Autoimmune thyroid diseases as a cost of physiological autoimmune surveillance.

Graves' disease (GD) and Hashimoto's thyroiditis (HT) are common autoimmune diseases of the thyroid gland, causing hyperthyroidism and hypothyroidism, respectively. Despite their opposing clinical manifestation, they have several enigmatic links. Here, we propose that GD and HT have the same fundamental origin: both diseases are the cost of a beneficial physiological process called autoimmune surveillance of hypersecreting mutants. Autoreactive T cells selectively eliminate mutant cells that hypersecrete the hormones and threaten to become toxic nodules. These T cells can trigger a humoral response in susceptible individuals, leading to the production of antibodies against thyroid antigens. This shared origin can explain similarities in incidence and risk factors between HT and GD, despite their opposite clinical phenotypes.

TMEM2 inhibits the development of Graves' orbitopathy through the JAK-STAT signaling pathway.

A mouse model was used to investigate the role of the hyaluronidase, transmembrane protein 2 (TMEM2), on the progression of Graves' orbital (GO) disease. We established a GO mouse model through immunization with a plasmid expressing the thyroid stimulating hormone receptor. Orbital fibroblasts (OFs) were subsequently isolated from both GO and non-GO mice for comprehensive in vitro analyses. The expression of TMEM2 was assessed using qRT-PCR, Western blot and immunohistochemistry in vivo. Disease pathology was evaluated by H&E staining and Masson's trichrome staining in GO mouse tissues. Our investigation revealed a notable reduction in TMEM2 expression in GO mouse orbital tissues. Through overexpression and knockdown assays, we demonstrated that TMEM2 suppresses inflammatory cytokines and reactive oxygen species production. TMEM2 also inhibits the formation of lipid droplets in OFs and the expression of adipogenic factors. Further incorporating Gene Set Enrichment Analysis of relevant GEO datasets and subsequent in vitro cell experiments, robustly confirmed that TMEM2 overexpression was associated with a pronounced upregulation of the JAK/STAT signaling pathway. In vivo, TMEM2 overexpression reduced inflammatory cell infiltration, adipogenesis, and fibrosis in orbital tissues. These findings highlight the varied regulatory role of TMEM2 in GO pathogenesis. Our study reveals that TMEM2 plays a crucial role in mitigating inflammation, suppressing adipogenesis, and reducing fibrosis in GO. TMEM2 has potential as a therapeutic target and biomarker for treating or alleviating GO. These findings advance our understanding of GO pathophysiology and provide opportunities for targeted interventions to modulate TMEM2 for therapeutic purposes.

Ancient DNA gives new insights into a Norman Neolithic monumental cemetery dedicated to male elites.

The Middle Neolithic in western Europe is characterized by monumental funerary structures, known as megaliths, along the Atlantic façade. The first manifestations of this phenomenon occurred in modern-day France with the long mounds of the Cerny culture. Here, we present genome-wide data from the fifth-millennium BCE site of Fleury-sur-Orne in Normandy (France), famous for its impressively long monuments built for selected individuals. The site encompasses 32 monuments of variable sizes, containing the burials of 19 individuals from the Neolithic period. To address who was buried at the site, we generated genome-wide data for 14 individuals, of whom 13 are males, completing previously published data [M. Rivollat et al., Sci. Adv. 6, eaaz5344 (2020)]. Population genetic and Y chromosome analyses show that the Fleury-sur-Orne group fits within western European Neolithic genetic diversity and that the arrival of a new group is detected after 4,000 calibrated BCE. The results of analyzing uniparentally inherited markers and an overall low number of long runs of homozygosity suggest a patrilineal group practicing female exogamy. We find two pairs of individuals to be father and son, buried together in the same monument/grave. No other biological relationship can link monuments together, suggesting that each monument was dedicated to a genetically independent lineage. The combined data and documented father­son line of descent suggest a male-mediated transmission of sociopolitical authority. However, a single female buried with an arrowhead, otherwise considered a symbol of power of the male elite of the Cerny culture, questions a strictly biological sex bias in the burial rites of this otherwise "masculine" monumental cemetery.

Interaction of MMP-9 in the active phase of Graves' disease with and without ophthalmopathy.

Thyroid eye disease (TED) is expressed as orbital inflammation, and serum levels of several proinflammatory cytokines have been studied among patients with Graves' disease (GD) with and without TED; however, a more sensitive and specific marker for the different phases of GD and TED is still lacking. Seventeen active TED, 16 inactive TED, 16 GD without TED, and 16 healthy controls were recruited. Serum IL-17A, MMP-2, MMP-3, and MMP-9 were measured by multiplex bead assay. TED hormone and eye parameters were evaluated, and their relationship with cytokine levels was analyzed. Serum MMP-9 was higher in active TED than healthy controls, whereas IL-17A was lower among these patients than in GD without TED and healthy controls. No differences were found in MMP-3 and MMP-2 concentrations. MMP-9 levels were lower in patients with inactive TED who underwent radioactive iodine (RAI) therapy and those on levothyroxine replacement. MMP-9 levels were elevated in patients on methimazole. A negative correlation was found between age at assessment and time of follow-up with MMP-9 levels in inactive TED. Free T3 and ophthalmometry values were positively correlated with MMP-9 in the GD without TED and inactive TED groups, respectively. In conclusion, serum MMP-9 was increased in patients with active TED and was related to the RAI treatment, longer follow-up time, and higher ophthalmometry in patients with inactive TED, as well as thyroid function in GD without TED. MMP-9 may be involved in both the active phase of TED and the active phase of inflammation related to GD.NEW & NOTEWORTHY Our study addresses clinical aspects of specific ophthalmological examination and serum cytokine concentrations of patients with Graves' disease (GD) with and without ophthalmopathy. Our findings suggest that MMP-9 may be involved in the active phase of ophthalmopathy and in the active phase of GD. The central question is whether MMP-9 is a potential target for future treatments.

Associations between immune cell traits and autoimmune thyroid diseases: a bidirectional two-sample mendelian randomization study.

Autoimmune thyroid diseases (AITDs), mainly including Graves' disease (GD) and Hashimoto's thyroiditis (HT), are common autoimmune disorders characterized by abnormal immune responses targeting the thyroid gland. We conducted a bidirectional two-sample MR analysis using the largest dataset of peripheral immune cell phenotypes from Sardinia, and the AITD dataset from the 10th round of the FinnGen and the UK Biobank project. Instrumental variables (IVs) were rigorously selected based on the three assumptions of MR and analyzed using the Wald ratio, inverse-variance weighted (IVW), MR-Egger, and weighted median methods. Additionally, sensitivity analyses were performed using Cochrane's Q, the Egger intercept, the MR-PRESSO, and the leave-one-out (LOO) method to ensure the robustness of the results. The Steiger test was utilized to identify and exclude potential reverse causation. The results showed that 3, 3, and 11 immune cell phenotypes were significantly associated with the risk of AITD. In GD, the proportion of naive CD4-CD8- (DN) T cells in T cells and the proportion of terminally differentiated CD4+T cells in T cells showed the strongest inducing and protective effects, respectively. In HT, lymphocyte count and CD45 on CD4+T cells showed the strongest inducing and protective effects, respectively. In autoimmune hypothyroidism, CD127 CD8+T cell count and terminally differentiated DN T cell count exhibited the strongest inducing and protective effects, respectively. Through MR analysis, our study provides direct genetic evidence of the impact of immune cell traits on AITD risk and lays the groundwork for potential therapeutic and diagnostic target discovery.

Enhanced predictive validity of integrative models for refractory hyperthyroidism considering baseline and early therapy characteristics: a prospective cohort study.

BACKGROUND: A subset of Graves' disease (GD) patients develops refractory hyperthyroidism, posing challenges in treatment decisions. The predictive value of baseline characteristics and early therapy indicators in identifying high risk individuals is an area worth exploration. METHODS: A prospective cohort study (2018-2022) involved 597 newly diagnosed adult GD patients undergoing methimazole (MMI) treatment. Baseline characteristics and 3-month therapy parameters were utilized to develop predictive models for refractory GD, considering antithyroid drug (ATD) dosage regimens. RESULTS: Among 346 patients analyzed, 49.7% developed ATD-refractory GD, marked by recurrence and sustained Thyrotropin Receptor Antibody (TRAb) positivity. Key baseline factors, including younger age, Graves' ophthalmopathy (GO), larger goiter size, and higher initial free triiodothyronine (fT3), free thyroxine (fT4), and TRAb levels, were all significantly associated with an increased risk of refractory GD, forming the baseline predictive model (Model A). Subsequent analysis based on MMI cumulative dosage at 3 months resulted in two subgroups: a high cumulative dosage group (average ≥ 20 mg/day) and a medium-low cumulative dosage group (average < 20 mg/day). Absolute values, percentage changes, and cumulative values of thyroid function and autoantibodies at 3 months were analyzed. Two combined predictive models, Model B (high cumulative dosage) and Model C (medium-low cumulative dosage), were developed based on stepwise regression and multivariate analysis, incorporating additional 3-month parameters beyond the baseline. In both groups, these combined models outperformed the baseline model in terms of discriminative ability (measured by AUC), concordance with actual outcomes (66.2% comprehensive improvement), and risk classification accuracy (especially for Class I and II patients with baseline predictive risk < 71%). The reliability of the above models was confirmed through additional analysis using random forests. This study also explored ATD dosage regimens, revealing differences in refractory outcomes between predicted risk groups. However, adjusting MMI dosage after early risk assessment did not conclusively improve the prognosis of refractory GD. CONCLUSION: Integrating baseline and early therapy characteristics enhances the predictive capability for refractory GD outcomes. The study provides valuable insights into refining risk assessment and guiding personalized treatment decisions for GD patients.

Comorbidity of Myasthenia gravis and Graves' disease as immune reconstitution-associated autoimmune disease in HIV infection: A case report and literature review.

BACKGROUND: Comorbidity of Myasthenia gravis (MG) and Graves' disease (GD) in treated HIV-infected individuals has rarely been described and little study has been done on the link between HIV-related immune reconstitution and autoimmune diseases occurring post antiretroviral therapy. CASE PRESENTATION: Here we report on a 33-year-old Chinese man with HIV infection who had been virologically suppressed since 2018. The patient was diagnosed with GD and was treated in 2020. Early in 2022, he developed fluctuating weakness and fatigue involving the bilateral extraocular muscles and limbs. With a positive neostigmine test, he was considered to have MG, but showed a poor response to oral medication. After multiple failed medication attempts, a thymectomy was finally performed to resolve his symptoms. The consecutive onset of immunological events may have partially resulted from immune reconstitution after viral control. CONCLUSIONS: This is a rare case of HIV-related immune reconstitution-associated autoimmune disease (IRAD) with comorbidity of MG and GD which was reported initially. Cooperation with multidisciplinary teams is essential to avoid misdiagnosis and to promote the overall health of HIV-infected patients.

Risk of non-thyroidal autoimmune diseases in patients with Graves' disease: a nationwide retrospective cohort study.

OBJECTIVE: Graves' disease (GD) is a major autoimmune thyroid disorder and associated with non-thyroidal autoimmune disease (NTAD). We aimed to investigate the risk of NTAD in patients with GD compared with age- and sex-matched controls and to evaluate whether the risk differs between individuals with or without Graves' ophthalmopathy (GO). METHODS: This was a retrospective cohort study using data from the Korean National Health Claims database. We included 77 401 patients with GD (2,310 with GO) and 77 401 age- and sex-matched controls. Risk of NTAD were compared between the entire cohort and within the GD cohort. RESULTS: During a mean follow-up period of 9 years, NTAD developed in 12 341 (16.1%) patients in the GD cohort. Risk for systemic lupus erythematosus (SLE) [adjusted hazard ratio (aHR):1.15, 95% confidence interval (CI): 1.02-1.29], vitiligo (aHR: 1.24, 95% CI: 1.10-1.40), and alopecia areata (aHR: 1.11, 95% CI: 1.10-1.40) were higher in the GD cohort than in the control cohort. In the GD cohort, risk for SLE (aHR: 1.60, 95% CI: 1.11-2.33), Sjogren's syndrome (aHR: 1.89, 95% CI: 1.30-2.74), and ankylosing spondylitis (aHR: 1.53, 95% CI: 1.08-2.17) were higher in the GO group than in the non-GO group. CONCLUSION: This study demonstrated an increased risk of SLE, vitiligo and alopecia areata in patient with GD. In the GD cohort, patients with GO had an increased risk of SLE, Sjogren's syndrome and ankylosing spondylitis. These findings suggest that importance of implementing a strategy for early detection of NTAD based on the presence of GO.

The efficacy and safety of selenium supplementation versus placebo in the treatment of Graves' orbitopathy: A systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: Selenium is a trace element crucial for thyroid function, and has potential therapeutic benefits in Graves' orbitopathy (GO). Therefore, we aim to evaluate its efficacy and safety in GO patients to provide valuable insights into its role as a therapeutic option for this condition. DESIGN: Systematic review and meta-analysis. PATIENTS: GO Patients treated with selenium compared to placebo. MEASUREMENTS: Clinical activity score (CAS), Graves' orbitopathy quality of life (GO-QOL), eye symptoms and signs, and adverse events. RESULTS: Out of 1684 records screened, four randomised controlled trials were included. Selenium was superior at 6 months in lowering the CAS (MD = -1.27, 95% confidence interval [CI] [-1.68, -0.85], p < .0001]), improving total GO-QOL (RR = 2.54, 95% CI [1.69-3.81], p < .00001), and improving the visual and the psychological functioning scores (MD = 10.84, 95% CI [4.94-16.73], p = .003), (MD = 12.76, 95% CI [8.51-17.00], p < .00001) respectively. Similarly, it significantly improved these outcomes at 12 months. It also showed a significant decrease in the palpebral aperture at 6 months (MD = -1.49, 95% CI [-2.90, -0.08], p = .04). However, no significant differences were observed in proptosis, soft tissue involvement, ocular motility, and adverse effects. CONCLUSIONS: Selenium is effective in reducing CAS and improving the palpebral aperture and GO-QOL in patients with GO. Additionally, it is safe and has promising therapeutic implications. However, further research is needed to validate its long-term efficacy and safety.

Quality of life and decision regret in patients with late-hypothyroidism after radioiodine treatment for Graves' disease.

OBJECTIVE: Patients with Graves' disease often engage in shared decision-making to select an individualised treatment regimen from multiple options. Radioactive iodine (RAI) is one of the treatment choices for their condition, aims to improve quality of life and well-being. Likewise, dissatisfaction with treatment outcomes can result in decision regret. We employed validated questionnaires to assess the prospective quality of life, decision regret and relative factors involved in decision-making of patients with late hypothyroidism after RAI therapy. METHODS: A questionnaire survey was conducted among patients in hypothyroidism status for more than 1 year after RAI therapy. Disease-specific and generic QoL were assessed using the short form of thyroid-related patient-reported outcome (ThyPRO-39) questionnaire. Patient satisfaction regarding their decision to undergo RAI was assessed using the Decision Regret Scale (DRS) and patients were asked about the importance of relative factors in decision-making. RESULTS: Of 254 patients who responded to the survey, the mean age of patients was 45.3 years (range: 18-78 years) and the median time from RAI therapy to survey was 4 years (range: 1-30 years). Patients' median and mean DRS score were 34.4 and 38.8 (range: 0-100), respectively. A total of 100 (39.4%) patients express absent-to-mild regret (score: 0-25), 154 (60.6%) patients express moderate-to-severe regret (score: >25). The mean score of the absent-to-mild regret group were significantly higher than those of the moderate-to-severe regret group on most ThyPRO-39 scales. A statistically significant positive correlation was observed between DRS score and most ThyPRO-39 scale score. There was a significant positive association between higher DRS score and longer time intervals after RAI treatment, a brief duration of hyperthyroidism, and the significance of long-time outpatient follow-up. More decision regret was negatively associated Iodine-free diet, ineffectiveness of ATD, fear of surgery. CONCLUSION: Impairment of quality of life was positively correlated with decision regret in patients with late-hypothyroidism after radioiodine therapy. Patients with insufficient information support before decision-making are more likely to have higher decision regret after treatment. Our findings suggest that health providers should fully communicate with patients and provide information support in multiple dimensions during the shared-decision-making process.

Paediatric thyroid disease.

The spectrum of thyroid disorders presenting to paediatricians is different to that seen by adult physicians. Referrals reflect cases detected by the neonatal screening programme for congenital hypothyroidism and many of the inherited defects of thyroid hormone generation or action will be manifest in early life. Autoimmune thyroid disease can be particularly challenging to manage in the young and the potential impact of thyroid status on neurodevelopment and schooling are key considerations throughout childhood and adolescence.

Use of a dosimetry-based RAI protocol for treatment of benign hyperthyroidism optimises response while minimising exposure to ionising radiation.

BACKGROUND: The optimal treatment strategy for radioiodine (RAI) treatment protocols for benign hyperthyroidism remains elusive. Although individualised activities are recommended in European Law, many centres continue to provide fixed activities. Our institution implemented a dosimetry protocol in 2016 following years of fixed dosing which facilitates the calculation of individualised activities based on thyroid volume and radioiodine uptake. METHODS: This was a retrospective study comparing success rates using a dosimetry protocol targeting an absorbed dose of 150 Gy for Graves' disease (GD) and 125 Gy for Toxic Multinodular Goiter (TMNG) with fixed dosing (200MBq for GD and 400MBq for TMNG) among 204 patients with hyperthyroidism. Success was defined as a non-hyperthyroid state at 1 year for both disease states. Results were analysed for disease specific or patient specific modulators of response. RESULTS: This study included 204 patients; 74% (n = 151) received fixed activities and 26% (n = 53) of activities administered were calculated using dosimetry. A dosimetry-based protocol was successful in 80.5% of patients with GD and 100% of patients with TMNG. Differences in success rates and median activity administered between the fixed (204Mbq) and dosimetry (246MBq) cohort were not statistically significant (p = .64) however 44% of patients with GD and 70% of patients with TMNG received lower activities following treatment with dosimetry as opposed to fixed activities. Use of dosimetry resulted in successful treatment and reduced RAI exposure for 36% of patients with GD, 70% of patients with TMNG, and 44% of patients overall. CONCLUSION: This retrospective clinical study demonstrated that treatment with a dosimetry-based protocol for TMNG and GD achieved comparable success rates to fixed protocols while reducing RAI exposure for over a third of patients with GD and most patients with TMNG. This study also highlighted that RAI can successfully treat hyperthyroidism for some patients with activities lower than commonplace in clinical practise. No patient or disease specific modulators of treatment response were established in this study; however, the data supports a future prospective trial which further scrutinises the individual patient factors governing treatment response to RAI.

Circular RNA circPHF16 enhances IL-17A expression and secretion by sequestering miR-378a-3p to activate the IL6ST axis in Graves' disease.

Interleukin-17A (IL-17A) plays a pivotal role in the pathogenesis of Graves' disease (GD), an autoimmune disorder affecting thyroid function, but the detailed regulatory mechanisms remain elusive. Circular RNAs (circRNAs) have emerged as key regulators of IL-17A expression and secretion in autoimmune diseases, yet their specific role in GD, especially within CD4 + T lymphocytes, are not well understood. In this study, a circRNA, circPHF16 (hsa_circ_0090364) was found to be highly expressed in the peripheral blood mononuclear cells and serum of GD patients. In vitro experiments in Jurkat T cells revealed that silencing of circPHF16 suppressed IL-17A expression and secretion, while overexpression of circPHF16 had the opposite effect. Furthermore, bioinformatics analysis demonstrated a circPHF16/miR-378a-3p/IL6ST pathway, in which circPHF16 regulates IL6ST expression, which, in turn, influences IL-17A expression and secretion by interacting with miR-378a-3p. In vivo studies in a mouse model of GD showed similar trends in molecular expression levels, consistent with competitive endogenous RNA interactions. Together the results of the study identify circPHF16 as a potential target in the development of new strategies for GD diagnosis and treatment, and thus, offer a theoretical foundation for clinical therapeutic approaches in GD.

NrCAM activates the NF-κB signalling pathway by competitively binding to SUMO-1 and promotes Th17 cell differentiation in Graves' disease.

This study aimed to explore the molecular mechanism of neuronal cell adhesion molecule (NrCAM) by regulating Th17 cell differentiation in the pathogenesis of Graves' disease (GD). Naïve CD4+ T cells were isolated from peripheral blood mononuclear cells of GD patients and healthy control (HC) subjects. During the differentiation of CD4+ T cells into Th17 cells, NrCAM level in GD group was improved. Interference with NrCAM in CD4+ T cells of GD patients decreased the percentage of Th17 cells. NrCAM overexpression in CD4+ T cells of HC subjects increased the percentage of Th17 cells and upregulated p-IκBα, p50, p65, c-Rel protein expressions, and NF-κB inhibitor BAY11-7082 partially reversed NrCAM effect. NrCAM overexpression promoted the degradation of IκBα, and overexpression of small ubiquitin-related modifier 1 (SUMO-1) inhibited IκBα degradation. NrCAM overexpression reduced IκBα binding to SUMO-1. During Th17 cell differentiation in HC group, NrCAM overexpression increased IL-21 levels and secretion, and IL-21 neutralizing antibody reversed this effect. IL-21 level was decreased after p65 interference in CD4+ T cells of HC subjects. p65 interacts with IL-21 promoter region. In conclusion, NrCAM binds to SUMO-1 and increases phosphorylation of IκBα, leading to activation of NF-κB pathway, which promotes Th17 cell differentiation.

Changes in bone density and microarchitecture following treatment of Graves' disease and the effects of vitamin D supplementation. A randomized clinical trial.

Thyrotoxicosis leads to loss of bone mass. Vitamin D is important to bone health. In this randomized, placebo-controlled trial, we showed that bone restoration did not improve when adding vitamin D supplementation to standard care of Graves' disease thyrotoxicosis. Bone density and microarchitecture improved markedly with treatment of thyrotoxicosis. PURPOSE: Vitamin D is important to skeletal health and ensuring a replete vitamin D status is recommended. In thyrotoxicosis, bone turnover is increased and bone mass density (BMD) reduced. We examined whether vitamin D supplementation improves bone recovery in thyrotoxicosis caused by Graves' disease (GD). METHODS: Using a double-blinded design, hyperthyroid patients with GD were randomized to vitamin D3 70 µg/day (2800 IU) or similar placebo as add-on to antithyroid drugs (ATD). At baseline and 9 months, we measured BMD and bone architecture using DXA and high resolution peripheral quantitative computerized tomography. Bone turnover markers (BTM) were measured at 3 months also. Effect of vitamin D versus placebo and the response to ATD treatment were analyzed using linear mixed modelling. RESULTS: Eighty-six GD patients were included (age 41 ± 14 years, 86% females). Compared to placebo, vitamin D3 did not improve BMD or microarchitecture. In response to ATD, BMD increased in the hip by 2% (95%CI: 1-4%). Cortical porosity decreased in tibia (- 7% [95%CI: - 12 to - 2%]) and radius [- 14% [95%CI: - 24 to - 3%]), and trabecular thickness increased (tibia (5% [95%CI: 2 - 9%]) and radius (4% [95%CI: 1-7%]). Changes in BTM, but not thyroid hormones, were associated with changes in BMD by DXA and with changes in the cortical compartment. CONCLUSION: In newly diagnosed GD, 9 months of high dose vitamin D3 supplementation does not offer benefit by improving skeletal health. Treatment of thyrotoxicosis is associated with the recovery of BMD and microarchitecture. GOV IDENTIFIER: NCT02384668.

Effect of previous administration of potassium iodine and different durations of low iodine diets for radioiodine therapy on the treatment of Graves' disease in iodine-rich areas.

PURPOSE: To examine whether adherence to a low-iodine diet (LID) enhances the therapeutic efficacy of radioiodine therapy (RAI) in Graves' hyperthyroidism (GH) in iodine-rich areas. METHODS: We retrospectively evaluated 185 patients with GH from Aichi (n = 114) and Hokkaido (n = 71) Prefectures. Patients aged ≥ 18 years with GH who underwent RAI between December 2012 and March 2022 were divided into subgroups based on pretreatment with anti-thyroid drug (ATD) or potassium iodide (KI). Patients were followed up with LID from 18 days (group A) or 7 days (group H) before RAI to 3 days after RAI. The dose of radioactive iodine 131 (131I) was adjusted to deliver > 100 Gy to the thyroid. The associations between urinary iodine concentration on UIC2 vs. 24hRU and UIC2 vs. the 1-year RAI success rate (SR) were investigated. RESULTS: Compared with UIC1, UIC2 was significantly decreased in all subgroups (P < 0.01). An inverse correlation between UIC2 and 24hRU was observed in the four groups; however, the difference was insignificant. The SR in groups A and H was 85% and 89%, respectively. Univariate analysis revealed no association between UIC2 and SR in each group. Additionally, stratification of the 185 patients into quartiles using UIC2 yielded no significant differences in SR (p = 0.79). CONCLUSIONS: LID sufficiently reduced UIC in patients undergoing RAI. Although a lower UIC2 may increase 24hRU, it did not increase the success of RAI. The benefit of LID in enhancing the efficacy of RAI in GH treatment remains uncertain.

New insights in thyroid diagnosis and treatment.

The prevalence of thyroid disease continues to rise. As a consequence, the research in the thyroid field has significantly increased over time. Thus, clinicians, and endocrinologists first, have to be aware of the important continuous progress achieved, in particular of thyroid cancer, to better manage their patients. This themed issue, titled "New Insights in Thyroid Diagnosis and Treatment," delves deep into contemporary hot topics in thyroid field. These papers included in the present issue are focused on several aspects in this area, such as imaging, molecular analysis, machine learning and radiomics, nuclear medicine, clinical, and laboratory. Seven papers centers around thyroid cancer. Three papers review imaging modalities for thyroid nodule/cancer assessment. Two papers report a comprehensive review of metabolic issues involving thyroid gland. Finally, a large overview about genetics of Graves' disease is reported in another study. Clinicians will find this issue very interesting.

The genetics of Graves' disease.

Graves' disease (GD) is the commonest cause of hyperthyroidism and has a strong female preponderance. Everyday clinical practice suggests strong aggregation within families and twin studies demonstrate that genetic factors account for 60-80% of risk of developing GD. In this review, we collate numerous genetic studies and outline the discoveries over the years, starting with historic candidate gene studies and then exploring more recent genome-wide linkage and association studies, which have involved substantial cohorts of East Asian patients as well as those of European descent. Variants in genes including HLA, CTLA4, and PTPN22 have been shown to have substantial individual effects on disease susceptibility. In addition, we examine emerging evidence concerning the possibility that genetic variants may correlate with relevant clinical phenotypes including age of onset of GD, severity of thyrotoxicosis, goitre size and relapse of hyperthyroidism following antithyroid drug therapy, as well as thyroid eye disease. This review supports the inheritance of GD as a complex genetic trait, with a growing number of more than 80 susceptibility loci identified so far. Future implementation of more targeted clinical therapies requires larger studies investigating the influence of these genetic variants on the various phenotypes and different outcomes of conventional treatments.

GSDMD mediated pyroptosis induced inflammation of Graves' orbitopathy via the NF-κB/ AIM2/ Caspase-1 pathway.

Gasdermin D (GSDMD) is a key executor which triggers pyroptosis as well as an attractive checkpoint in various inflammatory and autoimmune diseases but it has yet to prove its function in Graves'orbitopathy (GO). Our aim was to investigate GSDMD levels in orbital connective tissue and serum of GO patients and then assess the association between serum levels and patients' clinical activity score (CAS). Further, GSDMD-mediated pyroptosis and the underlying mechanism in inflammatory pathogenesis in the cultured orbital fibroblasts (OFs) of GO patients were examined. OFs were collected after tumor necrosis factor (TNF)-α or interferon (IFN)-γ treatment or combination treatment at different times, and the expression of GSDMD and related molecular mechanisms were analyzed. Then, we constructed the GSDMD knockout system with siRNA and the system was further exposed to the medium with or without IFN-γ and TNF-α for a specified time. Finally, we evaluated the production of interleukin (IL)-1ß and IL-18. We found that serum GSDMD levels were elevated and positively correlated with the CAS in GO patients. Meanwhile, the expression of GSDMD and N-terminal domain (NT-GSDMD) in orbital connective tissue of GO patients was augmented. Also, increased expression of GSDMD and related pyroptosis factors was observed in vitro model of GO. We further demonstrated that GSDMD-mediated pyroptosis induced inflammation via the nuclear factor kB (NF-κB)/absent in melanoma-2 (AIM-2)/caspase-1 pathway. In addition, blocking GSDMD suppressed proinflammatory cytokine production in GO. We concluded that GSDMD may be a biomarker as well as a potential target for the evaluation and treatment of inflammation related with GO.

The potential causal association between systemic lupus erythematosus and endocrine and metabolic disorders in the East Asian population: A bidirectional two-sample Mendelian randomization study.

OBJECTIVES: Observational studies indicate a significant correlation between systemic lupus erythematosus (SLE) and endocrine and metabolic disorders, but the causal association between SLE and endocrine and metabolic disorders remains unclear due to the reverse causality and confounding biases commonly presented in conventional observational research. This study endeavors to uncover the causal association between SLE and three common endocrine and metabolic disorders, including Graves' disease (GD), type 2 diabetes mellitus (T2DM), and osteoporosis (OP). METHODS: We used genome-wide association study data for SLE and three endocrine and metabolic disorders in an East Asian population, employing bidirectional two-sample Mendelian randomization (MR) analysis and sensitivity analysis to ascertain the causal association between SLE and endocrine and metabolic disorders. RESULTS: A multiplicative random-effect inverse-variance weighted approach revealed a significant positive correlation between SLE and an elevated risk of GD with an odds ratio (OR) of 1.12 (95% CI: 1.04-1.22, p < .01), and inverse-variance weighted (IVW) analysis also indicated that SLE increased the risk of OP with an OR of 1.035 (95% CI: 1.003-1.068, p < .05). Additionally, GD causally affected SLE in an IVW analysis after Bonferroni correction, with an OR of 1.33 (95% CI: 1.19-1.49, p < .05/3), but the application of multivariable MR analysis resulted in the absence of a causal association of GD on SLE (OR 1.047, 95% CI: 0.952-1.151, p > .05). Lastly, the robustness and validity of the findings were verified through a sensitivity analysis. CONCLUSIONS: We confirmed that SLE has a causal effect on GD as well as OP, but no evidence exists to substantiate a causal link between SLE and T2DM. Our study offers valuable contributions for uncovering the etiology of SLE and endocrine and metabolic disorders and furthering disease risk research while providing potential targets for disease monitoring and therapeutic intervention.