyroxine uptake and influence the action of propylthiouracil (PTU). Although it is relatively well documented that thyroid disorders are linked to the composition of the microbiota, the role of specific genera and the potential use of therapies targeting the microbiota are less clear.
Roles of GM-CSF in the Pathogenesis of Autoimmune Diseases: An Update.
Lotfi Noushin,Thome Rodolfo,Rezaei Nahid,Zhang Guang-Xian,Rezaei Abbas,Rostami Abdolmohamad,Esmaeil Nafiseh
Frontiers in immunology
Granulocyte-macrophage colony-stimulating factor (GM-CSF) was first described as a growth factor that induces the differentiation and proliferation of myeloid progenitors in the bone marrow. GM-CSF also has an important cytokine effect in chronic inflammatory diseases by stimulating the activation and migration of myeloid cells to inflammation sites, promoting survival of target cells and stimulating the renewal of effector granulocytes and macrophages. Because of these pro-cellular effects, an imbalance in GM-CSF production/signaling may lead to harmful inflammatory conditions. In this context, GM-CSF has a pathogenic role in autoimmune diseases that are dependent on cellular immune responses such as multiple sclerosis (MS) and rheumatoid arthritis (RA). Conversely, a protective role has also been described in other autoimmune diseases where humoral responses are detrimental such as myasthenia gravis (MG), Hashimoto's thyroiditis (HT), inflammatory bowel disease (IBD), and systemic lupus erythematosus (SLE). In this review, we aimed for a comprehensive analysis of literature data on the multiple roles of GM-CSF in autoimmue diseases and possible therapeutic strategies that target GM-CSF production.
Thyrotropin serum levels and coexistence with Hashimoto's thyroiditis as predictors of malignancy in children with thyroid nodules.
Zirilli Giuseppina,Salzano Giuseppina,Corica Domenico,Pajno Giovanni Battista,Mignosa Cristina,Pepe Giorgia,De Luca Filippo,Crisafulli Giuseppe
Italian journal of pediatrics
Thyroid cancer (TC) in childhood is a rare disease characterized by an excellent prognosis. Thyroid nodules in children, although less common than in adults, have a greater risk of malignancies, particularly in those cases associated with anamnestic, clinical and ultrasonographic risk factors.Among the factors, which have been found to be linked with an increased relative risk of TC in children, an important role seems to be possibly played by an underlying nodular Hashimoto's thyroiditis (HT) and by the serum levels of TSH.Aim of this Commentary was to specifically address this last point.According to the available pediatric literature on the relationships between these risk factors and phenotypical expression of TC in children, it is possible to conclude that: 1) It is not completely clarified if HT per se predisposes to malignancy or if it represents an incidental histologic finding in cases with TC or if it may be the result of an immune response against tumoral cells. 2) It is unclear whether phenotypic expression of TC is more severe in the cases with associated HT but normal TSH serum levels. 3) Persistently elevated TSH levels play an independent role as predictors of the likelihood of TC, especially in children but also in adults. 4) Patients with nodular HT and subclinical hypothyroidism need to be treated with Levothyroxine in order to prevent the development of both TC and severe thyroid dysfunctions.
Comprehensive research on thyroid diseases associated with autoimmunity: autoimmune thyroid diseases, thyroid diseases during immune-checkpoint inhibitors therapy, and immunoglobulin-G4-associated thyroid diseases.
Inaba Hidefumi,Ariyasu Hiroyuki,Takeshima Ken,Iwakura Hiroshi,Akamizu Takashi
Various thyroid diseases are associated with autoimmunity. Major autoimmune thyroid diseases are Graves' disease (GD) and Hashimoto's thyroiditis (HT). Thyrotropin receptor is an autoantigen in GD, and its immunogenicity has been examined. Immune-checkpoint inhibitor (ICI) is recently widely used for treatment of malignant tumors, but cases of thyroid diseases during ICI treatment have been increasing. Thyroid diseases during ICI therapy have been investigated in immunological and clinical aspects, and their Japanese official diagnostic guidelines were established. In addition, serum and tissue immunoglobulin-G4 levels have been examined in association with clinicopathological characteristics in GD, HT, and Riedel's thyroiditis. We review these diseases associated with thyroid autoimmunity and comprehensively discuss their potential application in future research and therapeutic options.
[Vitamin D and Hashimoto's disease].
Jamka Małgorzata,Ruchała Marek,Walkowiak Jarosław
Polski merkuriusz lekarski : organ Polskiego Towarzystwa Lekarskiego
It is probably that vitamin D may play an important role in the pathogenesis of Hashimoto's disease. Previous studies have shown a higher incidence of vitamin D deficiencies in patients with Hashimoto's disease compared to healthy subjects. Probably the severity of Hashimoto's disease may affect serum 25-hydroxycholecalciferol (25(OH)D) concentrations. In addition, a negative correlation between serum 25(OH)D concentrations and the level of antithyroid antibodies was observed. Moreover, vitamin D supplementation seems to be effective in reducing the levels of thyroid peroxidase (TPO) antibodies both in patients with deficiency and with normal concentrations of vitamin D. However, further studies are needed to more accurately determine the effect of vitamin D supplementation on the Hashimoto's disease.
The Impact of Obesity on Thyroid Autoimmunity and Dysfunction: A Systematic Review and Meta-Analysis.
Song Rong-Hua,Wang Bin,Yao Qiu-Ming,Li Qian,Jia Xi,Zhang Jin-An
Frontiers in immunology
To help inform decision making in the clinical setting, we carried out a systematic review and meta-analysis to estimate the association of thyroid disease risks with obesity. Pubmed, Embase, Web of Science, Cochrane database and Google Scholar electronic databases were searched from inception to October 31, 2018 without language restrictions to explore the relationship between thyroid disorders and obesity. The relative risk (RR) or odds risk (OR) for thyroid disorders were pooled using the SPSS and STATA software. A total of 22 studies were included in the study. (1) Meta-analysis showed that obesity was significantly associated with an increased risk of hypothyroidism (RR = 1.86, 95% CI 1.63-2.11, < 0.001). Meta-analyses after stratification further showed that obese population had increased risks of overt hypothyroidism (RR = 3.21, 95% CI 2.12-4.86, < 0.001) and subclinical hypothyroidism (RR = 1.70, 95% CI 1.42-2.03, < 0.001). (2) Further meta-analysis also showed obesity was clearly associated with Hashimoto's thyroiditis (RR = 1.91, 95% CI 1.10-3.32, = 0.022), but not with Graves' disease. (3) In the meta-analysis of antibodies, obesity was correlated with positive thyroid peroxidase antibody (TPOAb) (RR = 1.93, 95% CI 1.31-2.85, = 0.001), but not with positive thyroglobulin antibody (TGAb). Obesity was significantly related to hypothyroidism, HT, and TPOAb, implying that prevention of obesity is crucial for thyroid disorders. PROSPERO: CRD42018096897.
Hashimotos' thyroiditis: Epidemiology, pathogenesis, clinic and therapy.
Ragusa Francesca,Fallahi Poupak,Elia Giusy,Gonnella Debora,Paparo Sabrina Rosaria,Giusti Claudia,Churilov Leonid P,Ferrari Silvia Martina,Antonelli Alessandro
Best practice & research. Clinical endocrinology & metabolism
Hashimoto's thyroiditis (HT), the most frequent autoimmune thyroid disorders (AITDs), is the leading cause of hypothyroidism in the iodine-sufficient areas of the world. About 20-30% of patients suffers from HT, whose cause is thought to be a combination of genetic susceptibility and environmental factors that causes the loss of immunological tolerance, with a consequent autoimmune attack to the thyroid tissue and appearance of the disease. The pathologic features of lymphocytic infiltration, especially of T cells, and follicular destruction are the histological hallmark of autoimmune thyroiditis (AIT), that lead to gradual atrophy and fibrosis. An important role in the immune-pathogenesis of AITDs is due to chemokines and cytokines. In about 20% of patients, AITDs are associated with other organ specific/systemic autoimmune disorders. Many studies have demonstrated the relationship between papillary thyroid cancer and AITD. The treatment of hypothyroidism, as result of AIT, consists in daily assumption of synthetic levothyroxine.
The proportion of peripheral blood Tregs among the CD4+ T cells of autoimmune thyroid disease patients: a meta-analysis.
Chen Ziyi,Wang Yue,Ding Xi,Zhang Meng,He Mingqian,Zhao Yang,Hu Shiqian,Zhao Fengyi,Wang Jingya,Xie Baosong,Shi Bingyin
Autoimmune thyroid disease (AITD) is characterized by a loss of self-tolerance to thyroid antigen. Tregs, whose proportions are controversial among CD4+ T cell from AITD patients (AITDs), are crucial in immune tolerance. Considering that drugs might affect Treg levels, we assumed that the differences originated from different treatment statuses. Thus, we performed a meta-analysis to explore proportions of Tregs in untreated and treated AITDs. PubMed, Embase and ISI Web of Knowledge were searched for relevant studies. Review Manager 5.3 and Stata 14.0 were used to conduct the meta-analysis. Subgroup analysis based on different diseases and cell surface markers was performed. Egger linear regression analysis was used to assess publication bias. Approximately 1,100 AITDs and healthy controls (HCs) from fourteen studies were included. Proportions of Tregs among CD4+ T cells of untreated AITDs were significantly lower than those in HCs (p = 0.002), but were not in treated patients (p = 0.40). Subgroup analysis revealed lower proportions of Tregs in untreated Graves' disease patients (GDs) (p = 0.001) but did not show obvious differences in untreated Hashimoto's thyroiditis patients (HTs) (p = 0.62). Furthermore, proportions of circulating FoxP3+ Tregs were reduced in untreated GDs (p < 0.00001) and HTs (p = 0.04). No publication bias was found. In this first meta-analysis exploring proportions of circulating Tregs among CD4+ T cells of AITDs with different treatment statuses, we found that Tregs potentially contribute to the pathogenesis of AITD but function differently in GD and HT. Remarkably, FoxP3+ Tregs, which were decreased in both diseases, might be promising targets for novel therapies.
Selenium involvement in mitochondrial function in thyroid disorders.
Gheorghiu Monica Livia,Badiu Corin
Hormones (Athens, Greece)
Selenium (Se), an important oligoelement, is a component of the antioxidant system. Over the last decade, it has been ever more frequently discussed in the context of thyroid disorders. Graves' disease and Hashimoto's thyroiditis, differentiated thyroid cancer, and even endemic goiter may have common triggers that are activated by excess reactive oxygen species (ROS), which are involved in various stages of the pathogenesis of thyroid disorders. Most oxidative events occur in mitochondria, organelles that contain enzymes with Se as a cofactor. Mitochondria are responsible for the production of ATP in the cell and are also a major site of ROS production. Thyroid hormone status (the thyroid being the organ with the highest concentration of Se in the body) has a profound impact on mitochondria biogenesis. In this review, we focus on the role of Se in mitochondrial function in thyroid disorders with impaired oxidative stress, since both thyroid hormone synthesis and thyroid dysfunction involve ROS. The role of Se deficiency or its excess in relation to mitochondrial dysfunction in the context of thyroid disorders is therefore of interest.
A Literature Review of Painful Hashimoto Thyroiditis: 70 Published Cases in the Past 70 Years.
Peng Carol Chiung-Hui,Huai-En Chang Rachel,Pennant Majorie,Huang Huei-Kai,Munir Kashif M
Journal of the Endocrine Society
Painful Hashimoto thyroiditis (pHT) is a rare diagnosis, and optimal treatment remains unclear. To better characterize pHT, PubMed, Embase, Scopus, and Web of Science indexes were searched for case reports or case series reporting pHT, published between 1951 and February 2019. Seventy cases reported in 24 publications were identified. Female predominance (91.4%) and a median age of 39.00 years (interquartile range, 32.50-49.75 years) were observed. Among reported cases, 50.8% had known thyroid disease (including Hashimoto thyroiditis, Graves disease, and seronegative goiters), 83.3% had positive antithyroid peroxidase antibodies, and 71.2% had antithyroglobulin antibodies. Most cases did not have preceding upper respiratory tract symptoms or leukocytosis. Ultrasound features were consistent with Hashimoto thyroiditis. Thyroid function at initial presentation was hypothyroid (35.9%), euthyroid (28.1%), or thyrotoxic (35.9%). Cases evolved into hypothyroidism (55.3%) and euthyroidism (44.7%), whereas none became hyperthyroid after medical treatment. Thyroid size usually decreased after medical treatment. Most cases were empirically treated as subacute thyroiditis with corticosteroids, levothyroxine, or nonsteroidal anti-inflammatory drugs. However, no therapy provided sustained pain resolution. In subgroup analysis, low-dose oral prednisone (<25 mg/d) and intrathyroidal corticosteroid injection showed more favorable outcomes. Total thyroidectomy yielded 100% sustained pain resolution. Diagnosis of pHT is based on clinical evidence of Hashimoto thyroiditis and recurrent thyroid pain after medical treatment. The reference standard of diagnosis is pathology. Total thyroidectomy or intrathyroidal glucocorticoid injection should be considered if low-dose oral prednisone fails to achieve pain control.
[Thyroiditis: What's new in 2019?]
Rouland A,Buffier P,Petit J-M,Vergès B,Bouillet B
La Revue de medecine interne
Thyroiditis is a frequent and mostly benign disease that can sometimes disrupt the thyroid balance. Their diagnosis, as well as their aetiology, is a necessary step in the management of the patients. Painful thyroiditis includes acute thyroiditis of infectious origin and subacute thyroiditis. The first one can be treated by antibiotics or antifungals depending on the germ found. The second one will be treated with non-steroidal anti-inflammatory drugs or corticosteroids. In cases of Hashimoto's thyroiditis with overt hypothyroidism, replacement therapy with L-thyroxine will be adapted to the TSH level. As amiodarone treatment provides dysthyroidism, the thyroid status should be monitored regularly. Hypothyroidism will be treated using thyroid replacement therapy. Hyperthyroidism imposes a stop of amiodarone when it is possible. Treatment with synthetic antithyroid drugs (propyl-thio-uracil) or corticosteroids could be used whether there is an underlying thyroid disease or not. Immunotherapies with anti-PD-1/PDL1 or anti-CTLA-4 can also provide dysthyroidism. A monitoring of the thyroid assessment needs to be done in these patients, even if there are no clinical signs, which are not very specific in this context. The treatment of hypothyroidism will be based on thyroid replacement therapy according to the TSH level and the presence or absence of anti-TPO antibodies. Treatment of symptomatic hyperthyroidism may involve a prescription of beta-blockers, or synthetic antithyroid drugs in case of positive anti-TSH receptor antibodies. In all cases, it is desirable to contact an endocrinologist to confirm the diagnosis hypothesis and to decide on a suitable treatment.
Autoimmune thyroid disorders and rheumatoid arthritis: A bidirectional interplay.
Conigliaro Paola,D'Antonio Arianna,Pinto Sara,Chimenti Maria Sole,Triggianese Paola,Rotondi Mario,Perricone Roberto
Rheumatoid arthritis (RA) and autoimmune thyroid disease (AITD) can occur in the same patient in the autoimmune polyglandular syndrome 2. The association of the two conditions has been recognized long-time ago and the prevalence of AITD in patients with RA and vice versa is well assessed. Geographical variation of AITD and related autoantibodies in RA patients is partly due to ethnic and environmental differences of the studied populations. The impacts of thyroid disorders on RA outcome and vice versa are still controversy. In both AITD and RA genetic susceptibility and environmental factors play a synergic role in the development of the diseases. In this review we aimed at investigating the association of AITD and thyroid autoantibodies with RA, the common pathogenic pathways, the correlation with RA disease activity, and influence of the treatment.
Gut microbiota and metabolites in the pathogenesis of endocrine disease.
Fenneman Aline C,Rampanelli Elena,Yin Yue S,Ames Jesse,Blaser Martin J,Fliers Eric,Nieuwdorp Max
Biochemical Society transactions
Type 1 diabetes (T1D) and Hashimoto's thyroiditis (HT) are the two most common autoimmune endocrine diseases that have rising global incidence. These diseases are caused by the immune-mediated destruction of hormone-producing endocrine cells, pancreatic beta cells and thyroid follicular cells, respectively. Both genetic predisposition and environmental factors govern the onset of T1D and HT. Recent evidence strongly suggests that the intestinal microbiota plays a role in accelerating or preventing disease progression depending on the compositional and functional profile of the gut bacterial communities. Accumulating evidence points towards the interplay between the disruption of gut microbial homeostasis (dysbiosis) and the breakdown of host immune tolerance at the onset of both diseases. In this review, we will summarize the major recent findings about the microbiome alterations associated with T1D and HT, and the connection of these changes to disease states. Furthermore, we will discuss the potential mechanisms by which gut microbial dysbiosis modulates the course of the disease, including disruption of intestinal barrier integrity and microbial production of immunomodulatory metabolites. The aim of this review is to provide broad insight into the role of gut microbiome in the pathophysiology of these diseases.
Thyroid-Gut-Axis: How Does the Microbiota Influence Thyroid Function?
Knezevic Jovana,Starchl Christina,Tmava Berisha Adelina,Amrein Karin
A healthy gut microbiota not only has beneficial effects on the activity of the immune system, but also on thyroid function. Thyroid and intestinal diseases prevalently coexist-Hashimoto's thyroiditis (HT) and Graves' disease (GD) are the most common autoimmune thyroid diseases (AITD) and often co-occur with Celiac Disease (CD) and Non-celiac wheat sensitivity (NCWS). This can be explained by the damaged intestinal barrier and the following increase of intestinal permeability, allowing antigens to pass more easily and activate the immune system or cross-react with extraintestinal tissues, respectively. Dysbiosis has not only been found in AITDs, but has also been reported in thyroid carcinoma, in which an increased number of carcinogenic and inflammatory bacterial strains were observed. Additionally, the composition of the gut microbiota has an influence on the availability of essential micronutrients for the thyroid gland. Iodine, iron, and copper are crucial for thyroid hormone synthesis, selenium and zinc are needed for converting T4 to T3, and vitamin D assists in regulating the immune response. Those micronutrients are often found to be deficient in AITDs, resulting in malfunctioning of the thyroid. Bariatric surgery can lead to an inadequate absorption of these nutrients and further implicates changes in thyroid stimulating hormone (TSH) and T3 levels. Supplementation of probiotics showed beneficial effects on thyroid hormones and thyroid function in general. A literature research was performed to examine the interplay between gut microbiota and thyroid disorders that should be considered when treating patients suffering from thyroid diseases. Multifactorial therapeutic and preventive management strategies could be established and more specifically adjusted to patients, depending on their gut bacteria composition. Future well-powered human studies are warranted to evaluate the impact of alterations in gut microbiota on thyroid function and diseases.
The importance of nutritional factors and dietary management of Hashimoto's thyroiditis.
Ihnatowicz Paulina,Drywień Małgorzata,Wątor Paweł,Wojsiat Joanna
Annals of agricultural and environmental medicine : AAEM
Hashimoto (HT) is an autoimmune disease in which destruction of the thyroid occurs as a result of lymphocyte infiltration. It is caused by an increased level of titers of antibody against thyroid peroxidase (TPO) and thyroglobulin (TG). Because of that,in HT patients, changes are observed in the level and metabolism of thyroid hormones, which leads to unspecified physical and psychological symptoms. A high level of antibodies attacking thyroid antigens has been positively correlated with the symptoms. From the etiological point of view, the most important are genetic factors; however, environmental factors are necessary to provoke the immune system to attack until the process is over. Scientists indicate specified stress, toxification, microbiota dysbiosis and under- or over-nutrition, to name only a few. Dietotherapy of Hashimoto's is based on the proper nourishment of the body and regulation of the immune system by an anti-inflammatory diet. Observational and controlled trials have shown frequent nutrition deficiencies in HT patients. In literature, there is evidence for selenium, potassium, iodine, copper, magnesium, zinc, iron, vitamin A, C, D and B. The role of the proper level of protein intake, dietary fibre and unsaturated fatty acids, especially the n-3 family, has been indicated. HT patients should often eliminate lactose because of intolerance and interactions with levothyroxine and gluten because of possible interactions of gliadin with thyroid antigens. The article describes the nutrition factors of HT patients, and share nutrition recommendations for diet therapy.
Microorganisms associated to thyroid autoimmunity.
Cuan-Baltazar Yunam,Soto-Vega Elena
Autoimmune thyroid diseases are a group of diseases characterized by a dysfunction of the immune system concerning the thyroid gland, associated with hypothyroidism or hyperthyroidism. The thyroid gland autoimmunity has been recognized as multifactorial. It has been reported that microorganisms may play a role on the pathogenesis of Hashimoto's thyroiditis and Graves´ disease. These could explain the high incidence of the autoimmune thyroid diseases. Helicobacter Pylori (H. pylori) and Hepatitis C virus (HCV) are the microorganisms in which the association with autoimmune thyroid diseases is clearer. The pathophysiologic mechanisms are still not well defined. For H. pylori, molecular mimicry has been the most accepted mechanism. It has been proposed Hepatitis C virus as the trigger of the thyroid autoimmunity by exacerbating the production of thyroid auto-antibodies, while some mention that the real factor that triggers the thyroid autoimmunity is the treatment with Interferon alpha (IFN-alpha) by upregulating MHC class I and inducing ligation of CD40+ cells to thyrocytes. Other microorganisms such as Toxoplasma gondii, Human Immunodeficiency virus, Herpes virus and others have reported information about their association with thyroid autoimmune diseases There are no proposals on how these last microorganisms induce thyroid autoimmunity. There is still a lack of evidence on this topic. Further research must be done to determine the interaction of these microorganisms and the best way to manage these patients.
Vitamin D and Autoimmune Thyroid Diseases - a Review.
Miteva Mariya Zh,Nonchev Boyan I,Orbetzova Maria M,Stoencheva Snejana D
The essential biological action of vitamin D is regulation of calcium and phosphorus metabolism and preserving bone health. In recent years there have been reports about the extraskeletal actions of vitamin D and its role in the regulation of immune system. Vitamin D supplementation appears to reduce the incidence of cardiovascular diseases, cancer, and infections and be able to reduce all-cause mortality. Deficiency of vitamin D has been found to correlate with the increased incidence of autoimmune diseases, including type 1 diabetes mellitus, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis. Autoimmune thyroid diseases (AITD), including Graves' disease, Hashimoto's thyroiditis are relatively common autoimmune disorders affecting more than 5% of general population. It has been shown that vitamin D receptors (VDR) and 1-alpha hydroxylase are expressed in papillary thyroid cancer and normal thyroid tissue, suggesting local synthesis of 1,25(OH)2D in the thyroid. While VDR gene polymorphism has been found in much research to be associated with AITDs, very few studies have examined the impact of vitamin D deficiency on the incidence of AITDs in humans with conflicting results. This review focuses on the association between vitamin D and autoimmune thyroid diseases and summarizes the results of vitamin D supplementation studies in patients with AITD.
Hashimoto's thyroiditis: An update on pathogenic mechanisms, diagnostic protocols, therapeutic strategies, and potential malignant transformation.
Ralli Massimo,Angeletti Diletta,Fiore Marco,D'Aguanno Vittorio,Lambiase Alessandro,Artico Marco,de Vincentiis Marco,Greco Antonio
Hashimoto's thyroiditis, characterized by thyroid-specific autoantibodies, is one of the commonest autoimmune disorders. Although the exact etiology has not been fully elucidated, Hashimoto's thyroiditis is related to an interaction among genetic elements, environmental factors and epigenetic influences. Cellular and humoral immunity play a key role in the development of the disease; thus, a T and B cells inflammatory infiltration is frequently found. Histopathologic features of the disease include lymphoplasmacytic infiltration, lymphoid follicle formation with germinal centers, and parenchymal atrophy. Moreover, the occurrence of large follicular cells and oxyphilic or Askanazy cells is frequently associated to Hashimoto's thyroiditis. Clinically, Hashimoto's thyroiditis is characterized mainly by systemic manifestations due to the damage of the thyroid gland, developing a primary hypothyroidism. Diagnosis of Hashimoto's thyroiditis is clinical and based on clinical characteristics, positivity to serum antibodies against thyroid antigens (thyroid peroxidase and thyroglobulin), and lymphocytic infiltration on cytological examination. The mainstream of treatment is based on the management of the hypothyroidism with a substitution therapy. A relationship between Hashimoto's thyroiditis and a possible malignant transformation has been proposed in several studies and involves immunological/hormonal pathogenic links although specific correlation is still debated and needs to be further investigated with prospective studies.
Thyroid cancer and thyroid autoimmune disease: A review of molecular aspects and clinical outcomes.
Dias Lopes Natália Medeiros,Mendonça Lens Hannah Hamada,Armani André,Marinello Poliana Camila,Cecchini Alessandra Lourenço
Pathology, research and practice
Thyroid cancer (TC) is the most prevalent malignant neoplasm that affects the endocrine system. Hashimoto's thyroiditis (HT), also known as chronic lymphocytic thyroiditis, is the most common autoimmune thyroid disease (AITD) that, together with Graves' disease (GD), represent the main autoimmune diseases that affect the thyroid gland. Some studies suggest a greater risk of AITD and the development of TC, while others, investigate its relationship with TC progression and patient prognosis. In this review, we have analyzed published data on the molecular aspects related to the association between AITD and TC, addressing their influence on TC progression, diagnosis, and prognosis of the patients. MEDLINE database (PubMed) platform was used as a search engine and the original articles related to the topic were selected using the keywords combination "thyroid cancer and Hashimoto thyroiditis" or "thyroid carcinoma and thyroid autoimmune disease". After the selection, we categorized the main findings of the papers into four topics: antitumor immunity, tumor progression, diagnosis, and prognosis. Although most of the studies have pointed out the presence of AITD as a factor that increases the risk of TC, few molecular mechanisms to support this conclusion have been described. Additionally, little information is available to explain, pathophysiologically, the effects of autoimmunity in TC diagnosis, progression, and prognosis.
Vitamin D and Autoimmune Thyroid Disease-Cause, Consequence, or a Vicious Cycle?
Vieira Inês Henriques,Rodrigues Dírcea,Paiva Isabel
Vitamin D is a steroid hormone traditionally connected to phosphocalcium metabolism. The discovery of pleiotropic expression of its receptor and of the enzymes involved in its metabolism has led to the exploration of the other roles of this vitamin. The influence of vitamin D on autoimmune disease-namely, on autoimmune thyroid disease-has been widely studied. Most of the existing data support a relationship between vitamin D deficiency and a greater tendency for development and/or higher titers of antibodies linked to Hashimoto's thyroiditis, Graves' disease, and/or postpartum thyroiditis. However, there have also been some reports contradicting such relationships, thus making it difficult to establish a unanimous conclusion. Even if the existence of an association between vitamin D and autoimmune thyroid disease is assumed, it is still unclear whether it reflects a pathological mechanism, a causal relationship, or a consequence of the autoimmune process. The relationship between vitamin D's polymorphisms and this group of diseases has also been the subject of study, often with divergent results. This text presents a review of the recent literature on the relationship between vitamin D and autoimmune thyroid disease, providing an analysis of the likely involved mechanisms. Our thesis is that, due to its immunoregulatory role, vitamin D plays a minor role in conjunction with myriad other factors. In some cases, a vicious cycle is generated, thus contributing to the deficiency and aggravating the autoimmune process.
An update on the pathogenesis of Hashimoto's thyroiditis.
Weetman A P
Journal of endocrinological investigation
It is 70 years since Noel Rose embarked on his pioneering studies that lead to the discovery of autoimmune thyroiditis and the elucidation of Hashimoto's thyroiditis. This short review to honour his passing focuses on the developments in our understanding of the causes and pathogenesis of HT over the last five years. Recent genetic studies have reported heritability estimates for HT and associated diseases for the first time, and emphasised the complexity of the genetic factors involved, including monogenic forms of HT. Environmental factors continue to be elucidated, especially as a side effect of drugs which modulate the immune system therapeutically. Regarding pathogenetic mechanisms, multiple cytokine networks have been identified which involve the thyroid cells in a circuit of escalating proinflammatory effects, such as the expression of inflammasome components, and an array of different defects in T regulatory cells may underlie the loss of self-tolerance to thyroid autoantigens. Finally, a number of studies have revealed fresh insights into disease associations with HT which may have both pathological and clinical significance, the most intriguing of which is a possible direct role of the autoimmune process itself in causing some of the persistent symptoms reported by a minority of patients with levothyroxine-treated HT.
The Human Microbiota in Endocrinology: Implications for Pathophysiology, Treatment, and Prognosis in Thyroid Diseases.
Docimo Giovanni,Cangiano Angelo,Romano Roberto Maria,Pignatelli Marcello Filograna,Offi Chiara,Paglionico Vanda Amoresano,Galdiero Marilena,Donnarumma Giovanna,Nigro Vincenzo,Esposito Daniela,Rotondi Mario,Candela Giancarlo,Pasquali Daniela
Frontiers in endocrinology
The human microbiota is an integral component in the maintenance of health and of the immune system. Microbiome-wide association studies have found numerous diseases associated to dysbiosis. Studies are needed to move beyond correlations and begin to address causation. Autoimmune thyroid diseases (ATD) are one of the most common organ-specific autoimmune disorders with an increasing prevalence, higher than 5% worldwide. Most frequent manifestations of ATD are Hashimoto's thyroiditis and Graves' disease. The exact etiology of ATD remains unknown. Until now it is not clear whether bacterial infections can trigger ATD or modulate the efficacy of treatment and prognosis. The aim of our review is to characterize the microbiota and in ATD and to evaluate the impact of dysbiosis on treatment and prognosis. Moreover, variation of gut microbiome has been associated with thyroid cancer and benign nodules. Here we will characterize the microbioma in benign thyroid nodules, and papillary thyroid cancer to evaluate their implications in the pathophysiology and progression.
Gut microbiome and thyroid autoimmunity.
Virili Camilla,Stramazzo Ilaria,Centanni Marco
Best practice & research. Clinical endocrinology & metabolism
Intestinal microbiota gained attention due to its pleiotropic effect on intestinal barrier, nutrients metabolism and on immune system development and functions. Recent evidence pointed out a possible role of an altered gut microbiota composition in the pathogenesis and progression of several autoimmune disorders, occurring at gastrointestinal level or far apart. In thyroid autoimmune disorders, encompassing Hashimoto's thyroiditis, Graves' disease and thyroid-associated orbitopathy, the combined effect of environmental triggers and genetic predisposing background, lead to the loss of self-tolerance and to auto-aggressive damage, involving both cellular and humoral networks of immune system. This review is aimed at assessing the current knowledge about the studies published on the fecal microbiota composition in patients bearing thyroid autoimmune diseases. We further examined the reciprocal interaction between gut microbiota composition and the most used treatments for thyroid disorders.
Immunomodulatory Function of Vitamin D and Its Role in Autoimmune Thyroid Disease.
Zhao Rui,Zhang Wei,Ma Chenghong,Zhao Yaping,Xiong Rong,Wang Hanmin,Chen Weiwen,Zheng Song Guo
Frontiers in immunology
Vitamin D is one of the most important nutrients required by the human body. It is a steroid hormone that plays an important role in regulating calcium and phosphorus metabolism, and bone health. Epidemiological studies have revealed a close correlation between vitamin D and many common chronic diseases. Additionally, vitamin D has recently been shown to act as an immunomodulatory hormone, and, accordingly, vitamin D deficiency was uncovered as a risk factor for autoimmune thyroid diseases, although the underlying mechanisms are still unknown. It is therefore necessary to disclose the role and mechanism of action of vitamin D in the occurrence and development of autoimmune thyroid diseases. This knowledge will help design intervention and early treatment strategies for patients with autoimmune thyroid diseases who present with low levels of vitamin D.
Persisting symptoms in patients with Hashimoto's disease despite normal thyroid hormone levels: Does thyroid autoimmunity play a role? A systematic review.
Journal of translational autoimmunity
OBJECTIVE:Patients with hypothyroidism due to Hashimoto's disease (HD) may experience persisting symptoms despite normal serum thyroid hormone (TH) levels. Several hypotheses have been postulated to explain these persisting symptoms. We hypothesized that thyroid autoimmunity may play a role. DESIGN:A systematic literature review. METHODS:A PubMed search was performed to find studies investigating the relation between the presence of thyroid autoimmunity and (persisting) symptoms. Included studies were critically appraised by the Newcastle - Ottawa Scale (NOS) and then subdivided into (A) disease-based studies, comparing biochemically euthyroid patients with HD, and euthyroid patients with non-autoimmune hypothyroidism or euthyroid benign goitre, and (B) (general) population-based studies. Due to different outcome measures among all studies, meta-analysis of data could not be performed. RESULTS:Thirty out of 1259 articles found in the PubMed search were included in this systematic review. Five out of seven disease-based studies found an association between thyroid autoimmunity and symptoms or lower quality of life (QoL). Sixteen of 23 population-based studies found a comparable positive association. In total, the majority of included studies reported an association between thyroid autoimmunity and persisting symptoms or lower QoL in biochemically euthyroid patients. CONCLUSION:(Thyroid) autoimmunity seems to be associated with persisting symptoms or lower QoL in biochemically euthyroid HD patients. As outcome measures differed among the included studies, we propose the use of similar outcome measures in future studies. To prove causality, a necessary next step is to design and conduct intervention studies, for example immunomodulation vs. placebo preferably in the form of a randomized controlled trial, with symptoms and QoL as main outcomes.
Hashimoto's thyroiditis and coexisting disorders in correlation with HLA status-an overview.
Mikosch Peter,Aistleitner Adrian,Oehrlein Markus,Trifina-Mikosch Eva
Wiener medizinische Wochenschrift (1946)
Hashimoto's thyroiditis (HT), also known as chronic lymphocytic thyroiditis, is a frequent disorder of the thyroid gland caused by autoimmune-trigged lymphocytic infiltration and destruction of the thyroid gland. With the progressive destruction of the organ, the thyroid gland shrinks in size, thus commonly leading to hypothyroidism. 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 by HT itself. Several other disorders are known to be associated with HT. The etiology of HT seems to be multifactorial, including environmental influences such as iodine supply, infections, and stress as triggers of immune modulation. In addition, also a genetic background based on changes of the human leukocyte antigen (HLA) status seems to be evident. The paper will provide an overview of diseases related to HT, including their correlation to certain HLA patterns. This presentation should give a broader view on HT-related disorders and facilitate detailed examination and management of patients with HT.