Thyroid-stimulating Immunoglobulin Levels Research Articles

Clinical relevance of thyroid-stimulating immunoglobulin as a biomarker of the activity of thyroid eye disease.

Although it has been reported that thyroid-stimulating immunoglobulin (TSI) is associated with the clinical characteristics of thyroid eye disease (TED), there is a paucity of literature regarding the role of TSI in diagnosing active TED. This study investigated the relationship between the level of TSI and the activity of TED and assessed the cut-off value of TSI discriminating active TED from inactive TED. This cross-sectional study included 101 patients with TED. TSI was quantitatively measured with a cell-based bioassay using a chimeric TSH receptor and a cyclic adenosine monophosphate response element-dependent luciferase. The association between TSI and a variety of demographic and clinical features of TED was analysed. Multivariate regression analysis was performed to determine possible independent factors affecting the level of TSI. TSI level was higher in males than in females (p = 0.023) and smokers than in nonsmokers (p = 0.004). TSI level was inversely correlated with the duration of ocular symptoms (r = -0.295, p = 0.003). The level of TSI was also significantly different when compared to the thyroid function (p = 0.003), TED activity (p < 0.001), and TED severity (p = 0.001). Multivariate regression analysis revealed a significant relationship between TED activity and thyroid function jointly and the TSI level. The cut-off level of TSI for predicting active TED was a specimen-to-reference ratio of 406.7 (p < 0.001, area under the curve = 0.847, sensitivity 77.4%, specificity 81.3%). TSI was a functional biomarker strongly associated with TED activity even after being adjusted by other clinical characteristics. Serum TSI level may help identify patients with active TED in clinics.

Subcutaneous Tocilizumab for Thyroid Eye Disease

Purpose: To demonstrate the efficacy of subcutaneous tocilizumab (TCZ-SC) treatment for recalcitrant thyroid eye disease (TED) refractory to intravenous methylprednisolone (MP) and oral methotrexate (MTX).Case summary: (Case 1) A 52-year-old man, smoker, with hyperthyroidism presented with a 3-months history of TED. The initial clinical activity score (CAS) was 5 (total score of 7). High-dose intravenous MP and oral MTX failed to improve the symptoms. He was treated with four doses of 162 mg TCZ-SC at an interval of 2 weeks. Pre-treatment laboratory test results were within normal limits. CAS was reduced to 2 weeks after the final injection, and there were no recurrences during the 6-month follow-up. (Case 2) A 37-year-old woman, non-smoker, with a 3-months history of hyperthyroidism presented with conjunctival injection and upper eyelid erythema. The initial CAS was 4, and thyroid-stimulating immunoglobulin level was raised (475% of normal). The symptoms did not improve with 7.5 g intravenous MP and oral MTX. The patient was treated with 162 mg TCZ-SC. Pre-treatment laboratory test results were within normal limits. CAS was reduced to 1 after the final injection, and there were no recurrences during the 6-months follow-up.Conclusions: TCZ-SC improves symptoms of corticosteroid-resistant TED, and may be a reasonable option in recalcitrant TED cases. However, further studies are required to justify the use of TCZ-SC for TED.

Diagnostic accuracy of Immulite® TSI immunoassay for thyroid-associated orbitopathy in patients with recently diagnosed Graves' hyperthyroidism.

The Immulite® thyroid stimulating immunoglobulin (TSI) immunoassay is a relatively new commercial assay that has shown good diagnostic accuracy in Graves' hyperthyroidism (GH). However, its clinical utility in thyroid-associated orbitopathy (TAO) is less clear. The purpose of this study was to assess the diagnostic accuracy of the Immulite® TSI immunoassay for TAO and investigate the associations between TSI and other clinical measures. One hundred and forty patients that had been diagnosed with GH within the previous 12months were recruited. Identification and grading of TAO were performed at enrolment and serum samples were analysed using the Immulite® TSI immunoassay. Of the 140 participants recruited, 75 (53.6%) had TAO. Age, sex and time since GH diagnosis were similar between those with and without TAO (p ≥ 0.300). TSI level tended to decrease with increasing time from GH diagnosis (Spearman's ρ - 0.28, 95% CI - 0.43, - 0.12). TSI levels were higher among those with than those without TAO (median 4.0 vs. 2.7IU/L, respectively, p = 0.037). There was no correlation between TSI level and inflammatory index score (ρ = 0.14, 95% CI - 0.03, 0.30) or clinical severity (p = 0.527) among those with TAO. TSI level showed poor diagnostic accuracy for TAO (area under the receiver operating characteristic curve 0.60, 95% CI 0.51, 0.70). Although Immulite® TSI level was higher in the presence of TAO, it showed poor diagnostic accuracy and no correlation with clinical markers of TAO severity or activity.

Clinical efficacy of thyroid-stimulating immunoglobulin detection for diagnosing Graves’ disease and predictors of responsiveness to methimazole

BackgroundAs thyroid-stimulating immunoglobulins (TSI) are a sign of Graves' disease (GD), measuring TSI titers is becoming increasingly important for GD diagnosis. This study evaluated the diagnostic accuracy of a new fully automated TSI immunoassay (Immulite™ TSI assay) in GD patients and compared it to the third generation thyroid-stimulating hormone receptor antibody (TRAb) electrochemiluminescence assay (Elecsys Anti-TSHR assay). Additionally, clinical characteristics associated with responsiveness to methimazole in patients with newly diagnosed GD were preliminarily explored. MethodsThis study involved 324 subjects, comprising patients with untreated GD (GD-UT), Graves’ ophthalmopathy (GO) patients, GD patients who had been treated for > 12 months (GD-T), autoimmune thyroiditis (AIT) patients, and healthy subjects (HS). The Immulite™ TSI and Elecsys Anti-TSHR assay were performed on all samples. According to their responsiveness to methimazole, the GD-UT patients were divided into rapid and slow responder groups, and their clinical characteristics were compared. ResultsA receiver operating characteristic (ROC) curve analysis of GD-UT patients showed that the optimal TSI cut-off value was 0.57 IU/L. Logistic regression revealed that age and initial FT4 and TSI levels in the middle-dose methimazole group were related to a rapid response, while the initial FT4 level, but not TSI, in the high-dose group was also associated with a rapid response. ConclusionsThe clinical diagnostic performance of the Immulite™ TSI assay for diagnosing GD was comparable to that of the Elecsys Anti-TSHR assay. The initial FT4 and TSI levels can be used as predictors of the responsiveness to methimazole in patients with newly diagnosed GD.

Tocilizumab for the Management of Thyroid-Associated Orbitopathy.

To describe the efficacy of tocilizumab in the treatment of a cohort of patients with active thyroid-associated orbitopathy. Patients were identified with active thyroid-associated orbitopathy who were intolerant of or had progression of disease despite systemic corticosteroids and subsequently were treated with tocilizumab between January 2015 and December 2020. Clinical Activity Score, Thyroid-Associated Ophthalmopathy Scale score, and thyroid-stimulating immunoglobulin levels were assessed prior to initiation of tocilizumab, following the first dose, and after the completion of treatment. Eleven patients were candidates for and underwent treatment with tocilizumab, 9 of which met criteria for analysis. Average age was 55.6 years. Average time between onset of active thyroid-associated orbitopathy and completion of tocilizumab was 6.5 months. Average number of infusions was 4.2. There was a statistically significant reduction in Clinical Activity Score, Thyroid-Associated Ophthalmopathy Scale score, and thyroid-stimulating immunoglobulin levels when comparing pre-treatment values (mean Clinical Activity Score 6.78 ± 1.09, mean Thyroid-Associated Ophthalmopathy Scale score 10.2 ± 1.92, mean thyroid-stimulating immunoglobulin level 440.6 [%]) to values immediately following completion of treatment (mean Clinical Activity Score 0.44 ± 0.53, mean difference 6.3 points, p < 0.001 [95% CI, 5.5-7.2]; mean Thyroid-Associated Ophthalmopathy Scale score 1.2 ± 1.09, mean difference 9.0 points, p < 0.001 [95% CI, 7.2-10.8]; mean thyroid-stimulating immunoglobulin level 200.7 [%], mean difference 239.9 [%], p = 0.001 [95% CI, 124.3-355.4]). One patient had elevation of cholesterol following therapy induction. Patients were followed for an average of 23.6 months after treatment. No patients had recurrence of active disease after completion of tocilizumab. This study supports the use of tocilizumab as a therapy for the inflammatory phase of thyroid-associated orbitopathy.

Superior Sagittal Vein Thrombosis in the Setting of Thyroid Storm

A 25-year-old female with a two-month history of left lower quadrant pain, found to have an ovarian cyst and recently started on OCPs, presented to an outside medical center after a witnessed seizure with fever, tachycardia, and altered mental status. Her husband reported that she had been lethargic, complained of headaches, and had brief intermittent episodes of staring into space or stopping mid-task four days prior to the current event.On physical exam, she was hypertensive to 170/90s, tachycardic to 120s, febrile to 101, with hyperreflexia and altered mental status without focal deficits. Burch Wartofsky scale was calculated to be 50, suggestive of thyroid storm. Initial labs showed a suppressed TSH (<0.01 uIU/mL) and an elevated free T4 (7.27 ng/dL). Blood cultures and a lumbar puncture demonstrated no evidence of infection. A non-contrast brain CT showed no acute intracranial findings. She was started on propylthiouracil (PTU), propranolol, hydrocortisone, and Lugol’s solution. Thyrotropin Receptor Antibody and Thyroid Stimulating Immunoglobulin levels were elevated, confirming the diagnosis of Grave’s disease.After the initial management, her vital signs normalized and free T4 decreased to 4.2 (ng/dL), but she had no mental status improvement. Although she had no further seizure activity, she continued to have waxing and waning levels of consciousness. She then developed left sided focal deficits and was transferred to our hospital for the management of a possible cerebrovascular event. MRI and MRV of the brain were performed and demonstrated a thrombus within the superior sagittal sinus. She was started on heparin and bridged on warfarin prior to discharge. Her anti-thyroid regimen was down titrated, steroids tapered and discontinued, PTU changed to methimazole, and propranolol changed to metoprolol. Her mental status and focal deficits improved prior to discharge.Patients who present with hyperthyroidism and new-onset neurological symptoms, especially in the setting of OCP use or other risk factors for a hypercoagulable state, should be evaluated for possible cerebral venous thrombosis. The association between overt hyperthyroidism and acute venous thrombosis, especially at cerebral sites, has been documented in numerous case reports.

Oscillating Hypo-Hyperthyroidism; a Rare Type of Autoimmune Thyroiditis in Adolescence

Background: Spontaneous conversion of hypothyroidism to hyperthyroidism and vice versa is a unique autoimmune entity characterized by the oscillating activity of thyrotropin blocking inhibiting immunoglobulin (TBII) and thyroid-stimulating immunoglobulin (TSI). The simultaneous presence of both antibodies is a rare phenomenon in children. Clinical Case: At 11 years of age a female with Trisomy 21 and mild developmental delay had elevated TSH 5.4uIU/mL (0.4-4.5), normal thyroxine (T4), negative thyroglobulin peroxide antibody (anti-TPO), and thyroglobulin antibody (Anti-Tg). Levothyroxine (LT4) 1.2mcg/kg/day was started. At 12 years of age, she relocated, and the same treatment was continued. About 7 months later, she was referred for weight loss of 8lbs, tachycardia, high BP, suppressed TSH <0.015uIU/mL, high total T4 15.9ng/dL (4.5-12.0), and anti-TPO 38 IU/mL (<9). She was diagnosed with hyperthyroidism and LT4 was discontinued. Repeat lab showed persistently undetectable TSH, high T4, TBII 70 (normal <16%), and TSI 698 (<140 %). Methimazole (MMI) 0.38mg/kg/day and Atenolol 25mg daily was started for Grave’s disease.At 15 years of age, she presented with symptoms of hypothyroidism; 10lb weight gain in 2months, high TSH >150mIU/L, low FreeT4 0.12ng/dl (0.8-2), anti-TPO 95 IU/mL, and TSI 2.1 IU/L (0.0 - 0.55). MMI was discontinued and she was started on LT4 0.9mcg/kg/day. Repeat TFT’s 5weeks later showed a normal TSH and Free T4. Thyroid ultrasound showed a diffusely enlarged gland; right lobe - 3.9 x 2.0 x 2.0 cm (volume of: 7.6 mL) and left lobe 4.5 x 1.6 x 2.4 cm (volume: 8.6 mL) with increased vascularity on color Doppler consistent with diffuse thyroiditis. A year later, she developed hyperthyroid symptoms for the second time with 6lb weight loss, tachycardia, suppressed TSH <0.015uIU/mL, elevated free T4 >6.9ng/dl, TBII 8.6 U/L (<1.0), and TSI 12 IU/L. However, this time her TSI level was significantly higher than when she was hypothyroid. She was treated with MMI 0.15mg/kg/day which was increased to 0.3mg/kg/day, and 3months later she reverted to hypothyroidism; TSH 17.5uIU/mL, Low free T4 0.54ng/dl, normal total T3, with 15lb weight gain. Her MMI dose was lowered to 0.15mg/kg/day, however more definitive treatment options including thyroidectomy and radioactive iodine ablation was discussed with the family. Conclusion: The spectrum of autoimmune thyroid disorders span between extremes of Hashimoto’s thyroiditis and Graves’ disease, but rarely in adolescents, these conditions can co-exist, and management can be challenging and tedious to the patient, family, and physician. Since autoantibody status/titer may not always predict the clinical course, it is important for clinicians to keep a high index of suspicion of this process when the clinical course is atypical. Definitive therapy with thyroidectomy or radioactive iodine ablation may be a suitable option in these cases.

Cardiovascular Outcomes of Thyroidectomy or Radioactive Iodine Ablation for Graves’ Disease

BackgroundTreatment options for Graves’ disease (GD) include medical management with antithyroid medications, radioactive iodine (RAI) ablation, or total thyroidectomy (TT). Definitive treatment with RAI ablation may be associated with worse cardiovascular morbidity and mortality than TT. We sought to determine the rate of cardiovascular morbidity before and after definitive treatment for GD. MethodsThis study is a retrospective single-institution study of sequential adult patients with GD from 2012 to 2018 treated with RAI ablation or TT. Patients with prior thyroid surgery or RAI ablation with subsequent thyroidectomy were excluded. Demographic and clinical variables were collected from diagnosis of GD to last follow-up. Data analysis was performed with descriptive statistics, univariate analysis with Fisher's exact test for categorical variables and the Mann–Whitney U test for continuous variables. ResultsOne-hundred and eighty-four patients underwent definitive treatment for GD during the study period, of which 164 met inclusion criteria. One hundred and ten patients (67%) in the study group had TT and 54 (33%) had RAI ablation with a mean dose of 18.4 mCi (standard deviation 6.1). There were no differences in clinical or demographic factors in patients undergoing RAI ablation versus TT for definitive treatment including age, sex, thyroid-stimulating hormone level, free thyroxine level, or thyroid-stimulating immunoglobulin level at time of diagnosis, nor was there any difference in pretreatment cardiovascular comorbidity. Patients with TT had higher rates of resolution of arrhythmia after treatment than those undergoing RAI ablation, P = 0.02. There were no differences in treatment-related complications between the groups. ConclusionsFor patients undergoing definitive treatment for GD, TT is associated with improved rate of resolution of cardiac arrhythmia compared with RAI ablation.

SAT-410 Long Term Evaluation of TSH Receptor Antibodies and Thyroid Stimulating Immunoglobulin After Radioiodine Therapy for Thyrotoxicosis

Background Radioioactive iodine therapy (RAI) is an excellent choice to treat thyrotoxicosis, particularly Graves′ disease (GD) patients. After RAI therapy, it is well known that TSH receptor antibodies (TRAb) rise in GD patients and autoimmunity can eventually surge in patients with toxic multinodular or uninodular goiter (TNG). Recently, biological assay distinguishes stimulating TRAb, called thyroid stimulating immunoglobulin (TSI) bringing a new perspective on follow-up, as TSI is involved in Graves′ pathogenesis of persistent thyrotoxicosis and ophthalmopathy after RAI therapy. Objective Analyze TRAb and TSI levels after 6 and 12 months of RAI therapy for thyrotoxicosis. Patients and Methods Patients were evaluated prospectively immediately before and 6 to 12 months after RAI therapy for thyrotoxicosis. Thyroid hormones were all measured using immunoassays (Roche Diagnostics Ltd). TRAb was analyzed by Elecsys Anti-TSHR assay (Roche Diagnostics, Germany) and was considered negative if < 1.75 IU/L (analytical range: 0.3 to 40 IU/L). TSI was measured by Immulite TSI assay (Siemens Healthcare, UK) and was considered negative if < 0.55 IU/L (analytical range: 0.1 to 40 IU/L). Clinical data and comparison of assays were analyzed by SPSS and MedCalc softwares. Results From 2017 to 2019, 54 patients (44 females) were prospectively evaluated after 6 months of RAI therapy, mostly because of GD (40 patients). A high degree correlation was observed between TRAb and TSI (Spearman correlation coefficient =0.875; p < 0.0001, 95% CI 0.784 to 0.929). After 6 months, among patients with GD, 5/40 patients had negative TRAb levels and 2/40 had negative TSI levels, whereas all TNG patients had both negative TRAb and TSI levels. In GD group, 4 patients showed subclinical hyperthyroidism and relapse occurred in 1 case. All patients with TNG showed euthyroidism status with or without thyroid medications. One year after RAI therapy, we evaluated 32 patients (23 GD) and 4/23 of GD had negative TRAb levels and only 1/23 had negative TSI level. All patients with TNG had negative TRAb and TSI levels after one year fo treatment. Subclinical hyperthyroidism was diagnosed in 5 patients with GD but none with TNG. Along follow-up, 4 patients with clinical diagnosis of GD with TRAb negative before RAI therapy became positive after RAI therapy and 3 patients became TSI positive. Conclusions Long term after RAI therapy for thyrotoxicosis treatment, TRAb and TSI are still positive in most GD patients and few cases can even turned to positive levels. Nevertheless, in TNG patients, RAI therapy is safe as TRAb and TSI maintained at negative concentrations and thyrotoxicosis is properly resolved.

SAT-075 Pulmonary Hypertension in a Patient with Neonatal Graves Disease

INTRODUCTIONNeonatal hyperthyroidism is a transient disorder seen in neonates born to mothers with current or past history of Graves’ disease. We present a rare case of a Neonatal Graves’ disease with pulmonary hypertension (PH) which completely resolved with treatment of hyperthyroidism.CLINICAL CASEBaby B was a 3200 g term male born to a 40-year-old hypothyroid mother. He was prenatally diagnosed with Trisomy 21 and coarctation of the aorta (CoA). He developed respiratory distress soon after birth and was admitted to the NICU. His echocardiogram (echo) showed a large patent ductus arteriosus (PDA) and increased tortuosity of juxtaductal aorta with no significant gradient. Near-systemic pulmonary artery pressure was noted in the absence of any evidence of left heart failure. Cardiology determined his CoA to be hemodynamically insignificant and not the cause of his PH. Successive trials of 100% FiO2, Nitric Oxide (NO), and Sildenafil resulted in only minimal improvement of his PH.Thyroid function tests (TFT) obtained on day of life (DOL) 8 showed serum TSH of 0.01 uIU/ml [0.87 - 6.43] and FT4 of 3.5 ng/dl [0.9 - 1.5]. Further interaction with the mother revealed that she had a history of Graves’ disease treated with radioactive iodine (RAI) and resultant hypothyroidism. Baby B’s TSH receptor antibody (TRAb) and thyroid stimulating immunoglobulin levels were elevated at 7.38 IU/l [0-1.75] and 3.38 IU/l [0-0.55], respectively.He was thus diagnosed with Neonatal Graves’ disease and was started on Methimazole (MTZ) 1 mg/kg/day on DOL 8. Subsequently, potassium iodide was added. FT4 showed gradual normalization by DOL 15. Beta blockers were not added due to absence of hypertension or significant tachycardia. Serial echo showed improvement of PH, consistent with the decline in FT4 levels. Sildenafil and FiO2 were slowly weaned and discontinued by DOL 30. MTZ was then tapered and discontinued. A final echo showed complete resolution of PH, unobstructed aortic arch and persistent PDA.DISCUSSIONNeonatal hyperthyroidism occurs due to transplacental transfer of TRAb from mother to fetus, stimulating the fetal thyroid to make excessive thyroid hormones. Risk correlates with TRAb titers in the mother. Our patient had pulmonary hypertension which did not resolve with FiO2, NO and Sildenafil. However, it showed complete resolution with normalization of FT4 levels by antithyroid drugs. Hyperthyroidism commonly presents with systemic HTN, but we found 3 neonatal cases in the literature presenting with PH that resolved with treatment of hyperthyroidism. The mechanism is unclear, but hypotheses include increased clearance of pulmonary vasodilators and decreased clearance of pulmonary vasoconstrictor and decreased surfactant production/function(1).REFERENCES1) Oden J, Cheifetz IM. Neonatal thyrotoxicosis and persistent PH necessitating extracorporeal life support. Pediatrics 2005-115: e105-8.

Role of Maternal Thyroid-Stimulating Immunoglobulin in Graves' Disease for Predicting Perinatal Thyroid Dysfunction.

Objective To assess maternal thyroid-stimulating immunoglobulin (TSI) as a predictor of neonatal thyroid hyperthyroidism in pregnancies complicated by Graves' disease. Methods This is a 10-year retrospective study of patients with a history of Graves' disease and elevated TSI activity level defined as 1.3 times the normal. All subjects underwent cordocentesis for ultrasound findings of suspected fetal thyrotoxicosis (fetal tachycardia, oligohydramnios, hydrops, and thyromegaly). Neonatal diagnosis was made based on neonatal thyroid function testing or symptoms. Results Fourteen patients were included in the study, seven with active Graves' disease requiring antithyroid drug (“ATD group”) and seven with iatrogenic hypothyroidism on levothyroxine (“levothyroxine group”). Four cases (57%) of neonatal thyrotoxicosis were diagnosed in the levothyroxine group compared with two cases (28%) in the ATD group. The lowest maternal TSI level at which a neonate did not develop hyperthyroidism was 2.6 for the levothyroxine group and 2.5 for the ATD group. The odds ratio of a neonate from the levothyroxine group developing hyperthyroidism compared with one from the ATD group is 3.3 (95% confidence interval: 0.4–30.7). Conclusion For patients with Graves' disease, those with iatrogenic hypothyroidism and TSI > 2.5 times the basal level are at the highest risk for neonatal thyrotoxicosis.

SAT-602 Thyrotoxic Periodic Paralysis Precipitated by Glucocorticoid Injection

Background: Thyrotoxic periodic paralysis (TPP) is a rare manifestation of hypokalemia that is driven by thyrotoxicosis. TPP is associated with any etiology of thyrotoxicosis, though Graves’ disease is the most common. Some of the provoking factors for these episodes are a high carbohydrate meal, rest after heavy exercise, fasting, stress, alcohol intake, and pulse steroid therapy. Clinical Case: A 48-year-old man presented with acute-onset lower extremity paralysis. He had been in his usual state of health until two days prior to admission when he developed a streptococcal throat infection. He was given IM injections of 80mg methylprednisolone and 1g ceftriaxone in an urgent care clinic and discharged. Soon after discharge, he developed progressively worsening bilateral lower extremity soreness and weakness resulting in a fall. He was taken to the hospital by EMS, where he was found to have bilateral lower extremity paresis. He was anxious, mildly tachycardic, and had a non-tender, 25-gram diffuse goiter. No thyroid nodules were palpated nor did the patient exhibit cervical lymphadenopathy. Lid lag, a fine tremor, and onycholysis were also detected. Basic metabolic panel revealed a serum potassium of 2.3 mmol/L (ref: 3.5-5.1 mmol/L). An ECG was normal. He was given 60 mEq of oral potassium chloride and started on propranolol 10mg TID and reported symptomatic improvement within several hours. During hospitalization, the patient remained asymptomatic and his serum potassium remained normal. Thyroid function testing revealed an undetectable TSH, a Free T4 of 4.41 ng/dL (ref: 0.61-1.18 ng/dL), and a Free T3 of 10.29 pg/mL (ref: 2.5-3.9 pg/mL). Radionucleotide uptake scan of the thyroid showed diffusely increased uptake (81%) with no nodules, consistent with Graves’ disease. Thyrotropin receptor antibody and Thyroid stimulating immunoglobulin levels were elevated. He underwent successful radioactive iodine ablation. Serial laboratory testing was done and within six weeks the patient became hypothyroid. He is now treated with levothyroxine for post-ablative hypothyroidism. A literature search reveals case reports implicating steroids in the precipitation of TPP. Corticosteroids, along with thyroid hormone, increase the activity of sodium-potassium ATPase channels in skeletal muscle. Steroids also lead to hyperglycemia and subsequent increased insulin release that causes an intracellular shift of potassium. Conclusion: Though rare, TPP is important to recognize, as failure to treat underlying hyperthyroidism can lead to repeated episodes of hypokalemia and paralysis. This case highlights TPP precipitated by pulse glucocorticoid injection, described rarely in the literature. The potential of glucocorticoids to precipitate paralysis should be recognized when considering steroid treatment for other medical conditions in hyperthyroid patients.

MON-591 Thyroid Function and Autoimmunity Status after One and Three Months of Radioactive Iodine Therapy for Thyrotoxicosis

Background Radioioactive iodine therapy (RAI) is an excellent choice to treat thyrotoxicosis, particularly Graves´ disease (GD) patients. TSH receptor antibodies (TRAb) rise in GD patients and autoimmunity can surge after RAI. Objective Evaluate thyroid hormone function and autoimmunity 1 and 3 months after RAI therapy for thyrotoxicosis. Patients and Methods Patients were evaluated prospectively before and 1 and 3 months after RAI therapy for thyrotoxicosis. Thyroid hormones, TPO antibody (TPOAb) and thyroglobulin antibody (TgAb) were all measured using immunoassays (Roche Diagnostics Ltd). TRAb was determined by electrochemiluminescence assay (Cobas, Roche Diagnostics Ltd) with TRAb positive values >1.75 IU/L. Free T3 (FT3) and thyroid stimulating immunoglobulins (TSI) were determined by chemiluminescent immunoassays (Immulite, Siemens Healthcare Diagnostics) with TSI positive > 0.55 IU/L. All patients stopped antithyroid medications 2 to 4 weeks before RAI uptake and treatment and low iodine diet was recommended. Antithyroid medications were not introduced before 1 month. Results A total of 53 patients was prospectively evaluated (10 males), with mean age 46.7 ± 0.41 years-old (25 to 82). GD was the most frequent etiology of hyperthyroidism (83%), followed by toxic multinodular goiter (TMNG) (11%) and toxic adenoma (TA) (6%). TMNG and TA patients had no thyroid autoimmunity. TRAb was positive in 91% and TSI 92% among GD. TPOAb and TgAb were positive in 80% and 48%, respectively in GD patients. RAI uptake at 2 and 24 hours were high in all patients (38.4%±46% and 67%±34%, respectively). A single oral RAI was given with X=22±7.8 mCi (15 to 34 mCi). Only one GD patient developed hypothyroidism at 1 month, meanwhile 58% and 10.5 % were still in hyperthyroidism after 1 and 3 months, respectively. After RAI, none but one GD patient developed positive thyroid antibody (only TPOAb). TRAb levels significantly increased from baseline in 38% and 58% of GD patients after 1 and 3 months, respectively as well as TSI levels (48% and 64%). Conclusions RAI therapy is effective to treat thyrotoxicosis but hyperthyroidism is not achieve in short term. It is also safe as autoimmunity is rarely triggered but caution must be taken in those patients with pre-existent autoimmunity, as all thyroid antibodies can increase after this therapy.

Proinflammatory Effects of Calprotectin in Graves’ Orbitopathy

ABSTRACT Purpose: Early detection and control of inflammation are important to manage Graves’ orbitopathy (GO). We investigated the effects of calprotectin (S100A8/A9) on orbital fibroblast inflammation and GO pathogenesis. Methods: We measured serum calprotectin, S100A8 and S100A9 mRNA expression in orbital fat/connective tissue from GO patients and healthy controls, and proinflammatory cytokines in primary cultured orbital fibroblasts. Results: The serum levels of S100A8/A9 and the expression of S100A8/A9 mRNA in orbital tissue were higher in the GO patients than in the healthy controls. The serum calprotectin levels positively correlated with the clinical activity score and serum thyroid-stimulating immunoglobulin levels. In cultured GO orbital fibroblasts, S100A8/A9 increased the expression of interleukin (IL)-6, IL-8, and monocyte chemotactic protein-1, as well as the phosphorylation of extracellular signal-regulated kinase and nuclear factor-κB. Conclusion: We demonstrated the potential of calprotectin as a biomarker of GO severity and proinflammatory responses to S100A8/A9 in GO orbital fibroblasts.

Thyroid Isthmus Length and Iodine Turnover as Predictors of Successful Radioactive Iodine Therapy in Patients with Graves' Disease.

Radioactive iodine (RAI) therapy is an effective treatment option for Graves' disease. However, predicting treatment failures after RAI therapy remains controversial. The objective of this study was to investigate the factors associated with the success rate of RAI therapy for treatment of Graves' hyperthyroidism. Thyroid functional outcome, pre-RAI ultrasonographic features, and clinical parameters were evaluated retrospectively in 98 patients followed up for at least 12 months after RAI (mean RAI dose was 11.7 ± 1.8 mCi). Hypothyroidism was achieved in 59 patients (60.2%), and euthyroidism in 16 patients (16.3%), while 23 patients (23.5%) remained hyperthyroid. Age, sex, body mass index, pre-RAI thyroid function, or thyroid-stimulating immunoglobulin levels were not associated with treatment outcome. Length of thyroid isthmus (p = 0.028) and 2- to 24-hour iodine uptake ratios (p = 0.002) were significantly associated with treatment failure, which was defined as a persistent hyperthyroid status after RAI therapy. Patients with a longer isthmus had a higher risk of remaining hyperthyroid, with a threshold for isthmus length of 5.2 mm, with a sensitivity of 69.6% and specificity of 70.3% for treatment success. Measuring the length of the thyroid isthmus can be a simple and useful way to predict RAI treatment outcome.

Thyroid-stimulating immunoglobulins indicate the onset of dysthyroid optic neuropathy.

Recognition of dysthyroid optic neuropathy (DON) requires sensitive diagnostic tools. Clinical assessment may fail to reliably evaluate the acuteness of DON especially if signs for inflammation are missing. Aim of this cross-sectional study was to assess the relationship between thyroid-stimulating immunoglobulins (TSI) and onset of DON. At a multidisciplinary orbital center, serum TSI levels were measured in 180 consecutive patients with thyroid eye disease (TED) and 302 healthy controls with a FDA-cleared cell-based bioassay using a chimeric TSH receptor and a CRE-dependent luciferase. Thirty of 180 (16.7 %) patients with TED had DON of recent onset or a past history of DON (post-DON). Optic disk swelling was present and visual-evoked potentials were pathologic in all eyes with DON of recent onset, but in one of 13 (7.7 %) with post-DON, only (p = 0.005). 19/20 (96 %) patients with DON of recent onset were TSI-positive. TSI was associated with DON of recent onset (OR: 20.96; 95 % CI 1.064-412.85, p = 0.045). All controls were TSI negative. TSI correlated with the clinical activity score (R = 0.70, p < 0.001) and higher TSI-levels were noted in active vs. inactive TED (485.1 ± 132.3 vs. 277.7 ± 143.7 %, cut-off < 140 %; p < 0.001). Six of seven (85.7 %) patients with inactive TED with recent onset DON versus one of four (25 %) with active post-DON were TSI-positive (p = 0.006). A discriminatory cut-point of 377 SRR % for TSI was determined based on a ROC analysis (sensitivity: 0.95, specificity: 0.8). Serum TSI levels identify patients with DON of recent onset requiring urgent therapy.

Follow-Up of Newborns of Mothers with Graves' Disease

Overt neonatal Graves' disease is rare, but may be severe, even life threatening, with deleterious effects on neural development. The main objective of this study was to describe the course of thyrotropin (TSH) and free thyroxin (fT4) levels, as well as postnatal weight gain in relation to fT4 levels, in neonates born to women with Graves' disease without overt neonatal thyrotoxicosis. Such information is important to deduce the optimal schedule for evaluation. We conducted a retrospective chart review of neonates born to mothers with Graves' disease between January 2007 and December 2012. The records were reviewed for sex, gestational age, birth weight, maternal treatment during pregnancy, and maternal thyroid stimulating immunoglobulin (TSI) level. For each visit in the clinic, the data included growth parameters, presence of symptoms suspected for hyperthyroidism, blood test results (levels of TSH, fT4, and TSI), and treatment. Ninety-six neonates were included in the study (49 males), with a total of 320 measurements of thyroid function tests (TSH and fT4). Four neonates (4%) had overt neonatal Graves' disease; one of them along with nine others were born preterm. In 77 (92.9%) of the remaining 83 neonates (the subclinical group), fT4 levels were above the 95th percentile on day 5. All had normal fT4 on day 15. A negative association was found between fT4 and weight gain during the first two weeks. In this cohort, most neonates born to mothers with Graves' disease had a subclinical course with abnormal fT4 levels that peaked at day 5. After day 14, all measurements of fT4 returned to the normal range, although measurements of TSH remained suppressed for up to three months. Elevated fT4 was associated with poor weight gain.

Clinical characteristics of Graves' orbitopathy in patients showing discrepancy between levels from TBII assays and TSI bioassay

To investigate clinical characteristics of patients with Graves' orbitopathy (GO) who showed discrepancies between levels of thyroid-stimulating immunoglobulin (TSI) and thyrotropin-binding inhibitory immunoglobulin (TBII). Comparative case series. A total of 317 patients with GO in whom Mc4-TSI and M22-TRAb (third-generation TBII) were measured simultaneously. Patients were divided into four groups according to TRAb levels as followings: Group 1, TBII and TSI < median value; Group 2, TBII ≥ median, TSI < median; Group 3, TBII < median, TSI ≥ median; Group 4, both TBII and TSI ≥ median. Endocrine and ophthalmic clinical manifestations in each group. The median value of M22-TRAb was 6·11 IU/l and that of Mc4-TSI was 415·1 (SRR%). One hundred seventeen patients were classified as Group 1, 41 patients as Group 2, 41 patients as group 3 and 118 patients as group 4. Mean CAS was significantly higher in Groups 3 (2·2) and 4 (2·2) than in Groups 1 (1·6) and 2 (1·4; P = 0·001, ANOVA). Mean modified NOSPECS scores were significantly higher (P < 0·001, ANOVA) in Groups 3 (4·1) and 4 (4·1) than in Groups 1 (3·1) and 2 (2·3). The proportion of patients with hyperthyroidism was larger in Group 2 (85·4% [35/41 patients]) than in Group 3 (48·8% [20/41 patients]; P = 0·002). GO is more active and severe in patients with predominant Mc4-TSI than in patients with predominant M22-TRAb. Patients with hyperthyroidism were more likely to be included with patients with predominant M22-TRAb than with predominant Mc4-TSI.

Thyroid Function in Patients with Chronic Hepatitis C Virus Infection under Interferon Therapy

The study examined 60 HCV patients with normal baseline levels of TSH. The patients received subcutaneous pegylated interferon a-2b weekly in addition to oral ribavirin. Before the start of the interferon therapy, serum TSH, thyroglobulin-Ab (TG-Ab) and antiperoxidase antibodies (TPO-Ab) were measured. Three months after interferon therapy serum levels of TSH were measured to all patients; patients with abnormal TSH were subjected to the measurements of FT3, FT4, TPO-Ab, TG-Ab, and thyroid stimulating immunoglobulin levels (TSI). After 3 months of therapy, 48 patients (80%) had normal TSH, and 12 patients (20%) had abnormal TSH. Of 12 patients with abnormal TSH 10 (16.6%) had high levels of TSH (hypothyroidism), while the other two (3.4%) had low levels of TSH (Hyperthyroidism). Of 10 patients with hypothyroidisms, 6 patients (10%) had overt hypothyroidism and 4 patients (6.6%) had subclinical hypothyroidism. All patients with abnormal TSH had significant higher levels of TG-Ab, TPO-Ab and TSI (in cases with hyperthyroidism only) than the patients with normal levels of TSH (p < 0.001), the levels of TPO-Ab only of the most patients with abnormal TSH were above the normal reference range before the start of interferon therapy. Patients with hyperthyroidism, one was presented by clinical picture of overt hyperthyroidism, and the second by subclinical hyperthyroidism. All patients with overt hypo and hyperthyroidism received medical treatment, with normalization of levels of TSH and improvement of clinical symptoms and completed their course of interferon therapy Forty patients (66.6%) responded to interferon (-ve PCR for HCV), while 20 (33.3%) did not respond, 5 had TSH abnormalities that were significantly higher than those in patient with normal TSH {5/12 (41.6%).versus 15/48 (31%); p < 0.01}.

Measurement of thyroid stimulating immunoglobulins using a novel thyroid stimulating hormone receptor–guanine nucleotide-binding protein, (GNAS) fusion bioassay

Hyperthyroidism, defined by overproduction of thyroid hormones, has a 2-3% prevalence in the population. The most common form of hyperthyroidism is Graves' disease. A diagnostic biomarker for Graves' disease is the presence of immunoglobulins which bind to, and stimulate, the thyroid stimulating hormone receptor (TSHR), a G-protein coupled receptor (GPCR). We hypothesized that the ectopically expressed TSHR gene in a thyroid stimulating immunoglobulin (TSI) assay could be engineered to increase the accumulation of the GPCR pathway second messenger, cyclic AMP (cAMP), the molecule measured in the assay as a marker for pathway activation. An ectopically expressing TSHR-mutant guanine nucleotide-binding protein, (GNAS) Chinese hamster ovary (CHO) cell clone was constructed using standard molecular biology techniques. After incubation of the new clone with sera containing various levels of TSI, GPCR pathway activation was then quantified by measuring cAMP accumulation in the clone. The clone, together with a NaCl-free cell assay buffer containing 5% polyethylene glycol (PEG)6000, was tested against 56 Graves' patients, 27 toxic thyroid nodule patients and 119 normal patients. Using receiver operating characteristic analysis, when comparing normal with Graves' sera, the assay yielded a sensitivity of 93%, a specificity of 99% and an efficiency of 98%. Total complex precision (within-run, across runs and across days), presented as a percentage coefficient of variation, was found to be 7·8, 8·7 and 7·6% for low, medium and high TSI responding serum, respectively. We conclude that the performance of the new TSI assay provides sensitive detection of TSI, allowing for accurate, early detection of Graves' disease.