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Background: The rearranged during transfection (RET) proto-oncogene fusion is common in papillary thyroid cancer (PTC), varying across ethnic groups. However, comprehensive comparisons of RET fusion types are limited. This study aims to identify predominant RET fusions and analyze their clinicopathological characteristics in a cohort of Chinese thyroid cancer cases. Methods: This single-center retrospective cohort study analyzed thyroid cancer data, utilizing next-generation sequencing on formalin-fixed, paraffin-embedded tissue samples. Detailed clinicopathological data of thyroid cancer cases with RET fusions were collected. Results: Among 2300 thyroid cancer cases, RET fusions were exclusively found in PTC or differentiated high-grade thyroid carcinoma (DHGTC) cases (2234 cases), absent in other types (66 cases). Of the 2234 PTC or DHGTC cases, 113 (5.06%) exhibited RET fusions, including 100 primary cases. Coiled-coil domain containing 6 (CCDC6)-RET fusions predominated (78.0%, 78/100), with nuclear receptor coactivator 4 (NCOA4)-RET fusions representing 22.0% (22/100). NCOA4-RET fusions were more prevalent in patients aged 45 years and older (54.5% vs. 28.2%, p = 0.021) and DHGTC cases (p < 0.05) and associated with higher rates of lymph node metastases (90.9% vs. 67.9%, p = 0.032). CCDC6-RET fusion exhibited a higher prevalence of Hashimoto's thyroiditis (HT) (67.9% vs. 22.7%, p < 0.001) and elevated thyroglobulin antibody levels (14.11 [1.86–174.32] IU/mL vs. 2.01 [1.14–15.41] IU/mL, p = 0.018). Moreover, CCDC6-RET fusion predominantly occurred in classical PTC (56.4%, 44/78) and infiltrative follicular PTC (17.9%, 14/78), whereas NCOA4-RET fusion was more frequent in classical PTC (36.4%, 8/22), solid PTC (27.3%, 6/22), and DHGTC (27.3%, 6/22). RET fusions with compound mutations were associated with older age (≥45 years) and bilateral thyroid involvement. Follow-up data showed a higher recurrence rate in the RET fusion group compared with the BRAFV600E mutation group (5.0% vs. 0.0%, p = 0.018). Although the NCOA4-RET group showed a numerically higher recurrence rate compared with CCDC6-RET (9.1% vs. 3.8%), this difference was not statistically significant (p = 0.559). Conclusions:RET fusions are specific to PTC or DHGTC cases among Chinese thyroid cancer cases. CCDC6-RET and NCOA4-RET fusions exhibited distinct clinicopathological features, with NCOA4-RET being more aggressive. [ABSTRACT FROM AUTHOR]

Background: Exposure to particles with an aerodynamic diameter of ≤2.5 μm (PM2.5) is associated with the occurrence of thyroid dysfunction among pregnant women and neonates, but it is not known if this association occurs in the general population. We aimed to determine the association of prolonged exposure to PM2.5 with the prevalence of thyroid disorders among adults in China. Methods: A nationally representative cross-sectional study of thyroid disorders, iodine status, and diabetes status was carried out in all 31 provinces across China from 2015 to 2017. In total, 73,900 adults aged 18 years and older were included. Serum concentrations of thyroid hormones, thyrotropin, and thyroid antibodies and the urine iodine concentration were measured. The environmental concentration of PM2.5 for each participant's residential address at a spatial resolution of 1 × 1 km was estimated. Results: The average long-term exposure to PM2.5 at residential addresses was 66.41 μg/m3, ranging from 17.58 μg/m3 to 120.40 μg/m3. Compared with that of individuals with lower exposure levels, the prevalence of thyroid diseases such as autoimmune thyroiditis and subclinical hypothyroidism was greater in those with PM2.5 concentrations within the third quartile range (60.18 to 73.78 μg/m3). Compared with those in the first quartile (17.58 to 46.38 μg/m3), participants in the highest PM2.5 quartile (73.78 to 120.40 μg/m3) presented an increased risk of overt hypothyroidism (OR 1.23 [CI 0.94–1.61]), subclinical hypothyroidism (1.10 [1.01–1.21]), autoimmune thyroiditis (1.09 [1.00–1.18]), and thyroglobulin antibody positivity (1.17 [1.07–1.29]). However, there was no association between PM2.5 exposure and overt hyperthyroidism, subclinical hyperthyroidism, Graves' disease, or thyroid peroxidase antibody positivity (p > 0.05). Each 10 μg/m³ increase in the PM2.5 concentration was associated with an increased risk of overt hypothyroidism (OR 1.05 [1.00–1.11]), subclinical hypothyroidism (1.02 [1.00–1.03]), and thyroglobulin antibody positivity (1.02 [1.00–1.04]). Furthermore, a nearly linear exposure–response relationship was observed between long-term PM2.5 exposure and thyroglobulin antibody positivity. Conclusions: PM2.5 exposure was associated with thyroid disorders among Chinese adults. A dose–response relationship between PM2.5 exposure and autoimmune thyroiditis, as well as thyroglobulin antibody positivity, was also observed. [ABSTRACT FROM AUTHOR]

Background: Papillary thyroid cancer (PTC) and lymphocytic thyroiditis (LT) co-occur with a prevalence of about 30%. PTC harboring BRAFV600E (PTC-BRAF) confers a worse prognosis, but it is unclear if LT alters prognostic features and recurrence of PTC. Objective: We compared the prevalence of PTC-BRAF with and without LT. The risk of adverse pathological features in (i) PTC in the presence and absence of BRAF mutation, irrespective of LT status, was compared to (ii) PTC in the presence and absence of LT, irrespective of BRAF status. Methods: We searched PubMed, Embase, and Web of Science Core Collection for observational studies published from 2010 to June 2023 on adult patients with PTC. The search strategy yielded 47 studies with relevant data. Data of baseline characteristics, clinicopathological features, and the quality assessment tool were extracted by two reviewers. The study was registered with PROSPERO (CRD42023437492). Results: Of the 47 studies, 39 studies with a total cohort of 28 143, demonstrated that the odds of PTC-BRAF were significantly lower in the presence of LT compared to its absence (odds ratio [OR] 0.53, 95% confidence interval [CI]: 0.48–0.58, p < 0.00001). In PTC-BRAF patients, there was a positive association of central neck nodal disease (CNND), PTC > 1 cm, extra-thyroidal extension, American Joint Committee on Cancer (AJCC) Stage 3–4, and multifocality with pooled ORs of 1.54 (95% CI: 1.16–2.04), 1.14 (95% CI: 0.82–1.58), 1.66 (95% CI: 1.40–1.97), 1.53 (95% CI: 1.35–1.75), and 1.24 (95% CI: 1.11–1.40) respectively, compared to wild-type PTC, irrespective of LT status. In the same studies, PTC with LT patients had lower pooled ORs of 0.64 (95% CI: 0.51–0.81) for CNND, 0.83 (95% CI: 0.73–0.95) for PTC > 1 cm, 0.71 (95% CI: 0.58–0.86) for ETE, 0.84 (95% CI: 0.75–0.94) for AJCC Stage 3–4 compared to PTC without LT, irrespective of BRAF status. PTC recurrence was not affected by BRAF or LT, with pooled ORs of 1.12 (95% CI: 0.66–1.90, p = 0.67) and 0.60 (95% CI: 0.28–1.30, p = 0.20) respectively. Similar results were seen with recurrence expressed as hazard ratio in this limited data-set. Conclusion: The odds of PTC-BRAF are significantly lower in the presence of LT than without. PTC with LT, irrespective of BRAF status, was significantly associated with better prognostic factors. Further studies are required to evaluate if LT inhibits PTC-BRAF, and whether this is relevant to the role of immunotherapy in advanced thyroid cancer. [ABSTRACT FROM AUTHOR]

Background: Thyroid disorders are associated with various dietary factors and nutritional elements. The aim of this study was to investigate the relationships between dietary vitamin E intake and the prevalence of thyroid dysfunction and thyroid antibody positivity using data from the National Health and Nutrition Examination Survey (NHANES) database. Methods: Data from the NHANES database collected between 2007 and 2012 were analyzed. A total of 7,773 nonpregnant adults without preexisting thyroid diseases and possessing complete thyroid and vitamin E data were included in the study. The participants were categorized into tertiles based on their dietary vitamin E intake: the lowest group (T1: ≤4.53 mg), the intermediate group (T2: 4.54–8.10 mg), and the highest group (T3: ≥8.11 mg). We used a complex multistage probability sampling design in conjunction with R software. We compared thyroid indices, the prevalence of overt and subclinical hyperthyroidism or hypothyroidism, and the occurrence of thyroid antibody positivity among the three groups based on vitamin E intake. Weighted multinomial logistic regression was used to assess the association between dietary vitamin E intake and thyroid disorders. Restricted cubic splines (RCSs) were used to explore potential nonlinear associations. Results: The prevalence rates of subclinical hypothyroidism (SCH) were 3.63%, 3.07%, and 1.85% in T1, T2, and T3, respectively, indicating a decreasing trend (P-trend = 0.013). In the general population, high vitamin E intake (T3) was significantly associated with a lower prevalence of SCH (OR = 0.28, CI = 0.15–0.54, p < 0.001). Subgroup analysis revealed a more pronounced protective effect in males, with both moderate (T2, OR = 0.45, CI = 0.23–0.87, p = 0.020) and high (T3, OR = 0.19, CI = 0.09–0.39, p < 0.001) dietary vitamin E intake being associated with a lower prevalence of SCH. In addition, moderate (T2, OR = 0.59, CI = 0.37–0.93, p = 0.024) and high (T3, OR = 0.52, CI = 0.36-0.75, p < 0.001) dietary vitamin E intake was associated with a lower prevalence of autoimmune thyroiditis (AIT) in males. However, no significant association was observed among females. Conclusion: The findings of this study suggest that a higher intake of vitamin E is associated with lower prevalence rates of SCH and autoimmune thyroiditis among males. [ABSTRACT FROM AUTHOR]

Background: Hashimoto thyroiditis (HT) is the most common cause of hypothyroidism in iodine-sufficient areas. Selenium is an essential trace element required for thyroid hormone synthesis and exerts antioxidant effects. Therefore, it may be of relevance in the management of HT. Methods: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the effect of selenium supplementation on thyroid function (thyrotropin [TSH], free and total thyroxine [fT4, T4], free and total triiodothyronine [fT3, T3]), thyroid antibodies (thyroid peroxidase antibodies [TPOAb], thyroglobulin antibodies [TGAb], thyrotropin receptor antibody [TRAb]), ultrasound findings (echogenicity, thyroid volume), immune markers, patient-reported outcomes, and adverse events in HT. The study protocol was registered on PROSPERO (CRD42022308377). We systematically searched MEDLINE, Embase, CINHAL, Web of Science, Google Scholar, and the Cochrane CENTRAL Register of Trials from inception to January 2023 and searched citations of eligible studies. Two independent authors reviewed and coded the identified literature. The primary outcome was TSH in patients without thyroid hormone replacement therapy (THRT); the others were considered secondary outcomes. We synthesized the results as standardized mean differences (SMD) or odds ratio (OR), assessed risk of bias using the Cochrane RoB 2 tool, and rated the evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Results: We screened 687 records and included 35 unique studies. Our meta-analysis found that selenium supplementation decreased TSH in patients without THRT (SMD −0.21 [confidence interval, CI −0.43 to −0.02]; 7 cohorts, 869 participants; I2 = 0%). In addition, TPOAb (SMD −0.96 [CI −1.36 to −0.56]; 29 cohorts; 2358 participants; I2 = 90%) and malondialdehyde (MDA; SMD −1.16 [CI −2.29 to −0.02]; 3 cohorts; 248 participants; I2 = 85%) decreased in patients with and without THRT. Adverse effects were comparable between the intervention and control groups (OR 0.89 [CI 0.46 to 1.75]; 16 cohorts; 1339 participants; I2 = 0%). No significant changes were observed in fT4, T4, fT3, T3, TGAb, thyroid volume, interleukin (IL)-2, and IL-10. Overall, certainty of evidence was moderate. Conclusions: In people with HT without THRT, selenium was effective and safe in lowering TSH, TPOAb, and MDA levels. Indications for lowering TPOAb were found independent of THRT. [ABSTRACT FROM AUTHOR]

Background: It has often been reported that thyroid-specific autoimmune diseases (ADs), such as Hashimoto's thyroiditis and Graves' disease, could increase the risk of thyroid cancer, but the association between other ADs beyond thyroid and thyroid cancer has not been well investigated. This study aimed to examine the risk of thyroid cancer in patients with eight ADs compared with those without ADs. Methods: This nationwide retrospective matched cohort study was conducted to investigate the relationship of eight ADs (Hashimoto's thyroiditis, Graves' disease, type 1 diabetes mellitus, Sjogren's disease, inflammatory bowel disease [IBD], vitiligo, systemic lupus erythematosus, and rheumatoid arthritis [RA]) with the risk of incident thyroid cancer using the National Health Insurance Service-National Sample Cohort. The Cox-proportional hazard model was used to estimate the adjusted hazard ratio (HR) and confidence intervals (CI) for thyroid cancer in relation to each of AD compared with control group without AD. Results: During the average follow-up of 9.49 years, 138 thyroid cancer cases were newly developed in control group and 268 cases were occurred in group with 8 ADs. For all of study participants, the risk of thyroid cancer was significantly increased in patients with Hashimoto's thyroiditis (HR = 2.10 [1.57–2.81]), Graves' disease (HR = 2.67 [1.99–3.62]), IBD (HR = 2.06 [1.50–2.83]), vitiligo (HR = 1.71 [1.13–2.59]), RA (HR = 1.76 [1.07–2.90]), and total of 8 ADs (HR = 1.97 [1.60–2.42]) compared with control group without ADs. When ADs were divided into three types, thyroid-specific ADs (HR = 2.37 [1.85–3.03]) showed the strongest and significant association with thyroid cancer, followed by local ADs (HR = 1.83 [1.41–2.38]), and systemic ADs (HR = 1.77 [1.14–2.74]). Conclusions: Specific ADs—especially for thyroid-specific AD, vitiligo, IBD, and RA—were associated with increased risk for thyroid cancer. [ABSTRACT FROM AUTHOR]

Background: Previous studies have reported gut microbiome alterations in Hashimoto's autoimmune thyroiditis (HT) patients. Yet, it is unknown whether an aberrant microbiome is present before clinical disease onset in participants susceptible to HT or whether it reflects the effects of the disease itself. In this study, we report for the first time a comprehensive characterization of the taxonomic and functional profiles of the gut microbiota in euthyroid seropositive and seronegative participants. Our primary goal was to determine taxonomic and functional signatures of the intestinal microbiota associated with serum thyroid peroxidase antibodies (TPOAb). A secondary aim was to determine whether different ethnicities warrant distinct reference intervals for accurate interpretation of serum thyroid biomarkers. Methods: In this cross-sectional study, euthyroid participants with (N = 159) and without (N = 1309) TPOAb were selected from the multiethnic (European Dutch, Moroccan, and Turkish) HEalthy Life In an Urban Setting (HELIUS) cohort. Fecal microbiota composition was profiled using 16S rRNA sequencing. Differences between the groups were analyzed based on the overall composition (alpha and beta diversity), as well as differential abundance (DA) of microbial taxa and functional pathways using multiple DA tools. Results: Overall composition showed a substantial overlap between the two groups (p > 0.05 for alpha-diversity; p = 0.39 for beta-diversity), indicating that TPOAb-seropositivity does not significantly differentiate gut microbiota composition and diversity. Interestingly, TPOAb status accounted for only a minor fraction (0.07%) of microbiome variance (p = 0.545). Further exploration of taxonomic differences identified 138 taxa nominally associated with TPOAb status. Among these, 13 taxa consistently demonstrated nominal significance across three additional DA methods, alongside notable associations within various functional pathways. Furthermore, we showed that ethnicity-specific reference intervals for serum thyroid biomarkers are not required, as no significant disparities in serum thyroid markers were found among the three ethnic groups residing in an iodine-replete area (p > 0.05 for thyrotropin, free thyroxine, and TPOAb). Conclusion: These findings suggest that there is no robust difference in gut microbiome between individuals with or without TPOAb in terms of alpha and beta-diversity. Nonetheless, several taxa were identified with nominal significance related to TPOAb presence. Further research is required to determine whether these changes indeed imply a higher risk of overt HT. [ABSTRACT FROM AUTHOR]

This article discusses the role of selenium (Se) in the management of Hashimoto's thyroiditis (HT), a form of autoimmune thyroiditis. Selenium is an essential trace element that plays a crucial role in the production of thyroid hormones and immune system regulation. The article reviews the effects of selenium supplementation on various thyroid parameters and immune biomarkers, finding that it can decrease thyrotropin (TSH) levels and reduce thyroid peroxidase antibodies (TPOAb) titers. The study also confirms the safety of selenium supplementation at doses up to 200 μg/day. However, further research is needed to determine the clinical benefits of selenium supplementation in patients under levothyroxine treatment and to explore its potential interactions with other drugs. [Extracted from the article]

Background: There is some controversy on the potential relationship between autoimmune processes and clinicopathologic features as well as prognosis of differentiated thyroid cancer (DTC), and the evidence is limited by its largely retrospective nature. We examined the relationship between the presence of autoimmune thyroiditis (AT) and 1-year thyroid cancer treatment outcomes in a large multicenter study using prospectively collected data. Methods: We included data from consecutive DTC patients enrolled in the Italian Thyroid Cancer Observatory (ITCO) database (NCT04031339). We divided the groups according to the presence (AT) or absence (no autoimmune thyroiditis [noAT]) of associated AT. We used propensity score matching to compare the clinical features and outcomes between the two groups at 1-year follow-up. Results: We included data from 4233 DTC patients, including 3172 (75%) females. The American Thyroid Association (ATA) risk levels were as follows: 51% (2160/4233) low risk, 41.3% (1750/4233) intermediate risk, and 7.6% (323/4233) high risk. There were 1552 patients (36.7%) who had AT. Before propensity score matching, AT patients were significantly younger and had a smaller and bilateral tumor (p < 0.0001). Patients with AT more frequently fell into the low- and intermediate-risk categories, while the ATA high risk was more frequent among noAT patients (p = 0.004). After propensity score matching, patients with AT more frequently showed evidence of disease (structural/biochemical incomplete response) versus excellent/indeterminate response, compared with patients without AT (7.3% vs. 4.5%, p = 0.001), with an odds ratio of 1.86 ([confidence interval: 1.3–2.6], p = 0.0001). However, when considering only structural persistence as the outcome, no statistically significant differences were observed between patients with or without AT (3.4% vs. 2.7%, p = 0.35). The elevated risk associated with the ATA intermediate and high risk at diagnosis remained consistently statistically significant. Conclusions: In this large prospective series, biochemical persistence was more frequent, at 1-year follow-up, in AT patients. However, there was no significant association between the presence of AT and structural persistence of disease. These findings may be explained by the presence of a residual thyroid tissue. [ABSTRACT FROM AUTHOR]

Hashimoto's thyroiditis (HT) is a common autoimmune disease and current treatment aims to manage symptoms with ongoing hormone replacement therapy. Here we present the case of a 61-year-old female who experienced a sustained decrease in symptoms of HT as well as levels of thyroid-stimulating hormone and C-reactive protein after two prolonged water-only fasts at a residential health clinic. [ABSTRACT FROM AUTHOR]

Autoantibodies against thyroid proteins are present in several thyroid diseases. Thyroid-stimulating hormone receptor (TSHR) is a G-protein-coupled receptor (GPCR) that binds to thyroid-stimulating hormone (TSH) and stimulates production of thyroxine (T4) and triiodothyronine (T3). When agonized by anti-TSHR autoantibodies, aberrant production of thyroid hormone can lead to Graves' Disease (GD). In Hashimoto's thyroiditis (HT), anti-TSHR autoantibodies target the thyroid for immune attack. To better understand the role of anti-TSHR antibodies in thyroid disease, we generated a set of rat antimouse (m)TSHR monoclonal antibodies with a range of affinities, blocking of TSH, and agonist activity. These antibodies could be used to investigate the etiology and therapy of thyroid disease in mouse models and as building blocks in protein therapeutics that target the thyroid for treatment in either HT or GD. [ABSTRACT FROM AUTHOR]

Background: Autoimmune thyroid diseases (AITD) represent the most common autoimmune diseases. However, current therapies focus on relieving the symptoms instead of curing AITD, and new therapies to reverse the autoimmune attack on the thyroid are needed. HLA-DRβ1-Arg74 is the key HLA class II allele that triggers AITD by presenting pathogenic thyroglobulin (Tg) peptides that activate thyroid self-reactive T cells. We hypothesized that blocking the presentation of Tg peptides to T cells within the HLA-DRβ1-Arg74 peptide binding cleft could reverse the autoimmune response to the thyroid in AITD. Methods: The approach we used to block Tg peptide presentation within HLA-DRβ1-Arg74 is to design retro-inverso D-amino acid (RID) peptides that have high affinity to the HLA-DRβ1-Arg74 peptide binding pocket. Results: By using computational approaches and molecular dynamics simulations, we designed two RID peptides, RT-15 and VT-15, that blocked peptide binding to recombinant HLA-DRβ1-Arg74 molecule, as well as T cell activation in vitro. Furthermore, RT-15 and VT-15 blocked in vivo T cell activation by thyroglobulin in humanized NOD-DR3 mice induced with experimental autoimmune thyroiditis. Conclusions: In summary, we discovered two RID peptides that block thyroglobulin peptide binding to HLA-DRβ1-Arg74 and their presentation to T cells in AITD. These findings set the stage for a personalized medicine therapeutic approach for AITD patients who carry the DRβ1-Arg74 allele. This antigen-specific therapeutic strategy can potentially be extended to other autoimmune diseases. [ABSTRACT FROM AUTHOR]

This review on the 100th anniversary of the American Thyroid Association summarizes the remarkable progress attained during the past century regarding the pathogenesis and treatment of thyroid autoimmune diseases. Indeed, the general concept of autoimmune diseases in humans was established 70 years ago by thyroid investigators. Graves' disease is a paradigm for the rare occurrence of how autoimmunity can cause disease by stimulating rather than destroying an organ system. Therapeutic advances in the mid 20th century involving administration of thyroid hormones, thionamide drugs, and radioiodine have been hugely beneficial for human health. However, these approaches can only treat, but not cure, thyroid autoimmunity. Investigation of these diseases is facilitated by the identification of a limited number of specific autoantigens, whose molecular cloning has provided much information on their structure. This knowledge has led to highly sensitive and specific diagnostic tests, provided insight into novel aspects regarding the pathogenesis of thyroid autoimmunity, and has opened avenues for the development of new therapeutic agents. Immunotherapy for a cure as opposed to therapy of Graves' disease and Hashimoto's thyroiditis remains the holy grail for the 21st century. [ABSTRACT FROM AUTHOR]

Background: Hashimoto's thyroiditis is a common autoimmune thyroid disorder characterized by thyroid lymphocytic infiltrates and autoreactive antibodies against thyroglobulin (TgAbs) and thyroperoxidase. Final evolution of the disease can lead to hypothyroidism with destruction of the thyroid architecture. Interleukin-4 (IL-4) is involved in the humoral immune response and B cell activation required in autoimmune thyroiditis (AT) progression. We used our mouse model overexpressing IL-4 by thyrocytes (Thyr-IL4) to study the impact of a local IL-4 expression in AT using transgenic nonobese diabetic (NOD.H2h4) derived animals treated with iodide-supplemented water to increase the incidence of spontaneous AT (SAT). Methods: Thyr-IL4 NOD.H2h4 and nonpathogenic C57BL/6 animals aged 8 weeks were exposed to 0.05% sodium iodide (NaI) in their drinking water for 8 and 16 weeks. Circulating TgAbs and expression of intrathyroidal cytokines were quantified. Thyroid inflammation was assessed by classical histological analyses, including identification of some immune cell populations. The most sensitive parameter to evaluate the thyroid function, serum thyrotropin (TSH), was also measured at the end of the treatment. Results: Relative to wild-type (WT) animals, Thyr-IL4 NOD.H2h4 mice developed severe accelerated SAT with elevated serum TgAbs and numerous thyroid infiltrates mainly composed of CD4+/CD8+ T cells, B lymphocytes, and monocytes/macrophages. Thyroid expression of T helper (Th) Th1/Th2 cytokines was also enhanced, as well as IL-17. In contrast, excessive iodide supply did not induce TgAbs in WT and Thyr-IL4 SAT-resistant C57BL/6 animals. However, moderate leukocyte infiltrations in transgenic thyroids were evident compared to WT, but associated with a limited number of T and B cells and a different cytokine profile from Thyr-IL4 NOD.H2h4 mice. Finally, and despite their diverse immune responses, both transgenic strains presented marked thyroid enlargement and elevated serum TSH at the end of the treatment in contrast to their WT littermates. Conclusions: These findings demonstrated that ectopic expression of IL-4 from thyrocytes enhanced the severity of accelerated SAT in disease-prone Thyr-IL4 NOD.H2h4 animals and promoted thyroid leukocyte infiltration in SAT-resistant transgenic C57BL/6 mice. Moreover, impaired thyroid function emerged in both transgenic strains during the progression of the disease. [ABSTRACT FROM AUTHOR]

Over the past 10 years, consensus has developed regarding proper patient selection, surveillance strategy, and indications that warrant consideration of transition to surgical intervention in patients with papillary microcarcinoma (PMC) on active surveillance (AS).[1],[2] However, indications for levothyroxine (LT4) therapy during AS are not well defined. Up to this point, we have not programmatically offered LT4 therapy at the time of tumor progression for patients in our AS program. [Extracted from the article]

Background: The hypothalamus-pituitary-thyroid axis coordinates brain development and postdevelopmental function. Thyroid hormone (TH) variations, even within the normal range, have been associated with the risk of developing common psychiatric disorders, although the underlying mechanisms remain poorly understood. Methods: To get new insight into the potentially shared mechanisms underlying thyroid dysfunction and psychiatric disorders, we performed a comprehensive analysis of multiple phenotypic and genotypic databases. We investigated the relationship of thyroid disorders with depression, bipolar disorder (BIP), and anxiety disorders (ANXs) in 497,726 subjects from U.K. Biobank. We subsequently investigated genetic correlations between thyroid disorders, thyrotropin (TSH), and free thyroxine (fT4) levels, with the genome-wide factors that predispose to psychiatric disorders. Finally, the observed global genetic correlations were furthermore pinpointed to specific local genomic regions. Results: Hypothyroidism was positively associated with an increased risk of major depressive disorder (MDD; OR = 1.31, p = 5.29 × 10−89), BIP (OR = 1.55, p = 0.0038), and ANX (OR = 1.16, p = 6.22 × 10−8). Hyperthyroidism was associated with MDD (OR = 1.11, p = 0.0034) and ANX (OR = 1.34, p = 5.99 × 10−⁶). Genetically, strong coheritability was observed between thyroid disease and both major depressive (rg = 0.17, p = 2.7 × 10−⁴) and ANXs (rg = 0.17, p = 6.7 × 10−⁶). This genetic correlation was particularly strong at the major histocompatibility complex locus on chromosome 6 (p < 10−⁵), but further analysis showed that other parts of the genome also contributed to this global effect. Importantly, neither TSH nor fT4 levels were genetically correlated with mood disorders. Conclusions: Our findings highlight an underlying association between autoimmune hypothyroidism and mood disorders, which is not mediated through THs and in which autoimmunity plays a prominent role. While these findings could shed new light on the potential ineffectiveness of treating (minor) variations in thyroid function in psychiatric disorders, further research is needed to identify the exact underlying molecular mechanisms. [ABSTRACT FROM AUTHOR]

Background: The gut is a target organ of thyroid hormone (TH) that exerts its action via the nuclear thyroid hormone receptor α1 (TRα1) expressed in intestinal epithelial cells. THs are partially metabolized via hepatic sulfation and glucuronidation, resulting in the production of conjugated iodothyronines. Gut microbiota play an important role in peripheral TH metabolism as they produce and secrete enzymes with deconjugation activity (β-glucuronidase and sulfatase), via which TH can re-enter the enterohepatic circulation. Summary: Intestinal epithelium homeostasis (the finely tuned balance between cell proliferation and differentiation) is controlled by the crosstalk between triiodothyronine and TRα1 and the presence of specific TH transporters and TH-activating and -inactivating enzymes. Patients and experimental murine models with a dominant-negative mutation in the TRα exhibit gross abnormalities in the morphology of the intestinal epithelium and suffer from severe symptoms of a dysfunctional gastrointestinal tract. Over the past decade, gut microbiota has been identified as an essential factor in health and disease, depending on its compositional and functional profile. This has led to a renewed interest in the so-called gut-thyroid axis. Disruption of gut microbial homeostasis (dysbiosis) is associated with autoimmune thyroid disease (AITD), including Hashimoto's thyroiditis, Graves' disease, and Graves' orbitopathy. These studies reviewed here provide new insights into the gut microbiota roles in thyroid disease pathogenesis and may be an initial step toward microbiota-based therapies in AITD. However, it should be noted that cause-effect mechanisms remain to be proven, for which prospective cohort studies, randomized clinical trials, and experimental studies are needed. Conclusion: This review aims at providing a comprehensive insight into the interplay between TH metabolism and gut homeostasis. [ABSTRACT FROM AUTHOR]

The Rosalind Franklin Society (RFS) has announced the recipient of the 2023 RFS Award in Science for the journal Thyroid. The award recognizes the outstanding research and published work of women and underrepresented minority scientists, physicians, and engineers. The recipient, Aline C. Fenneman, Eveline Bruinstroop, Max Nieuwdorp, Anne H. van der Spek, and Anita Boelen, authored a comprehensive review titled "A Comprehensive Review of Thyroid Hormone Metabolism in the Gut and Its Clinical Implications." The review explores the role of the gut in thyroid hormone metabolism and its clinical implications, including the impact of gut microbiota on thyroid disease. The review provides new insights into the gut-thyroid axis and suggests potential microbiota-based therapies for autoimmune thyroid disease. However, further research is needed to establish cause-effect mechanisms. The lead author, Anita Boelen, is a Professor of Thyroid Hormone Metabolism at the Amsterdam University Medical Center and has published extensively in the field. [Extracted from the article]

Background: It is uncertain whether the presence of autoimmune thyroiditis (AIT) increases the risk of thyroid cancer in children with thyroid nodules. This study evaluated the association between AIT and thyroid cancer in pediatric patients with thyroid nodules. Methods: A cross-sectional study was performed of pediatric patients (<19 years old) with a thyroid nodule (≥1 cm) who underwent fine-needle aspiration in an academic pediatric thyroid center. AIT was defined by the presence of thyroid autoantibodies or diffusely heterogeneous sonographic echotexture. The primary outcome was diagnosis of thyroid cancer. The association of AIT with thyroid cancer was evaluated with univariable and multivariable logistic regression. Associations of AIT with subject and nodule characteristics were also assessed. Results: Four hundred fifty-eight thyroid nodules in 385 patients (81% female) were evaluated at a median age of 15.5 years (interquartile range 13.5–17.0). Thyroid cancer was present in 108 nodules (24%). AIT was present in 95 subjects (25%) and was independently associated with an increased risk of thyroid cancer (multivariable odds ratio [OR] 2.19, 95% confidence interval [CI] 1.32–3.62). Thyroid cancer was also independently associated with younger age, nodule size, and solitary nodules, but was not associated with serum thyrotropin concentration. AIT was not associated with the likelihood of subjects undergoing thyroid surgery (p = 0.17). AIT was less commonly associated with follicular thyroid carcinoma than with papillary thyroid carcinoma (OR 0.22, CI 0.05–1.06). Among papillary thyroid carcinomas, AIT was strongly associated with the diffuse sclerosing variant (OR 4.74, CI 1.33–16.9). AIT was not associated with the extent of local, regional, or distant disease at thyroid cancer diagnosis. Conclusions: AIT is independently associated with an increased risk of thyroid cancer in children with thyroid nodules. These findings suggest that the evaluation of thyroid autoantibodies and thyroid echotexture may inform thyroid cancer risk assessment and surgical decision-making in children with thyroid nodules. [ABSTRACT FROM AUTHOR]

Background: Autoimmune thyroid diseases are the most common types of autoimmune diseases, but their physiopathology is still relatively unexplored. Genotype-tissue expression (GTEx) is a publicly available repository containing RNAseq data, including profiles from thyroid. Approximately 14.8% of these glands were affected by focal lymphocytic thyroiditis and 6.3% were annotated as Hashimoto. We interrogated these data to improve the characterization of infiltrating cells and to identify new molecular pathways active in autoimmune thyroiditis. Materials and Methods: Histological GTEx images of 336 thyroid samples were classified into three categories, that is, non-infiltrated thyroid, small focal infiltrated thyroid, and extensive lymphoid infiltrated thyroid. Differentially expressed genes among these categories were identified and subjected to in silico pathway enrichment analysis accordingly. CIBERSORTx deconvolution was used to characterize infiltrating cells. Results: As expected, most of the transcriptional changes were dependent on tissue infiltration. Upregulated genes in tissues include—in addition to lineage-specific B and T cell genes—a broad representation of inhibitory immune checkpoint receptors expressed by B and T lymphocytes. CIBERSORTx analysis identified 22 types of infiltrating cells showed that T cells predominate 3:1 over B cells in glands with small infiltrates, only by 1.7:1 in those with large infiltrates. Follicular helper and memory CD4 T cells were significantly more abundant in glands with large infiltrates (p < 0.0001), but the most prominent finding in these glands was an almost sixfold increase in the number of naive B cells (p < 0.0001). A predominance of M2 macrophages over M1 and M0 macrophages was observed in the three gland categories (p < 0.001). Conclusions: Analysis of transcriptomic RNA-seq profiles constitutes a rich source of information for the analysis of autoimmune tissues. High-resolution transcriptomic data analysis of thyroid glands indicates the following: (a) in all infiltrated glands, active autoimmune response coexists with suppressor counteracting mechanisms involving several inhibitory checkpoint receptor pairs, (b) glands with small infiltrates contain an unexpected relatively high proportion of B lymphocytes, and (c) in highly infiltrated glands, there is a distinct transcriptomic signature of active tertiary lymphoid organs. These results support the concept that the autoimmune response is amplified in the thyroid tissue. [ABSTRACT FROM AUTHOR]

Background: The syndrome of thyrotoxicosis typically relies on radioactive iodine scans for establishing its etiology. Alternatively, the determination of thyrotropin (TSH) receptor antibodies (TRAbs) helps to distinguish Graves' disease (GD) from thyrotoxic thyroiditis. Current assays are impacted by limitations in sensitivity and/or turnaround time. Therefore, we decided to test a new assay for the detection of TSH receptor stimulating antibodies (TSAbs) and compare it with the clinically available assays. Methods: We enrolled 110 individuals in 5 cohorts: patients with incident or recurrent GD (cohort 1); patients with thyroiditis, painless or subacute (cohort 2); patients with Graves' orbitopathy/thyroid eye disease (TED) in cohort 3; patients with Hashimoto's thyroiditis (cohort 4), and a control group of normal volunteers (cohort 5). The patients were tested with the two clinically available assays: Roche Elecsys anti-TSHR assay (ROC-TBII) from Roche Diagnostics and Thyretain™ TSI Reporter BioAssay Kit (QUI-TSI) from Quidel. In addition, the samples were tested with the aequorin TSAb assay (OTS-TSI) provided by Otsuka Pharmaceutical Co., Ltd. (Tokyo, Japan). The data were collected in a cross-sectional manner before initiation of therapy. Results: We had 36 cases of GD, 17 cases of thyroiditis, 27 cases of TED, 10 cases of Hashimoto's thyroiditis, and 20 normal volunteers. OTS-TSI had 100% sensitivity and specificity in distinguishing GD from thyroiditis, identical with QUI-TSI but superior to ROC-TBII (sensitivity 86% and specificity 94.1%). OTS-TSI had 93% sensitivity and 100% specificity for the diagnosis of TED, compared with normal controls. QUI-TSI and ROC-TBII performed similarly in this analysis, demonstrating 82% sensitivity and 100% specificity. The range of detectable values for OTS-TSI was 20–29,000 mIU/L and the turnaround time was ≤6 hours, without the need for cell culture equipment. Conclusions: OTS-TSI performed excellently, though similarly to QUI-TSI, for the differential diagnosis of GD vs. thyroiditis, while being superior in that respect to ROC-TBII. Furthermore, OTS-TSI has superior sensitivity to QUI-TSI and ROC-TBII for TED diagnosis, while retaining high specificity. It has a short turnaround time and avoids the need for cell culture and sterility. Larger studies in U.S. populations are needed for its validation. [ABSTRACT FROM AUTHOR]

Background: Expression of natural killer group 2 member D (NKG2D) ligand (NKG2DL) plays a major role as a "danger signal" on stressed cells to promote removal of the latter by NKG2D-expressing cytotoxic lymphocytes. NKG2DL expression has been found in peripheral immune cells as well, such as in macrophages; however, the effect of this expression is yet to be determined. Methods: We determined instrumental variables (IVs; R2 <0.01 in linkage disequilibrium), explaining the major variance in major histocompatibility complex class I chain-related protein A (MICA) and B (MICB) gene expression levels from the expression-quantitative trait locus (eQTL) of NKG2DLs based on the RNA-seq analysis of peripheral blood mononuclear cells (PBMCs) from 381 Japanese. Simultaneously, the target outcomes were filtered by PheWAS from 58 health risks, using a community-based cohort study composed of 44,739 Japanese residents. Finally, we estimated the causal effect of gene expression levels on the outcomes using the Mendelian randomization approach. Results: We determined nine and four IVs, explaining 87.6% and 33.0% of MICA and MICB gene expression levels, respectively. In the association test, we identified 10 or 13 significant outcomes associated with the MICA or MICB eQTLs, respectively, as well as the causal effect of MICA expression on Graves' disease (GD) (p = 4.2 × 10−3; odds ratio per 1 S.D. difference in the expression: 0.983 [confidence interval: 0.971–0.995]), using the weighted median estimator, without significant pleiotropy (p > 0.05), and the results were consistent across the sensitivity analyses. Conclusions: Our study provide novel evidence associating NKG2DL expression with GD, an autoimmune thyroiditis; direction of the effect indicated the immunoregulatory role of MICA expression in PBMCs, suggesting the importance of further functional assays in inflammatory diseases. [ABSTRACT FROM AUTHOR]

Background: Vitamin A is a factor that suppresses immune responses, including T helper (Th)1 and Th17 responses. However, there has been no report showing the association between vitamin A-related genes (CYP26B1, RARB, and RARG) and the prognosis of autoimmune thyroid disease (AITD). The objective of this study was to clarify the association between vitamin A-related genes and the susceptibility and prognosis of AITD. Methods: We genotyped polymorphisms in genes encoding vitamin A-related molecules using the polymerase chain reaction-restriction fragment length polymorphism method. The proportion of T helper cells was analyzed by flow cytometry. Serum interleukin (IL)-17 and interferon (IFN)-γ were examined by enzyme-linked immunosorbent assay. Results:CYP26B1 rs3768641 GG genotype and G allele were significantly more frequent in patients with mild Hashimoto's thyroiditis (HT) than in those with severe HT (p = 0.0013 and 0.0024, respectively). The RARB rs1997352 CC genotype was significantly more frequent in HT patients than in controls (p = 0.0207). The proportion of Th17 cells was significantly higher in CYP26B1 rs2241057 TT genotype than C carrier (CC+CT genotypes) (p = 0.0385), in RARB rs1997352 A carrier (AA+AC genotypes) than those with CC genotype (p = 0.0246), and in RARG rs7398676 G carrier (GG+GT genotypes) than in TT genotype (p = 0.0249). In the RARB rs1997352 polymorphism, HT patients with a high concentration of IFN-γ (≥150 ng/mL) were more frequent in the CC genotype than in A carriers (AA+AC genotypes) (p = 0.0226). Serum levels of IL-17 were significantly elevated in subjects with the TT genotype of the CYP26B1 rs2241057 single nucleotide polymorphism (SNP) (p = 0.0026) and in subjects with the GG genotype of the CYP26B1 rs3798641 SNP (p = 0.030). Subjects with a high concentration of IL-17 (≥0.71 pg/mL) were more frequent in RARG 7398676 G carriers (GG+GT genotypes) than in TT genotype (p = 0.0218). Conclusions: Polymorphisms in the CYP26B1 gene were related to the proportion of Th17 cells, the level of IL-17 and the severity of HT. Polymorphisms in RAR were related to the proportion of Th17 cells, concentrations of IFN-γ and IL-17, and susceptibility to HT. [ABSTRACT FROM AUTHOR]

Background: Epigenetic disorders play an important role in the pathogenesis of autoimmune thyroiditis (AIT). Therefore, the study of the possible role of DNA methylation in AIT is of great significance to explore the pathogenesis of AIT. Methods: From May 2019 to June 2019, whole blood samples were collected from 176 AIT patients and 176 controls from different water iodine levels in Shandong Province, China. We used the Illumina Methylation 850K BeadChip to determine significant differences in methylation status of genes and used the MethylTarget™ assay to verify the methylation level in 176 cases and 176 controls. The relative mRNA levels of genes were detected by quantitative real-time-polymerase chain reaction. Results: There were multiple differential methylation sites in the HLA-DPB1 and PDCD1LG2 genes between the case and control population with different water iodine levels. Some target regions of HLA-DPB1 and PDCD1LG2 genes were negatively correlated with relative mRNA expression in the case and control populations and with different water iodine levels. Conclusions: There is differential methylation status in genomic DNA in patients with AIT. The methylation patterns of HLA-DPB1 and PDCD1LG2 genes related to cell adhesion molecule pathway may be different based on different water iodine levels. HLA-DPB1 and PDCD1LG2 genes related to the cell adhesion molecules pathway may play a role in the development of AIT. This study is registered with Chinese Clinical Trial Registry, www.chictr.org.cn , number ChiCTR2000039105. [ABSTRACT FROM AUTHOR]

Background: Autoimmune diseases tend to cluster in the same individual or in families. Four types of autoimmune polyglandular syndromes (APS) have been described based on the combination of endocrine and/or non-endocrine autoimmune diseases. In particular, type-3 APS is defined by the association of an autoimmune thyroid disease (ATD) and other autoimmune diseases and has a multifactorial etiology. The natural history of autoimmune diseases is characterized by three stages: potential, subclinical, and clinical. Methods: To determine the prevalence of organ-specific autoantibodies (anti-adrenal, anti-ovary [StCA], anti-pituitary [APA], anti-parietal cells [PCA], anti-tissue transglutaminase [tTGAb], anti-mitochondrial [AMA], anti-glutamic acid decarboxylase [GADA], anti-nicotinic acetylcholine receptor) in patients with ATD and to define the stage of the disease in patients with positive autoantibodies. From January 2016 to November 2018, 1502 patients (1302 female; age 52.7 ± 14.7 [mean ± standard deviation] years, range 18–86 years) with ATD (1285/1502 [85.6%] with chronic autoimmune thyroiditis and 217/1502 [14.4%] with Graves' disease) were prospectively enrolled. Results: The most common organ-specific autoantibodies were PCA (6.99%) and GADA (2.83%), while the prevalence of the remaining autoantibodies was ≤1%. All autoimmune diseases, but celiac disease, were predominant at the potential stage. Sex, ATD type, smoking habit, and coexistence of other autoimmune diseases correlated with the susceptibility to develop chronic atrophic gastritis (CAG) or autoimmune diabetes mellitus. Conclusions: The association between ATD and CAG was the most common manifestation of type-3 APS, mainly at the potential stage, that could lead to appropriate follow-up for early detection and timely treatment of the disease. [ABSTRACT FROM AUTHOR]

Background: Few small-scale studies have reported a genetic and familial predisposition in Hashimoto's thyroiditis (HT), however, quantified familial risk estimates from population-level data are unavailable. We aimed to estimate the incidence and familial risk of HT among first-degree relatives (FDR) according to age, sex, and family relationships. Methods: We conducted a population-based study in the general population of Korea from 2002 to 2017. Using the nationwide health insurance database, which has full population coverage and family relationship information, a cohort of 22 million individuals with blood-related FDR comprising 12 million families were followed up for a familial occurrence of HT. Age- and sex-adjusted incidence risk ratios (IRRs) were calculated in individuals with an affected FDR compared with those without an affected FDR. Results: Among 21,940,795 individuals, 234,912 had an HT-affected FDR, of whom 2425 familial cases developed HT with an incidence of 7.12/10,000 person-years. The familial risk for HT was 6.5-fold (95% confidence interval [CI]: 6.24–6.78) higher in individuals with versus without affected FDR. According to relationship, familial risks were IRR 102.71, IRR 7.80, IRR 5.54, and IRR 5.52 with an affected twin, sibling, mother, and father, respectively, and the corresponding incidence (/10,000 person-years) was 115.57, 10.66, 5.73, and 5.91. Same-sex twins had three times higher risk of developing HT than opposite-sex twins (IRR 121.01 vs. 21.46). The sex-specific familial risk was higher in males than females. The risks demonstrated age dependence, being higher in younger age groups. Conclusions: This study represents the largest population-based study of familial HT risk in Asia. We demonstrated elevated familial risk of incident HT among FDR, but with lower magnitude as those observed in previous studies. Familial risk increased with the degree of genetic relatedness among FDR indicating a prominent role of genetic factors in the familial aggregation of HT. Elevated risks in the younger age groups should motivate clinicians to screen people with a family history, especially those <30 years. [ABSTRACT FROM AUTHOR]

Background: Malnutrition in early life may permanently change the structure and function of the body, which lead to a number of diseases in adulthood. The effect of famine exposure during the early life on thyroid function and disorders remains unclear. This study investigated the association between exposure to the Great Chinese Famine (1959–1961) in early life and thyroid function and disorders in adulthood. Methods: Nine thousand eight hundred eighty-one subjects with appropriate birth dates derived from the Thyroid disorders, Iodine status, and Diabetes Epidemiological survey were included. Thyroid function and disorders were defined by the test results of blood sample and ultrasonography of all participants. Associations between famine exposure in early life and thyroid function and disorders in adulthood were assessed with binary logistic regression and linear regression. Results: Participants exposed to the Great Chinese Famine during the fetal stage was associated with a higher thyrotropin (TSH) level in adulthood (β = 0.024; p = 0.038), compared with the nonexposed participants. The association was significant among rural participants (β = 0.039; p = 0.02) but not in urban participants (β = 0.005; p = 0.77). Fetal-exposed group did not show a higher risk of thyroid disorders than the age-matched balanced control group, including overt hyperthyroidism, subclinical hyperthyroidism, overt hypothyroidism, subclinical hypothyroidism, autoimmune thyroiditis, and thyroid nodules (p > 0.05). Conclusions: Famine exposure during the fetal stage was associated with a higher TSH level in adulthood. The fetal stage could be the critical period for programming the pituitary–thyroid axis. [ABSTRACT FROM AUTHOR]

Background: Although studies have reported an increased risk for cognitive disorders in Hashimoto's thyroiditis (HT) patients, even in the euthyroid state, the mechanisms involved remain unclear. The hippocampus is a classic brain region associated with cognitive function, among which the formation of long-term potentiation (LTP) in the Schaffer collateral-CA1 pathway plays an important role in the process of learning and memory. Therefore, this study established a euthyroid HT model in mice and investigated whether and how HT itself has the ability to trigger LTP alterations accompanied by learning and memory abnormality. Methods: An experimental euthyroid HT model was established in NOD mice through immunization with porcine thyroglobulin (Tg). Morris water maze was measured to determine mice spatial learning and memory. We investigated the effect of HT on synaptic transmission and high-frequency stimulation-induced LTP in the Schaffer collateral-CA1 synapse of mice hippocampus in vivo. Then, animals were sacrificed for thyroid-related parameter measure as well as detection of cellular and molecular events associated with the induction of LTP. Results: HT mice showed intrathyroidal lymphocyte infiltration and rising serum thyroid autoantibody levels accompanied by normal thyroid function. The HT mice had poorer performance in Morris water maze than controls. These alterations were mirrored by abnormalities in synaptic plasticity in the Schaffer collateral-CA1 synapses of the hippocampus in vivo. The integrity of the synaptic structure is the premise for the production of LTP. As detected by transmission electron microscopy, the ultrastructure of synapse and astrocyte in the hippocampus were impaired in euthyroid HT mice. Additionally, Western blot and real-time polymerase chain reaction analyses confirmed that in HT mice, GS, GLAST, and GLT-1, key elements in glutamate–glutamine circulation located in astrocyte, were downregulated, accompanied by elevated levels of glutamate in the hippocampus, which impaired the material basis for LTP induction. NMDR2B expression in the hippocampus was also downregulated. Conclusion: HT can induce damage of LTP in the hippocampal Schaffer collateral-CA1 pathway in the euthyroid state, and this can be attributed, at least partly, to astrocytes impairment, which may underlie the deleterious effects of HT itself on hippocampal-dependent learning and memory function. [ABSTRACT FROM AUTHOR]

Background: There is a growing awareness that nutritional habits may influence risk of several inflammatory and immune-mediated disorders, including autoimmune diseases, through various mechanisms. The aim of the present study was to investigate dietary habits and their relationship with redox homeostasis in the setting of thyroid autoimmunity. Materials and Methods: Two hundred subjects (173 females and 27 males; median age, 37 years) were enrolled. None were under any pharmacological treatment. Exclusion criteria were any infectious/inflammatory/autoimmune comorbidity, kidney failure, diabetes, and cancer. In each subject, serum thyrotropin (TSH), free thyroxine, antithyroid antibodies, and circulating oxidative stress markers were measured. A questionnaire on dietary habits, evaluating the intake frequencies of food groups and adherence to the Mediterranean diet, was submitted to each participant. Results: Among the 200 recruited subjects, 81 (71 females and 10 males) were diagnosed with euthyroid Hashimoto's thyroiditis (HT); the remaining 119 (102 females and 17 males) served as controls. In questionnaires, HT subjects reported higher intake frequencies of animal foods (meat, p = 0.0001; fish, p = 0.0001; dairy products, p = 0.004) compared with controls, who reported higher intake frequencies of plant foods (legumes, p = 0.001; fruits and vegetables, p = 0.030; nuts, p = 0.0005). The number of subjects who preferentially consumed poultry instead of red/processed meat was lower in HT subjects than in controls (p = 0.0141). In logistic regression analysis, meat consumption was associated with increased odds ratio of developing thyroid autoimmunity, while the Mediterranean diet traits were protective. In HT subjects, serum advanced glycation end products (markers of oxidative stress) were significantly higher (p = 0.0001) than in controls, while the activity of glutathione peroxidase and thioredoxin reductase, as well as total plasma antioxidant activity, were lower (p = 0.020, p = 0.023, and p = 0.002, respectively), indicating a condition of oxidative stress. Stepwise regression models demonstrated a significant dependence of oxidative stress parameters on consumption of animal foods, mainly meat. Conclusions: The present study suggests a protective effect of low intake of animal foods toward thyroid autoimmunity and a positive influence of such nutritional patterns on redox balance and potentially on oxidative stress-related disorders. [ABSTRACT FROM AUTHOR]

Background: We aimed to examine the association of urinary iodine concentration with Hashimoto's thyroiditis (HT) risk, and particularly, to investigate whether the HT-related genetic variations might modify the effects of urinary iodine on HT in the Chinese Han population. Methods: We conducted a case–control study with 1723 Chinese (731 cases, 992 controls). The associations between urinary iodine concentration and HT risk were analyzed using logistic regression models. The effects of interactions between the genetic risk scores (GRSs) and urinary iodine on HT risk were assessed by including the respective interaction terms in the models. We also applied restricted cubic spline regression to estimate the possible nonlinear relationship. The multinomial logistic regression models were performed to determine the associations of urinary iodine with euthyroid-HT and hypothyroidism-HT. Results: After controlling for potential confounders, the odds of HT increased with increasing quartiles of urinary iodine concentration: adjusted odds ratios (ORs) and 95% confidence intervals [CIs] were 1.45 [1.06–1.99], 1.66 [1.17–2.34], and 2.07 [1.38–3.10] for the quartiles 2, 3, and 4, respectively, compared with the first quartile (p for trend <0.001). Multivariable restricted cubic spline regression analysis further demonstrated that there was a near-linear association between urinary iodine concentration and HT risk (p-overall <0.001; p-nonlinear = 0.074). However, we did not find significant interactions between urinary iodine and GRSs on the risk of HT (all p for interaction >0.05). Interestingly, we found that each increment of urinary iodine was associated with a more than twofold increase in the odds of hypothyroidism-HT (adjusted OR = 2.64 [CI = 1.73–4.05]), but not with euthyroid-HT (p > 0.05). Conclusions: Higher urinary iodine concentration was associated with increased risk of HT, and this association was near linear, indicating that increased urinary iodine has a continuous and graded impact on HT risk. Moreover, the iodine-HT association was not modified by genetic predisposition to HT. Interestingly, urinary iodine concentration was significantly associated with increased risk of hypothyroidism. [ABSTRACT FROM AUTHOR]

Background: Pediatric papillary thyroid carcinoma (PTC) is a rare malignancy, but with increasing incidence. Pediatric PTCs have distinct clinical and pathological features and even the molecular profile differs from adult PTCs. Somatic point mutations in pediatric PTCs have been previously described and studied, but complex information about fusion genes is lacking. The aim of this study was to identify different fusion genes in a large cohort of pediatric PTCs and to correlate them with clinical and pathological data of patients. Methods: The cohort consisted of 93 pediatric PTC patients (6–20 years old). DNA and RNA were extracted from fresh frozen tissue samples, followed by DNA and RNA-targeted next-generation sequencing analyses. Fusion gene-positive samples were verified by real-time polymerase chain reaction. Results: A genetic alteration was found in 72/93 (77.4%) pediatric PTC cases. In 52/93 (55.9%) pediatric PTC patients, a fusion gene was detected. Twenty different types of RET, NTRK3, ALK, NTRK1, BRAF, and MET fusions were found, of which five novel, TPR/RET, IKBKG/RET, BBIP1/RET, OPTN/BRAF, and EML4/MET, rearrangements were identified and a CUL1/BRAF rearrangement that has not been previously described in thyroid cancer. Fusion gene-positive PTCs were significantly associated with the mixture of classical and follicular variants of PTC, extrathyroidal extension, higher T classification, lymph node and distant metastases, chronic lymphocytic thyroiditis, and frequent occurrence of psammoma bodies compared with fusion gene-negative PTCs. Fusion-positive patients also received more doses of radioiodine therapy. The most common fusion genes were the RET fusions, followed by NTRK3 fusions. RET fusions were associated with more frequent lymph node and distant metastases and psammoma bodies, and NTRK3 fusions were associated with the follicular variant of PTC. Conclusions: Fusion genes were the most common genetic alterations in pediatric PTCs. Fusion gene-positive PTCs were associated with more aggressive disease than fusion gene-negative PTCs. [ABSTRACT FROM AUTHOR]

Background: Thyroglobulin (TG) is a key autoantigen in autoimmune thyroid diseases (AITD). Several single nucleotide polymorphisms (SNPs) in the TG locus were shown to be strongly associated with disease susceptibility in both humans and mice, and autoimmune response to TG is the earliest event in the development of thyroid autoimmunity in mice. The classical model of experimental autoimmune thyroiditis (EAT) is induced by immunizing mice with TG protein together with an adjuvant to break down immune tolerance. The classical EAT model has limited utility in genetic studies of TG since it does not allow testing the effects of TG sequence variants on the development of autoimmune thyroiditis. In this study, we have immunized CBA-J mice, an EAT-susceptible strain, with an adenovirus vector encoding the full-length human TG (hTG) to generate a model of EAT in which the TG sequence can be manipulated to test AITD-associated TG SNPs. Methods: We immunized CBA-J mice with hTG-expressing adenovirus following the well-recognized experimental autoimmune Graves' disease protocol that also uses an adenovirus vector to deliver the immunogen. Results: After hTG adenovirus immunizations, mice developed higher T cell proliferative and cytokine responses to hTG and TG2098 (a major T cell epitope in AITD) and higher titers of TG and thyroperoxidase autoantibodies compared with mice immunized with control LacZ-expressing adenovirus. The mice, however, did not develop thyroidal lymphocytic infiltration and hypothyroidism. Conclusions: Our data describe a novel murine model of autoimmune thyroiditis that does not require the use of adjuvants to break down tolerance and that will allow investigators to test the effects of hTG variants in the pathoetiology of Hashimoto's thyroiditis. [ABSTRACT FROM AUTHOR]

Background: MicroRNAs (miRNAs) are a class of critical epigenetic regulators involved in several autoimmune diseases. Our previous study reported an miR-326-induced increase in T helper (Th) 17 cells in a mouse model of Hashimoto's thyroiditis (HT), but the pathogenic effect of miR-326 in HT patients has not been verified. The goal of the present study was to explore the pathogenic role of miR-326 and its underlying molecular mechanism in HT patients. Methods: A total of 58 HT patients and 55 normal controls were enrolled in this study. We examined whether Th17 cells and miR-326 were aberrantly altered in the peripheral blood mononuclear cells (PBMCs) of HT patients with flow cytometry and real-time polymerase chain reaction. Levels of membrane interleukin (IL)-23R (mIL-23R) were determined by flow cytometry and Western blot to explore the critical role of mIL-23R in the development of Th17 cells. Isolated CD3+ T cells were used to further investigate the ectodomain shedding of mIL-23R by a disintegrin and metalloprotease (ADAM17). Furthermore, miR-326 inhibitor and mimics were transfected into PBMCs derived from HT patients and healthy controls to verify the regulation of ADAM17 by miR-326. Results: We observed elevated miR-326 levels in the PBMCs of HT patients compared with those in the PBMCs of healthy controls. Consistent with IL-23-induced STAT3 overactivation, substantially more HT patient-derived PBMCs differentiated into Th17 cells under polarization culture conditions, which may, at least in part, have resulted from enhanced mIL-23R levels. Furthermore, ADAM17, an ectodomain sheddase of mIL-23R, was targeted and negatively regulated by miR-326. Inhibiting ADAM17 might attenuate the ectodomain shedding of mIL-23R. Conclusions: Our findings suggest that the effect of miR-326 on the IL-23/IL-23R/Th17 cell axis in HT patients might be partially due to the targeting of ADAM17. [ABSTRACT FROM AUTHOR]

Objective and background: Hashimoto's thyroiditis (HT) is both a B cell- and T cell-mediated, organ-specific autoimmune disease. No current treatment for underlying pathological mechanisms is available for HT and once diagnosed it requires long-term levothyroxine (LT4) treatment in most patients. The aim of our study was to evaluate the effects of photobiomodulation (PBM) on HT patients regarding thyroid functions, thyroid autoantibody levels, and decrease in hormone replacement needs. Methods: A total of 350 patients, who were diagnosed with Hashimoto's thyroiditis, were included in our study. Patients were classified into two groups. Group 1 (n =210) received PBM and dietary supplementation such as vitamin D, iron, and selenium. Group 2 (n= 140) received dietary supplements only. Patients' needs for LT4 replacement levels, triiodothyronine (T3), thyroxine (T4), and TSH levels, T3/T4 ratio, and thyroid autoantibody levels were evaluated. Results: As we compare both groups, the increase in T3 levels and T3/T4 ratio was markedly superior in Group 1 (p = 0.0001). The decrease in thyroid peroxidase antibody (TPO Ab) levels was also significantly different between both groups (p = 0.0001). Hormone replacement needs were also significantly decreased in Group 1 compared with Group 2 (p = 0.03). Low-level laser therapy (LLLT) is 70 times more effective in increasing T3/T4 ratio (p = 0.001) and 15 times more effective in decreasing levothyroxine dosage. Conclusions: Our results are encouraging and PBM seems to be very effective in increasing T3/T4 ratio and decreasing TPO Ab levels and weekly dosages of LT4 replacement therapy. Anti-inflammatory properties of PBM are greatly responsible for these changes and PBM causes major improvements in HT-related symptoms of the patient. [ABSTRACT FROM AUTHOR]

Deborah Doniach MD, FRCP was born in Geneva, Switzerland in 1912. She attended high school at the Lycée Molière and medical school at the Sorbonne in Paris. Deborah married Israel (Sonny) Doniach in 1933. After the births of their two children, she resumed her studies at the Royal Free Hospital Medical School in London, graduating in 1945. After additional training in Immunopathology and Endocrinology, Dr. Doniach joined the faculty in the Department of Immunology at the Middlesex Hospital and rose to become Honorary Consultant Immunopathologist and full Professor of Clinical Immunology. During her career, Deborah enjoyed a long and fruitful collaboration with the chemist and immunologist Ivan Roitt. From their partnership sprang the seminal discovery that Hashimoto's thyroiditis is an autoimmune disease in which circulating antibodies target thyroglobulin, a normal thyroid protein. In addition, they demonstrated a separate antibody cytotoxic to thyrocytes, later found to target thyroid peroxidase. These novel insights ran counter to the prevailing scientific dogma contending that antibodies target only nonself antigens. Thus, the field of research into thyroid autoimmunity, and indeed into autoimmune diseases in general, was born. This work spawned a cadre of future investigators whose studies define our current understanding of thyroid autoimmunity and the broader spectrum of autoimmune disease. In her private life, Deborah was a free thinker who defied conventional norms of the day. She was vivacious, warm, and genuinely interested in everybody and everything. Deborah Doniach died on New Year's Day, 2004 at the age of 91. [ABSTRACT FROM AUTHOR]

Background: Incidental finding of differentiated thyroid microcarcinomas (DTMc) in patients undergoing thyroid surgery for benign indications has become increasingly common. Even though carcinogenesis might relate to the background disease of the gland, the incidence of DTMc in the setting of various thyroid disorders remains unclear. We designed the present study to address this question. Materials and Methods: We reviewed data from two prospectively collected databases of consecutive patients undergoing thyroid surgery in two high-volume tertiary care referral centers, one in the United States (A) and the other one in Greece (B) over 18 years. We collected data on the preoperative surgical indication, fine-needle aspiration (FNA) cytology, and surgical pathology. We excluded subjects operated for thyroid cancer or with high risk for malignancy (FNA suspicious for thyroid cancer, follicular neoplasm, suspicious for follicular neoplasm, follicular lesion of undetermined significance/atypia of undetermined significance, or preoperative features of malignancy) and those with postsurgical pathology consistent with papillary thyroid cancer (PTC) ≥1 cm in largest diameter. We divided our subjects based on pathology data into those with chronic lymphocytic thyroiditis (CLT), Graves' disease (GD), or multinodular goiter (MNG). Results: We reviewed 6096 cases of thyroid surgery (A: 2711, B: 3385). We included 3909 subjects in the analysis. Overall, 569 (14.6%) PTC subjects were identified (A: 221/2003 [11%], B: 348/1906 [18.3%], odds ratios [OR] = 0.56, p < 0.0001). CLT was present in 617 subjects; PTC sonographic was present in 143 subjects (23.2%) (A: 79/404 [19.6%], B: 64/213 [30%], OR = 0.56, p = 0.003). GD was present in 359 subjects; PTC was present in 37 subjects (10.3%) (A: 12/197 [6.1%], B: 25/162 [15.4%], OR = 0.36, p = 0.004). MNG was present in 2933 subjects; PTC was present in 389 subjects (13.3%) (A: 130/1402 [9.3%], B: 259/1531 [16.9%], OR = 0.50, p < 0.0001). The incidence of PTC was significantly higher in CLT compared with MNG (OR = 1.75, p < 0.0001) or GD (OR = 2.25, p < 0.0001) but not in MNG compared with GD (OR = 1.29, p > 0.05). Conclusions: Incidentally discovered PTC are more commonly identified in surgical specimens from subjects with CLT compared with patients with MNG, while patients with GD present with a lower incidence compared with both groups. These data support previously published findings that euthyroid Hashimoto thyroiditis favors carcinogenesis, while GD may have a protective role. [ABSTRACT FROM AUTHOR]

Background: An increased rate of recurrent miscarriage has been described in patients with autoimmune thyroid disease. However, there is a lack of studies that assess the rate of recurrent pregnancy loss (RPL) in patients with Hashimoto's thyroiditis (HT) isolated or with concurrent non-endocrine autoimmune disorders (NEAD). The objective of the study was to assess the rate of RPL in patients with HT isolated or accompanied with non-endocrine autoimmune diseases. Methods: This is a retrospective observational cohort study with a systematic review of the NEAD with concurrent HT in an outpatient Endocrinology Unit at a University Hospital. Among the 3480 consecutively examined women with HT, 87 patients met the criteria of RPL and represented the study group. Sixty-five of them had isolated HT and 22 women had HT+NEAD. Results: The rate of RPL in women with HT was 2.1% versus 5.64% observed in women with HT+NEAD (odds ratio = 2.78 [95% confidence interval 1.70–4.57]; p < 0.0001). On subdivision, this difference was still evident in euthyroid patients (p < 0.0001), while it disappeared in hypothyroid women (p = 0.21). The RPL did not correlate with the autoantibody concentrations nor in women with isolated HT nor in those with HT+NEAD. The presence of antiphospholipid syndrome (APS) explained RPL in 3 out of 22 (14%) patients with HT+NEAD, the remaining being related to different autoimmune disorders. Interestingly, even subtracting the patients with APS, RPL was more frequent in patients with poly-autoimmunity than in patients with isolated HT (p = 0.0013). Conclusions: The co-presence of NEAD is correlated with a higher risk of RPL in women with HT. The association with APS may explain only a fraction of RPL rate in patients with poly-autoimmunity. [ABSTRACT FROM AUTHOR]

Background: Hashimoto's thyroiditis (HT) is a common autoimmune disease of unknown origin. However, viral infections have been implicated as triggers for autoimmunity. Human leukocyte antigen (HLA) class I presents antigens to circulating immune cells and plays a crucial role in the defense against viral infections. This study aimed to investigate the presence of enterovirus and HLA class I expression in one of the largest HT thyroid tissue cohorts to date. In addition, viral receptors and viral immune response proteins were examined. Methods: Thyroid tissue samples from 46 HT patients were obtained using core needle biopsy. Thyroid tissue collected during neck surgery for other reasons than thyroid autoimmunity served as controls. Standard immunohistochemistry on formalin-fixed, paraffin-embedded tissue samples were used to detect HLA class I, enteroviral capsid protein 1 (VP1), and coxsackie and adenovirus receptor (CAR) in thyroid cells. A subset of the samples was examined with combined immunofluorescence staining for signal transducer and activator of transcription 1 (STAT1) and protein kinase R (PKR). Results: Significantly more HLA class I-positive samples were found in the HT group (31 out of 46 [67.4%]) than in the control group (5 out of 24 [20.8%]) (p < 0.001). Moreover, the semiquantitative score assessing the grade of HLA class I expression was significantly higher in the HT group (3.9 ± 3.1) than in the control group (0.5 ± 0.9) (p < 0.001). In addition, STAT1 was colocalized with HLA class I, and PKR and VP1 were also found and were colocalized together. VP1 was detected in both controls and the HT samples, with slightly more VP1+ thyroid cells in the HT samples (20.1% ± 16.4%) than in controls (14.9% ± 10.5%). Finally, the presence of CAR in thyroid cells was confirmed. Conclusion: The current study confirmed that HLA class I hyperexpression is a defining feature of HT. Thyroid cells express CAR, thus making them susceptible to enterovirus infection. The colocalization of HLA class I with STAT1 and VP1 with PKR indicates an intracellular, antiviral host response. These findings support the concept of a firm link between viral infection and autoimmune thyroid diseases. [ABSTRACT FROM AUTHOR]

Background: A subset of Hashimoto's thyroiditis (HT), reported as immunoglobulin G4 (IgG4) thyroiditis, is characterized by IgG4+ plasma cell-rich inflammation and marked sclerotic changes, which suggests a close relationship with immunoglobulin G4-related disease (IgG4-RD). However, to date, there is no consensus regarding the cutoff values used to define a significant IgG4+ plasma cell count in thyroid inflammation. We, therefore, sought to validate both the cutoff value of the comprehensive diagnostic criteria (CVC) and the cutoff value of thyroid-specific diagnostic criteria (CVT) for diagnosing IgG4 thyroiditis. Methods: One hundred twenty cases of HT were retrospectively reviewed. According to the CVC (IgG4+ plasma cells >10/HPF (high-power field) and IgG4+/IgG+ plasma cell ratio >40%) and the CVT (IgG4+ plasma cells >20/HPF and IgG4+/IgG+ plasma cell ratio >30%), cases were subclassified as IgG4 thyroiditis or non-IgG4 thyroiditis. Clinical, serological, sonographic, and histopathological characteristics of the two subsets, and the cases diagnosed as IgG4 thyroiditis using different thresholds were compared. Results: Both the CVC and CVT identified the same set of distinct clinical, laboratory, and sonographic features of the cases diagnosed as IgG4 thyroiditis. All 120 cases of HT were able to be divided into four distinct groups. Group A included the 25 cases who were assigned as IgG4 thyroiditis by both the CVC and CVT, whereas Group D included the 85 cases who did not meet either of the cutoff values. Group B and Group C comprised the borderline cases who only met one of the two thresholds. Based on histological evaluation, the cases in Group B who met the CVT demonstrated similar histological features of IgG4 thyroiditis. Conclusions: Although both of the cutoff values can efficiently distinguish IgG4 thyroiditis from its non-IgG4 counterpart, the thyroid-specific cutoff value (CVT, IgG4+ plasma cells >20/HPF, and IgG4+/IgG+ plasma cell ratio >30%) can better identify borderline cases of HT with more fibrotic changes, which may represent an early phase lesion of IgG4 thyroiditis. We propose a new series of clinical and pathological diagnostic clues for both endocrinologists and pathologists to improve the early recognition of IgG4 thyroiditis. [ABSTRACT FROM AUTHOR]

Second-generation molecular tests, Afirma GSC and Thyroseq v3, were released by 2018 with improved performance characteristics, permitting a greater proportion of patients with indeterminate nodules to avoid diagnostic hemithyroidectomy ([2],[3]). In February 2019, Steward I et al. i published a prospective, multicenter, blinded analysis of a multigene genomic classifier (Thyroseq v3) involving 286 nodules with all patients undergoing surgery ([3]). In contrast, the effect of increasing age was clearly visible in patients harboring the BRAF SP V600E sp mutation; young patients exhibited negligible rates of mortality, whereas patients aged 65+ exhibited disease-specific mortality rates approaching 50% at 15 years. In this retrospective study of 1103 patients, high-volume surgeons had a 15% disease recurrence rate whereas low-volume surgeons had a 27% disease recurrence rate (hazard ratio 1.46 [CI 1.08-1.96]) with a median follow-up time of 81 months. [Extracted from the article]

Background: Hashimoto's thyroiditis (HT) is a common autoimmune disease characterized by lymphoid infiltration of the thyroid gland, including both T- and B-cells. Early studies have shown that HT is a complex disorder affected by both environmental and genetic factors. Recently, the single nucleotide polymorphism (SNP) rs2276886 associated with the CXCL9 gene was identified as associated with autoimmune thyroid disease susceptibility in Japanese populations. The aim of the present study was to validate this result for HT in a Chinese Han population. Methods: Study subjects, including 688 HT cases and 1456 healthy controls, were recruited, and 10 SNPs located within the CXCL9 gene were genotyped. Genetic association analyses were performed by fitting logistic models. Bioinformatics tools, including RegulomeDB and GTEx were utilized to investigate the functional consequences of the SNPs found to be significantly associated with HT. Results: SNP rs2276886 was identified as significantly associated with the risk of HT (odds ratio [OR] = 1.25, p = 0.0006). No significant expression quantitative trait loci (eQTL) signals could be identified for CXCL9. Significant eQTL signals were found for other genes, including ART3, CXCL10, CXCL11, NAAA, PPEF2, and SCARB2. This SNP physically maps to the CXCL9 gene region; however, further bioinformatic analyses indicated that this SNP might be associated with the gene NAAA. Conclusions: The rs2276886 SNP was found to be significantly associated with HT susceptibility. However, our findings suggest that this SNP which maps to the chromosomal region 4q21.1 likely effects the NAAA gene (as opposed to the CXCL9 gene), but still contributes to the susceptibility to HT in Han Chinese populations. [ABSTRACT FROM AUTHOR]

In the clinical studies comparing patients with controls, a high risk of bias is present, as the patient is treated and is aware of having Hashimoto's disease. Persisting symptoms in patients with Hashimoto's disease despite normal thyroid hormone levels: Does thyroid autoimmunity play a role?. [Extracted from the article]

Autoimmune thyroid disease (ATD), but not serum free thyroxine or thyrotropin (TSH) concentrations, was found to be strongly genetically correlated with MDD and ANX. B Dear Editor: b In the February 2023 issue of I Thyroid i , Soheili-Nezhad et al. report the results of a study exploring a genetic link between thyroid dysfunction and common psychiatric disorders.[1] It is well known that ~10% of patients with autoimmune hypothyroidism have persisting symptoms, impaired quality of life (QoL), and even psychiatric comorbidity despite adequate levothyroxine treatment. Persisting symptoms in patients with Hashimoto's disease despite normal thyroid hormone levels: Does thyroid autoimmunity play a role?. [Extracted from the article]

Transmembrane protein 39A (TMEM39A) gene polymorphisms have been related to various autoimmune diseases, but the relationship between TMEM39A polymorphisms and autoimmune thyroid disease (AITD) remains unknown. This study was aimed at investigating whether the polymorphisms of the TMEM39A were associated with AITD in the Chinese Han population. A case–control study was performed in a total of 906 AITD patients and 744 healthy controls. Four single nucleotide polymorphisms, including rs1132200, rs12492609, rs2282175, and rs7629750, in TMEM39A were examined by polymerase chain reaction-ligase detection reaction. We found that the allele T of rs12492609 in TMEM39A was associated with AITD and Hashimoto's thyroiditis (HT) (p = 0.023; p = 0.028 respectively). Compared with controls, the frequency of haplotype CCA in AITD patients was higher than that in controls (p = 0.036), but the frequency of haplotype CTA in AITD and HT patients was lower than that in controls (p = 0.046; p = 0.047 respectively). In addition, the frequency of allele A at rs7629750 in AITD patients with onset age ≤18 years old was higher than that in AITD patients with onset age ≥19 (p = 0.046). Further, there was an obvious difference in the genotype distributions of rs12492609 and rs7629750 between HT patients with hypothyroidism and those without hypothyroidism (p = 0.034 and p = 0.023, respectively). Our study first reveals that the polymorphisms of the TMEM39A gene are associated with the susceptibility to AITD, especially for early-onset AITD and HT with hypothyroidism. [ABSTRACT FROM AUTHOR]

Background: Several single-nucleotide polymorphisms (SNPs) are known to increase the risk of Hashimoto's thyroiditis (HT); such SNPs reside in thyroid-specific genes or in genes related to autoimmunity, inflammation, and/or cellular defense to stress. The transcription factor Nrf2, encoded by NFE2L2, is a master regulator of the cellular antioxidant response. This study aimed to evaluate the impact of genetic variation in NFE2L2 on the risk of developing HT. Methods: In a case–control candidate gene association study, functional SNPs in the NFE2L2 promoter (rs35652124, rs6706649, and rs6721961) were examined either as independent risk factors or in combination with a previously characterized HT risk allele (rs28665122) in the gene SELENOS, encoding selenoprotein S (SelS). A total of 997 individuals from the north of Portugal (Porto) were enrolled, comprising 481 HT patients and 516 unrelated healthy controls. SELENOS and NFE2L2 SNPs were genotyped using TaqMan® assays and Sanger sequencing, respectively. Odds ratios (ORs) were calculated using logistic regression, with adjustment for sex and age. Expression of SelS was analyzed by immunohistochemistry in thyroid tissue from HT patients and control subjects. Molecular interactions between the Nrf2 and SelS pathways were investigated in thyroid tissues from mice and in rat PCCL3 thyroid follicular cells. Results: When all three NFE2L2 SNPs were considered together, the presence of one or more minor alleles was associated with a near-significant increased risk (OR = 1.43, p = 0.072). Among subjects harboring only major NFE2L2 alleles, there was no increased HT risk associated with heterozygosity or homozygosity for the SELENOS minor allele. Conversely, in subjects heterozygous or homozygous for the SELENOS risk allele, the presence of an NFE2L2 minor allele significantly increased HT risk by 2.8-fold (p = 0.003). Immunohistochemistry showed reduced expression of SelS in thyroid follicular cells of HT patients. In Nrf2 knockout mice, there was reduced expression of SelS in thyroid follicular cells; conversely, in PCCL3 cells, reducing SelS expression caused reduced activity of Nrf2 signaling. Conclusions: The NFE2L2 promoter genotype interacts with the SELENOS promoter genotype to modulate the risk of HT in a Portuguese population. This interaction may be due to a bidirectional positive feedback between the Nrf2 and SelS pathways. [ABSTRACT FROM AUTHOR]

Background: There is growing evidence that sphingosine-1-phosphate (S1P), a pleiotropic bioactive sphingolipid metabolite synthesized intracellularly by two closely related sphingosine kinases (SphKs), SphK1 and SphK2, is involved in inflammation. However, the role of SphKs/S1P/S1P receptors (S1PRs) in autoimmune thyroiditis (AIT) has not been studied to date. Methods: This study examined whether SphK1/S1P/S1PR1 signaling is aberrantly altered in thyroid tissues and serum of both AIT patients and a spontaneously autoimmune thyroiditis (SAT) mouse model. Murine CD4+T cells were employed to further investigate the downstream signaling of SphK1/S1P/S1PR1. Furthermore, a total of 102 NOD.H-2h4 mice, randomly divided into different groups, were used to investigate the therapeutic effect of S1PR1 blockade and its potential mechanism. Results: We found that components of the SphK1/S1P/S1PR1 pathway were abnormally expressed in patients with Hashimoto thyroiditis and in a SAT mouse model. In addition, S1P could activate signal transducer and activator of transcription 3 (STAT3) through S1PR1 and its downstream signaling pathways in CD4+T cells of NOD.H-2h4 mice. Furthermore, an in vivo study demonstrated that blocking S1PR1 by FTY720 administration could reduce the incidence and severity of thyroiditis and goiter in SAT mice in a time-dependent manner. The proportions of STAT3-related and inflammation-related cell subtypes, such as T helper 1, T helper 17, and follicular T helper cells, were elevated in the SAT group when compared to the control group, and these cell subtypes decreased after FTY720 administration. Furthermore, the downstream inflammatory cytokines of STAT3 were also downregulated after FTY720 administration. Conclusion: The present study shows that blocking Sphk1/S1P/S1PR1 signaling can ameliorate the severity of AIT, providing evidence of a promising therapeutic target for AIT. [ABSTRACT FROM AUTHOR]

Background: Recent intervention studies have suggested that selenium (Se) is an effective treatment for autoimmune thyroiditis (AIT). However, the exact effect of Se on AIT is unclear as well as the mechanism of action. The aim of the present study was to explore the effect of Se on thyroid peroxidase antibody (TPOAb) titers in patients with AIT and to analyze the potential impact of the genetic background on the effect of Se supplementation. Methods: This was a randomized, placebo-controlled, double-blind trial. Three hundred and sixty-four patients with elevated TPOAb (>300 IU/mL) were recruited and randomized to receive Se yeast 200 μg/day supplementation or placebo. Urinary iodine concentration, serum thyrotropin, free thyroxine, TPOAb, Se, malondialdehyde, and serum glutathione peroxidase activity were measured at baseline and follow-up. Ninety-six patients were genotyped for single nucleotide polymorphism r25191G/A in the selenoprotein P (SEPP1/SELENOP) gene. Results: The median urinary iodine concentration was 182 μg/L. Serum Se increased significantly (p < 0.001) after Se treatment. TPOAb titer decreased by 10.0% at 3 months and by 10.7% at 6 months after Se supplementation, while there was a moderate increase in TPOAb titers over the follow-up period in patients receiving placebo. Glutathione peroxidase activity significantly increased (p < 0.001), and malondialdehyde significantly decreased (p < 0.001) after 6 months of Se supplementation. TPOAb titers decreased to variable extents in patients with different genotypes of single nucleotide polymorphism r25191G/A after Se supplementation. Serum TPOAb titers in patients with the AA genotype showed a more significant decrease (by 46.2%) than those with the GA and GG genotypes (by 14.5 and 9.8% respectively) at 3 months of Se supplementation (p = 0.070). Conclusions: Se supplementation significantly reduced TPOAb titers in patients with AIT, and there may be an important genetic component influencing interindividual differences in the decrease in TPOAb titers. [ABSTRACT FROM AUTHOR]

The present study was to explore whether the polymorphisms of FAM167 A-BLK region are associated with the susceptibility to autoimmune thyroid disease (AITD). The second sequencing technology was undertaken for seven tag loci mapping of the FAM167 A-BLK region, namely, rs11250144, rs2618431, rs4840568, rs13277113, rs2248932, rs2736340, and rs922483, in 999 AITD patients, including 624 Graves' disease (GD) and 375 Hashimoto's thyroiditis individuals, and 797 healthy cohorts. In contrast to those in controls, allele C of rs11250144 and allele G of rs2618431 both showed increased frequencies in GD patients. Consistent with this, the frequency of genotype GG in rs2618431 was increased in GD patients. Similarly, compared with that in female controls, allele G of rs2618431 was increased in the female AITD patients. Likewise, the frequency of allele G in rs2618431 obviously declined in the female GD patients. Allele A of rs4840568 linked to the susceptibility of the AITD teenagers. Besides, allele C in rs11250144 was correlated with thyroid-associated ophthalmopathy (TAO). Moreover, allele C in rs11250144 increased the risk to TAO by 56.3%. Genetic variants of FAM167 A-BLK region may contribute to the susceptibility to AITD, which can be added as the genetic candidates for this disease. [ABSTRACT FROM AUTHOR]

Background: This study aimed to characterize the frequency of self-reported thyroid-related impaired sex life in patients with thyroid diseases, to examine its clinical correlates and relationship with overall quality of life (QOL), and to investigate the effect of treatment. Patients and Methods: Two separate patient samples with benign thyroid diseases were investigated: a cross-sectional sample (759 women and 118 men) treated at two Danish university hospital outpatient clinics, in 2007–2008, and a longitudinal sample (358 women and 74 men) undergoing treatment at the abovementioned centers, during 2008–2012, evaluated before and 6 months after therapy. The thyroid-specific QOL questionnaire ThyPRO was used to measure patient-evaluated thyroid-related sex life impairment. Biochemical and clinical variables were analyzed (i.e., age, education, degree of thyroid dysfunction, comorbidity, serum thyrotropin, total thyroxine, and triiodothyronine, as well as thyroperoxidase and thyrotropin receptor antibody concentrations). The SF-36 Health Survey was used to analyze the effect of impaired sex life on overall QOL. Results: In the cross-sectional sample, 36% of women and 31% of men reported what they perceived to be thyroid-attributable impaired sex life. Women with autoimmune thyroid diseases reported more impairment than those with non-autoimmune thyroid diseases. In patients with Graves' disease lower levels of educational attainment and in patients with toxic nodular goiter comorbidities were associated with impaired sex life. Overall QOL was lower in patients with thyroid-related sex life impairment. In the longitudinal sample, 42% of women and 33% of men had impaired sex life at baseline, which improved at 6 months follow-up only in women and, when analyzing individual diagnoses separately, statistically significantly among those with autoimmune hypothyroidism. Sexual impairment was associated with low education in patients with toxic nodular goiter and with high plasma triiodothyronine concentrations in patients with Graves' disease. In autoimmune hypothyroidism, a younger age was associated with sex life impairment. Conclusion: We found a high frequency of self-reported, thyroid-related sex life impairment in patients with benign thyroid diseases, especially in young women with autoimmune thyroid diseases. Self-perceived impaired sex life persisted in women treated for Graves' disease, suggesting that normalization of thyroid function was not sufficient to restore sexual function. [ABSTRACT FROM AUTHOR]