Graves' Orbitopathy Models: Valuable Tools for Exploring Pathogenesis and Treatment.

Graves' orbitopathy (GO) is the most common extrathyroidal complication of Graves' disease (GD) and severely affects quality of life. However, its pathogenesis is still poorly understood, and therapeutic options are limited. Animal models are important tools for preclinical research. The animals in some previous models only exhibited symptoms of hyperthyroidism without ocular lesions. With the improvements achieved in modeling methods, some progressive animal models have been established. Immunization of mice with A subunit of the human thyroid stimulating hormone receptor (TSHR) by either adenovirus or plasmid (with electroporation) is widely used and convincing. These models are successful to identify that the gut microbiota influences the occurrence and severity of GD and GO, and sex-related risk factors may be key contributors to the female bias in the occurrence of GO rather than sex itself. Some data provide insight that macrophages and CD8+ T cells may play an important pathogenic role in the early stage of GO. Our team also replicated the time window from GD onset to GO onset and identified a group of CD4+ cytotoxic T cells. In therapeutic exploration, TSHR derived peptides, fingolimod, and rapamycin offer new potential options. Further clinical trials are needed to investigate these drugs. With the increasing use of these animal models and more in-depth studies of the new findings, scientists will gain a clearer understanding of the pathogenesis of GO and identify more treatments for patients.

Thyroid Eye Disease: Epidemiology, Natural History, and Risk Factors.

BACKGROUND: Thyroid eye disease (TED) is an autoimmune disorder of the orbit and the most frequent extrathyroidal manifestation of Graves' disease but it may rarely occur in euthyroid/hypothyroid patients with chronic autoimmune thyroiditis. EPIDEMIOLOGY: TED is a relatively infrequent disorder, particularly in its severe forms. Men tend to have more severe TED at an older age. The prevalence of TED is lower than in the past among patients with recent onset Graves' hyperthyroidism, and moderate-to-severe forms requiring aggressive treatments are no more than 5% to 6% of all cases. NATURAL HISTORY: After an initial inflammatory (active) phase and a plateau phase, TED stabilizes and eventually inactivates (inactive or burnt-out phase) after an estimated period of 18-24 months. Minimal-to-mild TED often remits spontaneously, but complete restitutio ad integrum almost never occurs when TED is more than mild. RISK FACTORS: Several risk factors contribute to its development on a yet undefined genetic background. Cigarette smoking is the most important of them, but thyroid dysfunction (both hyper- and hypothyroidism), radioactive iodine therapy (if not accompanied by low-dose steroid prophylaxis), elevated thyrotropin receptor antibodies, and, probably, hypercholesterolemia represent relevant modifiable risk factors. Early diagnosis, control and removal of modifiable risk factors, and early treatment of mild forms of GO (local treatment and selenium) may effectively limit the risk of progression to more severe forms.

Current concepts regarding Graves' orbitopathy.

Graves' orbitopathy (GO) is an orbital autoimmune disorder and the main extrathyroidal manifestation of Graves' disease, the most common cause of hyperthyroidism. GO affects about 30% of Graves' patients, although fewer than 10% have severe forms requiring immunosuppressive treatments. Management of GO requires a multidisciplinary approach. Medical therapies for active moderate-to-severe forms of GO (traditionally, high-dose glucocorticoids) often provide unsatisfactory results, and subsequently surgeries are often needed to cure residual manifestations. The aim of this review is to provide an updated overview of current concepts regarding the epidemiology, pathogenesis, assessment, and treatment of GO, and to present emerging targeted therapies and therapeutic perspectives. Original articles, clinical trials, systematic reviews, and meta-analyses from 1980 to 2021 were searched using the following terms: Graves' disease, Graves' orbitopathy, thyroid eye disease, glucocorticoids, orbital radiotherapy, rituximab, cyclosporine, azathioprine, teprotumumab, TSH-receptor antibody, smoking, hyperthyroidism, hypothyroidism, thyroidectomy, radioactive iodine, and antithyroid drugs. Recent studies suggest a secular trend toward a milder phenotype of GO. Standardized assessment at a thyroid eye clinic allows for a better general management plan. Treatment of active moderate-to-severe forms of GO still relies in most cases on high-dose systemic-mainly intravenous-glucocorticoids as monotherapy or in combination with other therapies-such as mycophenolate, cyclosporine, azathioprine, or orbital radiotherapy-but novel biological agents-including teprotumumab, rituximab, and tocilizumab-have achieved encouraging results.

Serum CYR61 Levels are Associated with Graves' Ophthalmopathy and Smoking in Patients with Graves' Disease.

Smoking is a well-known risk factor for Graves' ophthalmopathy (GO) in patients suffering from Graves' disease (GD). Cysteine-rich angiogenic inducer 61 (CYR61), which has multiple physiological functions, has been shown to be associated with GD and GO. In this study, we aimed to investigate the association between smoking and CYR61 concentrations in GD patients with and without GO. Serum CYR61 was measured by ELISA. The association between CYR61 concentration and GO was assessed with binary logistic regression in all patients and in subgroups of smokers and nonsmokers. The Spearman correlation coefficient was used to determine the correlations between CYR61 concentration and clinical parameters. CYR61 levels were significantly higher in GD patients with GO than in patients without GO, in smokers than in nonsmokers and in individuals older than 50 years than in those younger than 50 years. The subgroup of "GO smokers" had the highest CYR61 levels [median (IQR), 119 pg/ml (129.8)], compared with "GO nonsmokers" [84.2 pg/ml (90.8), p=0.04], "no GO smokers" [88.9 pg/ml (109.8), p=0.01] and "no GO nonsmokers" [79.4 pg/ml (129.89), p=0.003]. For each unit increase in CYR61 concentration, the odds of having GO in smokers significantly and independently increased by 1% (OR=1.010; 95% CI: 1.002-1.018, p=0.012). In conclusion, our results indicate that smoking and age increase serum CYR61 levels in patients with GD and GO. The role of CYR61 as a predictor of GO in patients with GD should be evaluated in prospective studies.

The risk factors for Graves' ophthalmopathy.

PURPOSE: This review aimed to provide an overview of current research into the risk factors for Graves' ophthalmopathy (GO). METHODS: To find information about the risk factors for GO, the research database PubMed was searched and relevant articles were obtained to extract information about risk factors. RESULTS: Smoking has been widely accepted as an important risk factor and cigarette smoking cessation has been shown to improve the outcome and decrease the onset of GO. Radioactive iodine on the thyroid may induce hyperthyroidism and increase the occurrence of GO. Selenium deficiency is a risk factor for GO and the supplementation of selenium has been an adjuvant therapy. Decreasing stressful life events (SLE) may help improve GO. Imbalance in intestinal flora is essential to GO, with Yersinia enterocolitica and Escherichia coli both increased in the digestive tract of the individual with GO. In addition, controlling serum cholesterol may help improve GO since adipogenesis is an important pathological change in its pathogenesis. Considering the correlation between Graves' disease and GO, maintaining normal thyroid function hormone level is the first-line therapeutic strategy to prevent progression of GO. An increase in antibodies such as TSHR and IGF-1R is the main predictor of GO. Besides, gender and gene polymorphism are also risk factors towards GO. CONCLUSIONS: Risk factors for GO arise from five sources: physical and chemical environment, social-psychological environment, biological environment, the human organism, and genetic codes. Risk factors within these categories may interact with each other and their mechanisms in promoting the development of GO are complex. Research into risk factors for GO may promote emerging fields related to GO such as control of autoantibodies and intestinal microbiota.

Medial orbital wall decompression: Demographics influencing surgical follow-up and complications: Impacts on follow-up and complications.

OBJECTIVE: Identify the impact of demographics and social determinants of health on surgical follow-up and complications after medial orbital wall decompression (MOWD) secondary to thyroid associated orbitopathy (TAO). METHODS: Demographics and social determinants of health (age, sex, race, insurance status) for 46 patients undergoing MOWD secondary to TAO were correlated with post-operative compliance and surgical complications by chi-square analyses. RESULTS: Among 46 patients, 23 were compliant with follow-up. There was no statistically significant difference between compliance and non-compliance based on age (60.25 vs 56.4, p = .41), sex (71.9 % female vs 85.7 % female, p = .31), race (65.6 % white vs 71.4 % white, p = .70) or insurance status (59.4 % private vs 42.9 % private, p = .30). Complications were noted in 50 % of patients of which sinus infection was most common (47.8 % of complications) and epistaxis rare (4.3 % of complications). No correlation was noted between development of complications and compliance (p = .20). Likewise, age, race and insurance status did not correlate with complications. CONCLUSION: For patients undergoing MOWD, no correlations with compliance or complication rate were noted with age, sex, race, or insurance status. A larger cohort may be indicated to identify such patterns. The overall complication rate was 50 % and the increased number of visits may have economic impact. KEY POINTS: This study provides a unique chance to assess demographic correlates of compliance and complication while controlling for surgeon preference. There was no association between sociodemographics and compliance or complications.

Understanding the pathogenesis of Graves' orbitopathy: A new age paradigm.

Graves' orbitopathy or thyroid associated orbitopathy (TAO) is a disquieting condition both for the patient and the clinician. While the mainstay of treatment of the orbitopathy is corticosteroids, its action is non-specific. The arguments against its use also include multiple side effects and recurrence on stopping it. While some clinicians are complacent with the drug due to our long term experience with it, many are in search for specific so called 'targeted' treatment. The autoimmune process in TAO is rather complex where multiple cytokines act at more than one level making it challenging to control the inflammation. Hence, in order to discover better treatment strategies, having a sound understanding of the pathogenesis of the disease is essential.

[LIFESTYLE ADJUSTMENT AS THERAPEUTIC TOOL IN THYROID EYE DISEASE].

OBJECTIVES: Thyroid Eye Disease (TED), also known as Graves' ophthalmopathy, is the most frequent extrathyroidal manifestation of autoimmune dysthyroidism. The most common ocular signs are eyelid retraction, proptosis, and strabismus, alongside specific dermatopathies. This article aims to review the options to improve TED manifestation by lifestyle adjustment. RESULTS: Tobacco smoking is the strongest risk factor for the development of TED and is associated with increased incidence and severity of TED and reduction in response to treatment. Smoking cessation decreases the incidence of TED and compares the risk level of ex-smokers to the risk level of the general population. Selenium is a chemical element with anti-oxidative properties. Selenium levels were significantly lower in Graves' disease patients with TED compared with those without TED. A double-blinded, randomized-control trial demonstrated that supplementation of selenium was associated with improved quality of life, decreased ocular involvement, and slowed TED progression while taken for a limited period. Statins administration to thyroid patients is associated with a reduced risk of TED. Recently, a few studies have shown an increased risk of developing TED and increased severity depending on the level of lipids in the blood, which suggests that balancing blood lipid levels by statins or by low-fat diet can help prevent TED. CONCLUSIONS: Lifestyle adjustment might be critical for a significant portion of patients. By supporting smoking cessation, the recommendation of selenium supplementation for a limited period and reducing serum cholesterol levels can prevent the development of TED, reduce its severity, and improve the patient's quality of life.

Leptin receptor is a key gene involved in the immunopathogenesis of thyroid-associated ophthalmopathy.

Thyroid-associated ophthalmopathy (TAO), the most common and severe manifestation of Graves' disease (GD), is a disfiguring and potentially blinding autoimmune disease. The high relapse rate (up to 20%) and substantial side effects of glucocorticoid treatment further decrease the life quality of TAO patients. To develop novel therapies, we amid to explore the immunopathogenesis of TAO. To identify the key immune-related genes (IRGs) in TAO, we integrated the IRG expression profiles in thyrocytes from a GD patient set (GD vs healthy control) and a TAO patient set (TAO vs GD). Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), protein-protein interaction (PPI) and receiver operating characteristic (ROC) curve analyses identified the leptin receptor (LEPR) gene as the key IRG in TAO immunopathogenesis. Gene set enrichment analysis (GSEA) suggested enrichment of the antigen presentation pathway in TAO patients with higher LEPR. Increased LEPR expression was validated in TAO orbital tissues, and weighted gene co-expression network analysis (WGCNA) showed that cell adhesion processes were positively correlated with LEPR. Our study revealed that LEPR is a key gene in TAO immunopathogenesis and plays different roles in thyrocytes and orbital tissues. Our findings provide new insights into diagnostic and therapeutic biomarkers for TAO.

Neferine suppresses autophagy-induced inflammation, oxidative stress and adipocyte differentiation in Graves' orbitopathy.

Previous studies in Graves' orbitopathy (GO) patient-derived fibroblasts showed that inhibition of autophagy suppresses adipogenic differentiation. Autophagy activation is associated with inflammation, production of reactive oxygen species and fibrosis. Neferine is an alkaloid extracted from Nelumbo nucifera, which induces Nrf2 expression and inhibits autophagy. Here, we have elucidated the role of neferine on interleukin (IL)-13-induced autophagy using patient-derived orbital fibroblasts as an in vitro model of GO. GO patient-derived orbital fibroblasts were isolated and cultured to generate an in vitro model of GO. Autophagy was determined by Western blot detection of the markers such as Beclin-1, Atg-5 and LC3 and by immunofluorescence detection of autophagosome formation. Analysis of differentiation towards an adipogenic lineage was performed by Oil red O staining. The expression of inflammatory factors was detected by ELISA and semiquantitative RT-PCR. Neferine inhibited autophagy in GO orbital fibroblasts, as indicated by the suppression of IL-13-induced autophagosome formation, overexpression of autophagy markers, increased LC3-II/LC3-I levels and finally down-regulation of p62. Neferine suppressed IL-13-induced inflammation, ROS generation, fibrosis and adipogenic differentiation in GO patient-derived orbital fibroblasts. The anti-inflammatory, antioxidant and antiadipogenic effects of neferine were accompanied by the up-regulation of Nrf2. These results indicated that orbital tissue remodelling and inflammation in GO may be mediated by autophagy, and neferine suppressed autophagy-related inflammation and adipogenesis through a mechanism involving Nrf2.

Expression of Endogenous Putative TSH Binding Protein in Orbit.

Thyroid stimulating antibodies (TSAB) cause Graves' disease and contribute to Graves' Orbitopathy (GO) pathogenesis. We hypothesise that the presence of TSH binding proteins (truncated TSHR variants (TSHRv)) and/or nonclassical ligands such as thyrostimulin (α2ß5) might provide a mechanism to protect against or exacerbate GO. We analysed primary human orbital preadipocyte-fibroblasts (OF) from GO patients and people free of GO (non-GO). Transcript (QPCR) and protein (western blot) expression levels of TSHRv were measured through an adipogenesis differentiation process. Cyclic-AMP production by TSHR activation was studied using luciferase-reporter and RIA assays. After differentiation, TSHRv levels in OF from GO were significantly higher than non-GO (p = 0.039), and confirmed in ex vivo analysis of orbital adipose samples. TSHRv western blot revealed a positive signal at 46 kDa in cell lysates and culture media (CM) from non-GO and GO-OF. Cyclic-AMP decreased from basal levels when OF were stimulated with TSH or Monoclonal TSAB (M22) before differentiation protocol, but increased in differentiated cells, and was inversely correlated with the TSHRv:TSHR ratio (Spearman correlation: TSH r = -0.55, p = 0.23, M22 r = 0.87, p = 0.03). In the bioassay, TSH/M22 induced luciferase-light was lower in CM from differentiated GO-OF than non-GO, suggesting that secreted TSHRv had neutralised their effects. α2 transcripts were present but reduced during adipogenesis (p < 0.005) with no difference observed between non-GO and GO. ß5 transcripts were at the limit of detection. Our work demonstrated that TSHRv transcripts are expressed as protein, are more abundant in GO than non-GO OF and have the capacity to regulate signalling via the TSHR.

Orbital inflammatory disorders: new knowledge, future challenges.

PURPOSE OF REVIEW: This review aims to bring together recent advances in basic, translational and clinical research on the pathogenesis and treatment of orbital inflammatory conditions. RECENT FINDINGS: Basic science studies provide mechanistic insights into why the orbit is targeted for inflammation by autoimmune inflammatory disorders. Using Graves' disease as a test case reveals that endocrine pathways, such as the TSH and IGF1 receptor pathways play important roles in stimulating orbital inflammation. Furthermore, orbital tissues contain high concentrations of retinoids - byproducts of the visual pathway that diffuse across the sclera and can activate de novo transcription of inflammatory cytokines. Such cytokine expression places the orbit in a hyper-inflammatory 'resting' state, prone to respond to any additional systemic or local pro-inflammatory signals. The HIF2A--LOX pathway appears important for orbital tissue fibrosis. Lastly, bench-to-bedside studies of the IGF1R pathway have led to an FDA-approved drug, teprotumumab that represents a novel treatment approach for Graves' orbitopathy. Unfortunately, high drug costs and misplaced insurance company 'step-therapy' policies may block patients from receiving therapy that can protect vision and improve quality of life. SUMMARY: Improved understanding of orbital inflammatory conditions has led to a new drug and promises additional breakthroughs. Translational research is successful, but requires time, resources, and patience.

Risk Factors of Thyroid Eye Disease.

OBJECTIVE: To examine risk factors that might be associated with thyroid eye disease (TED) in patients with Graves' disease (GD), which may guide physicians in the prevention and management of TED. METHODS: Medline and Embase were searched for articles discussing risk factors of TED. Comparisons were made between GD patients with and without TED, and between active and inactive TED GD patients. Weighted mean differences (WMDs) and odds ratios (ORs) were determined for continuous and dichotomous outcomes, respectively. Results were pooled with random effects using the DerSimonian and Laird model. RESULTS: Fifty-six articles were included in the analysis. Smoking, inclusive of current and previous smoking status, was a significant risk factor for TED (OR: 2.401; CI: 1.958-2.945; P < .001). Statistical significance was found upon meta-regression between male sex and the odds of smoking and TED (ß = 1.195; SE = 0.436; P = .013). Other risk factors were also examined, and patients with TED were significantly older than those without TED (WMD: 1.350; CI: 0.328-2.372; P = .010). While both age (WMD: 5.546; CI: 3.075-8.017; P < .001) and male sex (OR: 1.819; CI: 1.178-2.808; P = .007) were found to be significant risk factors for active TED patients compared to inactive TED patients, no statistical significance was found for family history, thyroid status, cholesterol levels, or body mass index. CONCLUSION: Factors such as smoking, sex, and age predispose GD patients to TED, and TED patients to active TED. A targeted approach in the management of GD and TED is required to reduce the modifiable risk factor of smoking.

Thyroid Eye Disease Following COVID-19 Vaccine in a Patient With a History Graves' Disease: A Case Report.

A 50-year-old woman with a history of controlled Graves' disease without clinical ophthalmopathy presents with 2 months of left more than right periorbital swelling and proptosis. Her eye symptoms and signs began 3 days following her second vaccination against the COVID-19 virus. Orbital imaging, elevated thyroid stimulating immunoglobulin, and negative systemic work up for other diseases were consistent with a diagnosis of active thyroid eye disease. The temporal relationship to her vaccination was likely consistent with autoimmune/inflammatory syndrome associated with adjuvants. Clinicians should remind patients of the symptoms and signs of thyroid eye disease and to seek appropriate medical and ophthalmic advice if they occur after the COVID-19 vaccine.

Curcumin Suppresses TGF-ß1-Induced Myofibroblast Differentiation and Attenuates Angiogenic Activity of Orbital Fibroblasts.

Orbital fibrosis, a hallmark of tissue remodeling in Graves' ophthalmopathy (GO), is a chronic, progressive orbitopathy with few effective treatments. Orbital fibroblasts are effector cells, and transforming growth factor ß1 (TGF-ß1) acts as a critical inducer to promote myofibroblast differentiation and subsequent tissue fibrosis. Curcumin is a natural compound with anti-fibrotic activity. This study aims to investigate the effects of curcumin on TGF-ß1-induced myofibroblast differentiation and on the pro-angiogenic activities of orbital fibroblasts. Orbital fibroblasts from one healthy donor and three patients with GO were collected for primary cell culture and subjected to myofibroblast differentiation under the administration of 1 or 5 ng/mL TGF-ß1 for 24 h. The effects of curcumin on TGF-ß1-induced orbital fibroblasts were assessed by measuring the cellular viability and detecting the expression of myofibroblast differentiation markers, including connective tissue growth factor (CTGF) and α-smooth muscle actin (α-SMA). The pro-angiogenic potential of curcumin-treated orbital fibroblasts was evaluated by examining the transwell migration and tube-forming capacities of fibroblast-conditioned EA.hy926 and HMEC-1 endothelial cells. Treatment of orbital fibroblasts with curcumin inhibited the TGF-ß1 signaling pathway and attenuated the expression of CTGF and α-SMA induced by TGF-ß1. Curcumin, at the concentration of 5 µg/mL, suppressed 5 ng/mL TGF-ß1-induced pro-angiogenic activities of orbital fibroblast-conditioned EA hy926 and HMEC-1 endothelial cells. Our findings suggest that curcumin reduces the TGF-ß1-induced myofibroblast differentiation and pro-angiogenic activity in orbital fibroblasts. The results support the potential application of curcumin for the treatment of GO.

Unusual onset of thyroid associated orbitopathy during pregnancy: case report and review of literature.

BACKGROUND: Thyroid associated orbitopathy (TAO) is the most common extrathyroidal complication of Graves' disease. The disease course ranges from mild, where symptomatic therapy is sufficient, to severe, where high dose steroid administration or orbital decompression surgery is required. Women of their reproductive age are more likely to be affected. Although pregnancy is a state of enhanced immune tolerance, TAO may develop or worsen in 0.2-0.4% of pregnant women. CASE PRESENTATION: We present the case of a 19-year-old woman who has developed hyperthyroidism and progressive TAO during the second trimester of her third pregnancy, which has improved postpartum. The possible mechanisms and the importance of follow up in pregnancy is discussed. CONCLUSIONS: Expectant mothers with Graves' disease require follow up of eye signs throughout pregnancy, preferably in the setting of a thyroid-eye clinic.

Serum Vitamin D Deficiency Is an Independent Risk Factor for Thyroid Eye Disease.

PURPOSE: Thyroid eye disease (TED) is an inflammatory orbitopathy with significant impact on visual function and quality of life. Although studies have shown that patients who are deficient in vitamin D are more likely to develop autoimmune conditions, there are no studies demonstrating a definitive correlation between serum 25-hydroxyvitamin D (25(OH)D) deficiency and an increased risk of TED. METHODS: This retrospective case-control study compared serum 25(OH)D levels among 4 groups: 1) Graves disease (GD) patients with TED (n = 89); 2) GD patients without TED (n = 89); and healthy control patients matched to 3) the TED group (n = 356); and 4) the GD group (n = 356). The authors compared 25(OH)D level in the TED group measured within 1 year of TED diagnosis to the most recently measured 25(OH)D level in the GD group using Student t test of the log transformation of serum levels. Linear regression was used to control for other risk factors. Thyroid eye disease patients and GD patients were compared separately to their matched healthy control patients with linear mixed models. RESULTS: Thyroid eye disease patients displayed significantly lower serum 25(OH)D levels than GD patients (24.8 ± 13.2 ng/ml vs. 29.4 ± 13.3 ng/ml; p = 0.006). Controlling for smoking status and previous radioactive iodine treatment did not affect this statistically significant difference. CONCLUSIONS: Low serum vitamin D is associated with TED diagnosis. Assessing and supplementing vitamin D levels may be an important addition to the early management of GD patients. Future research should include longitudinal studies and prospective clinical trials to further explore the mechanism responsible for the observed association.Thyroid eye disease is an inflammatory orbitopathy associated with Graves disease. Vitamin D is a known immune system regulator. The authors show that vitamin D deficiency is associated with the development of thyroid eye disease.

Distinctive Features of Orbital Adipose Tissue (OAT) in Graves' Orbitopathy.

Depot specific expansion of orbital-adipose-tissue (OAT) in Graves' Orbitopathy (GO) is associated with lipid metabolism signaling defects. We hypothesize that the unique adipocyte biology of OAT facilitates its expansion in GO. A comprehensive comparison of OAT and white-adipose-tissue (WAT) was performed by light/electron-microscopy, lipidomic and transcriptional analysis using ex vivo WAT, healthy OAT (OAT-H) and OAT from GO (OAT-GO). OAT-H/OAT-GO have a single lipid-vacuole and low mitochondrial number. Lower lipolytic activity and smaller adipocytes of OAT-H/OAT-GO, accompanied by similar essential linoleic fatty acid (FA) and (low) FA synthesis to WAT, revealed a hyperplastic OAT expansion through external FA-uptake via abundant SLC27A6 (FA-transporter) expression. Mitochondrial dysfunction of OAT in GO was apparent, as evidenced by the increased mRNA expression of uncoupling protein 1 (UCP1) and mitofusin-2 (MFN2) in OAT-GO compared to OAT-H. Transcriptional profiles of OAT-H revealed high expression of Iroquois homeobox-family (IRX-3&5), and low expression in HOX-family/TBX5 (essential for WAT/BAT (brown-adipose-tissue)/BRITE (BRown-in-whITE) development). We demonstrated unique features of OAT not presented in either WAT or BAT/BRITE. This study reveals that the pathologically enhanced FA-uptake driven hyperplastic expansion of OAT in GO is associated with a depot specific mechanism (the SLC27A6 FA-transporter) and mitochondrial dysfunction. We uncovered that OAT functions as a distinctive fat depot, providing novel insights into adipocyte biology and the pathological development of OAT expansion in GO.

Predicting outcomes and complications following radioiodine therapy in Graves' thyrotoxicosis.

OBJECTIVE: Radioiodine (RAI) is an effective treatment for Graves' thyrotoxicosis but is associated with a failure rate of 15% and may be a risk factor for thyroid eye disease (TED) and weight gain. We sought to examine predictors of RAI failure, weight gain, TED and patient satisfaction. DESIGN: Retrospective cohort study. PATIENTS: A total of 655 episodes of RAI in Graves' thyrotoxicosis patients (2006-2015). MEASUREMENTS: Biochemical assessment, including TFTs and thyrotropin receptor antibodies (TRAb), clinical features (eg, TED, weight and thionamide use) and patient questionnaire. RESULTS: The treatment failure rate was 17%. Failure was greater with higher fT4 (P = 0.002) and higher TRAb (P = 0.004). Failure rate was 42.2% when TRAb >40 U/L. Median weight gain was 3.2 kg in those with normal fT4 prior to RAI and 5.8 kg when fT4 was elevated (P < 0.001). New TED developed in 7.6% but was not associated with post-RAI dysthyroidism. Treatment satisfaction was generally high (median response 8/10). CONCLUSIONS: Treatment failure after RAI occurs in predictable groups and this should be reflected in the information provided to patients. Weight gain is common and may not entirely be explained by a return to pre-thyrotoxic baseline. We were unable to detect any significant impact of post-RAI dysthyroidism on weight gain, TED or thyroid symptoms in this large cohort.

ROLE OF MAGNETIC RESONANCE IMAGING IN THE ASSESSMENT OF ACTIVE THYROID-ASSOCIATED OPHTHALMOPATHY PATIENTS WITH LONG DISEASE DURATION.

Objective: In thyroid-associated ophthalmopathy (TAO), long disease duration is negatively correlated with the response to immunosuppression treatment. The current treatment decision-making process does not involve magnetic resonance imaging (MRI); thus, we investigated the predictive value of MRI parameters for the immunosuppressive response in active moderate to severe TAO patients with different disease durations. Methods: We retrospectively analyzed the baseline MRI parameters of active TAO patients treated with guideline-recommended weekly glucocorticoid therapy in our center. Data were stratified by the quartile of disease duration. The signal intensity ratio (SIR) of T2-weighted images was used to describe the activity of extraocular muscles (EOMs). Results: Compared to the lowest quartile of disease duration, SIR values of EOMs were significantly lower in quartile 3 (Q3) and quartile 4 (Q4). Meanwhile, the clinical activity score (CAS) curve did not change in parallel and was not correlated with the SIR curve. In the highest quartile of disease duration, nonresponders had significantly lower SIR values of the most inflamed muscle (P = .03) and the medial rectus (P = .004) than did the responders, while no such significance was observed in patients within the lower 3 quartiles. A multivariable predictive model (including CAS, TAO duration, and SIR value) was established in each quartile. The fit of the model was better than CAS with regard to prognostic prediction and showed a high positive predictive value (Model 1: 86.67%; Model 2: 92.86%) and negative predictive value (Model 1: 88.89%; Model 2: 90%) in the top quartile. Conclusion: The anterior manifestation assessed by CAS is not always consistent with retro-orbital activity in long-term TAO patients. CAS is sufficient to reflect disease activity in short-term TAO patients. The supplementation of CAS with orbital MRI would be valuable in selecting appropriate active patients with a long disease duration. Abbreviations: AUC = area under the curve; CAS = clinical activity score; EOM = extraocular muscle; FT3 = free triiodothyronine; FT4 = free thyroxine; GC = glucocorticoid; ivGC = intravenous glucocorticoids; MRI = magnetic resonance imaging; NPV = negative predictive value; PPV = positive predictive value; SIR = signal intensity ratio; TAO = thyroid-associated ophthalmopathy; TRAb = thyroid-stimulating hormone receptor antibody; TSH = thyroid-stimulating hormone.