Graves' Ophthalmopathy Research Articles

Fine mapping of thyroglobulin gene identifies two independent risk loci for Graves' disease in Chinese Han population.

This study aimed to determine independent risk loci of Graves' disease (GD) in the thyroglobulin (TG) region. In this two-staged association study, a total of 9,757 patients with GD and 10,626 sex-matched controls were recruited from Chinese Han population. Illumina Human660-Quad BeadChips in the discovery stage and TaqMan SNP Genotyping Assays in the replication stage were used for genotyping. Trend test and logistic regression analysis were performed in this association study. In the discovery stage, rs2294025 and rs7005834 were the most highly associated susceptibility loci with GD in TG. In the replication phase, 7 SNPs, including rs2294025 and rs7005834, were selected for fine-mapping. Finally, we confirmed that rs2294025 and rs7005834 were the independent risk loci of GD in the combined populations. At the same time, there was no significant difference between the risk allele frequencies of rs2294025 and rs7005834 in different clinical phenotypes of GD. The fine mapping study of thyroglobulin identified two independent SNPs (rs2294025 and rs7005834) for GD susceptibility. However, no significant differences for rs2294025 and rs7005834 were observed, between the different clinical phenotypes of GD, including gender, Graves' ophthalmopathy (GO), and serum levels of thyrotropin receptor antibody, thyroid peroxidase antibody, and thyroglobulin antibody. These results provide a deeper understanding of the association mechanism of thyroglobulin and GD risk.

Simvastatin downregulates adipogenesis in 3T3-L1 preadipocytes and orbital fibroblasts from Graves' ophthalmopathy patients.

BackgroundSmoking is a strong risk factor for the development of Graves’ ophthalmopathy (GO). Immediate early genes (IEGs) are overexpressed in patients with active GO compared to healthy controls. The aim of this study was to study the effects of tobacco smoking and simvastatin on preadipocytes and orbital fibroblasts (OFs) in the adipogenic process.MethodsCigarette smoke extract (CSE) was generated by a validated pump system. Mouse 3T3-L1 preadipocytes or OFs were exposed to 10% CSE with or without simvastatin. Gene expression was studied in preadipocytes and OFs exposed to CSE with or without simvastatin and compared to unexposed cells or cells treated with a differentiation cocktail.ResultsIn 3T3-L1 preadipocytes, Cyr61, Ptgs2, Egr1 and Zfp36 expression levels were two-fold higher in cells exposed to CSE than in unexposed cells. Simvastatin downregulated the expression of these genes (1.6-fold, 5.5-fold, 3.3-fold, 1.4-fold, respectively). CSE alone could not stimulate preadipocytes to differentiate. Scd1, Ppar-γ and adipogenesis were downregulated in simvastatin-treated preadipocytes compared to nontreated preadipocytes 18-, 35- and 1.7-fold, respectively. In OFs, similar effects of CSE were seen on the expression of CYR61 (1.4-fold) and PTGS2 (3-fold). Simvastatin downregulated adipogenesis, PPAR-γ (2-fold) and SCD (27-fold) expression in OFs.ConclusionCSE upregulated early adipogenic genes in both mouse 3T3-L1 preadipocytes and human OFs but did not by itself induce adipogenesis. Simvastatin inhibited the expression of both early and late adipogenic genes and adipogenesis in preadipocytes and human OFs. The effect of simvastatin should be investigated in a clinical trial of patients with GO.

Intravenous glucocorticoids therapy in the treatment of Graves' ophthalmopathy: a systematic review and Meta-analysis.

To evaluate the benefit and harms of high-dose intravenous glucocorticoids (IVGC) as first-line treatment for Graves' ophthalmopathy (GO). A systematic review and Meta-analysis of randomized clinical trials (RCTs) comparing IVGC for the treatment of GO, with placebo or other treatments, were conducted. Electronic databases were searched, and standard methodological guidance of Cochrane Handbook for Systematic Reviews of Interventions was used. The primary outcome was overall response, and secondary outcomes included the improvement and change in clinical activity score (CAS), and adverse events. Ten RCTs were included in the Meta-analysis. Low quality evidence (one trial) showed that participants receiving IVGC achieved significantly higher response compared to participants receiving placebo [risk ratio (RR) 7.50, 95% confidence interval (CI) 1.14 to 49.26]. Moderate quality evidence (four trials) support appreciable benefit of IVGC in response compared with oral glucocorticoids (OGC), with of RR being 1.51 (95%CI 1.25 to 1.83). There was low quality evidence (one trial) compatible with appreciable benefit for IVGC plus orbital radiotherapy in response (RR 1.38, 95%CI 1.07 to 1.79), compared with OGC plus orbital radiotherapy. One IVGC versus rituximab trial provided moderate quality evidence suggesting that participants using IVGC achieved significantly lower response compared to participants using rituximab (RR 0.70, 95%CI 0.50 to 0.98). One IVGC versus mycophenolate mofetil (MMF) trial provided moderate quality evidence suggesting that participants using IVGC achieved significantly lower response compared to participants using MMF (RR 0.74, 95%CI 0.63 to 0.88). Very low quality evidence (one trial) showed that participants with dysthyroid optic neuropathy (DON) receiving IVGC were more likely to achieve response compared to participants receiving orbital decompression (RR 3.33, 95%CI 0.51 to 21.89). The current evidence is moderate quality, which is sufficient to support IVGC to be as the first-line treatment for moderate-to-severe GO, and the use of rituximab or MMF to be the second-line treatment instead of IVGC. However, the evidence is very low quality, which is insufficient to support the use of IVGC or orbital decompression as the first-line treatment of DON.

Clinical outcomes of graves ophthalmopathy

Clinical outcomes of graves ophthalmopathy - IJOOO- Print ISSN No: - 2581-5024 Online ISSN No:- 2581-5016 Article DOI No:- 10.18231/j.ijooo.2019.018, IP International Journal of Ocular Oncology and Oculoplasty-IP Int J Ocul Oncol Oculoplasty

Real-time ultrasound elastographic evaluation of extraocular muscle involvement in Graves’ ophthalmopathy

ABSTRACTPurpose: To evaluate the affected extraocular muscles (EOMs) of patients with Graves’ ophthalmopathy (GO) using real-time ultrasound elastography (UE) and to compare these results with those of healthy subjects.Methods: This prospective, comparative case series included 70 eyes of 35 patients with moderate-to-severe GO with type 2 orbitopathy (myogenic variant) according to their computed tomography (CT) scans. Forty-six eyes of 23 healthy subjects were evaluated as the control group. The strain ratio of orbital fat to medial rectus was calculated as the ratio of the medial rectus to orbital fat tissue, and the strain ratio of orbital fat to lateral rectus was calculated as the ratio of lateral rectus to orbital fat tissue.Results: The strain ratio of orbital fat to medial rectus was 3.03 ± 1.25 (range: 1.05–5.07) in the GO group, and 0.54 ± 0.20 (range: 0.14–1.08) in the control group (p = .0001). The strain ratio of orbital fat to lateral rectus was 0.97 ± 0.29 (range: 0.56–1.55) in the GO group, and 0.63 ± 0.23 (range: 0.18–1.09) in the control group (p = .0001).Conclusion: By using real-time UE, we found the medial and the lateral recti of GO patients to be stiffer compared to those of healthy subjects.

Treatment strategies for Graves’ ophthalmopathy: a network meta-analysis

PurposeVarious treatments have been investigated for Graves’ ophthalmopathy (GO). We aimed to provide an overall profile of the efficacy and tolerability of various interventions for active and moderate to severe...

Prevalence of increased intraocular pressure in patients with Graves' ophthalmopathy and association with ophthalmic signs and symptoms in the north-west of Iran.

IntroductionGraves’ ophthalmopathy (GO) is the most common extra-thyroidal manifestation of Graves' disease and is characterized by multiple ocular symptoms such as eyelid retraction, lid lag, proptosis, elevated intraocular pressure (IOP) and ultimately loss of vision. We aimed to investigate the prevalence of increased IOP in Graves' patients and association with ophthalmic signs and symptoms in north-west of Iran.Materials and methodsThis descriptive cross-sectional study recruited 93 patients with GO who were diagnosed based on clinical and laboratory examinations. A complete ocular examination and IOP measurements on forward gaze were performed using Goldman applanation tonometer.ResultsIn this study, 93 patients with GO were evaluated from 2016 to 2017. Among these patients, 67 (72.05%) were female and 27 (27.95%) were male. The most common complaints of patients were lid retraction (62.36%), puffy eyelids (58.06%) and proptosis (46.23%), respectively. The duration of disease was 0–24 months in most patients. Most subjects were at grade 3 according to NOSPECS classification. Nine patients (9.6%) had an IOP greater than or equal to 21 mmHg. The mean IOP in subjects was 16.61±3.42 mmHg. The mean IOP in males and smokers was significantly higher than that of females and nonsmokers. The mean IOP increased significantly with a higher grade of disease, duration of disease, age and smoking.ConclusionsAccording to the results, females comprised the majority of the study population, while ocular complications were more prevalent among males. The highest IOP was seen in old cases of GO. The most prevalent ocular signs in patients were eyelid retraction and periorbital edema. The least prevalent sign was glaucomatous optic neuropathy. In this study, the prevalence of intra-ocular hypertension was higher than that of the general population, especially in males, old cases with a drug history of antithyroid medication and smokers.

An experimental study on the induction of Graves′ hyperthyroidism with Graves′ ophthalmopathy in BALB/c mice by TSHR gene immunization

Objective To construct a model of Graves′ disease(GD) with (or) Graves′ ophthalmopathy(GO) in BALB/c mice by immunization with pcDNA3.1/TSHR289. Methods pcDNA3.1/TSHR289 was injected into the bilateral gastrocnemius muscle of 35 model mice and electroporation was immediately performed. 10 control mice were injected with sterile saline and electroporated, while 5 blank mice were injected with sterile saline only. Each group of mice was immunized at 1, 4, 7, and 10 weeks, respectively. Serum total T4, TSH, TSAb, and TSBAb were measured before immunization, 2 weeks after each immunization, as well as 5 and 8 weeks after the last immunization. CT scan was used to evaluate the morphological changes of the eyes of the mice.99mTcO4- imaging was used to measure the thyroid uptake function, and the pathological changes of the thyroid and orbital tissues were evaluated by HE staining. Results After the 2nd time immunization, the serum concentrations of TT4, TSAb and TSBAb in GD mice were significantly higher than those of control and blank groups(F=13.781, 31.435, 36.112, P<0.01, respectively). The TSH continued to be significantly lower than that of control and blank groups(F=13.966, P<0.01). After the 4th time immunizations, the ability of uptaking99mTcO4- in GD mice thyroid was significantly enhanced compared with the control group. The thyroid goiter with a large amount of lymphocyte infiltration, and the thyroid follicle was thin. CT scan of GO mice showed thickening and swelling of the extraocular muscles, and no abnormalities in tendon and muscle attachment points. HE staining showed thickening of extraocular muscle fibers, lymphocyte infiltration of extraocular muscles and orbital tissue, increased hyaluronic acid, and infiltration of fat cells. Conclusion GD or GO model can be successfully induced by multiple intramuscular injection of pcDNA3.1/TSHR289 in BALB/c mice. Key words: Graves′ disease; Graves ophthalmopathy; TSHR; Mice models; Electroporation

Matrix metalloproteinases-1, -13 and their tissue inhibitor-1 in endocrine ophthalmopathy

The study included 65 people (130 eyes) at the age of 43 (35-50) years. Three groups of subjects were formed: 32 patients with a moderate GO severity (clinical group), 18 patients with autoimmune thyroid pathology without GO (comparison group), and 15 healthy persons (control). The diagnosis was based on clinical, laboratory, and instrumental data. A comprehensive ophthalmologic examination and blood sampling for determination of MMP-1, -13, TIMP-1, sulfated glycosaminoglycans (sGAG) and antibodies to thyroid-stimulating hormone receptor (TSHRAbs) were conducted. The data were statistically processed using the program Statistica 10.0. An elevated level of MMP-13, observed in all GO patients (p<0.05). For the active phase of GOP, the comparison with the control group showed a 3.5-fold increase in MMP-13 (p<0.001) and 1.17-fold rise in TIMP-1 (p>0.05). Pulse glucocorticoid therapy reduced MMP-13 by 48.6% (p<0.001), TIMP-1 by 2.7% (p<0.001), and TSHRAbs - by 93% (p<0.001) compared with active GO, but these indicators were higher than the reference limits of control (p>0.05). In inactive GO, despite increased MMP-13, TIMP-1 decreased to the reference values (p=0.533). There were no significant differences in MMP-1 in groups of subjects (p=0.865). We have found imbalance between MMP-13 and TIMP-1 production in different activity phases of GO. Active GO is characterized by an increase in serum MMP-13 and TIMP-1. Dysregulation of intercellular matrix remodeling, possibly, underlies the development of extraocular muscles and retrobulbar tissue fibrosis in GO.

Value of Infrared Thermography Camera Attached to a Smartphone for Evaluation and Follow-up of Patients with Graves' Ophthalmopathy.

Purpose Graves' ophthalmopathy (GO) is the most common extra-thyroid manifestation of Graves' disease (GD). The Clinical Activity Score (CAS) has been widely used to evaluate GO inflammation severity and response to treatment; however, it is quite subjective. Infrared thermography (IRT) is a portable and low-cost device to evaluate local temperature and assess inflammation. The aim was to evaluate ocular temperature by IRT as an instrument for measuring inflammatory activity in GO and its correlation with CAS. Methods This is a cross-sectional study involving 136 consecutive GD patients (12 with CAS ≥ 3/7, 62 with CAS < 3 and 62 without apparent GO) with 62 healthy controls. Patients with active ophthalmopathy were prospectively evaluated. Exophthalmometry, CAS, and thermal images from caruncles and upper eyelids were acquired from all subjects. Results All eye areas of thermal evaluation had higher temperatures in GD patients with active ophthalmopathy (caruncles, p<0.0001; upper eyelids, p<0.0001), and it was positively correlated with CAS (r=0.60 and p<0.0001 at caruncles; r=0.58 and p<0.0001 at upper eyelids). No difference in temperature was found between other groups. Patients with active ophthalmopathy were prospectively evaluated after 6 or 12 months of the treatment and a significant difference was found in ophthalmometry (p=0.0188), CAS (p=0.0205), temperature of caruncles (p=0.0120), and upper eyelids (p=0.0066). Conclusions IRT was an objective and simple tool for evaluation and follow-up of inflammation in GO, allowed evidencing patients with significant inflammatory activity, and had a good correlation with the CAS score.

Study of RVT-1401 for the Treatment of Patients With Active, Moderate to Severe Graves' Ophthalmopathy ( GO )

Study of RVT-1401 for the Treatment of Patients With Active, Moderate to Severe Graves' Ophthalmopathy ( GO )

Differential modulation of CXCL8 versus CXCL10, by cytokines, PPAR-gamma, or PPAR-alpha agonists, in primary cells from Graves' disease and ophthalmopathy.

Thyrocytes secrete CXC chemokines, particularly (C-X-C motif) ligand (CXCL)8 and CXCL10; its physiopathological significance remains unclear. This study investigates the modulation of the secretion of CXCL8 vs. CXCL10, in human primary cells cultures of thyroid follicular cells (TFC) in Graves' disease (GD), and fibroblasts (OF) or preadipocytes (OP) from Graves' ophthalmopathy (GO). Cells were initially incubated with different concentrations of tumor necrosis factor (TNF)α (1, 5, 10 ng/mL). Then, CXCL8 and CXCL10 were measured in the supernatants of TFC, OF or OP cells basally and after 24 h of treatment with interferon (IFN)γ (1000 IU/mL) and/or TNFα (10 ng/mL), in presence/absence of the peroxisome proliferator activated receptor (PPAR)γ agonist pioglitazone (0, 0.1, 1, 5, 10, 20 μM), or the PPARα agonist fenofibrate (5, 10, 50, 100 μM). CXCL8, not CXCL10, was detected in basal conditions in TFC, OF and OP. CXCL8 secretion increased dose-dependently with increasing concentrations of TNFα. CXCL10 secretion was significantly stimulated by IFNγ (P < 0.01) and not by TNFα, whereas CXCL8 was induced by TNFα (P < 0.01), and inhibited by IFNγ (P < 0.01) in TFC, OF and OP. Combining TNFα and IFNγ, the IFNγ-induced CXCL10 secretion was synergistically increased (P < 0.01) while the TNFα-induced CXCL8 secretion (P < 0.01) was reversed in all cell types. Pioglitazone had no significant effect on the secretion of CXCL8 stimulated by TNFα, while inhibited CXCL10. Fenofibrate, in presence of IFNγ plus TNFα, dose-dependently inhibited both CXCL10 and CXCL8 release. We first show that TFC, OF, and OP secrete CXCL8 and CXCL10 differentially, sustained by specific proinflammatory cytokines or their combination. This could reflect a different role of the two chemokines in the course of the disease, as CXCL10 could be associated with the initial phase of the disease when IFNγ is preponderant, while CXCL8 could be associated with a later chronic phase of the disease, when TNFα prevails.

Does the dose of iodine-131 influence the incidence of Graves' ophthalmopathy?

Radioactive iodine-131 (RAI) is an established treatment for patients with Graves' hyperthyroidism. RAI is reported to be associated with a 20-30% incidence of development or exacerbation of Graves' ophthalmopathy (GO). This study compares the progression of GO in patients who had evidence or no evidence of GO before RAI therapy. Forty-eight patients were studied. One group had no evidence whereas the other group had evidence of GO before RAI treatment. All underwent RAI therapy. Group A (27 patients, 18 women, nine men, age: 19-68 with a mean of 49 years) had pre-existing exophthalmos. Group B consisted of 21 patients (13 women, eight men, age: 30-63 with a mean of 43 years) developed exophthalmos after treatment. All patients underwent RAI therapy and followed by ophthalmologists. The average administered dose in group A was 24.3 mCi (range: 10-36.2 mCi) compared with group B: 25.4 mCi (range: 13-35.9 mCi), P=0.60. Ten (37%) of the 27 patients in group A experienced worsening of symptoms post-treatment. There was no significant difference between the administered dose of RAI in patients with worsening symptoms, 25.1 mCi versus patients with stable symptoms, 24.5 mCi (P=0.82). However, group A developed GO symptoms earlier than group B (4.5 vs. 9.5 months), P=0.02. RAI is known to exacerbate ophthalmopathy. Our study showed it was not dose-dependent. Patients without a previous history of GO were observed to have a significantly delayed period for the development of symptoms.

Arrestin-β-1 Physically Scaffolds TSH and IGF1 Receptors to Enable Crosstalk.

Endogenously expressed TSH receptors (TSHRs) on orbital fibroblasts of patients with Graves ophthalmopathy (GO) use crosstalk with IGF1 receptors (IGF1R) to synergistically stimulate secretion of hyaluronan (HA), a major component of GO pathology. We previously showed crosstalk occurred upstream of mitogen-activated protein kinase (ERK) phosphorylation. Because other G protein-coupled receptors engage arrestin-β-1 (ARRB1) and ERK, we tested whether ARRB1 was a necessary component of TSHR/IGF1R crosstalk. HA secretion was stimulated by the TSHR-stimulating monoclonal antibodies M22 and KSAb1, or immunoglobulins from patients with GO (GO-Igs). Treatment with M22, as previously shown, resulted in biphasic dose-response stimulation of HA secretion. The high-potency phase was IGF1R dependent, and the low-potency phase was partly IGF1R independent. KSAb1 produced a monophasic dose-response stimulation of HA secretion, whose potency was lowered >20-fold after IGF1R knockdown. ARRB1 knockdown abolished M22's high-potency phase and lowered KSAb1's potency and efficacy. ARRB1 knockdown inhibited GO-Ig stimulation of HA secretion and of ERK phosphorylation. Last, ARRB1 was shown to be necessary for TSHR/IGF1R proximity. In contrast, ARRB2 knockdowns did not show these effects. Thus, TSHR must neighbor IGF1R for crosstalk in GO fibroblasts to occur, and this depends on ARRB1 acting as a scaffold. Similar scaffolding of TSHR and IGF1R by ARRB1 was found in human osteoblast-like cells and human thyrocytes. These findings support a model of TSHR/IGF1R crosstalk that may be a general mechanism for G-protein-coupled receptor/receptor tyrosine kinase crosstalk dependent on ARRB1.

Phase 2a Study of RVT-1401 for the Treatment of Patients With Moderate to Severe Active Graves' Ophthalmopathy ( GO )

Phase 2a Study of RVT-1401 for the Treatment of Patients With Moderate to Severe Active Graves' Ophthalmopathy ( GO )

MON-594 Report Of A Large Series Of Patients With Graves' Disease (with/without Graves' Ophthalmopathy) And Review Of The Literature, About The Association With Other Autoimmune Diseases

The two main clinical presentations of autoimmune thyroid disorders (AITD) are Graves’ disease (GD) and autoimmune thyroiditis (AT). The associations between thyroid disorders and other organ specific, or systemic autoimmune diseases in the same patient has been suggested, albeit discordant results have been reported in the literature. We focused on the association between GD and other autoimmune syndromes by searching in the literature. Moreover, we have carried out a prospective study investigating about the prevalence of other autoimmune disorders in 3209 GD patients [984 of whom with Graves’ ophthalmopathy (GO)], with respect to 1069 healthy controls, or 1069 with multinodular goiter, or 1069 patients with AT. Patients and controls were matched by age and gender, come from the same area, and had a similar iodine intake. A significant increase of the prevalence of autoimmune disorders in GD patients, with respect to the controls, has been observed. In particular, the most frequently observed associations were: vitiligo (2.6%), chronic autoimmune gastritis (2.4%), rheumatoid arthritis (1.9%), polymyalgia rheumatica (1.3%), multiple sclerosis (0.3%), celiac disease (1.1%), type 1 diabetes (0.9%), systemic lupus erythematosus and sarcoidosis (<0.1%), Sjogren disease (0.8%). In addition, 1.5% patients with GD had three associated autoimmune disorders. The prevalence of autoimmmune disorder in GO patients is higher (18.9%), with respect to GD patients without GO (15.6%). The pattern of the associated autoimmune disorders in GD was not significantly different from that observed in AT patients. These findings suggest to appropriately screen GD patients, who are still sick, or who develop new unspecific symptoms (even if during an appropriate treatment of hyperthyroidism), for the presence of other autoimmune disorders.

SUN-568 Steroid Induced Psychosis Complicating the Treatment of Graves Ophthalmopathy

Introduction: Graves‘disease is an autoimmune disorder in which the thyroid is activated by antibodies to the thyrotropin receptor. The annual incidence in women over a 20-year period is around 0.5 per 1000, with the highest risk of onset between the ages of 40 and 60 years; it is thus the most prevalent autoimmune disorder in the United States1. This is 1/10 as common in men as in women. Treatment of Graves’ disease can be complicated by intrinsic aspects of the disease itself and also by effects of the therapy chosen. Case report: A 49 year old man presented to our emergency department with a three month history of palpitations, weight loss, heat intolerance, sweating, eye irritation and tremors. Physical examination revealed tachycardia (107 bpm), a fine tremor to the outstretched hands, bilateral stare, diffuse thyromegaly with bruit. Labs: TSH < 0.005 (0.35-3.4 uIU/ml), TT3 604 (70 -190 ng/dl), TT4 25.28 (4.5 - 12.1ug/dl), TSI 341 (< 140 %). Treatment was started on methimazole 10mg TID and propranolol 20mg TID. He had homogenous activity with a 24 hour uptake of 78 % on thyroid isotope scan. Diagnosis of Graves ’ disease was made and he was treated with 6.1 mCi of RAI. One month later, the patient presented with stare, conjunctival chemosis, lid lag, increased lacrimation, restricted extra ocular muscle movements worse on upward gaze, and periorbital edema. He was seen by Ophthalmology and started on prednisone 60 mg PO daily, with improvement in ocular findings. Two weeks thereafter was started, patient presented with agitation and anxiety. TSH was 0.006, TT4 9.4, TT3 88. Steroid induced psychosis was diagnosed and the prednisone dose was reduced, then gradually tapered off. The psychosis resolved. Post 131I Hypothyroidism developed and he became euthyroid with L-thyroxine replacement. Discussion: Graves’ ophthalmopathy occurs in a mild form in 25% to 50% of patients with Graves’ disease, with about 3% to 5% of patients having severe eye disease. Smoking, high levels of pre-treatment T3 (more than twice the upper limit of normal) and RAI induced release of retro orbital antigens cross reacting with thyrotropin receptor antigen are associated with an increased risk of ophthalmopathy .The risk of developing ophthalmopathy is around 20% after RAI and the risk of severe ophthalmopathy is around 7%1. At least 12 months follow-up after RAI is essential as ophthalmopathy usually develops or worsens within 6 months after RAI but can occur even after 2 years. Early treatment with glucocorticoids in appropriately selected patients is recommended for active, moderate to severe and sight-threatening disease. Serious neuropsychiatric effects occur in about 6% of patients who receive steroids.3 Although the effects of glucocorticoids are unpredictable, the administered dose is the most significant risk factor for the development of neuropsychiatric symptoms. Dosage reduction typically results in clinical recovery.

SUN-569 Thyroid Associated Orbitopathy (TAO): An Unusual Presentation

Thyroid associated orbitopathy (TAO), frequently termed Graves ophthalmopathy, is part of an autoimmune process that can affect the orbital and periorbital tissue. The diagnosis of TAO is based on clinical orbital features, radiological criteria, and the potential association with thyroid disease. The orbital expression of the thyroid stimulating hormone receptor (TSHR) has been implicated in this condition which generally occurs in hyperthyroid patients due to Graves’ disease. In 20% of cases, patients are euthyroid or hypothyroid. The possibility of having different types of antibodies in Graves’ disease (stimulatory, blocking and/or neutral) can explain variations in thyroid function. Nevertheless, cases of TAO associated with Hashimoto’s thyroiditis (HT) have already been described. A 51-year-old non-smoker woman with a medical record of multinodular goitre and primary hypothyroidism under 75µg of levothyroxine complained of diplopia to her ophtalmologist. During the last 3-4 weeks, she described redness and swelling of the eyelids, foreign body sensation and blurred vision in her left eye. On physical examination, the ophthalmologist described a limitation on elevation of the left eye and vertical diplopia in levoversion. The patient was referred to the emergency department (ED) to perform a head and an orbit CT scan. The exam revealed: ‘…in relation to the left orbit, there is a clear thickening of the inferior rectus muscle and a less pronounced thickening of the medial rectus muscle. Aspects suggestive of Graves’ disease. The endocrinologist confirmed the patient medical record and excluded other signs/ symptoms of hypo/hyperthyroidism besides a weight loss of 5kg in the last 6 months. Analytical evaluation at the ER: TSH 0.002 µU/mL (N: 0.35-4.94), FT4 1.89 ng/dL (N: 0.7-1.48), FT3 5.87 pg/mL (N: 1.71-3.71). The levothyroxine was suspended and the patient initiated oral prednisolone 30mg/day, selenium 200µg/day and artificial tears. Two weeks later, the patient’s symptoms improved. Analytical evaluation: TSH receptor antibodies –TRAbs: 5.6U/L (N: 0-1.8), anti-thyroid antibodies: negative, TSH 0.002uU/mL (N: 0.35-4.94), FT4 1.64ng/dL (N: 0.7-1.48), FT3 4.30 pg/mL (N: 1.71-3.71). She continued corticosteroid therapy for 4 weeks and performed thiamazole during 8 weeks. Currently the patient is asymptomatic without medication. When TAO occurs in euthyroid or hypothyroid patients, the diagnosis is challenging. In this case report, the 9-year history of hypothyroidism pointed to the possibility of an orbitopathy associated with HT. However, the absence of anti-thyroid antibodies (anti TG and anti TPO) and the presence of TRAbs led the authors to the final diagnosis: Graves’ disease with thyrotropin-blocking antibodies (TBAb) and thyroid stimulating antibodies (TSAb). Although rare, a normal or subnormal thyroid function could not exclude the diagnosis of TAO.

SUN-622 Graves Disease Triggered by Lobectomy for Thyroid Cancer

Background: The incidence of Hashimoto thyroiditis as well as Graves disease in patients with thyroid cancer has been observed however molecular and pathophysiological basis of this association has only been hypothesized. Cases of new onset severe thyrotoxicosis and Graves ophthalmopathy shortly after lobectomy for thyroid cancer have not been described to our knowledge. Case: The patient is a 46-year-old woman who had a 2.5cm thyroid nodule. Fine needle aspiration showed atypia of undetermined significance and subsequent thyroid genomic classifier test Thyroseq confirmed positive for fusions involving THADA and IGF2BP3. Since THADA positive nodules are usually associated with low risk thyroid carcinoma and non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), thyroid lobectomy was advised. Prior to surgery the patient had positive thyroid peroxidase antibodies and was treated with low dose levothyroxine only during two pregnancies. Surgical pathology confirmed 2.5 cm NIFTP and 2 foci of papillary thyroid microcarcinoma of 0.5mm and 1mm with the background of chronic lymphocytic thyroiditis (Hashimoto). No further therapy was advised. At 6 weeks after left thyroid lobectomy the patient presented for a follow up clinically euthyroid with thyroid stimulating hormone (TSH) of 3 mcIU/mL. Two weeks after this regular follow up visit she started having severe periorbital swelling, double vision and bulging of her eyes that was followed by shortness of breath, palpitations, anxiety, sweating and weight loss. She presented to emergency room and was found to have suppressed TSH and positive TSI and TBII antibodies with high titer. After stabilization of hyperthyroidism with methimazole completion thyroidectomy was performed on patient request. Surgical pathology of the right thyroid lobe showed scattered papillary hyperplasia, chronic inflammation, focal atrophy and lymphoid follicles. Six weeks after completion thyroidectomy the patient is clinically euthyroid on levothyroxine and with significantly improved ophthalmopathy. TSI and TBII antibodies remain positive and continue to downtrend. Conclusion: As partial thyroidectomy for low-risk thyroid carcinoma is becoming increasingly convenient method of therapy we may encounter more surgically triggered autoimmune thyroid disorders in the future.

MON-589 Prognostic Predictors of Initial Response of Graves' Disease to Antithyroid Drugs: A Single Center Experience

Prognostic Predictors of Initial Response of Graves’ disease to Antithyroid Drugs: A Single Center Experience Background: Conservative therapy with antithyroid drugs (ATD) is the first-line therapy of Graves' disease (GD) in many areas of the world. Based on the high incidence of relapse after stoppage of ATD, studies were conducted to suggest clinical & laboratory predictors selecting patients most likely to have a remission, this would subject only these patients to the potential risks & inconvenience of ATD. Hence, the aim of our study was to determine the prognostic factors of the initial response of GD six months following initiation of ATD. Subjects & Methods: A single-center prospective study including newly diagnosed patients with GD recruited for 6 months (1st July - 31st December 2017). The studied prognostic factors were: age, sex, goiter size, smoking history, presence of Graves ophthalmopathy, Family history of thyroid disorders, serum TSH, FT3, FT4, FT3:FT4 [ initial, 3 & 6 months after ATD], TRAbs, thyroid volume by US, vascularity & peak systolic velocity of inferior thyroid artery by color Doppler [ initial & 6 months after ATD]. All patients were offered ATD (carbimazole). Patients were followed up for 6 months every 6 weeks with modification of the dose if needed. Patients were subdivided into responders & non-responders after the 6 months period Results: 71 patients with GD; 28 males & 43 females with a mean age of 36.5±10.4 yrs were enrolled. 41% of our patients (29/71) responded to ATD, while 59% (42/71) failed to respond. Euthyroidism was achieved in 15% of pts after 3 months of ATD with almost doubling of this figure after 6 months. In univariate regression analysis; Male gender (p<0.001), current smoking (p=0.001), large pre-treatment goiter size (p = 0.022), high FT3 & FT4 at 3 & 6 months after ATD (p<0.001), high TRAb at baseline (p= 0.03) & 6 months after ATD ( p= 0.002), large total thyroid volume (TV) by US at baseline (p< 0.001) & 6 months after ATD ( p=0.001) and high thyroid vascularity at baseline (p=0.02) are predictors of poor early response to carmbimazole. Serum TRAb at baseline & 6 months after ATD are good predictors for early response to ATD with cut off value ≤ 35 at baseline (86.2 % sensitivity & 42.8 % specificity) & cut off value ≤ 24 after 6 months (93.1% sensitivity, 42.3 % specificity). ROC curves of TV by the US at baseline & 6 months after ATD are good predictors for response to ATD with the cut-off value of 65.5 ml at baseline (83.3% sensitivity, 73.1% specificity) & cut off value ≤15 ml after 6 months (51.7% sensitivity, 97.6% specificity) Conclusions: Patients with GD with large pre-treatment goiter size clinically & by the US, male gender, smokers, high TRAb at baseline & 6 months after ATD, high FT3 & FT4 levels at 3 & 6 months after ATD responded less favorably to initial carbimazole therapy. These finding may help us to sort which patients are better candidates for early definitive therapy.